WO2005107762A2 - Certain chemical entities, compositions, and methods - Google Patents

Certain chemical entities, compositions, and methods Download PDF

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Publication number
WO2005107762A2
WO2005107762A2 PCT/US2005/015666 US2005015666W WO2005107762A2 WO 2005107762 A2 WO2005107762 A2 WO 2005107762A2 US 2005015666 W US2005015666 W US 2005015666W WO 2005107762 A2 WO2005107762 A2 WO 2005107762A2
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
mmol
chemical entity
benzamide
methyl
Prior art date
Application number
PCT/US2005/015666
Other languages
French (fr)
Other versions
WO2005107762A3 (en
Inventor
Xiangping Qian
Andrew I. Mcdonald
Han-Jie Zhou
Luke W. Ashcraft
Bing Yao
Hong Jiang
Jennifer Kuo Chen Huang
Jianchao Wang
David J. Morgans, Jr.
Bradley P. Morgan
Gustave Bergnes
Dashyant Dhanak
Steven D. Knight
Nicholas D. Adams
Cynthia A. Parrish
Kevin Duffy
Duke Fitch
Rosanna Tedesco
Original Assignee
Cytokinetics, Inc.
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cytokinetics, Inc., Smithkline Beecham Corporation filed Critical Cytokinetics, Inc.
Priority to MXPA06012796A priority Critical patent/MXPA06012796A/en
Priority to AU2005240178A priority patent/AU2005240178B2/en
Priority to JP2007511593A priority patent/JP4805916B2/en
Priority to NZ550811A priority patent/NZ550811A/en
Priority to CA2565695A priority patent/CA2565695C/en
Priority to EP05762665A priority patent/EP1742907A4/en
Priority to BRPI0510663-0A priority patent/BRPI0510663A/en
Publication of WO2005107762A2 publication Critical patent/WO2005107762A2/en
Publication of WO2005107762A3 publication Critical patent/WO2005107762A3/en
Priority to IL178860A priority patent/IL178860A/en
Priority to NO20065504A priority patent/NO20065504L/en

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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00Carboxylic acid amides
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10Antimycotics
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00Antineoplastic agents
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    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P37/00Drugs for immunological or allergic disorders
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    • A61P9/00Drugs for disorders of the cardiovascular system
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    • C07C235/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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    • C07C235/48Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C235/50Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C235/52Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C237/22Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C255/00Carboxylic acid nitriles
    • C07C255/49Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07C259/00Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • C07C271/08Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C271/08Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C275/40Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
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    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503Five-membered rings
    • C07F9/6506Five-membered rings having the nitrogen atoms in positions 1 and 3
    • CCHEMISTRY; METALLURGY
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    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14The ring being saturated

Definitions

  • This invention relates to chemical entities which are inhibitors of one or more mitotic kinesins and are useful in the treatment of cellular proliferative diseases, for example cancer, hype ⁇ lasias, restenosis, cardiac hypertrophy, innnune disorders, fungal disorders, and inflammation.
  • 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.
  • microtubules fo ⁇ n other types of cellular structures, 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.
  • kinesins organize microtubules into the bipolar structure that is the mitotic spindle. Kinesins mediate movement of chromosomes along spindle microtubules, as well as structural changes in the mitotic spindle associated with specific phases of mitosis. Experimental perturbation of mitotic kinesin function causes malformation or dysfunction of the mitotic spindle, frequently resulting in cell cycle arrest and cell death.
  • the invention relates to methods for treating cellular proliferative diseases, and for treating disorders by inliibiting the activity of one or more mitotic kinesins.
  • Ri is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
  • X is -CO or-SO 2 -;
  • R 2 is hydrogen or optionally substituted lower alkyl
  • W is -CR 4 -, -CH 2 CR 4 - 5 or N
  • R 3 is -CO-R 7 , hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, cyano, optionally substituted sulfonyl, or optionally substituted aryl
  • R 4 is hydrogen or optionally substituted alkyl
  • R 5 is hydrogen, hydroxyl, optionally substituted amino, optionally substituted heterocyclyl; or optionally substituted lower alkyl
  • R 6 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
  • R is optionally substituted lower alkyl,
  • R 5 is not hydroxyl or optionally substituted amino
  • Rg is not optionally substituted alkoxy, optionally substituted aralkoxy, optionally substituted heteroaralkoxy, or optionally substituted amino.
  • R 2 , R 3 , R 5 , R 6 , and W are as described for compounds of Formula I and wherein Rn 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, optionally 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-,
  • composition comprising a pharmaceutical excipient and at least one chemical entity described herein.
  • Also provided is a method of modulating CENP-E kinesin activity which comprises contacting said kinesin with an effective amount of at least one chemical entity described herein.
  • a method of inhibiting CENP-E which comprises contacting said kinesin with an effective amount of at least one chemical entity described herein.
  • a method for the treatment of a cellular proliferative disease comprising administering to a subject in need thereof at least one chemical entity described herein.
  • a method for the treatment of a cellular proliferative disease comprising administering to a subject in need thereof a composition comprising a pharmaceutical excipient and at least one chemical entity described herein.
  • a composition comprising a pharmaceutical excipient and at least one chemical entity described herein.
  • the use of at least one chemical entity described herein for the manufacture of a medicament for treating a disorder associated with CENP-E kinesin activity are generally intended to have 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:
  • Alkyl encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms.
  • Ci-C ⁇ alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • 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 two points of attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms.
  • Co alkylene indicates a covalent bond and Ci alkylene is a methylene group.
  • alkyl residue having a specific 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-butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl.
  • “Lower alkyl” refers to alkyl groups having one to four carbons.
  • Cycloalkyl indicates a saturated hydrocarbon ring group, having the specified number of carbon atoms, usually from 3 to 7 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl as well as bridged and caged saturated ring groups such as norbornane.
  • alkoxy is meant an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, 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.
  • Acyl refers to the groups (alkyl)-C(O)-; (cycloalkyl)-C(O)-; (aryl)-C(O)-;
  • a C ⁇ -C 6 alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • amino is meant the group -NH 2 .
  • aminocarbonyl refers to the group -CONR b R c , where R b is chosen from H, optionally substituted Ci-C ⁇ alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R c is chosen from hydrogen and optionally substituted C ⁇ -C 4 alkyl; or R b and R c taken together with the nitrogen to which they are bound, form an optionally substituted 5- to 7-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from C]-C 4 alkyl, aryl, heteroaryl, aryl-C]-C alkyl-, heteroaryl-C)-C 4 alkyl-, C r C 4 haloalkyl-, -OC ⁇ -C 4 alkyl, -OC 1 -C
  • Aryl encompasses: 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • 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.
  • bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocycloalkyl ring.
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene 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 valence 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 does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • aryloxy refers to the group -O-aryl.
  • aralkyl refers to a residue in which an aryl moiety is attached to the parent structure via an alkyl residue. Examples include benzyl-, phenethyl-, phenylvinyl-, phenylallyl and the like.
  • heteroarylkyl refers to a residue in which a heteroaryl moiety is attached to the parent structure via an alkyl residue. Examples include furanylmethyl-, pyridinylmethyl-, pyrimidinylethyl and the like.
  • halo includes fluoro, chloro, bromo, and iodo, and the term
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • 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 number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • 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.
  • heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered cycloalkyl ring.
  • 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.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaiyl 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 5,6,7,8-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.
  • heteroarylkyl 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)l -ethyl.
  • a "leaving group” or “atom” is any group or atom that will, under the reaction 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.
  • Protecting group has the meaning conventionally associated with it in 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. Wuts, Protective Groups in Organic Synthesis, Third Edition, Jolm Wiley & Sons, New York (1 99), which is incoiporated herein by reference in its entirety.
  • a hydroxyl protected form is where at least one of the hydroxyl groups present in a compound is protected with a hydroxyl protecting group.
  • amines and other reactive groups may similarly be protected.
  • 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 least one of the foregoing heteroatoms.
  • Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolinyl, 2,4-imidazolidinyl, 2,3- pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperdyl, and 2,5-piperzinyl.
  • Mo ⁇ holinyl groups are also contemplated, including 2-mo ⁇ holinyl and 3 -mo ⁇ holinyl (numbered wherein the oxygen is assigned priority 1).
  • 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 change 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.
  • sulfanyl includes the groups: -S-( optionally substituted ( -
  • sulfanyl includes the group Cj-C alkylsulfanyl.
  • sulfinyl includes the groups: -S(O)-H, -S(O)-( optionally substituted (C ⁇ -C6)alkyl), -S(O)-optionally substituted aryl), -S(O)-optionally substituted heteroaryl), -S(O)-(optionally substituted heterocycloalkyl); and -S(O)-(optionally substituted amino).
  • sulfonyl includes the groups: -S(O 2 )-H, -S(O 2 )-( optionally substituted (C ⁇ - )alkyl), -S(O 2 )-optionally substituted aryl), -S(O 2 )-optionally substituted heteroaryl), -S(O 2 )-(optionally substituted heterocycloalkyl) ,-S(O )-(optionally substituted alkoxy), -S(O 2 )-optionally substituted aryloxy), -S(O 2 )-optionally substituted heteroaryloxy), -S(O 2 )-(optionally substituted heterocyclyloxy); and -S(O 2 )-(optionally substituted amino).
  • substituted 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 exceeded.
  • substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic inte ⁇ nediates.
  • 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.
  • 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.
  • substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl 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 2 alkyl)O- (e.g., methylenedioxy-), -SR , guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NR b R c , halo, cyano, nitro, -COR b , -CO 2 R b , -CONR b R c , -OCOR b , -OCO 2 R a , -
  • substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl refer respectively to alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl 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 a , -OR b , -O(C ⁇ -C 2 alkyl)O- (e.g., methylenedioxy-), -SR b , guanidine, guanidine wherein one or more of the
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent 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 a , -OR b , -O(C ⁇ -C 2 alkyl)O- (e.g., methylenedioxy-), -SR b , guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NR b R°, halo, cyano, nitro, -COR b , -CO 2 R b , -CONR b R c , -OCOR b , -OCO 2 R a , -O
  • a substituted alkoxy group is "polyalkoxy" or -O-(optionally substituted alkylene)-(optionally substituted alkoxy), and includes groups such as -OCH 2 CH 2 OCH 3 , and residues of glycol ethers such as polyethyleneglycol, and -O(CH 2 CH 2 O) x CH 3 , where x is an integer of 2-20, such as 2-10, and for example, 2-5.
  • Another substituted alkoxy group is hydroxyalkoxy or -OCH 2 (CH 2 ) y OH, where y is an integer of 1-10, such as 1-4.
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-
  • -C 4 alkylphenyl cyano, nitro, oxo (as a substituted for heteroaryl), -CO 2 H, -C(O)OC ⁇ -C 4 alkyl, -CON(d-C 4 alkyl)(C ⁇ -C 4 alkyl), -CONH(C ⁇ -C 4 alkyl), -CONH 2 , -NHC(O)(d-C 4 alkyl), -NHC(O)(phenyl), -N(C]-C 4 alkyl)C(O)(C ⁇ -C 4 alkyl), -N(C,-C 4 alkyl)C(O)(phenyl), -C(O)C,-C 4 alkyl, -C(O)C ⁇ -C 4 phenyl, -C(O)C,-C 4 alkyl, -C(O)C ⁇ -C 4 phenyl, -C(O)C,-C 4 haloalkyl,
  • substituted amino refers to the group -NHR d or -NR d R d where each R d is independently chosen from: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl, sulfinyl and sulfonyl, wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaiyl 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 a , -OR b , -O(C ⁇ -C 2 alkyl)O- (e.g.,
  • substituted amino also refers to the group -NR ⁇ wherein R e and
  • R f together with the nitrogen to which they are bound, form an optionally substituted 5- to 7- membered nitrogen-containing, non-aromatic, heterocycle which optionally contains 1 or 2 additional heteroatoms chosen from nitrogen, oxygen, and sulfur.
  • Compounds of Formula I-XIII include, but are not limited to, optical isomers of compounds of Fo ⁇ nula I-XIII, racemates, and other mixtures thereof.
  • 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 example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column.
  • HPLC high-pressure liquid chromatography
  • compounds of Formula I-XIII include Z- and E- fo ⁇ ns (or cis- and trans- fo ⁇ ns) of compounds with carbon-carbon double bonds.
  • chemical entities of the present invention include all tautomeric forms of the compound.
  • Compounds of Formula I- XIII also includes crystal forms such as polymo ⁇ hs and clathrates.
  • Chemical entities of the present invention include, but are not limited to compounds of Formula I-XIII and all pha ⁇ naceutically acceptable forms thereof.
  • Pharmaceutically acceptable fo ⁇ ns of the compounds recited herein include pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof.
  • the compounds described herein are in the form of pharmaceutically acceptable salts.
  • the terms “chemical entity” and “chemical entities” also encompass pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures.
  • “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate,
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pha ⁇ naceutically 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.
  • a suitable organic solvent may be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • prodrugs also fall within the scope of chemical entities, for example ester or amide derivatives of the compounds of Formula I-XIII.
  • the term "prodrug” includes any compound that becomes a compound of Formula I-XIII when administered to a patient, e.g., upon metabolic processing of the prodrug.
  • Examples 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.
  • the prodrug is a phosphate ester.
  • 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.
  • chelate refers to the chemical entity formed by the coordination of a compound to a metal ion at two (or more) points.
  • non-covalent complex refers to the chemical entity formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule.
  • complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • an active agent is used to indicate a chemical entity which has biological activity.
  • an “active agent” is a compound having pha ⁇ naceutical utility.
  • an active agent may be an anti-cancer therapeutic.
  • antimitotic refers to a drug for inhibiting or preventing mitosis, for example, by causing metaphase arrest. Some antirumour drugs block proliferation and are considered antimitotics.
  • a therapeutically effective amount of a chemical entity of 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 be an 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 arnount 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 therapeutically effective amount is an amount sufficient to shrink a cancerous tumor.
  • inhibitortion indicates a significant decrease in the baseline 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 chemical 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 more other factors that in turn affect CENP-E activity.
  • the presence of the chemical entity(ies) may decrease CENP-E activity by directly binding to CENP-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.
  • 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 aberrant activity of certain cell-types.
  • 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 develop; b) inhibiting the disease; c) slowing or arresting the development of clinical symptoms; and/or d) relieving the disease, that is, causing the regression of clinical symptoms.
  • "Patient” refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods of the invention can be useful in both human therapy and veterinary applications. In some embodiments, the patient is a mammal; in some embodiments the patient is human; and in some embodiments the patient is chosen from cats and dogs.
  • the present invention is directed to a class of novel chemical entities that are inhibitors of one or more mitotic kinesins.
  • the chemical entities described herein inhibit the mitotic kinesin, CENP-E, particularly human CENP-E.
  • CENP-E is a plus end-directed microtubule motor essential for achieving metaphase chromosome alignment.
  • CENP-E accumulates during inteiphase and is degraded following completion of mitosis.
  • Microinjection of antibody directed against CENP-E or overexpression of a dominant negative mutant of CENP-E causes mitotic arrest with prometaphase chromosomes scattered on a bipolar spindle.
  • CENP-E mediates localization to kinetochores and also interacts with the mitotic checkpoint kinase hBubRl. CENP-E also associates with active forms of MAP kinase. Cloning of human (Yen, et al., Nature, 359(6395):536-9 (1992)) CENP-E has been reported. In Thrower, et al., EMBO J., 14:918-26 (1995) partially purified native human CENP-E was reported on. Moreover, the study reported that CENP-E was a minus end-directed microtubule motor.
  • CENP-E See, PCT Publication No. WO 99/13061, which is inco ⁇ orated herein by reference.
  • the chemical entities inhibit the mitotic kinesin, CENP-
  • HSET see, U.S. Patent No. 6,361,993, which is inco ⁇ orated herein by reference
  • MCAK see, U.S. Patent No. 6,331,424, which is inco ⁇ orated herein by reference
  • RabK-6 see U.S. Patent No. 6,544,766, which is inco ⁇ orated herein by reference
  • Kif4 see, U.S. Patent No. 6,440,684, which is inco ⁇ orated herein by reference
  • MKLP1 see, U.S. Patent No. 6,448,025, which is inco ⁇ orated herein by reference
  • KiflS see, U.S. Patent No.
  • Kid see, U.S. Patent No. 6,387,644, which is inco ⁇ orated herein by reference
  • Mppl, CMK ⁇ , KinI-3 see, U.S. Patent No. 6,461,855, which is inco ⁇ orated herein by reference
  • Kip3a see, PCT Publication No. WO 01/96593, which is inco ⁇ orated herein by reference
  • Kip3d see, U.S. Patent No. 6,492,151, which is inco ⁇ orated herein by reference
  • KSP see, U.S. Patent No. 6,617,115, which is inco ⁇ orated herein by reference.
  • 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.
  • 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, hype ⁇ lasias, restenosis, cardiac hypertrophy, immune disorders, fungal disorders and inflammation.
  • the present invention provides at least one chemical entity chosen from compounds of Fo ⁇ nula I
  • Ri is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; • X is -CO or-SO 2 -;
  • R 2 is hydrogen or optionally substituted lower alkyl
  • W is — CR4-, -CH 2 CR -, or N
  • R 3 is -CO-R 7 , hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, cyano, optionally substituted sulfonyl, or optionally substituted aryl
  • is hydrogen or optionally substituted alkyl
  • R 5 is hydrogen, hydroxyl, optionally substituted amino, optionally substituted heterocyclyl; or optionally substituted lower alkyl
  • R 6 is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteraiyloxy, optionally substituted alkoxycarbonyl-, optionally substituted aminocarbonyl-, optionally substituted aryl, optionally substituted heteroaiyl, optionally substituted heterocyclyl, or optionally substituted aralkyl
  • R 7 is optionally substituted lower
  • Ri is optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ri is optionally substituted aryl. In some embodiments, Ri is optionally substituted phenyl. In some embodiments, Ri is phenyl substituted with one, two or three groups independently selected from optionally substituted heterocyclyl, optionally substituted alkyl, sulfonyl, halo, optionally substituted amino, optionally substituted sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaiyloxy; acyl, hydroxyl, nitro, cyano, optionally substituted aryl, and optionally substituted heteroaiyl-.
  • Rj is chosen from 3-halo-4- isopropoxy-phenyl, 3-cyano-4-isopropoxy-phenyl, 3-cyano-4-isopropylamino-phenyl, 3- chloro-4-isopropylamino-phenyl, 3-cyano-4-trifluoroisopropyloxyphenyl, 3-chloro-4- trifluoroisopropyloxyphenyl, 3-cyano-4-cylobutyloxyphenyl, 3-chloro-4-cylobutyloxyphenyl, 3-cyano-4-cylopropyloxyphenyl, and 3-chloro-4-cylopropyloxyphenyl.
  • Ri is 3-halo-4-isopropoxy-phenyl or 3-cyano-4-isopropoxy-phenyl.
  • R 2 is hydrogen.
  • X is -CO-.
  • W is — CR - and R is hydrogen.
  • the compounds described herein possess a potentially chiral center, for example, when W is — CR 4 -.
  • the invention contemplates the use of pure enantiomers and mixtures of enantiomers, including racemic mixtures, although the use of a substantially optically pure enantiomer will generally be prefened.
  • 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
  • the stereogenic center at W is as shown below:
  • R 3 is -CO-R 7 ; hydrogen; optionally substituted lower alkyl; cyano; optionally substituted sulfonyl; optionally substituted aryl; or optionally substituted heterocyclyl. In some embodiments, R 3 is optionally substituted lower alkyl. In some embodiments, R 3 is lower alkyl that is optionally substituted with a hydroxyl or a phosphate ester thereof, lower alkyl that is optionally substituted with a lower alkoxy, lower alkyl that is optionally substituted with an optionally substituted amino group, or lower alkyl that is optionally substituted with CO-R 8 where R 8 is hydroxyl or optionally substituted amino.
  • R5 is hydrogen, hydroxyl, or optionally substituted lower alkyl. In some embodiments, R 5 is hydrogen.
  • the compounds described herein possess a potentially chiral center when R 5 is not hydrogen.
  • the invention contemplates the use of pure enantiomers and mixtures of enantiomers, including racemic mixtures, although the use of a substantially optically pure enantiomer will generally be preferred.
  • 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 91.5% enantiomeric excess.
  • R 6 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted alkyl (such as wherein the alkyl group is substituted with an optionally substituted amino group or wherein the alkyl group is optionally substituted cycloalkyl-).
  • R 6 is phenyl substituted with one or two of the following substituents: optionally substituted heteroaiyl, optionally substituted amino, aralkoxy,' halo, hydroxymethyl-, hydroxy, cyano, alkoxy, phenyl, phenoxy, methylenedioxy, ethylenedioxy, sulfonyl, aminocarbonyl, carboxy, alkoxycarbonyl, nitro, heteroaralkoxy, aralkoxy, and optionally substituted heterocyclyl.
  • substituents optionally substituted heteroaiyl, optionally substituted amino, aralkoxy,' halo, hydroxymethyl-, hydroxy, cyano, alkoxy, phenyl, phenoxy, methylenedioxy, ethylenedioxy, sulfonyl, aminocarbonyl, carboxy, alkoxycarbonyl, nitro, heteroaralkoxy, aralkoxy, and optionally substituted heterocyclyl.
  • R 2 , R 3 , R 5 , R 6 , and W are as described for compounds of Formula I and wherein Ri 1 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, optionally substituted aryloxy, optionally substituted heterocyclyl, or optionally substituted heteroaryl oxy; and Rj 3 is hydrogen, acyl, optionally substituted alkyl-, optionally substituted alkoxy, halo, hydroxyl, nitro, cyano, optionally substituted amino, alkylsulfonyl-, alkylsulfonamido-
  • R ⁇ 2 is optionally substituted lower alkoxy, optionally substituted lower alkyl, or optionally substituted amino-.
  • R ⁇ 2 is chosen from isopropoxy, isopropylamino, trifluoroisopropyloxy, cylobutyloxy, and cylopropyloxy.
  • Rj 2 is lower alkoxy (such as propoxy) or 2,2,2- trifluoro-l-methyl-ethoxy.
  • R [2 is propoxy or 2,2,2-trifluoro-l -methyl - ethoxy.
  • R ⁇ 2 is not -O-(CH 2 ) n NH 2 or -O-(CH 2 ) 4 NH(CH ) wherein n is
  • Rn and R ⁇ 2 taken together, form an optionally substituted carbocyclic or heterocyclic ring.
  • Rn and R ⁇ 2 taken . together, fo ⁇ n a methylenedioxy or ethylenedioxy ring.
  • Rj 2 and R ]3 taken together, fo ⁇ n an optionally substituted carbocyclic or heterocyclic ring.
  • Rn and R] 3 taken together, form an optionally substituted carbocyclic or heterocyclic ring.
  • Rj 3 is hydrogen
  • R 2 and Rn taken together, form an optionally substituted carbocyclic or heterocyclic ring, i.e., R], X, N, and R 2 , taken together, form an optionally substituted carbocyclic or heterocyclic ring.
  • a substituted carbocyclic or heterocyclic ring i.e., R]
  • X, N, and R 2 taken together, form an optionally substituted carbocyclic or heterocyclic ring.
  • a substituted a substituted
  • 2,4-dioxo-l,4-dihydro-2H-quinazolin-3-yl ring is fo ⁇ ned, e.g.,
  • phenyl ring is optionally substituted.
  • a 4-oxo-4H- quinazolin-3-yl ring is formed, e.g.,
  • a 4-oxo-4H- pyridopyrimidin-3-yl ring is formed, e.g.,
  • R, S, T, and LT is nitrogen with the others being -CH and wherein the pyridine ring is optionally substituted.
  • R ⁇ 4 is chosen from 7,8-dihydro-imidazo[l,2-c][l,3]oxazin-2-yl, 3a,7a-dihydro-lH-benzoimidazol-2-yl, imidazo[2,l-b]oxazol-6-yl, oxazol-4-yl, 5,6,7,8-tetrahydro-imidazo[ 1 ,2-a]pyridin-2-yl, lH-[l,2,4]triazol-3-yl, 2,3-dihydro-imidazol-4-yl, lH-imidazol-2-yl, imidazo[ 1 ,2-a]pyridin-2-yl, thiazol-2-yl, thiazol-4-yl, pyrazol-3-yl, and lH-imidazol-4-yl, each of which is optionally substituted with one, two, or three groups chosen from optional
  • R ⁇ 4 is chosen from lH-imidazol-2-yl, imidazo[l,2-a]pyridin-2-yl; and lH-imidazol-4-yl, each of which is optionally substituted with one or two groups chosen from optionally substituted lower alkyl, halo, and acyl.
  • R ⁇ 5 is hydrogen.
  • R 9 is chosen from optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted arylalkoxy, optionally substituted amino and optionally substituted lower alkyl.
  • R 9 is lower alkyl substituted with hydroxyl or optionally substituted amino.
  • R 9 is lower alkyl substituted with hydroxyl, amino, N-methylamino, or N,N-dimethyl amino.
  • R 5 and Rg together with the atoms to which they are attached, form an optionally substituted 2H-[l,2,3]triazol-4-yl; an optionally substituted 1H- benzoimidazol-2-yl; an optionally substituted piperazinyl ring; an optionally substituted mo ⁇ holinyl ring; or an optionally substituted lH-Imidazol-4-yl ring; an optionally substituted isoxazol-4-yl ring.
  • R fo ⁇ n an optionally substituted heterocyclic ring; in each case, provided that if W is N, then R 5 is not hydroxyl or optionally substituted amino, and R 6 is not optionally substituted alkoxy, optionally substituted aralkoxy, optionally substituted heteroaralkoxy, or optionally substituted amino.
  • Also provided is at least one chemical entity chosen from compounds of
  • R 3 and R ⁇ together with the atoms to which they are bound, form an optionally substituted 5- 7 membered heterocycle which optionally may include one or two additional heteroatoms.
  • R 3 and R ⁇ together with the atoms to which they are attached, form an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, or an optionally substituted l,2,3,4-tetrahydro-quinolin-3-yl ring.
  • the compounds can be named and numbered using AutoNom version 2.1 ,
  • ChemDraw Ultra 6.0, Cambridgesoft, Cambridge, MA; Struct ⁇ >Name algorithm of ChemDraw Ultra 9.0, Cambridgesoft, Cambridge, MA or ISIS-DRAW.
  • the chemical entity is a prodrug, such as a phosphate ester, of one of the compounds listed in Table 1, 2, 3, 4, 5, or 6.
  • the chemical entity is chosen from (35)-4-[4-(2-acetyl-l-methyl-lH-imidazol-4-yl)phenyl]-3- [( ⁇ 3-chloro-4-[(l-methylethyl)oxy]phenyl ⁇ carbonyl)amino]butyl dihydrogen phosphate; and (3S)-3-[( ⁇ 3-chloro-4-[(l-methylethyl)oxy]phenyl ⁇ carbonyl)amino]-4-[4-(8- methylimidazo[ 1 ,2- ⁇ ] ⁇ yridin-2-yl)phenyl]butyl dihydrogen phosphate.
  • the chemical entities described herein can be prepared by following the procedures set forth, for example, in PCT WO 99/13061, U.S. Patent No. 6,420,561 and PCT WO 98/56756, each of which is incorporated herein by reference.
  • the starting materials and other reactants are commercially available, e.g., from Aldrich Chemical Company, Milwaukee, WI, or may be readily prepared by those skilled in the art using commonly employed synthetic methodology.
  • solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like.
  • solvents used in the reactions of the present invention are inert organic solvents.
  • esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid with the appropriate alkanol, generally under acidic conditions.
  • amides may be prepared using conventional amidation procedures, for example amides may be prepared by treating an activated carboxylic acid with the appropriate amine.
  • a lower-alkyl ester such as a methyl ester of the acid may be treated with an amine to provide the required amide, optionally in presence of trimethylalluminium following the procedure described in Tetrahedron Lett. 48, 4171-4173, (1977).
  • Carboxyl groups may be protected as alkyl esters, for example methyl esters, which esters may be prepared and removed' using conventional procedures, one convenient method for converting carbomethoxy to carboxyl is to use aqueous lithium hydroxide.
  • a desired base addition salt can be prepared by treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
  • an inorganic or organic base such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; such as ethylenediamine, and cyclic amines, such as cyclohexylamine, piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as glycine and arginine
  • ammonia primary, secondary, and tertiary amines
  • primary, secondary, and tertiary amines such as ethylenediamine, and cyclic amines, such as cyclohexylamine, piperidine, morpholine, and piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • a desired acid addition salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric
  • Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
  • Formula 103 in an inert solvent such as DCM are added an excess (such as about 1.2 equivalents) of pentafluorotrifluoroacetate and a base such as triethylamine at about 0 °C.
  • the reaction mixture is stirred for about 1 h.
  • the product, a compound of Formula 105, is isolated and purified.
  • Formula 105 in a polar, aprotic solvent are added an excess (such as about 1.2 equivalents) of a compound of formula R 7 (CO)-CH(NHR 2 )-CH(R 5 )(R 6 ) and a base such as N, N- diisopropylethylamine.
  • the reaction is monitored by, for example, LC/MS, to yield a compound of Formula 107 wherein R 7 is NH 2 , which is isolated and optionally purified.
  • ,R 6 in a compound of Formula 203 is a halide, alkyl halide, or aiyl halide. This halide can be converted to various other substituents using a variety of reactions using techniques known in the art and further described in the examples below.
  • R ⁇ in a compound of Formula 203 is an alkyl or aryl amine.
  • the amine moiety can be alkylated, acylated, converted to the sulfonamide, and the like using techniques known in the art and further described below.
  • R 6 in a compound of Formula 203 is an alkyl alcohol or an aryl alcohol. The hydroxyl moiety can be converted to the corresponding ether or ester using techniques known in the art.
  • Formula 401 wherein n is 0, 1, or 2 in an inert solvent such as THF at about 0°C is added an excess (such as about 2 equivalents) of LAH (such as a 1.0 M solution in THF). After stirring for about 2 hours, the product, a compound of Formula 403, is isolated and used without further purification.
  • an inert solvent such as THF at about 0°C is added an excess (such as about 2 equivalents) of LAH (such as a 1.0 M solution in THF).
  • the hydroxyl group is converted to a protected amino group.
  • the protecting group is phthamide, it can be made as follows. To a stirred solution of a compound of Formula 403 in an inert solvent such as THF are added an excess (such as about 1.1 equivalents) of isoindole-l ,3-dione and triphenylphosphine. An excess (such as about 1.1 equivalents) of DEAD is then added dropwise and the reaction is stirred for about 30 min. The product, a compound of Formula 405, is isolated and purified. [00131] Referring to Reaction Scheme 4, Step 3, the Boc protecting group is then removed to form the corresponding free amine.
  • Fomiula 407 in an inert solvent such as DMF are added a compound of Formula 105 and a base such as diisopropylethylamine at room temperature.
  • the reaction mixture is stirred ovemight.
  • the product, a compound of Fomiula 409, is isolated and purified.
  • Refening to Reaction Scheme 4, Step 5 the amine protecting group, PG, is then removed. If the amine protecting group, PG, is a phthalimide, it can be removed is follows.
  • a solution of a compound of Formula 409 in a polar, protic solvent such as methanol is added an excess (such as about 10 equivalents) of hydrazine hydrate.
  • reaction mixture is sti ⁇ ed at about 50 °C for about 5 h, and then cooled to room temperature.
  • the product, a compound of Fo ⁇ nula 411 is isolated and optionally, purified. Conditions for removing other protecting groups are known to those of skill in the art.
  • the free amine of a compound of Fo ⁇ nula 411 can be acylated, alkylated, reductively alkylated, or sulfonylated using techniques known to those of skill in the art. [00135] Reaction Scheme 5
  • stereoisomers can be obtained from mixtures using techniques known in the art.
  • a free amine of Fo ⁇ nula 605 is dissolved in an inert organic solvent (such as 1PA) and warmed to 60°C.
  • a resolving agent such as dibenzoyl-D-tartaric acid
  • the reaction mixture is left to crystallize by cooling to room temperature over 16 hours under continuing agitation.
  • the desired isomer is isolated and purified in the usual manner.
  • an optically active amine of Formula 607 can be prepared from the corresponding aryl aldehyde as shown in Reaction Scheme 5.
  • Step 1 a solution of a compound of Formula
  • the amine of Formula 605 can be then resolved using techniques known in the art. For example, a 0 °C solution of the amine of Fomiula 605 in an inert solvent such as ethyl acetate is saturated with hydrochloric acid (gas). The resulting salt is collected by filtration and dried in vacuo. Z-N-Acetylleucine sodium salt is added slowly to a stirred solution of the aforementioned salt in water. Crystals form overnight and are removed by filtration, washed with a small amount of cold water, and recrystallized from absolute methanol. The crystalline salt of Formula 607a is isolated and optionally purified.
  • Formula 707 in an inert solvent such as acetonitrile is added an excess (such as about 1.1 equivalents) of RsR ⁇ CH-Z wherein Z is a leaving group and a base such as K 2 CO 3 .
  • the reaction mixture is heated to about 80 °C under microwave irradiation for about 30 min followed by filtration and concentration in vacuo.
  • the product, a compound of Formula 709, is isolated and optionally purified.
  • aprotic solvent such as DMF was activated using techniques known in the art and further described in the example as follows. 1 ,2-Dibromoethane was added to the zinc solution under nitrogen. The mixture was heated using a heat gun for about 30 seconds until gas starts to evolve from the solution, indicating the activation of the zinc. The mixture was then allowed to cool to room temperature followed by the addition of TMSC1, and allowed to stir at room temperature for 30 min. A solution of a compound of Formula 701 in a dry degassed polar, aprotic solvent such as DMF was added to the zinc solution, and the reaction mixture was stirred for 1 hour at room temperature. The solution of 702 is used for the next step.
  • the chemical entities of the invention find use in a variety of applications involving alteration of mitosis.
  • mitosis may be altered in a variety of ways; that is, one can affect mitosis either by increasing or decreasing the activity of a component in the mitotic pathway. Stated differently, mitosis may be affected (e.g., disrupted) by disturbing equilibrium, either by inhibiting or activating certain components. Similar approaches may be used to alter meiosis.
  • the chemical entities of the invention are used to inhibit mitotic spindle formation, thus causing prolonged cell cycle arrest in mitosis.
  • inhibitor in this context is meant decreasing or interfering with mitotic spindle formation or causing mitotic spindle dysfunction.
  • mitotic spindle fo ⁇ nation herein is meant organization of microtubules into bipolar structures by mitotic kinesins.
  • mitotic spindle dysfunction herein is meant mitotic arrest.
  • the chemical entities of the invention bind to, and/or inhibit the activity of, one or more mitotic kinesin.
  • the mitotic kinesin is human, although the chemical entities may be used to bind to or inhibit the activity of mitotic kinesins from other organisms.
  • inhibit means either increasing or decreasing spindle pole separation, causing malformation, i.e., splaying, of mitotic spindle poles, or otherwise causing morphological perturbation of the mitotic spindle.
  • variants and/or fragments of such protein and more particularly, the motor domain of such protein are included within the definition of a mitotic kinein for these purposes.
  • the chemical entities of the invention are used to treat cellular proliferation diseases.
  • diseases which can be treated by the chemical entities provided herein include, but are not limited to, cancer (further discussed below), autoimmune disease, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, cellular proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, and the like.
  • Treatment includes inhibiting cellular proliferation, It is appreciated that in some cases the cells may not be in an abnomial state and still require treatment.
  • the invention herein includes application to cells or individuals afflicted or subject to impending affliction with any one of these disorders or states, [00154]
  • the chemical entities, pharmaceutical formulations and methods provided herein are particularly deemed useful for the treatment of cancer including solid tumors such as skin, breast, brain, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that can be treated include, but are not limited to:
  • sarcoma angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma
  • myxoma rhabdomyoma. fibroma, lipoma and teratoma;
  • Lung bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, Iymphoma, chondromatous hamartoma, mesothelioma;
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, Iymphoma), stomach '(carcinoma, Iymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, Iymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);
  • kidney adenocarcinoma, Wilm's tumor [nepliroblastoma], Iymphoma, leukemia
  • bladder and urethra squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);
  • Liver hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
  • Bone osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant Iymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
  • Nervous system skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblasto a, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
  • Gynecological uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli- Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botiyoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma);
  • Hematologic blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome). Hodgkin's disease, non-Hodgkin's Iymphoma [malignant Iymphoma];
  • Skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and
  • treatment of cancer includes treatment of cancerous cells, including cells afflicted by any one of the above-identified conditions.
  • cancerous cell includes a cell afflicted by any one of the above identified conditions.
  • kit having at least one chemical entity described herein and a package insert or other labeling including directions treating a cellular proliferative disease by administering an effective amount of the at least one chemical entity.
  • the chemical entity in the kits of the invention is particularly provided as one or more doses for a course of treatment for a cellular proliferative disease, each dose being a pharmaceutical formulation including a pharmaceutical excipient and at least one chemical entity described herein.
  • a mitotic kinesin or at least one chemical entity described herein is non-diffusably bound to an insoluble support having isolated sample receiving areas (e.g., a microtiter plate, an array, etc.).
  • the insoluble support may be made of any composition to which the sample can be bound, is readily separated from soluble material, and is otherwise compatible with the overall method of screening.
  • the surface of such supports may be solid or porous and of any convenient shape.
  • suitable insoluble supports include microtiter plates, arrays, membranes and beads. These are typically made of glass, plastic (e.g., polystyrene), polysaccharides, nylon or nitrocellulose, TeflonTM, etc. Microtiter plates and arrays are especially convenient because a large number of assays can be carried out simultaneously, using small amounts of reagents and samples. The particular manner of binding of the sample is not crucial so long as it is compatible with the reagents and overall methods of the invention, maintains the activity of the sample and is nondiffusable.
  • Particular methods of binding include the use of antibodies (which do not sterically block either the ligand binding site or activation sequence when the protein is bound to the support), direct binding to "sticky" or ionic supports, chemical crosslinking, the synthesis of the protein or agent on the surface, etc. Following binding of the sample, excess unbound material is removed by washing. The sample receiving areas may then be blocked through incubation with bovine serum albumin (BSA), casein or other innocuous protein or other moiety.
  • BSA bovine serum albumin
  • the chemical entities of the invention may be used on their own to inhibit the activity of a mitotic kinesin. In some embodiments, at least one chemical entity of the invention is combined with a mitotic kinesin and the activity of the mitotic kinesin is assayed.
  • Kinesin activity is known in the art and includes one or more of the following: the ability to affect ATP hydrolysis; microtubule binding; gliding and polymerization/depolymerization (effects on microtubule dynamics); binding to other proteins of the spindle; binding to proteins involved in cell-cycle control; serving as a substrate to other enzymes, such as kinases or proteases: and specific kinesin cellular activities such as spindle pole separation.
  • the ATPase hydrolysis activity assay utilizes 0,3 M PCA (perchloric acid) and malachite green reagent (8.27 mM sodium molybdate II, 0.33 mM malachite green oxalate, and 0.8 mM Triton X-l 00).
  • PCA perchloric acid
  • malachite green reagent 8.27 mM sodium molybdate II, 0.33 mM malachite green oxalate, and 0.8 mM Triton X-l 00.
  • 10 ⁇ L of the reaction mixture is quenched in 90 ⁇ L of cold 0.3 M PCA.
  • Phosphate standards are used so data can be converted to mM inorganic phosphate released.
  • ATPase assays known in the art include the luciferase assay.
  • ATPase activity of kinesin motor domains also can be used to monitor the effects of agents and are well known to those skilled in the art.
  • ATPase assays of kinesin are performed in the absence of microtubules.
  • the ATPase assays are performed in the presence of microtubules.
  • Different types of agents can be detected in the above assays.
  • the effect of an agent is independent of the concentration of microtubules and ATP.
  • the effect of the agents on kinesin ATPase can be decreased by increasing the concentrations of ATP, microtubules or both.
  • the effect of the agent is increased by increasing concentrations of ATP, microtubules or both.
  • Chemical entities that inhibit the biochemical activity of a mitotic kinesin in vitro may then be screened in vivo.
  • In vivo screening methods include assays of cell cycle distribution, cell viability, or the presence, morphology, activity, distribution, or number of mitotic spindles.
  • Methods for monitoring cell cycle distribution of a cell population, for example, by flow cytometiy are well known to those skilled in the art, as are methods for determining cell viability. See for example, U.S. Patent 6,437,115, hereby inco ⁇ orated by reference in its entirety.
  • Microscopic methods for monitoring spindle formation and malformation are well known to those of skill in the art (see, e.g., Whitehead and Rattner (1998), J. Cell Sci. 111:2551-61; Galgio et al, (1996) J. Cell Biol,, 135:399-414), each incoiporated herein by reference in its entirety.
  • the chemical entities of the invention inhibit one or more mitotic kinesins.
  • IC 50 defined as the concentration of the chemical entity at which the activity of the mitotic kinesin is decreased by fifty percent relative to a control.
  • the at least one chemical entity has an IC5 0 of less than about 1 mM, In some embodiments, the at least one chemical entity has an IC 50 of less than about 100 ⁇ M. In some embodiments, the at least one chemical entity has an IC 50 of less than about 10 ⁇ M. In some embodiments, the at least one chemical entity has an IC 5 0 of less than about 1 ⁇ M. In some embodiments, the at least one chemical entity has an IC 5 0 of less than about 100 nM.
  • the at least one chemical entity has an IC 5 0 of less than about 10 nM. Measurement of IC5 0 is done using an ATPase assay such as described herein. [00163] Another measure of inhibition is Kj. For chemical entities with IC 5 S less than
  • the K, or I j is defined as the dissociation rate constant for the interaction of the compounds described herein, with a mitotic kinesin.
  • the at least one chemical entity has a K, of less than about 100 ⁇ M, In some embodiments, the at least one chemical entity has a K, of less than about 10 ⁇ M. In some embodiments, the at least one chemical entity has a K, of less than about 1 ⁇ M. In some embodiments, the at least one chemical entity has a K, of less than about 100 nM. In some embodiments, the at least one chemical entity has a Kj of less than about 10 nM.
  • the K, for a chemical entity is detennined from the IC50 based on three assumptions and the Michaelis-Menten equation. First, only one compound molecule binds to the enzyme and there is no cooperativity, Second, the concentrations of active enzyme and the compound tested are known (i.e., there are no significant amounts of impurities or inactive forms in the preparations). Third, the enzymatic rate of the enzyme-inhibitor complex is zero. The rate (i.e., compound concentration) data are fitted to the equation:
  • V ⁇ V max E 0 V is the observed rate
  • V ma ⁇ is the rate of the free enzyme
  • lo is the inhibitor concentration
  • Eo is the enzyme concentration
  • Kj is the dissociation constant of the enzyme-inhibitor complex.
  • GI 50 defined as the concentration of the chemical entity that results in a decrease in the rate of cell growth by fifty percent.
  • the at least one chemical entity has a GI 50 of less than about 1 mM.
  • the at least one chemical entity has a GI50 of less than about 20 ⁇ M.
  • the at least one chemical entity has a GI 50 of less than about 10 ⁇ M.
  • the at least one chemical entity has a GI5 0 of less than about 1 ⁇ M, In some embodiments, the at least one chemical entity has a GI 50 of less than about 100 nM.
  • the at least one chemical entity has a GI5 0 of less than about 10 nM.
  • Measurement of GI 50 is done using a cell proliferation assay such as described herein. Chemical entities of this class were found to inhibit cell proliferation.
  • In vitro potency of small molecule inhibitors is determined, for example, by assaying human ovarian cancer cells (SKOV3) for viability following a 72-hour exposure to a 9-point dilution series of compound. Cell viability is determined by measuring the absorbance of formazon, a product formed by the bioreduction of MTS/PMS, a commercially available reagent.
  • Anti-proliferative compounds that have been successfully applied in the clinic to treatment of cancer have GIso's that vary greatly.
  • paclitaxel GI5 0 is 4 nM
  • doxorubicin is 63 nM
  • 5-fluorouracil is 1 ⁇ M
  • hydroxyurea is 500 ⁇ M (data provided by National Cancer Institute, Developmental Therapeutic Program, http://dtp.nci.nih.gov/). Therefore, compounds that inhibit cellular proliferation, i ⁇ espective of the concentration demonstrating inhibition, have potential clinical usefulness.
  • the mitotic kinesin is bound to a support, and a compound of the invention is added to the assay.
  • the chemical entity of the invention is bound to the support and a mitotic kinesin is added.
  • Classes of compounds among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells.
  • assays may be used for this pu ⁇ ose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, ftmctional assays (phosphorylation assays, etc.) and the like.
  • the determination of the binding of the chemical entities of the invention to a mitotic kinesin may be done in a number of ways.
  • the chemical entity is labeled, for example, with a fluorescent or radioactive moiety, and binding is determined directly. For example, this may be done by attaching all or a portion of a mitotic kinesin to a solid support, adding a labeled test compound (for example a chemical entity of the invention in which at least one atom has been replaced by a detectable isotope), washing off excess reagent, and determining whether the amount of the label is that present on the solid support.
  • a labeled test compound for example a chemical entity of the invention in which at least one atom has been replaced by a detectable isotope
  • labeled herein is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, etc.
  • Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc.
  • the complementary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above.
  • the label can directly or indirectly provide a detectable signal.
  • the kinesin proteins may be labeled at tyrosine positions using 125 I, or with fluorophores.
  • more than one component maybe labeled with different labels; using l25 I for the proteins, for example, and a fluorophor for the antimitotic agents.
  • the chemical entities of the invention may also be used as competitors to screen for additional drug candidates.
  • Candidate agent or drug candidate or grammatical equivalents as used herein describe any molecule, e.g., protein, oligopeptide, small organic molecule, polysaccharide, polynucleotide, etc., to be tested for bioactivity, They may be capable of directly or indirectly altering the cellular proliferation phenotype or the expression of a cellular proliferation sequence, including both nucleic acid sequences and protein sequences. In other cases, alteration of cellular proliferation protein binding and/or activity is screened. Screens of this sort may be performed either in the presence or absence of microtubules.
  • exogenous agents include candidate agents which do not bind the cellular proliferation protein in its endogenous native state termed herein as "exogenous" agents.
  • exogenous agents further exclude antibodies to the mitotic kinesin,
  • Candidate agents can encompass numerous chemical classes, though typically they are small organic compounds having a molecular weight of more than 100 and less than about 2,500 daltons.
  • Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding and lipophilic binding, and typically include at least an amine, carbonyl-, hydroxyl-, ether, or carboxyl group, generally at least two of the functional chemical groups.
  • the candidate agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups.
  • Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines. pyrimidines, derivatives, structural analogs or combinations thereof.
  • Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means. Known phaimacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, and/or amidification to produce structural analogs.
  • a second sample comprises at least one chemical entity of the present invention, a mitotic kinesin and a drug candidate. This may be performed in either the presence or absence of microtubules.
  • the binding of the dmg candidate is determined for both samples, and a change, or difference in binding between the two samples indicates the presence of a dmg candidate capable of binding to a mitotic kinesin and potentially inhibiting its activity. That is, if the binding of the dmg candidate is different in the second sample relative to the first sample, the dmg candidate is capable of binding to a mitotic kinesin.
  • the binding of the candidate agent to a mitotic kinesin is determined through the use of competitive binding assays.
  • the competitor is a binding moiety known to bind to the mitotic kinesin, such as an antibody, peptide, binding partner, ligand, etc. Under certain circumstances, there may be competitive binding as between the candidate agent and the binding moiety, with the binding moiety displacing the candidate agent.
  • the candidate agent is labeled. Either the candidate agent, or the competitor, or both, is added first to the mitotic kinesin for a time sufficient to allow binding, if present. Incubations may be performed at any temperature which facilitates optimal activity, typically between 4 and 40°C,
  • Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high throughput screening. Typically between 0.1 and 1 hour will be sufficient. Excess reagent is generally removed or washed away. The second component is then added, and the presence or absence of the labeled component is followed, to indicate binding,
  • the competitor is added first, followed by the candidate agent.
  • Displacement of the competitor is an indication the candidate agent is binding to the mitotic kinesin and thus is capable of binding to, and potentially inhibiting, the activity of the mitotic kinesin.
  • either component can be labeled.
  • the presence of label in the wash solution indicates displacement by the agent.
  • the candidate agent is labeled, the presence of the label on the support indicates displacement.
  • the candidate agent is added first, with incubation and washing, followed by the competitor.
  • the absence of binding by the competitor may indicate the candidate agent is bound to the mitotic kinesin with a higher affinity,
  • the candidate agent is labeled, the presence of the label on the support, coupled with a lack of competitor binding, may indicate the candidate agent is capable of binding to the mitotic kinesin.
  • Inhibition is tested by screening for candidate agents capable of inhibiting the activity of a mitotic kinesin comprising the steps of combining a candidate agent with a mitotic kinesin as above, and determining an alteration in the biological activity of the mitotic kinesin.
  • the candidate agent should both bind to the mitotic kinesin (although this may not be necessary), and alter its biological or biochemical activity as defined herein.
  • the methods include both in vitro screening methods and in vivo screening of cells for alterations in cell cycle distribution, cell viability, or for the presence, mo ⁇ ohology, activity, distribution, or amount of mitotic spindles, as are generally outlined above.
  • differential screening may be used to identify dmg candidates that bind to the native mitotic kinesin but cannot bind to a modified mitotic kinesin.
  • Positive controls and negative controls may be used in the assays. Suitably all control and test samples are performed in at least triplicate to obtain statistically significant results. Incubation of all samples is for a time sufficient for the binding of the agent to the protein. Following incubation, all samples are washed free of non-specifically bound material and the amount of bound, generally labeled agent determined. For example, where a radiolabel is employed, the samples may be counted in a scintillation counter to determine the amount of bound compound.
  • reagents may be included in the screening assays. These include reagents like salts, neutral proteins, e.g., albumin, detergents, etc which may be used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions, Also reagents that otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc., may be used. The mixture of components may be added in any order that provides for the requisite binding. [00185] Accordingly, the chemical entities of the invention are administered to cells.
  • administered administration of a therapeutically effective dose of at least one chemical entity of the invention to a cell either in cell culture or in a patient.
  • therapeutically effective dose herein is meant a dose that produces the effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for systemic versus localized delivery, age. body weight, general health, sex, diet, time of administration, dmg interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art.
  • cells herein is meant any cell in which mitosis or meiosis can be altered.
  • a "patient” for the pu ⁇ oses of the present invention includes both humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, and more particularly, the patient is human.
  • Chemical entities of the invention having the desired phaimacological activity may be administered, in some embodiments, as a pharmaceutically acceptable composition comprising an pharmaceutical excipient, to a patient, as described herein.
  • the chemical entities may be formulated in a variety of ways as discussed below.
  • the concentration of the at least one chemical entity in the fo ⁇ nulation may vary from about 0,1-100 wt.%.
  • the agents may be administered alone or in combination with other treatments, i.e., radiation, or other chemotherapeutic agents such as the taxane class of agents that appear to act on microtubule formation or the camptothecin class of topoisomerase I inhibitors.
  • other chemotherapeutic agents may be administered before, concurrently, or after administration of at least one chemical entity of the present invention.
  • at least one chemical entity of the present invention is co- administered with one or more other chemotherapeutic agents.
  • co-administer it is meant that the at least one chemical entity is administered to a patient such that the at least one chemical entity as well as the co-administered compound may be found in the patient's bloodstream at the same time, regardless when the compounds are actually administered, including simultaneously.
  • the administration of the chemical entities of the present invention can be done in a variety of ways, including, but not limited to, orally, subcutaneously, intravenously, intranasally, transdermally, intrapeiitoneally, intramuscularly, intrapulmonary, vaginally, rectally, or intraocularly. In some instances, for example, in the treatment of wounds and inflammation, the compound or composition may be directly applied as a solution or spray.
  • Pharmaceutical dosage forms include at least one chemical entity described herein and one or more pharmaceutical excipients.
  • pharmaceutical excipients are secondaiy ingredients which function to enable or enhance the delivery of a dmg or medicine in a variety of dosage forms (e.g.: oral fo ⁇ ns such as tablets, capsules, and liquids; topical fo ⁇ ns such as dermal, opthalmic, and otic forms; suppositories; injectables; respiratory forms and the like).
  • Pha ⁇ naceutical excipients include inert or inactive ingredients, synergists or chemicals that substantively contribute to the medicinal effects of the active ingredient.
  • pharmaceutical excipients may function to improve flow characteristics, product uniformity, stability, taste, or appearance, to ease handling and administration of dose, for convenience of use, or to control bioavailability. While pha ⁇ naceutical excipients are commonly described as being inert or inactive, it is appreciated in the art that there is a relationship between the properties of the pharmaceutical excipients and the dosage forms containing them.
  • Oral solid dosage forms such as tablets will typically comprise one or more pharmaceutical excipients, which may for example help impart satisfactory processing and compression characteristics, or provide additional desirable physical characteristics to the tablet.
  • Such pharmaceutical excipients may be selected from diluents, binders, glidants, lubricants, disintegrants, colors, flavors, sweetening agents, polymers, waxes or other solubility-retarding materials.
  • compositions for intravenous administration will generally comprise intravenous fluids, i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily carried by the circulatory system and assimilated.
  • intravenous fluids i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily carried by the circulatory system and assimilated.
  • Such fluids are prepared with water for injection USP.
  • Dosage forms for parenteral administration will generally comprise fluids, particularly intravenous fluids, i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily earned by the circulatory system and assimilated.
  • fluids are typically prepared with water for injection USP.
  • Fluids used commonly for intravenous (IV) use are disclosed in Remington, The Science and Practice of Pharmacy [full citation previously provided], and include: • alcohol, e.g., 5% alcohol (e.g., in dextrose and water (“D/W”) or D/W in no ⁇ nal saline solution ("NSS”), including in 5% dextrose and water (“D5/W”), or D5/ ⁇ V in NSS); • synthetic amino acid such as Aminosyn, FreAmine, Travasol, e.g., 3.5 or 7; 8,5; 3.5, 5.5 or 8.5 % respectively; ammonium chloride e.g., 2.14%; dextran 40, in NSS e.g., 10% or in D5/W e.g., 10%; dextran 70, in NSS e.g., 6% or in D5/W e.g., 6%; dextrose (glucose, D5/W) e.g., 2.5
  • the pH of such IV fluids may vary, and will typically be fiTM 3.5 to 8 as known in the art.
  • the chemical entityies of the invention can be administered alone or in combination with other treatments, i.e., radiation, or other therapeutic agents, such as the taxane class of agents that appear to act on microtubule fo ⁇ nation or the camptothecin class of topoisomerase I inhibitors.
  • other therapeutic agents can be administered before, concurrently (whether in separate dosage forms or in a combined dosage form), or after administration of an active agent of the present invention.
  • N-bromo-succinirnide (216 mg, 1 ,21 mmol) was sti ⁇ ed at 23 °C for 15 min. The reaction mixture was then concentrated in vacuo and the cmde residue diluted with EtOAc (30 mL), washed with brine (10 mL), and concentrated in vacuo. The resulting residue was purified by flash column chro atogi-aphy (silica gel, 1 :1 EtOAc:hexanes) to give 210 mg (35%») of bro oketone 20. LRMS (M+H + ) m/z 495.1.
  • N- bromosuccinimide (190 mg, 1.1 mmol) at 50 °C for 2 hours.
  • the solvents were removed in vacuo. and the resulting residue was partitioned between water (10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo.
  • the residue was then purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide intermediate 8 (55 mg, 23%), which was characterized by LC/MS (LRMS (M+H + ) m/z: 452,1),
  • urea 9 (152 mg, 0.29 mmol) as a glassy solid, which was determined to be pure enough for use in subsequent transfo ⁇ nations (LC/MS (LRMS (M+H + ) m'z: 518.2), [00318]
  • LC/MS LRMS (M+H + ) m'z: 518.2
  • sodium borohydride 260 mg, 6.90 mmol
  • Nitrile 3 (1,92 g, 6,9 mmol) was stined with sodium methoxide in methanol (27,7 mL, 13,9 mmol, 0.5 M) and hydroxylamine hydrochloride (964 mg, 13.9 mmol) under an atmosphere of nitrogen at 50 °C for 2 hours, It was then cooled to room temperature and the solvents were removed in vacuo. The residue was partitioned between saturated aqueous ammonium chloride solution (30 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL).
  • Nitrile 2 (765 mg, 2.4 mmol) was stirred with sodium methoxide in methanol
  • N-bromo-succinimide (46 mg, 0.25 mmol) was sti ⁇ ed at 23 °C for 15 min. The reaction mixture was then concentrated in vacuo, and the crude residue was diluted with EtOAc (30 mL), washed with brine (10 mL), and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 4:1 EtOAc:hexanes) to give 50 mg (46%) of bromoketone 32. LRMS (M+H + ) m/z 438.1.

Abstract

Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are disclosed.

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 mitotic kinesins and are useful in the treatment of cellular proliferative diseases, for example cancer, hypeφlasias, restenosis, cardiac hypertrophy, innnune 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 foπn other types of cellular structures, 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.
[0004] 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 mitotic spindle. Kinesins mediate movement of chromosomes along spindle microtubules, as well as structural changes in the mitotic spindle associated with specific phases of mitosis. Experimental 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 inliibiting the activity of one or more mitotic kinesins.
[0007] Provided is at least one chemical entity chosen from compounds of Formula I
Figure imgf000003_0001
Formula I
and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein
Ri is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; X is -CO or-SO2-;
R2 is hydrogen or optionally substituted lower alkyl; W is -CR4-, -CH2CR4-5 or N; R3 is -CO-R7, hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, cyano, optionally substituted sulfonyl, or optionally substituted aryl; R4 is hydrogen or optionally substituted alkyl; R5 is hydrogen, hydroxyl, optionally substituted amino, optionally substituted heterocyclyl; or optionally substituted lower alkyl; R6 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 embodiments, if W is N, then R5 is not hydroxyl or optionally substituted amino, and Rg 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
Figure imgf000004_0001
(Formula II) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, R3, R5, R6, and W are as described for compounds of Formula I and wherein Rn is optionally substituted heterocyclyl, optionally substituted lower alkyl, nitro, cyano, hydrogen, sulfonyl, or halo; Rι2 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 Rι3 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 III
Figure imgf000005_0001
(Formula IH) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, R3, Re, Ri ι, Rι2, and Rι3 are as described for compounds of Formula II.
[0011] Also provided is at least one chemical entity chosen from compounds of
Formula IV
Figure imgf000005_0002
(Formula IV) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, Re, Rn, Rι2, and R13 are as described for compounds of Formula III.
[0012] Also provided is at least one chemical entity chosen from compounds of
Formula y
Figure imgf000006_0001
(Formula V) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, R3, Rn, R12, arid R]3 are as described for compounds of Formula III and wherein R14 is optionally substituted heteroaryl; and R15 is chosen from hydrogen, halo, hydroxyl, and lower alkyl. [0013] Also provided is at least one chemical entity chosen from compounds of
Formula VI
Figure imgf000006_0002
(Formula VI) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, R6, Rn, Rι2, and R[3 are as described for compounds of Formula III.
[0014] Also provided is at least one chemical entity chosen from compounds of
Formula VII
Figure imgf000007_0001
(Formula VII) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, R6, Rn, R12, and Rj3 are as described for compounds of Formula III and wherein RQ is chosen from optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted arylalkoxy, optionally substituted amino and optionally substituted lower alkyl. [0015] Also provided is composition comprising a pharmaceutical excipient and at least one chemical entity described herein.
[0016] Also provided is a method of modulating CENP-E kinesin activity which comprises contacting said kinesin with an effective amount of at least one chemical entity described herein.
[0017] Also provided is a method of inhibiting 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 administering to a subject in need thereof at least one chemical entity described herein.
[0019] Also provided is a method for the treatment of a cellular proliferative disease comprising administering 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 one 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 have 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 occuirence is independent of its definition at every other occurrence.
[0024] The following abbreviations and terms have the indicated meanings throughout: A Acc — acetyl BBoocc = t-butyloxy carbonyl BBuu = butyl cc-- = cyclo CCBBZZ = carbobenzoxy = benzyloxycarbonyl DDCCMM = dichloromethane = methylene chloride = CH2C1 DDCCEE = dichloroethane DEAD = diethyl azodicarboxylate DIC = diisopropylcarbodiimide DIEA = N,N-diisopropylethylamine DMAP = 4-N,N-dimethylaminopyridine DMF = N,N-dimethylfoπnamide DMSO = dimethyl sulfoxide Et = ethyl Fmoc = 9-fluorenylmethoxycarbonyl GC = gas chromatography HATU — O-(7-Azabenzotriazol-l -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate HOAc = acetic acid HOBt = hydroxybenzotriazole LAH = lithium aluminum hydride Me = methyl mesyl = methanesulfonyl NCS = N-chlorosuccinimide Ph = phenyl Py = pyridine rt = room temperature sat'd = saturated s- = secondary t- = tertiary TES = triethylsilyl TFA = trifluoroacetic acid THF = tetrahydrofuran TMS - trimethylsilyl tosyl = p-toluenesulfonyl [0025] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 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 it 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 one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable. [0027] "Alkyl" encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For example Ci-Cδalkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. Examples 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 two points of attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, Co alkylene indicates a covalent bond and Ci alkylene is a methylene group. When an alkyl residue having a specific 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-butyl, isobutyl and t-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to alkyl groups having one to four carbons. [0028] "Cycloalkyl" indicates a saturated hydrocarbon ring group, having the specified number of carbon atoms, usually from 3 to 7 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl as well as bridged and caged saturated ring groups such as norbornane.
[0029] By "alkoxy" is meant an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, 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 (alkyl)-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. Acyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C2 acyl group is an acetyl group having the formula CH3(C=O)-. [0031] By "alkoxycarbonyl" is meant an ester group of the formula (alkoxy)(C=O)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a Cι-C6alkoxycarbonyl 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 -NH2.
[0033] The term "aminocarbonyl" refers to the group -CONRbRc, where Rb is chosen from H, optionally substituted Ci-Cβ alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and Rc is chosen from hydrogen and optionally substituted Cι-C4 alkyl; or Rb and Rc taken together with the nitrogen to which they are bound, form an optionally substituted 5- to 7-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N, 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)-C4 alkyl-, CrC4 haloalkyl-, -OCι-C4 alkyl, -OC1-C4 alkylphenyl, - C1-C4 alkyl-OH, -OCt-C4 haloalkyl, halo, -OH, -NH2, -C C4 alkyl-NH2, -N(CrC4 alkyl)(C]-C4 alkyl), -NH(Cι-C4 alkyl), -N(C C4 alkyl)(Cι-C4 alkylphenyl), -NH(Cι-C alkylphenyl), cyano, nitro, oxo (as a substitutent for heteroaryl), -CO2H, -C(0)OC,-C4 alkyl, -CON(Cj-C4 alkyl)(d-C4 alkyl), -CONH(C,-C4 alkyl), -CONH2, -NHC(O)(Cι-C4 alkyl), -NHC(O)(phenyl), -N(C,-C4 alkyl)C(O)(C,-C4 alkyl), -N(Cι-C4 alkyl)C(O)(phenyl), -C(O)C C4 alkyl, -C(O)C C4 phenyl, -C(O)C,-C4 haloalkyl, -OC(O)Cι-C4 alkyl, -SO2(Cι-C4 alkyl), -SO2(phenyl), - SO2(C,-C4 haloalkyl), -SO2NH2, -SO2NH(Cι-C alkyl), -SO2NH(phenyl), - NHSO2(Cι-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C,-C4 haloalkyl). [0034] "Aryl" encompasses: 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring 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 one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocycloalkyl ring. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene 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 valence 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, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
[0035] The teπn "aryloxy" refers to the group -O-aryl.
[0036] The term "aralkyl" refers to a residue in which an aryl moiety is attached to the parent structure via an alkyl residue. Examples include benzyl-, phenethyl-, phenylvinyl-, 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. Examples 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 number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
[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 heteroaiyl 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 5,6,7,8-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)l -ethyl.
[0042] A "leaving group" or "atom" is any group or atom that will, under the reaction 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 event or circumstance may or may not occur, and that the description includes instances where 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 be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible and/or inherently unstable.
[0044] "Protecting group" has the meaning conventionally associated with it in 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. Wuts, Protective Groups in Organic Synthesis, Third Edition, Jolm Wiley & Sons, New York (1 99), which is incoiporated herein by reference in its entirety. 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 other 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 least one of the foregoing heteroatoms. Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolinyl, 2,4-imidazolidinyl, 2,3- pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperdyl, and 2,5-piperzinyl. Moφholinyl groups are also contemplated, including 2-moφholinyl and 3 -moφholinyl (numbered wherein 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 change 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-( optionally substituted ( -
C6)alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl). Hence, sulfanyl includes the group Cj-C alkylsulfanyl.
[0048] The term "sulfinyl" includes the groups: -S(O)-H, -S(O)-( optionally substituted (Cι-C6)alkyl), -S(O)-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(O2)-H, -S(O2)-( optionally substituted (Cι- )alkyl), -S(O2)-optionally substituted aryl), -S(O2)-optionally substituted heteroaryl), -S(O2)-(optionally substituted heterocycloalkyl) ,-S(O )-(optionally substituted alkoxy), -S(O2)-optionally substituted aryloxy), -S(O2)-optionally substituted heteroaryloxy), -S(O2)-(optionally substituted heterocyclyloxy); and -S(O2)-(optionally 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 exceeded. When a substituent is oxo (i.e., =O) then 2 hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic inteπnediates. 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, heterocycloalkyl, 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]-C2 alkyl)O- (e.g., methylenedioxy-), -SR , guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NRbRc, halo, cyano, nitro, -CORb, -CO2Rb, -CONRbRc, -OCORb, -OCO2Ra, -OCONRbRc, -NR°CORb, -NRcCO2Ra, -NRcCONRbRc, -CO2Rb, -CONRbRc, -NRcCORb, -SORa, -SO2Ra, -S02NRbRc, and -NRcSO2Ra, where Ra is chosen from optionally substituted Ci-Cβ alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R is chosen from H, optionally substituted Ci-Cβ alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and RG is chosen from hydrogen and optionally substituted Cι-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 Cι-C alkyl, aryl, heteroaryl, aryl-Cι-C alkyl-, heteroaryl-Cι-C4 alkyl-, Cj-C4 haloalkyl-, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(Cj-C4 alkyl)(Cι-C4 alkyl), -NH(Cι-C4 alkyl), -N(Ci-C4 alkyl)(Cj-C4 alkylphenyl), -NH(Cι-C4 alkylphenyl), cyano, nitro, oxo (as a substituted for heteroaryl), -C02H, -C(O)OC1-C alkyl, -CON(CrC4 alkyl)(Cι-C4 alkyl), -CONH(Cι-C4 alkyl), -CONH2, -NHC(O)(Cι-C4 alkyl), -NHC(O)(phenyl), -N(C C4 alkyl)C(θχC!-C4 alkyl), -N(C,-C alkyl)C(O)ψhenyl), -C(O)C]-C4 alkyl, -C(O)Cι-C4 phenyl, -C(O)C C4 haloalkyl, -OC(O)Cι-C4 alkyl, -SO2(Cι-C4 alkyl), - SO2(phenyl), -SO2(Cι-C4 haloalkyl), -SO2NH2, -SO2NH(Cι-C4 alkyl), -SO2NH(phenyl), - NHSO2(d-C4 alkyl), -NHSO2(ρhenyl), and -NHSO2(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 heteroaryl)-C(O)-; and (substituted heterocycloalkyl)-C(O)-, wherein the gi-oup is attached to the 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 or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from: -Ra, -ORb, -O(Cι-C2 alkyl)O- (e.g., methylenedioxy-), -SRb, guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NRbRc, halo, cyano, nitro, -CORb, -CO2Rb, -CONRbR°, -OCORb, -OCO2Ra, -OCONRbRc, -NR°CORb, -NR°CO2Ra, -NR°CONRbRc, -CO2Rb, -CONRbRc, -NRcCORb, -SORa, -SO2Ra, -SO2NRbR°, and -NRcSO2Ra, where Ra is chosen from optionally substituted Cι-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; Rb is chosen from H, optionally substituted Cj- ; alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and Rc is chosen from hydrogen and optionally substituted Cι-C4 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 Cι-C4 alkyl, aryl, heteroaryl, aryl-Cι-C4 alkyl-, heteroaryl-C]-C4 alkyl-, Cj-C4 haloalkyl-, 3Cι-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(Cι-C4 alkyl)(Cι-C4 alkyl), -NH(C C4 alkyl), -N(Cι-C4 alkyl)(Cι-C4 alkylphenyl), -NH(Cι-C4 alkylphenyl), cyano, nitro, oxo (as a substituted for heteroaryl), -CO2H, -C(0)OCι-C4 alkyl, -CON(Cι-C4 alkyl)(Cι-C4 alkyl), -CONH(Cι-C4 alkyl), -CONH2, -NHC(O)(CrC4 alkyl), -NHC(O)(phenyl), -N(C C4 alkyl)C(O)(C]-C4 alkyl), -N(Cι-C4 alkyl)C(O)(phenyl), -C(O)C C4 alkyl, -C(O)d-C4 phenyl, -C(O)Cι-C4 haloalkyl, -OC(O)d-C4 alkyl, -SO2(Cι-C4 alkyl), - SO2(phenyl), -SO2(CrC4 haloalkyl), -S02NH2, -SO2NH(Cι-C4 alkyl), -SO2NH(phenyl), - NHSO2(Cι-C4 alkyl), -NHS02(phenyl), and -NHSO2(Cι-C4 haloalkyl). [0053] The term "substituted alkoxy" refers to alkoxy wherein the alkyl constituent 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: -Ra, -ORb, -O(Cι-C2 alkyl)O- (e.g., methylenedioxy-), -SRb, guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NRbR°, halo, cyano, nitro, -CORb, -CO2Rb, -CONRbRc, -OCORb, -OCO2Ra, -OCONRbRc, -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -CO2Rb, -CONRbRc, -NR°CORb, -SORa, -SO2Ra, -SO2NRbR°, and -NRcSO2Ra, where Ra is chosen from optionally substituted C]-C<, alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R is chosen from H, optionally substituted Cι-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R° is chosen from hydrogen and optionally substituted Cι-C4 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 C1-C4 alkyl, aryl, heteroaryl, aryl-Cj-C4 alkyl-, heteroaryl-Cj-C4 alkyl-, Cj-C4 haloalkyl-, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -CrC4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -Cι-C4 alkyl-NH2, -N(C,-C4 alkyl)(Cι-C4 alkyl), -NH(Cι-C4 alkyl), -N(Cι-C4 alkyl)(Cι-C alkylphenyl), -NH(C C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for heteroaryl), -CO2H, -C(O)OCι-C4 alkyl, -CON(C,-C alkyi)(Cι-C4 alkyl), -CONH(Cι-C4 alkyl), -CONH2, -NHC(O)(Cι-C4 alkyl), -NHC(O)(phenyl), -N(Cι-C4 alkyl)C(O)(Cι-C4 alkyl), -N(d-C4 alkyl)C(O)(phenyl), -C(O)d-C4 alkyl, -C(O)Cι-C4 phenyl, -C(O)d-C4 haloalkyl, -OC(O)d-C4 alkyl, -SO2(CrC4 alkyl), - SO2(phenyl), -SO2(Cι-C4 haloalkyl), -SO2NH2, -SO2NH(d-C4 alkyl), -SO2NH(phenyl), - NHSO2(C,-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C!-C4 haloalkyl). In some embodiments, a substituted alkoxy group is "polyalkoxy" or -O-(optionally substituted alkylene)-(optionally substituted alkoxy), and includes groups such as -OCH2CH2OCH3, and residues of glycol ethers such as polyethyleneglycol, and -O(CH2CH2O)xCH3, where x is an integer of 2-20, such as 2-10, and for example, 2-5. Another substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, 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(O)- wherein the group is attached to the parent structure through the carbonyl functionality and wherein substituted 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: -Ra, -ORb, -O(d-C2 alkyl)0- (e.g., methylenedioxy-), -SRb, guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NRbRc, halo, cyano, nitro, -CORb, -CO2Rb, -CONRbR°, -OCORb, -OCO2Ra, -OCONRbRc, -NRcCORb, -NR°CO2Ra, -NRcCONRbR°, -CO2Rb, -CONRbRc, -NRcCORb, -SORa, -SO2Ra, -SO2NRbRc, and -NRcSO2Ra, where Ra is chosen from optionally substituted Cι-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; Rb is chosen from H, optionally substituted Ci-d alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R° is chosen from hydrogen and optionally substituted d-C4 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-Cι-C4 alkyl-, heteroaryl-Cι-C4 alkyl-, Cj-C haloalkyl-, -OCi-Q. alkyl, -OC,-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC]-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C,-C4 alkyl)(CrC4 alkyl), -NH(Cι-C4 alkyl), -N(Cι-C4 alkyl)(Cι-C4 alkylphenyl), -NH(C!-C4 alkylphenyl), cyano, nitro, oxo (as a substituted for heteroaryl), -CO2H, -C(O)OCι-C4 alkyl, -CON(d-C4 alkyl)(Cι-C4 alkyl), -CONH(Cι-C4 alkyl), -CONH2, -NHC(O)(d-C4 alkyl), -NHC(O)(phenyl), -N(C]-C4 alkyl)C(O)(Cι-C4 alkyl), -N(C,-C4 alkyl)C(O)(phenyl), -C(O)C,-C4 alkyl, -C(O)Cι-C4 phenyl, -C(O)C,-C4 haloalkyl, -OC(O)C C4 alkyl, -SO2(Cι-C4 alkyl), - SO2(phenyl), -SO2(d-C4 haloalkyl), -SO2NH2, -S02NH(Cι-C4 alkyl), -SO2NH(phenyl), - NHSO2(Cι-C4 alkyl), -NHSO2(phenyl), and -NHSO2(d-C4 haloalkyl). (0055] The teπn "substituted amino" refers to the group -NHRd or -NRdRd where each Rd is independently chosen from: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl, sulfinyl and sulfonyl, wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaiyl 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: -Ra, -ORb, -O(Cι-C2 alkyl)O- (e.g., methylenedioxy-), -SRb, guanidine, guanidine wherein one or more of the guanidine hydrogens are replaced with a lower-alkyl group, -NRbRc, halo, cyano, nitro, -COR , -CO2Rb, -CONRbRc, -OCORb, -OCO2Ra, -OCONRbRc, -NRcCORb, -NR°CO2Ra, -NRcCONRbR°, -CO2Rb, -CONRbRc, -NRcCORb, -SORa, -SO2Ra, -SO2NRbRc, and -NRcSO2Ra, where Ra is chosen from optionally substituted Cι-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; Rb is chosen from H, optionally substituted Ci-Q alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and Rc is chosen from hydrogen and optionally substituted Cι-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 Cι-C alkyl, aryl, heteroaryl, aryl-C]-C4 alkyl-, heteroaryl-Cι-C4 alkyl-, C1-C4 haloalkyl-, -OC1-C4 alkyl, -Od-C4 alkylphenyl, -C C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2j -N(CrC4 alkyl)(d-C4 alkyl), -NH(Cι-C4 alkyl), -N(Cι-C alkyl)(Cι-C alkylphenyl), -NH(C]-C4 alkylphenyl), cyano, nitro, oxo (as a substituted for heteroaryl), -CO2H, -C(O)Od-C4 alkyl, -CON(Cι-C4 alkyl)(d-C4 alkyl), -CONH(d-C4 alkyl), -CONH2, -NHC(O)(C C4 alkyl), -NHC(O)(phenyl), -N(C,-C4 alkyl)C(O)(Cι-C4 alkyl), -N(CrC4 alkyl)C(O)(phenyl), -C(O)C,-C4 alkyl, -C(0)Cι-C4 phenyl, -C(O)Cι-C4 haloalkyl, -OC(O)d-C4 alkyl, -SO2(Cι-C4 alkyl), - SO2(ρhenyl), -SO2(Cι-C4 haloalkyl), -SO2NH2, -SO2NH(Cι-C4 alkyl), -SO2NH(phenyl), - NHSO2(d-C4 alkyl), -NHSO2(phenyl), and -NHSO2(d-C4 haloalkyl); and wherein optionally substituted acyl, alkoxycarbonyl, sulfmyl and sulfonyl are as defined herein.
[0056] The term "substituted amino" also refers to the group -NR^ wherein Re and
Rf, together with the nitrogen to which they are bound, form an optionally substituted 5- to 7- membered nitrogen-containing, non-aromatic, heterocycle which optionally contains 1 or 2 additional heteroatoms chosen from nitrogen, oxygen, and sulfur.
[0057] Compounds of Formula I-XIII include, but are not limited to, optical isomers of compounds of Foπnula I-XIII, 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 example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column. In addition, compounds of Formula I-XIII include Z- and E- foπns (or cis- and trans- foπns) of compounds with carbon-carbon double bonds. Where compounds of Formula I-XIII exists in various tautomeric forms, chemical entities of the present invention include all tautomeric forms of the compound. Compounds of Formula I- XIII also includes crystal forms such as polymoφhs and clathrates. [0058] Chemical entities of the present invention include, but are not limited to compounds of Formula I-XIII and all phaπnaceutically acceptable forms thereof. Pharmaceutically acceptable foπns 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 acceptable 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, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate,
1! fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2- hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC- (CH2)n-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 is 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 phaπnaceutically 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 recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
[0061] As noted above, prodrugs also fall within the scope of chemical entities, for example ester or amide derivatives of the compounds of Formula I-XIII. The term "prodrug" includes any compound that becomes a compound of Formula I-XIII when administered to a patient, e.g., upon metabolic processing of the prodrug. Examples 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 Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Phaπnaceutical Association and Pergamon Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985, each of which are incoφorated 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 compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (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 phaπnaceutical 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 antirumour drugs block proliferation and are considered antimitotics.
[0067] The term "therapeutically effective amount" of a chemical entity of 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 be an 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 arnount 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 therapeutically effective amount is an amount sufficient to shrink a cancerous tumor.
[0068] The teπn "inhibition" indicates a significant decrease in the baseline 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 chemical 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 more 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 CENP-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 aberrant 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 develop; b) inhibiting the disease; c) slowing or arresting the development of clinical symptoms; and/or d) relieving the disease, that is, causing the regression of clinical symptoms. [0071] "Patient" refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods of the invention can be useful in both human therapy and veterinary applications. In some embodiments, the patient is a mammal; in some embodiments the patient is human; and in some embodiments the patient is chosen from cats and dogs.
[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 herein inhibit the mitotic kinesin, CENP-E, particularly human CENP-E. CENP-E is a plus end-directed microtubule motor essential for achieving metaphase chromosome alignment. CENP-E accumulates during inteiphase and is degraded following completion of mitosis. Microinjection of antibody directed against CENP-E or overexpression of a dominant negative mutant of CENP-E causes mitotic arrest with prometaphase chromosomes scattered on a bipolar spindle. The tail domain of CENP-E mediates localization to kinetochores and also interacts with the mitotic checkpoint kinase hBubRl. CENP-E also associates with active forms of MAP kinase. Cloning of human (Yen, et al., Nature, 359(6395):536-9 (1992)) CENP-E has been reported. In Thrower, et al., EMBO J., 14:918-26 (1995) partially purified native human CENP-E was reported on. Moreover, the study reported that CENP-E was a minus end-directed microtubule 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 incoφorated herein by reference.
[0073] In some embodiments, the chemical entities inhibit the mitotic kinesin, CENP-
E, as well as modulating one or more of the human mitotic kinesins selected from HSET (see, U.S. Patent No. 6,361,993, which is incoφorated herein by reference); MCAK (see, U.S. Patent No. 6,331,424, which is incoφorated herein by reference); RabK-6 (see U.S. Patent No. 6,544,766, which is incoφorated herein by reference); Kif4 (see, U.S. Patent No. 6,440,684, which is incoφorated herein by reference); MKLP1 (see, U.S. Patent No. 6,448,025, which is incoφorated herein by reference); KiflS (see, U.S. Patent No. 6,355,466, which is incoφorated herein by reference); Kid (see, U.S. Patent No. 6,387,644, which is incoφorated herein by reference); Mppl, CMKφ, KinI-3 (see, U.S. Patent No. 6,461,855, which is incoφorated herein by reference); Kip3a (see, PCT Publication No. WO 01/96593, which is incoφorated herein by reference); Kip3d (see, U.S. Patent No. 6,492,151, which is incoφorated herein by reference); and KSP (see, U.S. Patent No. 6,617,115, which is incoφorated 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, hypeφlasias, restenosis, cardiac hypertrophy, immune disorders, fungal disorders and inflammation.
[0076] Accordingly, the present invention provides at least one chemical entity chosen from compounds of Foπnula I
Figure imgf000023_0001
Formula I
and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein
Ri is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; X is -CO or-SO2-;
R2 is hydrogen or optionally substituted lower alkyl; W is — CR4-, -CH2CR -, or N; R3 is -CO-R7, hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, cyano, optionally substituted sulfonyl, or optionally substituted aryl; ^ is hydrogen or optionally substituted alkyl; R5 is hydrogen, hydroxyl, optionally substituted amino, optionally substituted heterocyclyl; or optionally substituted lower alkyl; R6 is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteraiyloxy, optionally substituted alkoxycarbonyl-, optionally substituted aminocarbonyl-, optionally substituted aryl, optionally substituted heteroaiyl, optionally substituted heterocyclyl, or optionally substituted aralkyl; and R7 is optionally substituted lower alkyl, optionally substituted aryl, hydroxyl, optionally substituted amino, optionally substituted aralkoxy, or optionally substituted alkoxy; provided that if W is N, then R5 is not hydroxyl or optionally substituted amino, and R6 is not optionally substituted alkoxy, optionally substituted aralkoxy, optionally substituted heteroaralkoxy, or optionally substituted amino. [0077] In some embodiments, Ri is optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ri is optionally substituted aryl. In some embodiments, Ri is optionally substituted phenyl. In some embodiments, Ri is phenyl substituted with one, two or three groups independently selected from optionally substituted heterocyclyl, optionally substituted alkyl, sulfonyl, halo, optionally substituted amino, optionally substituted sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaiyloxy; acyl, hydroxyl, nitro, cyano, optionally substituted aryl, and optionally substituted heteroaiyl-. In some embodiments, Rj is chosen from 3-halo-4- isopropoxy-phenyl, 3-cyano-4-isopropoxy-phenyl, 3-cyano-4-isopropylamino-phenyl, 3- chloro-4-isopropylamino-phenyl, 3-cyano-4-trifluoroisopropyloxyphenyl, 3-chloro-4- trifluoroisopropyloxyphenyl, 3-cyano-4-cylobutyloxyphenyl, 3-chloro-4-cylobutyloxyphenyl, 3-cyano-4-cylopropyloxyphenyl, and 3-chloro-4-cylopropyloxyphenyl. In some embodiments, Ri is 3-halo-4-isopropoxy-phenyl or 3-cyano-4-isopropoxy-phenyl. [0078] In some embodiments, R2 is hydrogen. [0079] hi some embodiments, X is -CO-.
[0080] In some embodiments,W is — CR - and R is hydrogen.
[0081] In some embodiments, the compounds described herein possess a potentially chiral center, for example, when W is — CR4-. The invention contemplates the use of pure enantiomers and mixtures of enantiomers, including racemic mixtures, although the use of a substantially optically pure enantiomer will generally be prefened. 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. In some embodiments, the stereogenic center at W is as shown below:
Figure imgf000025_0001
[0082] In some embodiments, R3 is -CO-R7; hydrogen; optionally substituted lower alkyl; cyano; optionally substituted sulfonyl; optionally substituted aryl; or optionally substituted heterocyclyl. In some embodiments, R3 is optionally substituted lower alkyl. In some embodiments, R3 is lower alkyl that is optionally substituted with a hydroxyl or a phosphate ester thereof, lower alkyl that is optionally substituted with a lower alkoxy, lower alkyl that is optionally substituted with an optionally substituted amino group, or lower alkyl that is optionally substituted with CO-R8 where R8 is hydroxyl or optionally substituted amino.
[0083] In some embodiments, R5 is hydrogen, hydroxyl, or optionally substituted lower alkyl. In some embodiments, R5 is hydrogen.
[0084] In some embodiments, the compounds described herein possess a potentially chiral center when R5 is not hydrogen. The invention contemplates the use of pure enantiomers and mixtures of enantiomers, including racemic mixtures, although the use of a substantially optically pure enantiomer will generally be preferred. 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 91.5% enantiomeric excess.
[0085] In some embodiments, R6 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted alkyl (such as wherein the alkyl group is substituted with an optionally substituted amino group or wherein the alkyl group is optionally substituted cycloalkyl-). In some embodiments, R6 is phenyl substituted with one or two of the following substituents: optionally substituted heteroaiyl, 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 II
Figure imgf000026_0001
(Formula II) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, R3, R5, R6, and W are as described for compounds of Formula I and wherein Ri 1 is optionally substituted heterocyclyl, optionally substituted lower alkyl, nitro, cyano, hydrogen, sulfonyl, or halo; Rι2 is hydrogen, halo, optionally substituted alkyl, optionally substituted amino, optionally substituted sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heterocyclyl, or optionally substituted heteroaryl oxy; and Rj3 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, Rn is chloro or cyano.
[0088] In some embodiments, Rι2 is optionally substituted lower alkoxy, optionally substituted lower alkyl, or optionally substituted amino-. In some embodiments, Rι2 is chosen from isopropoxy, isopropylamino, trifluoroisopropyloxy, cylobutyloxy, and cylopropyloxy. In some embodiments, Rj2 is lower alkoxy (such as propoxy) or 2,2,2- trifluoro-l-methyl-ethoxy. In some embodiments, R[2 is propoxy or 2,2,2-trifluoro-l -methyl - ethoxy. hi some embodiments, Rι2 is not -O-(CH2)nNH2 or -O-(CH2)4NH(CH ) wherein n is
4 or 5.
[0089] In some embodiments Rn and Rι2, taken together, form an optionally substituted carbocyclic or heterocyclic ring. In some embodiments, Rn and Rι2, taken . together, foπn a methylenedioxy or ethylenedioxy ring. In some embodiments, Rj2 and R]3, taken together, foπn an optionally substituted carbocyclic or heterocyclic ring. In some embodiments, Rn and R]3, taken together, form an optionally substituted carbocyclic or heterocyclic ring.
[0090] In some embodiments, Rj3 is hydrogen.
[0091] In some embodiments, R2 and Rn, taken together, form an optionally substituted carbocyclic or heterocyclic ring, i.e., R], X, N, and R2, taken together, form an optionally substituted carbocyclic or heterocyclic ring. In certain embodiments, a substituted
2,4-dioxo-l,4-dihydro-2H-quinazolin-3-yl ring is foπned, e.g.,
Figure imgf000027_0001
wherein the phenyl ring is optionally substituted. In other embodiments, a 4-oxo-4H- quinazolin-3-yl ring is formed, e.g.,
Figure imgf000028_0001
wherein the phenyl ring is optionally substituted. In certain embodiments, a 4-oxo-4H- pyridopyrimidin-3-yl ring is formed, e.g.,
Figure imgf000028_0002
wherein one of R, S, T, and LT 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 compounds of
Formula III
Figure imgf000028_0003
(Formula III) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, R3, R6, Rn, R12, and Rj3 are as described for compounds of Formula II.
[0093] Also provided is at least one chemical entity chosen from compounds of
Formula IV
Figure imgf000029_0001
(Foπnula IV) and phaπnaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, Rό, Rn, R12, and R[3 are as described for compounds of Foπnula III.
[0094] Also provided is at least one chemical entity chosen from compounds of
Formula V
Figure imgf000029_0002
(Formula V) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, R3, Rn, R12, and Rj3 are as described for compounds of Formula III and wherein Ri is optionally substituted heteroaryl; and R15 is chosen from hydrogen, halo, hydroxyl, and lower alkyl. [0095] In some embodiments, Rι4 is chosen from 7,8-dihydro-imidazo[l,2-c][l,3]oxazin-2-yl, 3a,7a-dihydro-lH-benzoimidazol-2-yl, imidazo[2,l-b]oxazol-6-yl, oxazol-4-yl, 5,6,7,8-tetrahydro-imidazo[ 1 ,2-a]pyridin-2-yl, lH-[l,2,4]triazol-3-yl, 2,3-dihydro-imidazol-4-yl, lH-imidazol-2-yl, imidazo[ 1 ,2-a]pyridin-2-yl, thiazol-2-yl, thiazol-4-yl, pyrazol-3-yl, and lH-imidazol-4-yl, each of which is optionally substituted with one, two, or three groups chosen from optionally substituted lower alkyl, halo, acyl, sulfonyl, cyano, nitro, optionally substituted amino, and optionally substituted heteroaryl. [0096] In some embodiments, Rι4 is chosen from lH-imidazol-2-yl, imidazo[l,2-a]pyridin-2-yl; and lH-imidazol-4-yl, each of which is optionally substituted with one or two groups chosen from optionally substituted lower alkyl, halo, and acyl. [0097] In some embodiments, Rι5 is hydrogen.
[0098] Also provided is at least one chemical entity chosen from compounds of
Formula VI
Figure imgf000030_0001
(Formula VI) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, R6, Rn, Rι2, and Rι3 are as described for compounds of Foπnula III.
[0099] Also provided is at least one chemical entity chosen from compounds of
Formula VII
Figure imgf000031_0001
(Foπnula VII) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein R2, Re, Rn, R12, and Rι are as described for compounds of Formula III and wherein R9 is chosen from optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted arylalkoxy, optionally substituted amino and optionally substituted lower alkyl. [00100] In some embodiments, R9 is lower alkyl substituted with hydroxyl or optionally substituted amino. In some embodiments, R9 is lower alkyl substituted with hydroxyl, amino, N-methylamino, or N,N-dimethyl amino.
[00101] Also provided is at least one chemical entity chosen from compounds of
Formula VIII
Figure imgf000031_0002
(Foπnula VIII) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein Ri, X ,W, R3, R^ R6, and R7 are as defined for compounds of Formula I and wherein R and R5, together with the atoms to which they are bound, form an optionally substituted 5- 7 membered heterocycle which optionally may include one or two additional heteroatoms. [00102] In some embodiments,, R2 taken together Avith R5, form an optionally substituted pyrrolidinyl ring or optionally substituted piperidinyl ring. [00103] Also provided is at least one chemical entity chosen from compounds of
Formula LX
Figure imgf000032_0001
(Formula IX) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein Ri, X ,W, R2, R3, R , and R7 are as defined for compounds of Formula I and wherein R5 and R6, together with the atoms to which they are bound, form an optionally substituted 5- 7 membered heterocycle which optionally may include one or two heteroatoms. [00104] In some embodiments, R5 and Rg, together with the atoms to which they are attached, form an optionally substituted 2H-[l,2,3]triazol-4-yl; an optionally substituted 1H- benzoimidazol-2-yl; an optionally substituted piperazinyl ring; an optionally substituted moφholinyl ring; or an optionally substituted lH-Imidazol-4-yl ring; an optionally substituted isoxazol-4-yl ring.
[00105] Also provided is at least one chemical entity chosen from compounds of
Formula X
Figure imgf000033_0001
(Formula X) and phaπnaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein Ri, X ,W, R4, R5, R6 and R7 are as defined for compounds of Formula I and wherein R2 and R3, taken together with the atoms to which they are attached, form an optionally substituted 3- to 7-membered heterocyclic ring. [00106] In some embodiments, R2 and R3, taken together with the atoms to which they are attached, foπn an optionally substituted 3- to 7-membered heterocyclic ring. In' some embodiments, they form an aziridinyl ring.
[00107] Also provided is at least one chemical entity chosen from compounds of
Formula XI
Figure imgf000033_0002
(Formula XI) and phaπnaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein W, R , R4, R5, R6 and R7 are as defined for compounds of Formula I and wherein
Ri, X, N, and R2, taken together, fonn a substituted 2,4-dioxo-l,4-dihydro-2H-quinazolin-3- yl, 4-oxo-4H-quinazolin-3-yl, or 4-oxo-4H-pyridopyrimidin-3-yl ring. [00108] Also provided is at least one chemical entity chosen from compounds of Formula XII
Figure imgf000034_0001
(Formula XII) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodmgs, and mixtures thereof, wherein Ri, W, R4, R5, and R6 are as defined for compounds of Foπnula I and wherein -X-N(R2)- is -C=N-; and
X taken together with R foπns an optionally substituted heterocyclic ring; in each case, provided that if W is N, then R5 is not hydroxyl or optionally substituted amino, and R6 is not optionally substituted alkoxy, optionally substituted aralkoxy, optionally substituted heteroaralkoxy, or optionally substituted amino. [00109] In certain embodiments, -X-N(R2)- is -C=N-; and X taken together with R3 forms an optionally substituted heterocyclic ring, including but not limited to 3H- [l,3,4]oxadiazol-2-one; 4,5-dihydro-oxazole; thiazole; imidazole; 3,5-dihydro-imidazol-4~ one; or 3H-pyrimidin-4-one, each of which is optionally substituted. [00110] Also provided is at least one chemical entity chosen from compounds of
Formula XIII
Figure imgf000034_0002
(Formula XIII) and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein Ri, X ,W, R2, R4, R5, and R7 are as defined for compounds of Formula I and wherein
R3 and Rό, together with the atoms to which they are bound, form an optionally substituted 5- 7 membered heterocycle which optionally may include one or two additional heteroatoms. [00111] In some embodiments, R3 and R^, together with the atoms to which they are attached, form an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, or an optionally substituted l,2,3,4-tetrahydro-quinolin-3-yl ring. [00112] Also provided is at least one chemical entity chosen from compounds recited in Table 1, 2, 3, 4, 5, or 6, and phannaceutically acceptable salts, solvates, chelates, nonr covalent complexes, prodmgs, and mixtures thereof.
[00113] The compounds can be named and numbered using AutoNom version 2.1 ,
ChemDraw Ultra 6.0, Cambridgesoft, Cambridge, MA; Struct<=>Name algorithm of ChemDraw Ultra 9.0, Cambridgesoft, Cambridge, MA or ISIS-DRAW.
TABLE 1
N-{ l-[4-(δ-Bromo-5-methyl- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl } -3 -cyano-4- isopropoxy-benzamide
N-( 1 - { 4-[2-( 1 -Acetylamino-ethyl)- 1 - ethyl- 1 H-imidazol-4-yl] -benzyl } -3 - hydroxy-propyl)-3-chloro-4-(2,2,2- trifluoro- 1 -methyl-ethoxy)-benzamide
N-(l-{4-[2-acetyl-l-ethyl-lH- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-(isopropoxy)-
Figure imgf000035_0001
benzamide N-{ l-[4-(8-ethyl-imidazo[l,2- a]pyridin-2-yl)-benzyl] -3 -hydroxypropyl} -3 -cyano-4-isopropoxy- benzamide
N-{l-[4-(8-isopropenyl-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl} -3 -cyano-4-isopropoxy- benzamide
N-( 1 - { 4- [2-( 1 -Acetylamino-propyl)- 1 - ethyl- 1 H-imidazol-4-yl] -benzyl } -3 - hydroxy-propyl)-3 -chloro-4- (isopropoxy)-benzamide
Figure imgf000036_0001
N-( 1 - {4- [2-( 1 -Acetylamino-ethyl)-l - » χ 0Xr -v^"*^ ethyl- 1 H-imidazol-4-yl] -benzyl } -3 - XX hydroxy-propyl)-3-chloro-4- tH-< isopropoxy-benzamide N- [ 1 -(4- { 2-[ 1 -(Acetyl-metliyl-amino)- ethyl]-l-ethyl-lH-imidazol-4-yl}- benzyl)-3 -hydroxy-propyl] -3 -chloro-4- (2,2,2-trifluoro- 1 -methyl-ethoxy)- benzamide
N-( 1 - {4- [2-( 1 -Acetylamino-ethyl)- 1 - propyl- 1 H-imidazol-4-yl] -benzyl} -3 - hydroxy-propyl)-3 -chloro-4- isopropoxy-benzamide
Figure imgf000036_0002
N-{l-[4-(8-chloro-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl} -3 -cyano-4-isopropoxy-
Figure imgf000037_0001
benzamide
N-{ 1 -[4-(8-trifluoromethyl- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl } -3 -cyano-4- isopropoxy-benzamide
N-(l-{4-[2-[l-(Acetyl-methyl-amino)- ethyl] - 1 -ethyl- 1 H-imidazol-4-yl] - benzyl} -3-hydroxy-propyl)-3-cyano-4- isopropoxy-benzamide
N- { 1 -[4-(8-Bromo-imidazo [1,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl}-3-chloro-4-isopropoxy- benzamide
N-( 1 - {4- [2-( 1 - Acetylamino-ethyl)- 1 - isopropyl- 1 H-imidazol-4-yl] -benzyl } - 3-hydroxy-propyl)-3-chloro-4- isopropoxy-benzamide
N-( 1 - {4- [2-( 1 -Acetylamino-ethyl)- 1 - ethyl-lH-imidazol-4-yl]-benzyl}-3- hydroxy-propyl)-3-chloro-4-(2,2,2- trifluoro- 1 -methyl-ethoxy)-benzamide
Figure imgf000037_0002
ABS N-(2-(2-amino-2-methyl- propionylamino)- 1 - {4-[8-( 1 -hydroxy- ethyl)-imidazo[l,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy- benzamide N-(l-{4-[2-[l-(3-methyl-ureido)- ethyl] - 1 -ethyl- 1 H-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-methyl-imidazo[ 1 ,2-a]pyridin- 2-yl]-benzyl} -ethyl)-3-cyano-4- isopropoxy-benzamide
N-(l-{4-[2-Acetyl-l-ethyl-lH- imidazol-4-yl]-benzyl ) -3 -hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide N-( 1 - {4-[2-( 1 -Acetylamino-2-methyl- propyl)- 1 -ethyl- 1 H-imidazol-4-yl]- benzy 1 } -3 -hydroxy-propyl)-3 -chloro- 4-(2,2,2-trifluoro- 1 -methyl-ethoxy)- benzamide
N- { 1 -[4-(8-chloro-imidazo[l ,2- a]pyridin-2-yl)-benzyl] -3 -hydroxy- butyl}-3-cyano-4-isopropoxy-
Figure imgf000038_0001
benzamide N- { 1 -[4-(8-Bromo-imidazo [1,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl } -3 -cyano-4-isopropoxy- benzamide
Figure imgf000039_0001
Figure imgf000039_0002
N-{ l-[4-(8-methyl-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-carbamoyl- propyl } -3 -cyano-4-isόpropoxy- benzamide ABS N-(2-(2-dimethylamino-acetylamino)- 1 - {4-[8-(l -hydroxy-ethyl)- imidazo[l,2-a]pyridin-2-yl]-benzyl}- ethyl)-3-cyano-4-isopropoxy- benzamide
N-{l-[4-(8-acetyl-imidazo[l,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-cyano-4-isopropoxy- benzamide
Figure imgf000039_0004
ABS N-(2-(2-dimethylamino-acetylamino)- l-{4-[8-(l-hydroxy-ethyl)- imidazo[l,2-a]pyridin-2-yl]-benzyl}- ethyl)-3-chloro-4-isopropoxy- benzamide
N-( 1 - { 4- [2-( 1 -Acetylamino-ethyl)- 1 - cyclopropylmethyl- 1 H-imidazol-4-yl]- benzy 1 } -3 -hydroxy-propyl)-3 -cl loro- 4-isopropoxy-benzamide
N-{ l-[4-(8-isopropyl-imidazo[l ,2- a]pyridin-2-yl)-benzyl] -3 -hydroxypropyl} -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- benzamide
N-(l-{4-[2-(l-formylamino-ethyl)-l- ethyl-lH-imidazol-4-yl]-benzyl}-3- hydroxy-propyl)-3 -chloro-4- isopropoxy-benzamide
N-(l-{3-fluoro-4-[2-(l-methyl- lhydroxy-ethyl)-l-ethyl-lH-imidazol- 4-yl]-benzyl}-3-hydroxy-propyl)-3-
Figure imgf000040_0001
chloro-4-isopropoxy-benzamide N-(2-(2-dimethylamino-acetylamino)- l-{4-[8-bromo-imidazo[l,2-a]pyridin- 2-yl] -benzyl } -ethyl)-3 -chloro-4- isopropoxy-benzamide
Figure imgf000041_0001
ABS N-{ l-[2-fluoro-4-(8-methyl- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl}-3-cyano-4- isopropoxy-benzamide
N-(l-{4-[2-acetyl-l-(3- hydroxypropyl)- 1 H-imidazol-4-yl]- benzyl } -3 -hydroxy-prop'yl)-3 -chloro-
Figure imgf000041_0002
4-isopropoxy-benzamide
N-{ l-[4-(8-acetyl-5-methyl- imidazo [ 1 ,2-a]pyridin-2-yl)-benzyl] -3 - hydiOxy-propyl}-3-cyano-4- i sopropoxy-benzamide
N-(l-{4-[2-(l-Acetylamino-2-methyl- propyl)- 1 -ethyl- 1 H-imidazol-4-yl]- benzyl}-3-hydroxy-propyl)-3-chloro- 4-isopropoxy-benzamide
N-[l-[4-(2-acetyl-l-ethyl-lH- imidazol-4-yl)-benzyl]-2-(2-hydroxy- acetylamino)-ethyl]-3-chloro-4-(2,2,2- trifluoiO-l-methyl-ethoxy)-benzamide
Figure imgf000041_0003
N-(l-{4-[2-/-butyl-l-ethyl-lH- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide
N-(2-(2-dimethylamino-acetylamino)- 1 - { 4- [8-bromo-imidazo [ 1 ,2-a]pyridin- 2-yl]-benzyl}-ethyl)-3-cyano-4-
Figure imgf000042_0001
isopropoxy-benzamide
Figure imgf000042_0002
N-(l-{4-[2-acetyl-l-methyl-lH- imidazol-4-yl]-benzyl}-3-carbamoyl- propyl)-3 -chloro-4-isopropoxy- benzamide
Figure imgf000042_0003
N-( 1 - {4-[2-isobutyryl- 1 -methyl- 1 H- imidazol-4-yl] -benzyl } -3 -hydroxy- propyl)-3 -chloro-4-isopropoxy- benzamide
N-( 1 - {4- [2-acetyl- 1 -(2-hydroxy-ethyl)- 1 H-imidazol-4-yl] -benzyl } -3 -hydroxy- propyl)-3-chloro-4-isopropoxy- benzamide N-( 1 - { 4- [2-( 1 -methyl- 1 -hydroxy- ethyl)- 1 -ethyl- 1 H-imidazol-4-yl]-
Figure imgf000043_0001
benzyl}-3-hydroxy-propyl)-3-chloro- c X 4-(2,2,2-trifluoro-l-mefhyl-ethoxy)- > benzamide
N-( 1 - { 3 -fluoro-4- [2-acetyl- 1 -methyl- 1 H-imidazol-4-yl]-benzyl } -3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide
N-[l-[4-(8-Bromo-imidazo[l,2- a]pyridin-2-yl)-benzyl]-2-(2-oxo- tetrahydro-pyrimidin- 1 -yl)-ethyl] -3 -
Figure imgf000043_0002
cyano-4-isopropoxy-benzamide
N-(l-{4-[2-(3-hydroxy-pent-3-yl)-l- ethyl-lH-imidazol-4-yl]-benzyl}-3- hydroxy-propyl)-3-cyano-4-
Figure imgf000043_0003
isopropoxy-benzamide N-(l-{4-[2-acetyl-l-methyl-lH- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-(2,2,2-trifluoro-l- methyl-ethoxy)-benzamide
N-{ 1 -[4-(8-(l -hydroxy-ethyl)- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl } -3-cyano-4- isopropoxy-benzamide N-( 1 - {4- [2-( 1 -hydroxy- 1 -methyl- ethyl)- 1 -(2,2,2-trifluoroethyl)- 1 H- imidazol-4-yl] -benzyl } -3 -hydroxy- propyl)-3 -chloro-4-isopropoxy- benzamide
N-[l -[4-(2-acetyl- 1 -ethyl- 1 H- imidazol-4-yl)-benzyl]-2-(2-hydroxy- acetylamino)-ethyl]-3-clιloiO-4- isopropoxy-benzamide
Figure imgf000044_0001
Figure imgf000044_0002
N-(2-(2-amino-2-methyl- propionylamino)- 1 - {4-[8-( 1 -hydroxy- ethyl)-imidazo[l,2-a]pyridin-2-yl]- benzyl } -ethyl)-3 -cyano-4-isopropoxy-
Figure imgf000044_0003
benzamide N-(2-(2-amino-propionylamino)- 1 - {4- [8-(l -hydroxy-ethyl)-imidazo[l ,2- a]pyridin-2-yl]-benzyl}-ethyl)-3- chloro-4-isopropoxy-benzamide
N-(l -{4-[2-acetyl-l-methyl- 1 H- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3 -cyano-4-isopropoxy- benzamide
N-(l-{4-(5,5-dimethyl-7,8-dihydro- imidazo[ 1 ,2-c] [ 1 ,3]oxazin-2-yl)- benzyl}-3-hydroxy-propyl)-3-chloro- 4-isopropoxy-benzamide
N-( 1 - { 4-[2-isobutyryl- 1 -methyl- 1 H- imidazol-4-yl]-benzyl } -3 -hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide
N-(l-{4-(8-methyl-5,6,7,8-tetrahydro- imidazo [ 1 ,2-a]pyridin-2-yl)-benzyl } - 3 -hydroxy-propy l)-3 -cyano-4- isopropoxy-benzamide
N-( 1 - { 4-[2-acetyl- 1 -propyl- 1 H- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3 -chloro-4-isopropoxy- benzamide
Figure imgf000045_0001
X N-(l-{4-[2-acetyl-l-ethyl-lH- imidazol-4-yl]-benzyl}-2-carbamoyl- ethy l)-3 -chloro-4-isopropoxy- benzamide
N-( 1 - {4-[2-acetyl- 1 -methyl- 1 H- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3 -chloro-4-isopropoxy- benzamide
N-(2-(2-amino-propionylamino)-l-{4- [8-methyl-imidazo[ 1 ,2-a]pyridin-2-yl]- benzyl } -ethyl)-3 -cyano-4-isopropoxy- benzamide N-(l-{4-[2-(l-hydroxy-2-methyl- propyl)- 1 -ethyl- 1 H-imidazol-4-yl] - benzyl } -3 -hydroxy-propyl)-3 -chloro- 4-(2,2,2-trifluoro- 1 -methyl-ethoxy)- benzamide N-(l-{3-fιuoro-4-[2-(l-hydroxy-l- methyl-ethyl)- 1 -ethyl- 1 H-imidazol-4- y 1] -benzyl } -3 -hydroxy-propyl)-3 - chloro-4-(2,2,2-trifluoro- 1 -methyl- ethoxy)-benzamide
N-( 1 - {4- [2-propionyl- 1 -methyl- 1 H- imidazol-4-yl] -benzyl} -3 -hydroxy- propyl)-3-cyano-4-isopropoxy-
Figure imgf000046_0001
benzamide N-( 1 - { 4-[2-( 1 -hydroxy- 1 -methyl- ethyl)-l-(2,2,2-trifluoroethyl)-lH- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3 -cyano-4-isopropoxy- benzamide
N-(l - {4-[2-(l -formylamino-ethyl)- 1 - methyl- 1 H-imidazol-4-yl]-benzyl } -3 - hydroxy-propyl)-3 -chloro-4- isopropoxy-benzamide
N-(2-(2-hydroxy-acetylamino)-l-{4- [8-(l-hydroxy-ethyl)-imidazo[l,2- a]pyridin-2-yl] -benzyl }-ethyl)-3- chloro-4-isopropoxy-benzamide
N-(3-fluoro- 1 - {4-[2-(l -hydroxy- 1- methyl-ethyl)- 1 -methyl- 1 H-imidazol- 4-yl] -benzyl } -3 -hydroxy-propyl)-3 - cyano-4-isopropoxy-benzamide
N-(l-{4-[2-(l-acetylamino-ethyl)-l- methyl-lH-imidazol-4-yl]-benzyl}-3- hydroxy-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
Figure imgf000047_0001
N-(2-(2-amino-2-methyl- propionylamino)- 1 - {4- [8-methyl- imidazo [ 1 ,2-a]pyridin-2-yl] -benzyl } - ethyl)-3 -cyano-4-isopropoxy- benzamide
N-{l-[4-(S-methyl-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propy 1 } -3 -chloro-4-isopropoxy- benzamide
N-(l-{4-[2-/-butyl-l-methyl-lH- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide
N-(l-{4-[2-t-butyl-l-methyl-lH- imidazol-4-yl]-benzyl}-3-carbamoyl- butyl)-3 -cyano-4-isopropoxy- benzamide
N- { 1 - [4-(8-methyl-imidazo [ 1 ,2- a]pyridin-2-yl)-benzyl]-3-carbamoyl- propyl } -3 -chloro-4-isopropoxy- benzamide
N-(l-{4-[2-(l-hydroxy-l-methyl- ethyl)- 1 -ethyl- 1 H-imidazol-4-yl] - benzyl } -3 -hydroxy-propyl)-3 -cyano-4- isopropoxy-benzamide
Figure imgf000048_0001
N-( 1 - {3-fluoro-4-[2-acetyl- 1 -methyl- lH-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3 -chloro-4-isopropoxy- benzamide
N-(l-{4-[2-acetyl-l-methyl-lH- imidazol-4-yl]-benzyl}-3-carbamoyl- propyl)-3-chloro-4-isopropoxy-
Figure imgf000049_0001
benzamide
Figure imgf000049_0002
-methyl- 1 H- -3 -hydroxyopropoxy-
Figure imgf000049_0003
N-{ l-[4-(δ-methyl-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl}-3-cyano-4-(2,2,2-trifluoiO-l- methyl-ethoxy)-benzamide
N-(2-(2-hydroxy-acetylamino)-l-{4- [8-methyl-imidazo[l,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-cyano-4-isopropoxy- benzamide
Figure imgf000049_0004
N-( 1 - {4-[2-( 1 -hydroxyimino-ethyl)- 1 - methyl- 1 H-imidazol-4-yl] -benzyl } -3 - hydroxy-propyl)-3 -chloro-4- isopropoxy-benzamide
N-(l-{4-[2-(3-hydroxy-pent-3-yl)-l- ethyl-lH-imidazol-4-yl]-benzyl}-3- hydroxy-propyl)-3 -cl loro-4- isopropoxy-benzamide
N-(2-(2-dimethylamino-acetylamino)- l-{4-[8-methyl-imidazo[l,2-a]pyridin- 2-yl]-benzyl}-ethyl)-3-chloro-4- i sopropoxy-benzamide
N-(l-{4-[2-acetyl-l-(2,2,2-trifluoro- ethyl)- 1 H-imidazol-4-yl] -benzyl } -3 - hydroxy-propyl)-3-chloro-4-
Figure imgf000050_0001
isopropoxy-benzamide
N-(2-(3-hydroxy-propionylamino)- 1 - {4-[8-bromo-imidazo[l,2-a]pyridin-2- yl]-benzyl}-ethyl)-3-chloro-4- isopropoxy-benzamide
N-(2-(2-hydroxy-acetylamino)- 1 - {4- [8-bromo-imidazo [ 1 ,2-a]pyridin-2-yl] - benzyl}-ethyl)-3-chloro-4-isopropoxy- benzamide
Figure imgf000050_0002
ABS N-(2-(2-amino-2-methyl- propionylamino)- 1 - {4-[8-bromo- imidazo[l,2-a]pyridin-2-yl]-benzyl}- ethyl)-3 -chloro-4-isopropoxy- benzamide
N-[l~[4-(2-t-butyl-l-methyl-lH- imidazol-4-yl)-benzyl]-2-ureido- ethyl]-3-cyano-4-isopropoxy- benzamide
N- { 1 -[4-(8-methyl-imidazo [1,2- a]pyridin-2-yl)-benzyl]-3-carbamoyl- propyl } -3-chloro-4-isopropoxy- benzamide
N-( 1 - {4- [2-(l -hydroxypropyl)- 1 -ethyl- 1 H-imidazol-4-yl]-benzyl } -3-hydroxy- propyl)-3 -chloro-4-isopropoxy- benzamide
N-(l-{4-[2-acetyl-l-methyl-lH- imidazol-4-yl] -benzyl }-2-carbamoyl- ethyl)-3-chloro-4-isopropoxy- benzamide
N-(2-(2-hydroxy-acetylamino)-l-{4- [8-methyl-imidazo[l,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy- benzamide
Figure imgf000051_0001
N-(l-{4-[2-acetyl-l-methyl-lH- imidazol-4-yl] -benzyl } -3-hydroxy- piOpyl)-3-chloro-4-(2,2,2-trifluoro- 1 ■ methyl-ethoxy)-benzamide
N-(l-{4-[2-isobutyryl-l-ethyl-lH- imidazol-4-yl] -benzyl } -3 -hydroxy- propyl)-3-chloro-4-isopropoxy- benzamide
N- { 1 - [4-(8-( 1 -hydroxy-ethyl)- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- carbamoyl-propyl } -3 -chloro-4- isopropoxy-benzamide
N-(l-{4-[2-(l-hydroxy-l-methyl- ethyl)-l -ethyl-1 H-imidazol-4-} ]- benzyl}-3-hydroxy-propyl)-3-chloro- 4-isopropoxy-benzamide
Figure imgf000052_0002
' %xx N-{ l-[4-(8-bromo-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-carbamoyl- propyl } -3-chloro-4-isopropoxy- benzamide
N-(2-(2-hydroxy-propionylamino)- 1 - {4- [8-bromo-imidazo [l,2-a]pyridin-2- yl] -benzyl } -ethyl)-3 -chloro-4- isopropoxy-benzamide
Figure imgf000052_0003
N-{l-[4-(δ-(carbamoyl)-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl } -3 -cyano-4-isopropoxy- benzamide
N-{ 1 -[4-(8-(l -hydroxy-ethyl)- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl } -3-cyano-4- isopropoxy-benzamide
N-[l-[4-(2-t-butyl-l-methyl-lH- imidazol-4-yl)-benzyl]-2- (acetylamino)-ethyl] -3 -cyano-4- isopropoxy-benzamide
N-{ l-[2-fluoro-4-(8-methyl- imidazof 1 ,2-a]pyridin-2-yl)-benzyl] -3 - hydroxy-propyl } -3 -chloro-4- isopropoxy-benzamide
N-{ l-[4-(8-methyl-imidazo[l,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- 1 H-imidazol-4-yl]-
Figure imgf000053_0001
benzyl } -3 -hydroxy-propyl)-3 -cyano-4- (2,2,2-trifluoro- 1 -methyl-ethoxy)- ^ benzamide N-( 1 - { 4-[2-( 1 -Acetylamino-ethyl)- 1 - methyl- 1 H-imidazol-4-yl]-benzyl } -3 - hydroxy-propyl)-3 -chloro-4- isopropoxy-benzamide
N-(l-{4-[2-r-butyl-l-methyl-lH- imidazol-4-yl]-benzyl}-3-carbamoyl- propyl)-3-cyano-4-isopropoxy- benzamide
Figure imgf000054_0001
ABS H N-{l-[4-(4-methyl-3a,7a-dihydro-lH- CI '— N H benzoimidazol-2-yl)-benzyl]-3- hydroxy-p H O \ cX H ropyl } -3 -chloro-4- isopropoxy-benzamide
N-( 1 - { 2,3 ,5 ,6-tetrafluoro-4- [2-t-butyl- 1 -methyl- 1 H-imidazol-4-yl] -benzyl } - 3 -hydroxy-propyl)-3 -cyano-4- isopropoxy-benzamide
N-(l-{4-[2-acetyl-l-methyl-lH- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3 -cyano-4-( 1 -fluoro-prop-2- yloxy)-benzamide
N-( 1 - {4-[2-r-butyl- 1 -methyl-1 H- imidazol-4-yl] -benzyl } -3-hydroxy- propyl)-3-chloro-4-isopropoxy- benza ide N-( 1 - {4-[2-( 1 -hydroxy- 1 -methyl- ethyl)- 1 -ethyl- 1 H-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[l,2-a]pyridin-2-yl)- benzyl] -3 -hydroxy-propyl } -3 -cyano-4- isopropoxy-benzamide
N-{ l-[4-(8-(l-hydroxy-ethyl)- imidazo [ 1 ,2-a] pyridin-2-yl)-benzyl] -3 - carbamoyl-propyl } -3-cyano-4- isopropoxy-benzamide
N-(l-{4-[2-(l-hydroxy-2-methyl- propyl)- 1 -ethyl- 1 H-imidazol-4-yl]- benzyl}-3-hydroxy-propyl)-3-chloiO- 4-i sopropoxy-benzamide
N-( 1 - {4- [2-( 1 -hydroxy- 1 -methyl- ethyl)- 1 -methyl- 1 H-imidazol-4-yl] - benzyl } -3 -hydroxy-propyl)-3 -chloro- 4-isopropoxy-benzamide
N-( 1 - {4-[2-isopropenyl- 1 -methyl- 1 H- imidazol-4-y 1] -benzyl } -3 -hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide
Figure imgf000055_0001
N-(l-{4-[2-acetyl-l-isopropyl-lH- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3 -chloro-4-isopropoxy- benzamide
N-(l - {4-[2 -trifluoromethyl- 1 -methyl - lH-imidazol-4-yl]~benzyl}-3-hydroxy- propyl)-3 -cyano-4-isopropoxy- benzamide
N-(2-{4:[2-t-butyl-l-methyl-lH- imidazol-4-yl]-phenyl } - 1 -( 1 H- [l,2,4]triazol-5-yl)-ethyl)-3-cyano-4- isopropoxy-benzamide
N-{ l-[3-chloro-4-(8-methyl- imidazo[ 1 ,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl } -3-cyano-4- isopropoxy-benzamide
N- { 1 - [4-(3 -methyl-imidazo [2,1- b]oxazol-6-yl)-benzyl]-3-hydroxy- buty 1 } -3 -cyano-4-isopropoxy- benzamide
N-(2-(2-hydroxy-propionylamino)- 1 - {4-[8-(l-hydroxy-ethyl)-imidazo[l,2- a]pyridin-2-yl]-benzyl } -ethyl)-3 - chloro-4-isopropoxy-benzamide
Figure imgf000056_0001
N-(l-hydroxy-l-{4-[2-t-butyl-l- methyl- 1 H-imidazol-4-yl] -phenyl } -4- hydroxy-butyl)-3 -chloro-4- i sopropoxy-benzamide
N-( 1 - { 4-[2-acetyl- 1 -ethyl- 1 H- imidazol-4-yl]-benzyl} -2-(N,N- dimethylcarbamoyl)-ethyl)-3-chloro-4- isopropoxy-benzamide
N-(2-(2-hydroxy-propionylamino)- 1 - {4-[8-methyl-imidazo[l,2-a]pyridin-2- yl] -benzyl } -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- 1 methyl- ethyl)- 1 -methyl- 1 H-imidazol-4-yl] - benzyl}-3-hydroxy-propyl)-3-cyano-4- isopropoxy-benzamide
N-(l-{4-[2-[l-(acetylamino)-propyl]- 1 -ethyl- 1 H-imidazol-4-yl] -benzyl } -3 - hydroxy-propyl)-3-chloro-4-(2,2,2-
Figure imgf000057_0001
trifluoro- 1 -methyl-ethoxy)-benzamide N-[ 1 -[4-(2-t-butyl- 1 -methyl- 1 H- imidazol-4-yl)-benzyl]-2-(3-methyl- ureido)-ethyl] -3 -cyano-4-isopropoxy- benzamide
N-( 1 - (4-[2-(cyclopropylcarbonyl)- 1 - methyl- 1 H-imidazol-4-yl]-benzyl } -3 - hydroxy-propyl)-3 -cyano-4-
Figure imgf000058_0001
isopropoxy-benzamide
Figure imgf000058_0002
N-( 1 - {4- [2-( 1 -hydroxy- 1 methyl- ethyl)- 1 -ethyl- 1 H-imidazol-4-yl]- benzyl}-2-carbamoyl-ethyl)-3-chloro- 4-isopropoxy-benzamide
N-[ 1 -[4-(2-t-butyl-l -methyl- 1 H- imidazol-4-yl)-benzyl]-2-(l-methyl- ureido)-ethyl]-3-chloro-4-isopropoxy- benzamide
N- { 1 -[4-(8-hydroxymethyl- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl } -3 -cyano-4-
Figure imgf000058_0003
isopropoxy-benzamide N-( 1 - {4-[2-t-butyl- 1 -(2-hydroxyethyl)- 1 H-imidazol-4-yl] -benzyl} -3-hydroxy- propyl)-3 -cyano-4-isopropoxy- benzamide
N-[l-[4-(8-methyl-imidazo[l ,2- a]pyridin-2-yl)-benzyl]-2-ureido- ethyl]-3-cyano-4-isopropoxy- benzamide
N-(l-{4-[2-(methylsulfonyl)-l-methyl- 1 H-imidazol-4-yl]-benzyl } -3 -hydroxy- propyι)-3-cyano-4-isbpropoxy- benzamide
N-( 1 - { 3 -fluoro-4- [2-acetyl- 1 -ethyl- lH-imidazol-4-yl]-benzyl}-3-hydroxy- piOpyl)-3-chloro-4-(2,2,2-trifluoiO-l- 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-(2- {4-[2-t-butyl- 1 -methyl- 1 H- imidazol-4-yl] -phenyl }- 1 -(5-methyl- [l,2,4]oxadiazol-3-yl)-ethyl)-3-cyano-
Figure imgf000059_0001
4-isopropoxy-benzamide N-{ 1 -[2,6-difluoiO-4-(8-chloro- imidazo [ 1 ,2-a]pyridin-2-yl)-benzyl]-3 - hydroxy-propyl}-3-cyano-4- isopropoxy-benzamide
N-( 1 - { 4-[2-( 1 -hydroxy-2,2-dimethyl- propyl)- 1 -methyl- 1 H-imidazol-4-yl] - benzyl } -3-hydroxy-propyl)-3-cyano-4-
Figure imgf000060_0001
isopropoxy-benzamide - 1 - -3-
N-( 1 - {4- [2-( 1 -hydroxy- 1 methyl- ethyl)- 1 -methyl- 1 H-imidazol-4-yl]- benzyl } -3-carbamoyl-propyl)-3 - chloro-4-isopropoxy-benzamide
N-(2-(2-amino-propionylamino)- 1 - {4- [8-(l-hydroxy-ethyl)-imidazo[l,2- a] pyridin-2-yl] -benzyl } -ethyl)-3 - cyano-4-isopropoxy-benzamide N-(l-{4-[2-(l-hydroxy-lmethyl- ethyl)- 1 -methyl- 1 H-imidazol-4-yl]- benzyl } -3 -hydroxy-propyl)-3 -chloro- 4-(2,2,2 -trifluoro- 1 -methyl-ethoxy) -benzamide
Figure imgf000060_0003
N-(2-(2-amino-propionylamino)- 1 - {4- [8-bromo-imidazo[l,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy- benzamide
N-(l-{4-[2-(l-acetylamino-ethyl)-l- ethyl-lH-imidazol-4-yl]-benzyl}-2- methylcarbamoyl-ethyl)-3-chloro-4- isopropoxy-benzamide
Figure imgf000061_0001
N-(l-{4-[2-acetyl-l-ethyl-lH- imidazol-4-yl] -benzyl } -2- dimethylcarbamoyl-ethyl)-3-chloro-4- (2,2,2-trifluoro- 1 -methyl-ethoxy)- benzamide
Figure imgf000061_0002
Figure imgf000061_0005
N-(2-(2-hydroxy-propionylamino)- 1 - {4-[S-methyl-imidazo[l,2-a]pyridin-2- yl] -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-
Figure imgf000061_0003
benzamide ABS N-(2-(2-amino-2-methyl- propionylamino)- 1 - {4- [8-methyl- imidazo[l,2-a]pyridin-2-yl]-benzyl}- ethyl)-3-chloro-4-isopropoxy- benzamide
Figure imgf000061_0004
N-{l-[4-(8-methyl-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl}-2,3-dichhloro-4-isopropoxy- benzamide
N-(l-{4-[2-acetyl-l-ethyl-lH- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-chloro-4-(2,2,2-trifluoro- 1 -
Figure imgf000062_0001
methyl-ethoxy)-benzamide
N-( 1 - { 3 -fluoro-4-[2-acetyl- 1 -methyl- lH-imidazσl-4-yl]-benzyl}-3-hydroxy- propyl)-3 -cyano-4-(2,2,2-trifluoro- 1 - methyl-ethoxy)-benzamide
N-{ 1 -[4-(8-(l -hydroxy-ethyl)- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl } -3 -chloro-4-
Figure imgf000062_0002
isopropoxy-benzamide
N-[l-[4-(2-/-butyl-l-methyl-lH- imidazol-4-yl)-benzyl]-2-(2-oxo- tetrahydro-pyrimidin- 1 -yl)-ethyl] -3 - cyano-4-isopropoxy-benzamide
N-[l-[4-(2-t-butyl-l-methyl-lH- imidazol-4-yl)-benzyl]-3 - hydroxycarbamoyl -propyl] -3 -cyano-4- isopropoxy-benzamide
Figure imgf000062_0003
N-{l-[4-(5-methyl-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl}-3-cyano-4-isopropoxy- benzamide
N-( 1 - {4-[2-acetyl- 1 -methyl- 1 H- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-(isopropylamino)- benzamide
N- [ 1 -[4-(2-t-butyl- 1 -methyl- 1 H- imidazol-4-yl)-benzyl] -2- (foπnylamino)-ethyl] -3 -cyano-4- ispropoxy-benzamide
N-(l-{4-(2-Acetyl-oxazol-4-yl)- benzyl}-3-hydroxy-propyl)-3-cyano-4- isopropoxy-benzamide
N-(2-(2-amino-acetylamino)-l-{4-[8- bromo-imidazo[l,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy-
Figure imgf000063_0001
benzamide N-(2-(2-hydroxy-2-methyl- propionylamino)-l-{4-[8-bromo- imidazo[l,2-a]pyridin-2-yl]-benzyl}- ethyl)-3-chloro-4-isopropoxy- benzamide
Figure imgf000063_0002
N-(2-{4-[5-t-butyl-l-methyl-lH- [ 1 ,2,4] triazol-3 -yl] -phenyl } - 1 - ( [ 1 ,2,4] oxadiazol-3-yl)-ethyl)-3 -cyano- 4-isopropoxy-benzamide
N-(l-{4-[2-/-butyl-l-methyl-lH- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-2-amino-3-chloro-4- isopropoxy-benzamide
N-( l-{4-[2-(l -acetylamino-ethyl)- 1- ethyl-lH-imidazol-4-yl]-benzyl}-3- carbamoy l-propyl)-3 -chloro-4-(2 ,2 ,2- trifluoro- 1 -methyl-ethoxy)-benzamide
Figure imgf000064_0001
ABS N-(2-(2-amino-3 -hydroxy- propionylamino)- 1 - {4- [8-bromo- imidazo[l,2-a]pyridin-2-yl]-benzyl}- ethyl)-3 -chloro-4-isopropoxy- benzamide
N-{l-[2,6-difluoro-4-(8-methyl- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl}-3-chloro-4- isopropoxy-benzamide
N-{l-[4-(8-amino-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy~ propyl } -3 -cyano-4-isopropoxy- benzamide
Figure imgf000064_0002
Figure imgf000065_0001
N- { 1 -[4-(8-( 1 -methyl- 1 -hydroxy- ethyl)-imidazo[l,2-a]pyridin-2-yl)- benzyl] -3 -hydroxy-propyl } -3-cyano-4-
Figure imgf000065_0002
isopropoxy-benzamide
Figure imgf000065_0003
N-(l-{4-[2-(l-(ethoxycarbonylamino)- ethyl)- 1 -ethyl- 1 H-imidazol-4-yl] - benzyl } -3 -hydroxy-propyl)-3 -chloro- 4-(2,2,2-trifluoro- 1 -methyl -ethoxy)- benzamide
N-{l-[4-(imidazo[l,2-a]pyridin-2-yl)- benzyl]-3-hydroxy-propyl}-3-cyano-4- isopropoxy-benzamide
N-(2- {4-[2-t-butyl- 1 -methyl-1 H- imidazol-4-yl]-phenyl } - 1 -( 1 H- imidazol-2-yl)-ethyl)-3-cyano-4- i sopropoxy-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-{ l-[4-(8-(l-hydroxypropyl)- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl}-3-chloro-4- isopropoxy-benzamide
Figure imgf000066_0001
N-[ 1 -[4-(2-t-butyl- 1 -(2-aminoethyl)- 1 H-imidazol-4-yl)-benzyl]-2-(2- hydroxy-acetylamino)-ethyl] -3 -chloro- 4-isopropoxy-benzamide
N-(l-{4-[2-/-butyl-l -methyl- 1H- imidazol-4-yl] -benzyl } -3-hydroxy- propyl)-3-chloro-4-isopropoxy- benzamide
N-(2-(2-hydroxy-propionylamino)- 1 - {4-[8-methyl-imidazo[l,2-a]pyridin-2- yl] -benzyl } -ethyl)-3-chloro-4- isopropoxy-benzamide
N-[ 1 - [4-(2-t-butyl- 1 -methyl- 1 H- imidazol-4-yl)-benzyl]-2-(3-hydroxy- ureido)-ethyl]-3-cyano-4-isopropoxy- benzamide
N-(2-(3-amino-propionylamino)-l-{4- [8-bromo-imidazo[l,2-a]pyridin-2-yl]- benzyl } -ethyl)-3-chloro-4-isopropoxy- benzamide
N-(2-{4-[2-t-butyl- 1 -methyl- 1 H- imidazol-4-yl]-phenyl } - 1 - ([1 ,2,4] oxadiazol-3 -yl)-ethyl)-3-cyano-
Figure imgf000067_0001
4-isopropoxy-benzamide N-(2-(2-amino-3-hydroxy- propionylamino)- 1 - {4-[8-bromo- imidazo[l,2-a]pyridin-2-yl]-benzyl}- ethyl)-3-chloro-4-isopropoxy- benzamide
N-{l-[4-(8-nitro-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl}-3-cyano-4-isopropoxy- benzamide N-{ l-[2,6-difluoro-4-(8-methyl- 5,6,7,8-tetrahydro-imidazo[l,2- a]pyridin-2-yl)-benzyl]-3-hydroxy- propyl } -3 -chloro-4-isopropoxy- benzamide N-(l-{4-[2-acetyl-l-ethyl-lH- imidazol-4-yl] -benzyl } -2- methylcarbamoyl-ethyl)-3-chloro-4- (2,2,2-trifluoro- 1 -methyl-ethoxy)- benzamide
N-(2-(2-amino-propionylamino)-l-{4- [8-methyl-imidazo[l,2-a]pyridin-2-yl]- benzyl } -ethyl)-3 -chloro-4-isopropoxy- benzamide
N-[l-[4-(8-bromo-imidazo[l,2- a]pyridin-2-yl)-benzyl]-2-(2-oxo- imidazolidinyl)-ethyl]-3-chloro-4-
Figure imgf000068_0001
isopropoxy-benzamide N-[ 1 - [4-(2-( 1 -hydroxy- 1 -methyl- ethyl)- 1 -methyl- 1 H-imidazol-4-yl)- benzyl]-2-(2-amino-propionylamino)- ethyl]-3-chloro-4-isopropoxy- benzamide
N-( 1 - {4-[2-acetyl- 1 -butyl- 1 H- imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3 -chloro-4-isopropoxy- benzamide
N-(l-{4-[2-(l-acetylamino-ethyl)-l- ethyl-lH-imidazol-4-yl]-benzyl}-2- carbamoyl-ethyl)-3-chloro-4- isopropoxy-benzamide
N-(l-{4-[4-t-butyl-lH-imidazol-2-yl]- benzyl}-3-hydroxy-propyl)-3-cyano-4- isopropoxy-benzamide
Figure imgf000069_0001
FΛC Ύ X Ύ N-(l-{4-[2-(2,2-dimethyl-propyl)-l- X X YNY methyl- 1 H-imidazol-4-yl] -benzyl } -3 - hydroxy-propyl)-3 -cyano-4- i sopropoxy-benzamide ABS V ■ °χX N-(2-(2-hydroxy-propionylamino)- 1 - Q r r X {4-[8-(l -hydroxy-ethyl)-imidazo[l ,2- a]pyridin-2-yl]-benzyl}-ethyl)-3- cyano-4-isopropoxy-benzamide
Figure imgf000070_0001
N-(l-{3-fluoro-4-[2-(l-hydroxy-l- methyl-ethyl)- 1 -methyl- 1 H-imidazol- 4-yl] -benzyl } -3 -hydroxy-propyl)-3 - chloro-4-isopropoxy-benzamide
N-(l-{4-[2-(l-hydroxy-ethyl)-l- methyl- lH-imidazol-4-yl] -benzyl} -3- hydroxy-propyl)-3 -cyano-4- isopropoxy-benzamide
N-( 1 - {4-[5-r-butyl- 1 -methyl- 1 H- [l,2,4]triazol-3-yl]-benzyl}-3- hydroxy-propyl)-3 -cyano-4- i sopropoxy-benzamide
Figure imgf000070_0002
Figure imgf000070_0003
1 - 2-
Figure imgf000071_0001
N-(2-(acetylamino)-l-{4-[8-methyl- imidazo [ 1 ,2-a]pyridin-2-yl] -benzyl } - ethyl)-3-cyano-4-isopropoxy- benzamide
N-( 1 - { 4- [2-t-butyl- 1 -(2-aminoethyl)- lH-imidazol-4-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isόpropoxy- benzamide
N-( 1 - {4- [2-( 1 -methoxyimino-ethyl)- 1 - metyl- 1 H-imidazol-4-yl]-benzyl} -3- hydroxy-propyl)-3 -chloro-4- isopropoxy-benzamide
N-{ l-[4-(8-(3-hydroxy-propenyl)- imidazo[l,2~a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl } -3-cyano-4-
Figure imgf000071_0002
isopropoxy-benzamide
N-(2-(2-dimethylamino-acetylamino)- 1 - {4-[8-carbamoyl-imidazo [ 1 ,2- a]pyridin-2-yl]-benzyl}-ethyl)-3- cyano-4-isopropoxy-benzamide
Figure imgf000071_0003
N-( 1 - { 3 -fluoro-4- [2-acetyl- 1 -methyl- lH-imidazol-4-yl]-benzyl}-3-hydroxy- piOpyl)-3-chloro-4-(2,2,2-trifluoro-l- methyl-ethoxy)-benzamide
N-(2-(2-amino-acetylamino)-l-{4-[8- biOino-imidazo[l,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-cyano-4-isopropoxy- benzamide
N-(2- {4-[2-acetyl-l -methyl- 1 H- imidazol-4-yl] -phenyl } - 1 -(5-methyl- [l,2,4]oxadiazol-3-yl)-ethyl)-3-cyano- 4-isopropoxy-benzamide
N-[l-[4-(2-/-butyl-l-methyl-lH- imidazol-4-yl)-benzyl]-2-hydroxy-3- azido-propyl]-3-cyano-4-isopropoxy- benzamide
N-(l-{4-[5-/-butyl-4-methyl-lH- imidazol-2-yl]-benzyl}-3-hydroxy- propyl)-3-cyano-4-isopropoxy- benzamide
N-{ 1 -[4-(8-(l -hydroxy-ethyl)- imidazo[l,2-a]pyridin-2-yl)-benzyl]-3- hydroxy-propyl } -3 -cyano-4- isopropoxy-benzamide
Figure imgf000072_0001
N-( 1 - { 4-[5-t-butyl-4-methyl- 1 H- imidazol-2-yl] -benzyl } -3 -hydroxy- propyl)-3-chloro-4-isopropoxy- benzamide
N-(l -{4-[2-(l -acetylamino-ethyl)- 1 - methyl-lH-imidazol-4-yl]-benzyl}-3- hydroxy-propyl)-3-chloro-4-(2,2,2- trifluoro- 1 -methyl-ethoxy)-benzamide
N-(l-{4-[2-t-butyl-l-methyl-lH- 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-isopropoxy- benzamide
N-( 1 - { 4-[2-t-butyl- 1 -methyl- 1 H- imidazol-4-yl]-benzyl}-2-hydroxy- propyl)-3 -cyano-4-i sopropoxy- benzamide
N-(2-(2-amino-propionylamino)-l-{4- [8-bromo-imidazo[l,2-a]pyridin-2-yl]- benzyl}-ethyl)-3-chloro-4-isopropoxy- benzamide
Figure imgf000073_0001
Figure imgf000074_0001
hydiOxybutan-2-yl)-4-isopropoxybenzamide (S)-N-( 1 -(4-(2-acetyl- 1 -ethyl- 1 H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4- isopropoxybenzamide N-((S)- 1 -(4-(2-( 1 -acetamidoethyl)- 1 -ethyl- 1 H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3- chloro-4-isopropoxybenzamide 3-chloro-N-((S)-l-(4-(l-ethyl-2-(2-hydroxypropan-2-yl)-lH-imidazol-4-yl)phenyl)-4- hydroxybutan-2-yl)-4-(l ,1,1 -trifluoropropan-2-yloxy)benzamide
N-((S)- 1 -(4-(2-( 1 -acetamidoethyl)- 1 -ethyl- 1 H-imidazol-4-yl)phenyl)-4-hydroxybutan-2-yl)-3- chloro-4-( 1,1,1 -trifluoropiOpan-2-yloxy)benzamide (S)-N-(l-(4-(2-acetyl-l-(2,2,2-trifluoroethyl)-lH-imidazol-4-yl)phenyl)-4-hydiOxybutan-2- yl)-3-chloro-4-isopropoxybenzamide 3-chloro-N-((S)-4-hydroxy-l-(4-(8-(l-hydroxyethyl)imidazo[l,2-a]pyridin-2-yl)phenyl)butan- 2-yl)-4-isopropoxybenzamide (S)-3-chloro-N-(l-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[l,2-a]pyridin-2- yl)phenyl)propan-2-yl)-4-isopropoxybenzamide 3 -chloro-N-((S)- 1 -(2-(dimethylamino)acetamido)-3-(4-(8-( 1 -hydroxyethyl)imidazo[ 1 ,2- a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide 3-Cyano-N-((lS)-3-hydroxy- 1 - {[4-(8-methylimidazo[ 1 ,2- ]pyridin-2- yl)phenyl]methyl } propyl)-4-[( 1 -methylethyl)oxy]benzamide; 3 -Chloro-N- [( 1 _S)-3 -hydroxy- 1 -( {4-[8-(l -hydroxyethyl)imidazo[ 1 ,2- ]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide 3-Chloro-N-[(lS)-2-[(N^V-dimethylglycyl)amino]-l-({4-[8-(l-hydroxyethyl)imidazo[l,2- ]pyιidin-2-yl]phenyl } methyl)ethyl] -4- [(1 -methylethyl)oxy]benzamide
N-((lS)-2-(D-Alanylamino)-l-{[4-(8-bromoimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}ethyl)- 3-chloro-4-[(l -methylethyl)oxy]benzamide 3-Chloro-N-((lS)-2-[(2-methylalanyl)amino]-l-{[4-(8-methylimidazo[l,2-α]pyridin-2- yl)phenyl]methyl} ethyl)-4-[( 1 -methyl ethyl)oxy]benzamide 3 -Chloro-N-(( 1 S)-2-[(NN-dimethylglycyl)amino]- 1 - { [4-(8-methylimidazo[ 1 ,2-α]pyridin-2- yl)phenyl]methyl} ethyl)-4-[( 1 -methyl ethyl)oxy]benzamide N-((lR)-4-Amino-l-{[4-(8-methylimidazo[l,2-fl]pyridin-2-yl)phenyl]methyl}-4-oxobutyl)-3- chloro-4-[(l -methyl ethyl)oxy]benzamide N-((liϋ)-l-{[4-(2-acetyl-l-methyl-lH-imidazol-4-yl)phenyl]methyl}-4-amino-4-oxobutyl)-3- chloro-4-[( 1 -methyl ethyl)oxy]benzamide 3-Cyano-N-[( 1 S)-3-hydroxy-l -( {4-[8-(l -hydroxyethyl)imidazo[ 1 ,2-α]pyridin-2- yljphenyl }methyl)propyl]-4-[( 1 -methylethyl)oxy]benzamide 3-Chloro-N-((lS)-3-hydroxy-l-{[4-(8-methylimidazo[l,2-α]pyridin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide 3-Cyano-N-[(lS)-2-[(N,N-dimethylglycyl)amino]- 1 -( {4-[8-(l -hydroxyethyl)imidazo[ 1 ,2- α]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 3-Cyano-N-((lS)-2-[(N:N-dimethylglycyl)amino]-l-{[4-(8-methylimidazo[l,2-o]pyridin-2- yl)phenyl]methyl} ethyl)-4-[(l -methylethyl)oxy]benzamide;
Ν-((l R)- 1 - { [4-(2-Acetyl- 1 -methyl- 1 Η-imidazol-4-yl)phenyl]methyl } -4-amino-4-oxobutyl)-3 - cyano-4-[(l-methylethyl)oxy]benzamide N-[(lR)-4-Amino-l-({4-[2-(l-hydroxy-l-methylethyl)-l-methyl-lH-imidazol-4- yl]phenyl}methyl)-4-oxobutyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide
N-[(lS)-2-(D-Alanylamino)-l-({4-[l-(2-aminoethyl)-2-(l,l-dimethylethyl)-lH-imidazol-4- yl]phenyl}methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide
N-((l S)-2- {4-[ 1 -(2-Aminoethyl)-2-(l , 1 -dimethylethyl)- 1 H-imidazol-4-yl]phenyl} - 1 - {[(2- methylalanyl)amino]methyl } ethyl)-3 -chloro-4-[( 1 -methyl ethyl)oxy]benzamide
N-[(l S)-2-(D-Alanylamino)-,l -( {4-[ 1 -(2-aminoethyl)-2-(l , 1 -dimethylethyl)- lH-imidazol-4- yljphenyl }methyl)ethyl]-3-cyano-4-[( 1 -methylethyl)oxy]benzamide
N-(( 1 S)-2- {4-[ 1 -(2- Aminoethyl)-2-( 1 , 1 -dimethylethyl)- 1 H-imidazol-4-yl]phenyl } - 1 -
{[(hydroxyacetyl)amino]methyl}ethyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide
N-((l S)-2- {4-[ 1 -(2-Aminoethyl)-2-(l ,1 -dimethylethyl)- 1 H-imidazol-4-yl]phenyl} -1 - {[(2- methylalanyl)amino]methyl}ethyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide
N-((l S)-2- {4-[ 1 -(2-Aminoethyl)-2-(l , 1 -dimethylethyl)- 1 H-imidazol-4-yl]phenyl} - 1 - {[(N,N- dimethylglycyl)amino]methyl}ethyl)-3 -cyano-4- [(1 -methyl ethyl)oxy]benzamide
3-Chloro-N-[(15)-2-{4-[8-(l-hydroxyethyl)imidazo[l,2-α]pyridin-2-yl]phenyl}-l-({[(2^)-2- hydroxypropanoyl]amino}methyl)ethyl]-4-[(l-methylethyl)ox}']benzamide
Ν-((lS)-2-[(Aminocarbonyl)amino]-l-{[4-(8-biOmoimidazo[l,2-a]pyridin-2- yl)phenyl]methyl}ethyl)-3-chloro-4-[(l-methylethyl)oxy]benzamide
N- {(1 S)-2-[4-(8-Bromoimidazo[l ,2-a]pyridin-2-yl)phenyl]-l -[(2-oxotetrahydro-l (2H)- pyrimidinyl)methyl]ethyl}-3-chloro-4-[(l-methylethyl)oxy]benzamide
N-{(lS)-2-[4-(8-Bromoimidazo[l,2-a]pyridin-2-yl)phenyl]-l-[(2-oxohexahydro-lH-l,3- diazepin- 1 -yl)methyl] ethyl } -3 -chloro-4-[( 1 -methyl ethyl)oxy]benzamide
N-((l S)-2-[(Aminocarbonothioyl)amino]-l - {[4-(8-bromoimidazo[l ,2-a]pyridin-2- yl)phenyl]methyl } ethyl)-3 -chloro-4-[( 1 -methyl ethyl)oxy]benzamide
2-(4-{(2S)-2-[({3-Cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-3-[(l,2,3-thiadiazol-
4-ylcarbonyl)amino]propyl}phenyl)imidazo[l,2-a]pyridine-8-carboxamide
N-((lS)-2-[(Aminosulfonyl)amino]-l-{[4-(8-methylimidazo[l,2-a]pyridin-2- yl)phenyl]methyl}ethyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide
(3S)-3-[({3-Chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4-[2-(l,l- dimethyl ethyl)- 1 -methyl- 1 H-imidazol-4-yl]phenyl }butanoic acid
N-[(lS)-2-[(Aminosulfonyl)amino]-l-({4-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4- yl]phenyl}methyl)ethyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide N-((l S)- 1 - { [4-( lH-Benzimidazol-2-yl)phenyl]methyl } -3 -hydroxypropyl)-3-chloro-4-[( 1 - methylethyl)oxy]benzamide
3-Chloro-N-[(l S)-3-hydroxy- 1 -( {4-[5-(trifluoromethyl)- lH-benzimidazol-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-((lS)-l-{[4-(5,6-dimethyl-lH-benzimidazol-2-yl)ρhenyl]methyl}-3- hydroxypropyl)-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-[(lS)-3-hydroxy-l-({4-[5-(methyloxy)-lH-benzimidazol-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-((lS)-l-{[4-(5-chloro-lH-benzimidazol-2-yl)phenyl]methyl}-3-hydroxypropyl)-
4- [( 1 -methylethyl)oxy]benzamide
3 -Chloro-N-(( 1 S)-3 -hydroxy- 1 - { [4-(4-methyl- lH-benzimidazol-2-yl)phenyl]methyl } propyl)-
4-[(l -methylethyl)oxy]benzamide
3-Chloro-N-((lS)-l-{[4-(6-chloiO-lH-imidazo[4,5-&]pyridin-2-yl)phenyl]methyl}-3- hydrox)φropyl)-4-[(l-methylethyl)oxy]benzamide
Ethyl 2-(4-{(2S)-2-[({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl } phenyl)- 1 H-benzimidazole-5-carboxylate
2-(4-{(2S)-2-[({3-Chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)-lH-benzimidazole-5-carboxylic acid
N-((lS)-3-Amino-l-{[4-(lH-benzimidazol-2-yl)phenyl]methyl}propyl)-3-chloro-4-[(l- methylethyl)oxy]benzamide
3 -Cyano-N-(( 1 S)- 1 - { [4-(8-cyanoimidazo[ 1 ,2-σ]pyridin-2-yl)phenyl]methyl } -3 - hydroxypropyl)-4-[( 1 -methylethyl)oxy]benzamide
N-(( 1 S)- 1 - { [4-(8-Chloroimidazo[ 1 ,2-α]pyridin-2-yl)phenyl]methyl } -3-hydroxypropyl)-3 - cyano-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-[(lS)-3-hydiOxy-l-({4-[8-(trifluoromethyl)imidazo[l,2-α]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-((l S)-3-hydroxy-l - {[4-(8-hydroxyimidazo[l ,2-α]pyridin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide
2-(4-{(2S)-2-[({3-Cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)imidazo[l,2-α]pyridine-7-carboxamide
Ethyl 2-(4-{(2S)-2-[({3-cyano-4-[(l-methylethyl)oxy]ρhenyl}carbonyl)amino]-4- hydiOxybutyl}phenyl)imidazo[l,2-α]pyridine-7-carboxylate 3-Cyano-N-((lS)-3-hydroxy-l-{[4-(8-nitiOimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}ρropyl)-
4-[(l -methylethyl)oxy]benzamide
N-((l»S)-l-{[4-(8-Aminoimidazo[l,2-fl]pyridin-2-yl)phenyl]methyl}-3-hydroxypropy])-3- cyano-4-[(l-methylethyl)oxy]benzamide
2-(4- {(2S)-2-[( {3-Cyano-4-[(l -methylethyl)oxy]ρhenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)imidazo[l,2-α]pyridine-8-carboxamide
3-Cyano-N-[(lS)-3-hydroxy-,l-({4-[8-(hydroxymethyl)imidazo[l,2-β]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
N-[(lS)-l-({4-[S-(Aminomethyl)imidazo[l,2-«]pyιidin-2-yl]phenyl}methyl)-3- hydroxypropyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide
N-((lS)-l-{[4-(8-Acetylimidazo[l,2-fl]pyridin-2-yl)phenyl]methyl}-3-hydroxypiOpyl)-3- cyano-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-[(lS)-3-hydroxy-l -({4-[8-(l -hydroxy- 1 -methylethyl)imidazo[ 1 ,2-«]pyridin-2-
) ]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-[(15)-3-hydroxy-l-({4-[8-(l-hydroxyethyl)imidazo[l,2- ]pyι din-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-((l 5)-3 -hydroxy- 1 - {[4-(8-methyl-5,6,7,8-tetrahydroimidazo[ 1 ,2-α]pyridin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide
3 -Cyano-N-[( 1 S)- 1 -( {4-[2-( 1 , 1 -dimethylethyl)- 1 -(2-hydroxyethyl)- lH-imidazol-4- yl]phenyl }methyl)-3 -hydroxypropyl] -4- [(1 -methyl ethyl)oxy]benzamide
N-[(lS)-l-({4-[l-[2-(Acetylamino)ethyl]-2-(l,l-dimethylethyl)-lH-imidazol-4- yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-{(lS)-3-hydiOxy-l-[(4-{8-[(l^)-l-hydiOxyethyl]imidazo[l,2-α]pyridin-2- yl} phenyl)methyl]propyl } -4-[( 1 -methyl ethyl)oxy]benzamide
3-Cyano-N-{(lS)-3-hydroxy-l-[(4-{8-[(l,5)-l-hydroxyethy]]imidazo[l,2-fl]pyridin-2- yl}phenyl)methyl]propyl}-4-[(l-methylethyl)oxy]benzamide
3-ChloiO-N-[(lS)-3-hydiOxy-l-({4-[8-(l-hydiOxypropyl)imidazo[l,2- ]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
N-(( 1 S)- 1 - { [4-(8-Bromoimidazo[ 1 ,2-β]pyridin-2-yl)phenyl]methyl } -3 -hydroxypropyl)-3- chloro-4-[( 1 -methyl ethyl)oxy]benzamide
3-Chloro-N-((l1S)-l-{[4-(8-chloroimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[(l-methylethyl)oxy]benzamide 3-Chloro-N-[(lS)-3-hydroxy-l-({4-[8-(l-hydroxy-2-methylpropyl)imidazo[l,2-α]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
N-[(17?)-4-Amino-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-α]pyridin-2-yl]ρhenyl}methyl)-4- oxobutyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide
N-[(lΛ)-4-Amino-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-α]pyridin-2-yl]phenyl}methyl)-4- oxobutyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-((lS)-l-{[4-(3-fluoro-8-methylimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[( 1 -methyl ethyl)oxy]benzamide
3-Cyano-N-((lS)-l-{[4-(3-fluoro-8-methylimidazo[l,2- ]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[(l -methylethyl)oxy]benzamide
3-Chloro-N-((lS)-2-hydiOxy-l-{[4-(8-methylimidazo[l,2-α]pyridin-2- yl)phenyl]methyl } ethyl)-4-[(l -methylethyl)oxy]benzamide
3-Chloro-4-[(l-methylethyl)oxy]-N-[(lS)-2-[4-(8-methylimidazo[l,2-α]pyridin-2-yl)phenyl]-
1 -(4-mo holinylmethyl)ethyl]benzamide
3-Chloro-N-((lS)-2-(4-hydiOxy-l-ρiperidinyl)-l-{[4-(8-methylimidazo[l,2-α]pyridin-2- yl)phenyl]methyl } ethyl)-4-[(l -methylethyl)oxy]benzamide
3-Chloro-N-((lS)-2-(3-hydroxy-l-pyrrolidinyl)-l-{[4-(8-methylimidazo[l,2-α]pyridin-2- yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-(( 1 S)-2-[(2S)-2-(hydroxymethyl)-l -pyrrolidinyl]- 1 -{ [4-(8-methylimidazo[ 1 ,2- α]pyιidin-2-yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-((llS)-2-[(2i?)-2-(hydroxymethyl)-l-pyrrolidinyl]-l-{[4-(8-methylimidazo[l,2-
«]pyridin-2-yl)phenyl]methyl } ethyl)-4-[(l -methylethyl)oxy]benzamide
3-Chloro-4-[(l-methylethyl)oxy]-N-((lS)-2-[4-(8-methylimidazo[l,2-σ]pyridin-2-yl)phenyl]-
1 - { [(2,2,2-trifluoroethyl)amino]methyl} ethyl)benzamide
3 -Chloro-N-(( 1 S)-2-[(2-hydroxyethyl)amino]- 1 - { [4-(8-methylimidazo[ 1 ,2-α]pyridin-2- yl)phenyl] methyl} ethyl)-4-[(l -methylethyl)oxy]benzamide
3-Cyano-N-((lS)-l-{[4-(8-ethyl-5-methylimidazo[l,2-fl]pyridin-2-yl)phenyl]methyl}-3- hydroxyproρyl)-4-[(l-methylethyl)oxy]benzamide
Methyl (3S)-3-[({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4-
[(phenylcarbonyl)amino]phenyl}butanoate
3-Chloro-N-[(lS)-3-hydroxy-l-({4-[(phenylcarbonyl)amino]phenyl}methyl)propyl]-4-[(l- methylethyl)oxy]benzamide 3-Chloro-N-{(lS)-l-[(4-{[(4-chlorophenyl)carbonyl]amino}phenyl)methyl]-3- hydroxypropyl}-4-[(l-methylethyl)oxy]benzamide
Phenylmethyl (4-{(2S)-2-[({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)carbamate
3-Chloro-N-((15)-3-hydroxy-l-{[4-({[2-
(methy]amino)phenyl]carbonyl}amino)phenyl]methyl}propyl)-4-[(l- methylethyl)oxy]benzamide ,
N-(4- {(2S)-2-[( {3-Chloro-4-[( 1 -methylethyl)oxy]phenyl} carbonyl)amino]-4- hydroxybutyl } phenyl)-4-pyridinecarboxamide
3-Chloro-N-[(lS)-l-({4-[(cyclohexylcarbonyl)amino]phenyl}methyl)-3-hydroxypropyl]-4-[(l- methylethyl)oxy]benzamide
3-Chloro-N-[(lS)-l-({4-[(3,3-dimethylbutanoyl)amino]phenyl}methyl)-3-hydroxypropyl]-4-
[(1 -methylethyl)oxy]benzamide
3-Chloro-N-[(lS)-3-hydroxy-l-({4-[(phenylacetyl)amino]phenyl}methyl)propyl]-4-[(l- methylethyl)oxy]benzamide
3-Chloro-N- {(15)-3 -hydroxy- 1 -[(4- {[(phenylamino)carbonyl]amino }phenyl)methyl]propyl } -
4- [( 1 -methylethyl)oxy]benzamide
3-Cyano-N-((lS)-3-hydroxy-l-{[4-(8-methyl-5-oxo-5,6-dihydroimidazo[l,2-c]pyrimidin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-((lS)-3-hydroxy-l-{[4-(l-methyl-3-oxo-2,3-dihydro-lH-imidazo[l,2-α]imidazol-
6-yl)phenyl]methyl } propyl)-4-[( 1 -methyl ethyl)oxy]benzamide
3-Cyano-N-((lS)-3-hydroxy-l-{[4-(8-oxo-7,8-dihydroimidazo[l,2- ]pyrazin-2- yl)phenyl]memyl}propyl)-4-[(l-methylethyl)oxy]benzamide
2,3-Dichloro-N-((15)-3-hydroxy-l-{[4-(8-methylimidazo[l,2-α]pyridin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide
N-((lS)-3-Ηydroxy-l-{[4-(8-methylimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}propyl)-4-[(l- methylethyl)oxy] -3 -nitrobenzamide
3-Chloro-N-[(lS)-2-[(hydroxyacetyl)amino]-l-({4-[8-(l-hydroxyetlιyl)imidazo[l,2-α]pyridin-
2-yl]phenyl } methyl)ethyl]-4- [( 1 -methylethyl)oxy]benzamide
3-Chloro-N-[(lS)-2-{4-[8-(l-hydroxyethyl)imidazo[l,2-α]pyridin-2-yl]phenyl}-l-({[(2R)-2- hydroxypropanoyl]amino}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-[(lS)-2-{4-[8-(l-hydroxyethyl)imidazo[l,2-α]pyridin-2-yl]phenyl}-l-({[(2S)-2- hydroxypropanoyl]amino}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-[(15)-2-[(N V-dimethylglycyl)amino]-l-({4-[8-(l-hydroxyethyl)imidazo[l,2- α]pyridin-2-yl]ρhenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide
N-[(l S)-2-(D-Alanylamino)- 1 -( {4-[8-( 1 -hydroxyethyl)imidazo[ 1 ,2-fl]ρyridin-2- yl]phenyl}methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-[(15)-3-hydroxy-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-α]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
3 -Chloro-N-(( 1 S)-2- {4-[8-(l -hydroxyethyl)imidazo[ 1 ,2-α]pyridin-2-yl]phenyl } - 1 - { [(2- methylalanyl)amino]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide
(3S)-3 - [( { 3 -Chloro-4- [( 1 -methylethyl)oxy]phenyl } carbonyl)amino] -4- {4-
[(phenylcarbonyl)amino]phenyl }butanoic acid
3-Chloro-N-{(lS)-3-hydroxy-l-[(4-imidazo[l,2- ]pyιidin-6-ylphenyl)methyl]propyl}-4-[(l- methylethyl)oxy]benzamide
3-Chloro-N-[( 1 S)-l -( {4-[2-(l , 1 -dimethylethyl)imidazo[l ,2-α]pyridin-6-yl]phenyl}methyl)-3- hydroxypropyl]-4-[( 1 -methyl ethyl)oxy]benzamide
3-Chloro-N-{(lιS)-3-hydroxy-l-[(4-imidazo[l,2- ]pyridin-2-ylphenyl)methyl]propyl}-4-[(l- methylethyl)oxy]benzamide
3-Chloro-N- {(1 S)-3-hydroxy-l -[(4-imidazo[ 1 ,2- ]pyrimidin-2-ylphenyl)methyl]propyl } -4-
[( 1 -methylethyl)oxy]benzamide
3-Chloro-N-((lS)-3-hydiOxy-l-{[4-(5-methylimidazo[l,2- ]ρyridin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-((lS)-3-hydroxy-l-{[4-(7-methylimidazo[l,2-α]pyrimidin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-{(lS)-3-hydiOxy-l-[(4-imidazo[2,l-i][l,3]thiazol-6-ylphenyl)methyl]butyl}-4-
[( 1 -methylethyl)oxy]benzamide
3-Cyano-N-((15)-3-hydroxy-l-{[4-(3-methylimidazo[2,l-6][l,3]tl iazol-6- yl)phenyl]methyl}butyl)-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-((15)-l-{[4-(2,3-dihydroimidazo[2,l- ?][l,3]thiazol-6-yl)phenyl]methyl}-3- hydroxybutyl)-4-[( 1 -methyl ethyl)oxy]benzamide
3-Cyano-N-((15)-l-{[4-(l,l-dioxido-253-dihydroimidazo[2,l-/3][l,3]thiazol-6- yl)phenyl]methyl}-3-hydroxybutyl)-4-[(l-methylethyl)oxy]benzamide
N-[(l S)-l -( {4-[ 1 -(3-Aminopropyl)-2-(l , 1 -dimethylethyl)-lH-imidazol-4-yl]phenyl}methyl)- 3-hydroxypropyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide
3-Cyano-4-[(l-methylethyl)oxy]-N-[(lS)-2-[4-(8-methylimidazo[l,2-α]ρyridin-2-yl)ρhenyl]- l-(5-methyl-l,2,4-oxadiazol-3-yl)ethyl]benzamide
3-Cyano-N-[(lS)-l-({4-[8-(3,5-dimethyl-4-isoxazolyl)imidazo[l,2-fl]pyridin-2- yl]phenyl}methyl)-3-hydroxypropyl]-4-[(l-methylethyl)oxy]benzamide
3 -Cyano-N-((lS)-3 -hydroxy- 1 - {[4-(8-ρhenylimidazo[l ,2-β]ρyridin-2- yl)phenyl]methyl}propyl)-4-,[(l-methylethyl)oxy]benzamide
3-Cyano-N-[(lS)-3-hydroxy-l-({4-[8-(lH-pyrazol-4-yl)imidazo[l,2-ώr]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-[(lS)-3-hydroxy-l-({4-[8-(4-isoxazolyl)imidazo[l,2-fl]pyιidin-2- yl]phenyl } methyl)propyl] -4-[( 1 -methyl ethyl)oxy]benzamide
N-((lS)-l-{[4-(8-Acetylimidazo[l,2-fl]pyridin-2-yl)phenyl]methyl}-3-hydroxyproρyl)-3- chloro-4-[( 1 -methylethyl)oxy]benzamide
Ethyl (2£)-3-[2-(4-{(25)-2-[({3-cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydiOxybutyl}phenyl)imidazo[l,2-α]pyridin-S-yl]-2-propenoate
(2£)-3-[2-(4-{(25)-2-[({3-Cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)imidazo[l,2-α]pyridin-8-}'l]-2-propenoic acid
N-{(lS)-l-[(4-{8-[(l£)-3-Amino-3-oxo-l-propen-l-yl]imidazo[l,2-α]pyridin-2- yl }phenyl)methyl] -3 -hydroxypropyl } -3 -cyano-4-[( 1 -methylethyl)oxy]benzamide
N-[(lS)-l-({4-[8-(3-Amino-3-oxopropyl)imidazo[l,2- ]pyridin-2-yl]phenyl}methyl)-3- hydroxypropyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-((l S)- 1 - {[4-(3-chloro-8-methylimidazo[ 1 ,2-α]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[( 1 -methylethyl)oxy]benzamide
N-((lS)-l-{[4-(3-Chloro-8-methylimidazo[l,2-β]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-[(l S)- 1 -( {3-fluoro-4-[2-( 1 -hydroxy- 1 -methylethyl)- 1 -methyl- lH-imidazol-4- yl]phenyl}methyl)-3-hydroxypropyl]-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-((lS)-2-hydroxy-l-{[5-(8-methylimidazo[l,2-α]pyridin-2-yl)-2- pyridinyl]methyl} ethyl)-4-[(l -methylethyl)oxy]benzamide
3-Clιloro-N-((lS)-2-hydroxy-l-{[5-(8-methylimidazo[l,2-α]pyridin-2-yl)-2- thienyl]methyl } ethyl)-4-[(l -methylethyl)oxy]benzamide
3-Chloro-N-[(lS)-l-({4-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4-yl]-2- fluorophenyl } methyl)-3 -hydroxypropyl] -4-[( 1 -methyl ethyl)oxy]benzamide
3 -Chloro-N- [( 1 S)- 1 -( {4-[2-( 1 , 1 -dimethylethyl)-l -methyl- lH-imidazol-4-yl]-2,6- difluorophenyl } methyl)-3 -hydroxypropyl] -4-[( 1 -methylethyl)oxy]benzamide
3-Chloro-N-[(lS)-l-({2-chloro-4-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4- yl]phenyl}methyl)-3-hydiOxypiOpyl]-4-[(l-methylethyl)oxy]benzamide
3-Chloro-N-[(lS)-l-({5-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4-yl]-2- pyridinyl } methyl)-3 -hydroxypropyl] -4- [( 1 -methylethyl)oxy]benzamide
3-Chloro-N-((lS)-l-{[2-chloiO-4-(8-methylimidazo[l,2-α]pyridin-2-yl)ρhenyl]methyl}-3- hydroxypropyl)-4-[( 1 -methylethyl)oxy]benzamide
3-Chloro-N-((l S)- 1 - {[2-chloro-4-(8-chloroimidazo[ 1 ,2-α]pyridin-2-yl)phenyl]methyl} -3- hydroxypropyl)-4-[( 1 -methylethyl)oxy]benzamide
3-ChloiO-N-((lS)-l-{[2,5-difluoiO-4-(S-methylimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4- [( 1 -methylethyl)oxy]benzamide
3-Chloro-N-((lS)-l-{[3-chloro-4-(8-methylimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[( 1 -methyl ethyl)oxy]benzamide
3-Chloro-Ν-[(lS)-l-({4-[2-(l,l-dimethylethyl)-l-methyl-lΗ-imidazol-4-yl]phenyl}methyl)-
3-(methylamino)-3-oxopropyl]-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-[(l S)-2- {4-[2-(l ,1 -dimethyiethyl)-l -methyl- 1 H-imidazol-4-yl]phenyl}-l -
({[(phenylamino)carbonyl]amino}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-[(l S)-2- {4-[2-( 1 , 1 -dimethylethyl)-l -methyl- 1 H-imidazol-4-yl]phenyl} - 1 -
({[(ethylamino)carbonyl]amino}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide
N-[(lS)-2-(Aminosulfonyl)-l-({4-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4- yl]phenyl}methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide
3-Cyano-N-((l S)-2- {4-[2-(l , 1 -dimethylethyl)- 1 -methyl-1 H-imidazol-4-yl]phenyl} -1 -
{ [(methylsulfonyl)amino]methyl } ethyl)-4-[( 1 -methyl ethyl)oxy]benzamide
3-Cyano-N-{(lS)-2-{4-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4-yl]phenyl}-l-[({[(2- hydroxyethyl)amino]carbonyl}amino)methyl]ethyl}-4-[(l-methylethyl)oxy]benzamide
N-[(S)-l-[4-(2-tert-Butyl-l-methyl-lH-imidazol-4-yl)-benzyl]-2-(2-methoxy-ethanoylamino)- ethyl]-3-cyano-4-isopropoxy-benzamide
(4R)-4-[({3-Cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-5-{4-[2-(l,l- dimethylethyl)- 1 -methyl- 1 H-imidazol-4-yl]phenyl } pentanoic acid
3-Cyano-N-{(lS)-2-{4-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4-yl]phenyl}-l-[(2-oxo- 1 -imidazolidinyl)methyl] ethyl } -4-[( 1 -m ethyl ethyl)oxy]benzamide N-((lS)-2-Amino-l-{[4-(8-methylimidazo[l,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-cyano- 4-[(l -methylethyl)oxy]benzamide N-((l S)-2-(Acetylamino)- 1 - { [4-(8-methylimidazo[ 1 ,2-a]ρyridin-2-yl)ρhenyl]methyl} ethyl)-3- cyano-4-[(l-methylethyl)oxy]benzamide 3 -Chloro-N-(( 1 S)-2- { [(2R)-2-hydroxypropanoyl] amino} - 1 - { [4-(8-methylimidazo [ 1 ,2- a]pyιidin-2-yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide 3-Chloro-N-[(l S)-2-[(N,N-dimethylglycyl)amino]-l -({4-[2-(l -hydroxy-1 -methylethyl)-l - methyl-lH-imidazol-4-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 3-Cyano-N-[(l S)-2-[(N,N-dimethylglycyl)amino]-l -( {4-[2-(l -hydroxy-1 -methylethyl)-l - methyl- 1 H-imidazol-4-yl]phenyl } methyl)ethyl]-4-[( 1 -methylethyl)oxy]benzamide 3 -chloro-N-((S)-4-hydroxy- 1 -(4-(l -methyl-2-((R)- 1 -(2-oxopyrrolidin- 1 -yl)ethyl)- 1 H- imidazol-4-yl)phenyl)butan-2-yl)-4-isopropoxybenzamide 3-chloro-N-((S)-4-hydroxy-l -(4-(l -methyl-2-((R)-l -(2-oxopyrrolidin-l -yl)ethyl)-l H- imidazol-4-yl)phenyl)butan-2-yl)-4-( 1,1,1 -trifluoropropan-2-yloxy)benzamide 3 -chloro-N-((S)-4-hydroxy- 1 -(4-(l -methyl-2-((R)- 1 -(2-oxooxazolidin-3 -yl)ethyl)- 1 H- imidazol-4-yl)phenyl)butan-2-yl)-4-isopropoxybenzamide 3-chloro-N-((S)-4-hydroxy-l -(4-(l -methyl-2-((R)-l -(2-oxooxazolidin-3-yl)ethyl)-l H- imidazol-4-yl)phenyl)butan-2-yl)-4-( 1,1,1 -trifluoropropan-2-yloxy)benzamide
[00114] Particular compounds include those shown in the following tables:
Figure imgf000084_0001
TABLE 2
Figure imgf000084_0002
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
TABLE 3
Figure imgf000094_0002
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000101_0002
Figure imgf000101_0001
TABLE 4
Figure imgf000101_0003
Figure imgf000102_0002
Figure imgf000102_0001
TABLE 5
Figure imgf000102_0003
Figure imgf000103_0001
TABLE 6 N-[2-(4-Benzyloxy-pheny])-l-methylcarbamoyl-ethyl]-2,3-dichloro-4-isopropoxy-benzarnide 3-(3H-Imidazol-4-yl)-2-(4-trifluoromethyl-benzenesulfonylanιino)-propionic acid N-(2-Biphenyl-4-yl- 1 -methylcarbamoyl-ethyl)-benzamide N-(l-Carbamoyl-2-phenyl-ethyl)-3-chloro-4-(2,2,2-trifluoro-l-methyl-ethoxy)-benzamide; N-(l-Carbamoyl-2-phenyl-ethyl)-4-fluoro-benzamide 4-[2-(4-tert-Butoxy-3-chloro-benzoylamino)-2-methylcarbamoyl-ethyl]-benzoic acid tert-butyl ester N-[2-(4-Benzyloxy-phenyl)-l-methylcarbamoyl-ethyl]-3-clιloro-4-isopropylamino-benzamide 2-Benzyl-3-(3-clιloro-4-isopiOpoxy-benzoylamino)-propionic acid Naphthalene-2-carboxylic acid [2-(4-benzyloxy-phenyl)-l -methylcarbamoyl-ethyl]-amide Quinoline-7-carboxylic acid [2-(4-benzyloxy-phenyl)-l -methylcarbamoyl-ethyl]-amide l-Isopropyl-lH-benzoimidazole-5-carboxylic acid [2-(4-benzyloxy-phenyl)-l-methylcarbamoyl-ethyl]- amide 5-Biphenyl-4-ylmethyl-2-(3-chloro-4-isopropoxy-phenyl)-3,5-dihydro-imidazol-4-one 5-Biphenyl-4-ylmethyl-2-(3-chloro-4-isopropoxy-phenyl)-3H-imidazole-4-carboxylic acid methyl ester 5-Biphenyl-4-ylmethyl-2-(3-clιloro-4-isopropoxy-phenyl)-3H-imidazole-4-carboxylic acid methylamide 4-(4-{4-[2-(3-Chloro-4-isopropoxy-phenyl)-4,5-dihydro-oxazol-4-ylmethyl]-phenoxy}- [l,2,5]thiadiazol-3-yl)-moφholine 4-(4-Benzyloxy-benzyl)-2-(3-c oro-4-isopropoxy-phenyl)-4,5-dihydro-oxazole 3-Biphenyl-4-ylmethyl-5-(3-chloro-4-isopropoxy-phenyl)-3H-[l,3,4]oxadiazol-2-one l-(3-Chloro-4-isopropoxy-benzoyl)-3-(4-iodo-phenyl)-pyrrolidine-2-carboxylic acid methylamide 3-(4-Bromo-phenyl)-l-(3-clιloro-4-isopropoxy-benzoyl)-pynOlidine-2-carboxylic acid methyl ester -Biphenyl-4-yl-l -(3-chloro-4-isopropoxy-benzoyl)-pyrrolidine-2-carboxylic acid methylamide -(3-Chloro-4-isopropoxy-benzoyl)-3-phenyl-piperidine-2 -carboxylic acid methylamide -(3-Chloro-4-isopropoxy-benzoyl)-4-phenyl-piperidine-2-carboxylic acid methylamide -(3-Chloro-4-isopropoxy-benzoyl)-4-phenyl-piperazine-2 -carboxylic acid methylamide
(2-Biphenyl-4-ylmethyl-aziridin-l-yl)-(3-clιloro-4-isopropoxy-phenyl)-methanone
3-Biphenyl-4-yl-N-carbamoylmethyl-2-(6-chloro-7-isopropoxy-2,4-dioxo-l,4-dihydro-2H-quinazolin- 3-yl)-propionamide
3-Biphenyl-4-yl-N-carbamoylmethyl-2-(6-chloro-7-isopropoxy-4-oxo-4H-quinazolin-3-yl)- propionamide
3-Biphenyl-4-yl-N-carbamoylmethyl-2-(8-chloro-7-isopropoxy-4-oxo-4H-quinazolin-3-yl)- propionamide
3 -Chloro-4-isopropoxy-N-( 1,2,3 ,4-tetrahydro-quinolin-3-yl)-benzamide
3-Chloro-4-isopropoxy-N-(4-phenyl-pyrrolidin-3-yl)-benzamide
3-Chloro-4-isopropoxy-N-(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-benzamide
3-Chloro-4-isopropoxy-N-( 1 -methyl- 1 H-imidazol-4-ylmethyl)-benzamide
3-Chloro-4-isopropoxy-N-(2-phenoxy-ethyl)-benzamide
N-[2-(4-Benzyl-piperazin-l-yl)-ethyl]-3-chloro-4-isopropoxy-benzamide N-( 1 H-Benzoimidazol-2-ylmethyl)-3-clιloro-4-isopropoxy-benzamide
3-Chloro-4-isopropoxy-N-(5-methyl-2-phenyl-2H-[l,2,3]triazol-4-ylmethyl)-benzamide
[00115] In some embodiments, the chemical entity is a prodrug, such as a phosphate ester, of one of the compounds listed in Table 1, 2, 3, 4, 5, or 6. In some embodiments, the chemical entity is chosen from (35)-4-[4-(2-acetyl-l-methyl-lH-imidazol-4-yl)phenyl]-3- [({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]butyl dihydrogen phosphate; and (3S)-3-[({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4-[4-(8- methylimidazo[ 1 ,2-α]ρyridin-2-yl)phenyl]butyl dihydrogen phosphate. [00116] The chemical entities described herein can be prepared by following the procedures set forth, for example, in PCT WO 99/13061, U.S. Patent No. 6,420,561 and PCT WO 98/56756, each of which is incorporated herein by reference. The starting materials and other reactants are commercially available, e.g., from Aldrich Chemical Company, Milwaukee, WI, or may be readily prepared by those skilled in the art using commonly employed synthetic methodology. [00117] Unless specified otherwise, the teπns "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents. [00118] In general, esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid with the appropriate alkanol, generally under acidic conditions. Likewise, amides may be prepared using conventional amidation procedures, for example amides may be prepared by treating an activated carboxylic acid with the appropriate amine. Alternatively, a lower-alkyl ester such as a methyl ester of the acid may be treated with an amine to provide the required amide, optionally in presence of trimethylalluminium following the procedure described in Tetrahedron Lett. 48, 4171-4173, (1977). Carboxyl groups may be protected as alkyl esters, for example methyl esters, which esters may be prepared and removed' using conventional procedures, one convenient method for converting carbomethoxy to carboxyl is to use aqueous lithium hydroxide.
[00119] The salts and solvates mentioned herein may as required be produced by methods conventional in the art. For example, if an inventive compound is an acid, a desired base addition salt can be prepared by treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; such as ethylenediamine, and cyclic amines, such as cyclohexylamine, piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. [00120] If a compound is a base, a desired acid addition salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, or the like.
[00121] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
Reaction Scheme 1
Figure imgf000106_0001
Figure imgf000106_0002
[00122] Referring to Reaction Scheme 1, Step 1, to a solution of a compound of
Formula 103 in an inert solvent such as DCM are added an excess (such as about 1.2 equivalents) of pentafluorotrifluoroacetate and a base such as triethylamine at about 0 °C. The reaction mixture is stirred for about 1 h. The product, a compound of Formula 105, is isolated and purified.
[00123] Referring to Reaction Scheme 1, Step 2, to a solution of a compound of
Formula 105 in a polar, aprotic solvent are added an excess (such as about 1.2 equivalents) of a compound of formula R7(CO)-CH(NHR2)-CH(R5)(R6) and a base such as N, N- diisopropylethylamine. The reaction is monitored by, for example, LC/MS, to yield a compound of Formula 107 wherein R7 is NH2, which is isolated and optionally purified.
Reaction Scheme 2
Figure imgf000107_0001
[00124] Referring to Reaction Scheme 2, to a solution of a compound of Formula 201 in a polar, aprotic solvent such as DMF are added an excess (such as about 1.2 equivalents) of a compound of Formula 105 and a base such as diisopropylethylamine at room temperature. The reaction mixture is monitored by, for example, LC/MS. After completion, a primary or secondaiy amine in an inert solvent such as THF and HBTU is added to the reaction solution. The reaction mixture is stirred for about 2 days. The product, a compound of Foπnula 203 wherein R7 is optionally substituted amino, is isolated and purified. [00125] In certain embodiments, ,R6 in a compound of Formula 203 is a halide, alkyl halide, or aiyl halide. This halide can be converted to various other substituents using a variety of reactions using techniques known in the art and further described in the examples below.
[00126] In other embodiments, Rό in a compound of Formula 203 is an alkyl or aryl amine. Again, the amine moiety can be alkylated, acylated, converted to the sulfonamide, and the like using techniques known in the art and further described below. [00127] In yet other embodiments, R6 in a compound of Formula 203 is an alkyl alcohol or an aryl alcohol. The hydroxyl moiety can be converted to the corresponding ether or ester using techniques known in the art.
Reaction Scheme 3
Figure imgf000107_0002
301 303 [00128] Referring to Reaction Scheme 3, to a solution of a compound of Formula 301 in a polar, aprotic solvent such as DMF added glycinamide hydrochloride, a base such as diisopropylethylamine, and HBTU. The reaction mixture is stiπ-ed for about 15 hours. The product, a compound of Formula 303, is isolated and purified.
Reaction Scheme 4
Figure imgf000108_0001
Figure imgf000108_0002
[00129] Referring to Reaction Scheme 4, Step 1 , to a stiπed solution of a compound of
Formula 401 wherein n is 0, 1, or 2 in an inert solvent such as THF at about 0°C is added an excess (such as about 2 equivalents) of LAH (such as a 1.0 M solution in THF). After stirring for about 2 hours, the product, a compound of Formula 403, is isolated and used without further purification.
[00130] Referring to Reaction Scheme 4, Step 2, the hydroxyl group is converted to a protected amino group. If the protecting group is phthamide, it can be made as follows. To a stirred solution of a compound of Formula 403 in an inert solvent such as THF are added an excess (such as about 1.1 equivalents) of isoindole-l ,3-dione and triphenylphosphine. An excess (such as about 1.1 equivalents) of DEAD is then added dropwise and the reaction is stirred for about 30 min. The product, a compound of Formula 405, is isolated and purified. [00131] Referring to Reaction Scheme 4, Step 3, the Boc protecting group is then removed to form the corresponding free amine. One of skill in the art will appreciate that this should be accomplished in such a manner as to leave the other protected amine intact. For example, to a solution of a compound of Formula 405 in a nonpolar, aprotic solvent such as DCM is added an acid, such as TFA, at room temperature. The reaction mixture is stiπed for about 20 min. The product, a compound of Formula 407, is isolated and used without further purification.
[00132] Referring to Reaction Scheme 4, Step 4, to a solution of a compound of
Fomiula 407 in an inert solvent such as DMF are added a compound of Formula 105 and a base such as diisopropylethylamine at room temperature. The reaction mixture is stirred ovemight. The product, a compound of Fomiula 409, is isolated and purified. [00133] Refening to Reaction Scheme 4, Step 5, the amine protecting group, PG, is then removed. If the amine protecting group, PG, is a phthalimide, it can be removed is follows. To a solution of a compound of Formula 409 in a polar, protic solvent such as methanol is added an excess (such as about 10 equivalents) of hydrazine hydrate. The reaction mixture is stiπed at about 50 °C for about 5 h, and then cooled to room temperature. The product, a compound of Foπnula 411, is isolated and optionally, purified. Conditions for removing other protecting groups are known to those of skill in the art. [00134] The free amine of a compound of Foπnula 411 can be acylated, alkylated, reductively alkylated, or sulfonylated using techniques known to those of skill in the art. [00135] Reaction Scheme 5
Figure imgf000109_0001
601 603 605
Figure imgf000110_0001
607a 607b
[00136] In certain compounds of the invention, particular stereoconfiguration may be prefened for the compound of Foπnula I-XIII. For the sake of brevity in the remaining description of the synthesis of compounds of Foπnula I-XIII, it should be understood that either single isomer or a mixture of isomers can be employed to give the conesponding product.
[00137] Particular stereoisomers can be obtained from mixtures using techniques known in the art. For example, some embodiments, a free amine of Foπnula 605 is dissolved in an inert organic solvent (such as 1PA) and warmed to 60°C. In a separate vessel, a resolving agent (such as dibenzoyl-D-tartaric acid) is dissolved, such as in the same warm solvent, and then quickly added (with agitation) to the warm amine solution. The reaction mixture is left to crystallize by cooling to room temperature over 16 hours under continuing agitation. The desired isomer is isolated and purified in the usual manner. [00138] In some embodiments, an optically active amine of Formula 607 can be prepared from the corresponding aryl aldehyde as shown in Reaction Scheme 5. [00139] Referring to Reaction Scheme 5, Step 1 , a solution of a compound of Formula
601 and an excess of ammonium acetate in nitroethane is heated to about reflux for about 8 hours. The product, a compound of Formula 603, is isolated and optionally purified. [00140] Referring to Reaction Scheme 5, Step 2, to an about 0 °C solution of a reducing agent such as sodium borohydride in an inert solvent such as tetrahydrofuran is added an excess (such as about 1.2 equivalents) of borane-tetrahydrofuran complex. The resulting solution is stirred at room temperature for about 15 minutes. A compound of Formula 603 in an inert solvent such as tetrahydrofuran is added dropwise, and the resulting solution is refluxed for about 4 hours. The product, a compound of Formula 605, is isolated and optionally purified,
[00141] The amine of Formula 605 can be then resolved using techniques known in the art. For example, a 0 °C solution of the amine of Fomiula 605 in an inert solvent such as ethyl acetate is saturated with hydrochloric acid (gas). The resulting salt is collected by filtration and dried in vacuo. Z-N-Acetylleucine sodium salt is added slowly to a stirred solution of the aforementioned salt in water. Crystals form overnight and are removed by filtration, washed with a small amount of cold water, and recrystallized from absolute methanol. The crystalline salt of Formula 607a is isolated and optionally purified. [00142] The mother liquors, which were rich in a compound of Formula 607b, are combined, made strongly alkaline, and washed three times with diethyl ether. The combined organic layers are washed with water and dried over sodium sulfate. Hydrochloric acid is passed through the solution until the precipitation of hydrochloride salt is complete. The same procedure as above can be applied with Z>-N-acetylleucine salt. The crystalline compound of Formula 607b is isolated and optionally purified.
Reaction Scheme 6
Figure imgf000111_0001
701 703 705
Figure imgf000111_0002
[00143] Referring to Reaction Scheme 6, Step 1 , to a solution of a compound of
Formula 701 in a polar protic solvent such as methanol is added an excess (such as about 2 equivalents) of SOCl2. After stirring overnight at ambient temperature, the product, a compound of Formula 703, is isolated and used without further purification. [00144] Referring to Reaction Scheme 6, Step 2, to a solution of a compound of
Formula 703 in a polar, protic solvent such as ethanol is added an excess (such as about 5 equivalents) of N2H4 H2O. The reaction mixture is heated to reflux and stiπ-ed for about 3 h. Upon cooling, the product, a compound of Formula 705, is isolated and purified. [00145] Referring to Reaction Scheme 6, Step 3, to a solution of a compound of
Formula 705 in an inert solvent such as THF is added an excess (such as about 1.1 equivalents) of carbonyldiimidazole. The reaction mixture is heated to reflux and stirred for 1.5 h. Upon cooling, the product, a compound of Fomiula 707, is isolated and purified. [00146] Referring to Reaction Scheme 6, Step 4, to a solution of a compound of
Formula 707 in an inert solvent such as acetonitrile is added an excess (such as about 1.1 equivalents) of RsRδCH-Z wherein Z is a leaving group and a base such as K2CO3. The reaction mixture is heated to about 80 °C under microwave irradiation for about 30 min followed by filtration and concentration in vacuo. The product, a compound of Formula 709, is isolated and optionally purified.
[00147] Referring to Reaction Scheme 6, Step 5. to a compound of Formula 709 is added an excess of a primary amine in an inert solvent such as THF. The reaction mixture is heated to about about 100 °C under microwave irradiation for about 4 h. The product, a compound of Formula 711 , is isolated and purified. Reaction Scheme 7
Figure imgf000112_0001
[00148] Referring to Reaction Scheme 7, Stepl, to a suspension of zinc powder in a dry degassed polar, aprotic solvent such as DMF was activated using techniques known in the art and further described in the example as follows. 1 ,2-Dibromoethane was added to the zinc solution under nitrogen. The mixture was heated using a heat gun for about 30 seconds until gas starts to evolve from the solution, indicating the activation of the zinc. The mixture was then allowed to cool to room temperature followed by the addition of TMSC1, and allowed to stir at room temperature for 30 min. A solution of a compound of Formula 701 in a dry degassed polar, aprotic solvent such as DMF was added to the zinc solution, and the reaction mixture was stirred for 1 hour at room temperature. The solution of 702 is used for the next step.
[00149] Referring to Reaction Scheme 7, Steρ2, to a solution of 702 was aadded a solution of a compound of Formula 703 ( here Xi is Br or I) in a dry degassed polar, aprotic solvent such as DMF, and a palladium catalyst and a ligand such as Pd (dba3), and tri-o- tolylphospine. The reaction mixture was stiπ-ed for 3 hour. The product, a compound of Fomiula 704 is isolated and purified.
[00150] Once made, the chemical entities of the invention find use in a variety of applications involving alteration of mitosis. As will be appreciated by those skilled in the art, mitosis may be altered in a variety of ways; that is, one can affect mitosis either by increasing or decreasing the activity of a component in the mitotic pathway. Stated differently, mitosis may be affected (e.g., disrupted) by disturbing equilibrium, either by inhibiting or activating certain components. Similar approaches may be used to alter meiosis. [00151] In some embodiments, the chemical entities of the invention are used to inhibit mitotic spindle formation, thus causing prolonged cell cycle arrest in mitosis. By "inhibit" in this context is meant decreasing or interfering with mitotic spindle formation or causing mitotic spindle dysfunction. By "mitotic spindle foπnation" herein is meant organization of microtubules into bipolar structures by mitotic kinesins. By "mitotic spindle dysfunction" herein is meant mitotic arrest.
[00152] The chemical entities of the invention bind to, and/or inhibit the activity of, one or more mitotic kinesin. In some embodiments, the mitotic kinesin is human, although the chemical entities may be used to bind to or inhibit the activity of mitotic kinesins from other organisms. In this context, "inhibit" means either increasing or decreasing spindle pole separation, causing malformation, i.e., splaying, of mitotic spindle poles, or otherwise causing morphological perturbation of the mitotic spindle. Also included within the definition of a mitotic kinein for these purposes are variants and/or fragments of such protein and more particularly, the motor domain of such protein.
[00153] The chemical entities of the invention are used to treat cellular proliferation diseases. Such disease states which can be treated by the chemical entities provided herein include, but are not limited to, cancer (further discussed below), autoimmune disease, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, cellular proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, and the like. Treatment includes inhibiting cellular proliferation, It is appreciated that in some cases the cells may not be in an abnomial state and still require treatment. Thus, in some embodiments, the invention herein includes application to cells or individuals afflicted or subject to impending affliction with any one of these disorders or states, [00154] The chemical entities, pharmaceutical formulations and methods provided herein are particularly deemed useful for the treatment of cancer including solid tumors such as skin, breast, brain, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that can be treated include, but are not limited to:
• Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma. fibroma, lipoma and teratoma;
• Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, Iymphoma, chondromatous hamartoma, mesothelioma;
• Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, Iymphoma), stomach '(carcinoma, Iymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, Iymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);
• Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nepliroblastoma], Iymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);
• Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
• Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant Iymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
• Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblasto a, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
• Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli- Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botiyoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma);
• Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome). Hodgkin's disease, non-Hodgkin's Iymphoma [malignant Iymphoma];
• Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and
• Adrenal glands: neuroblastoma. As used herein, treatment of cancer includes treatment of cancerous cells, including cells afflicted by any one of the above-identified conditions. Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of the above identified conditions. [00155] Another useful aspect of the invention is a kit having at least one chemical entity described herein and a package insert or other labeling including directions treating a cellular proliferative disease by administering an effective amount of the at least one chemical entity. The chemical entity in the kits of the invention is particularly provided as one or more doses for a course of treatment for a cellular proliferative disease, each dose being a pharmaceutical formulation including a pharmaceutical excipient and at least one chemical entity described herein. [00156] For assay of mitotic kinesin-modulating activity, generally either a mitotic kinesin or at least one chemical entity described herein is non-diffusably bound to an insoluble support having isolated sample receiving areas (e.g., a microtiter plate, an array, etc.). The insoluble support may be made of any composition to which the sample can be bound, is readily separated from soluble material, and is otherwise compatible with the overall method of screening. The surface of such supports may be solid or porous and of any convenient shape. Examples of suitable insoluble supports include microtiter plates, arrays, membranes and beads. These are typically made of glass, plastic (e.g., polystyrene), polysaccharides, nylon or nitrocellulose, Teflon™, etc. Microtiter plates and arrays are especially convenient because a large number of assays can be carried out simultaneously, using small amounts of reagents and samples. The particular manner of binding of the sample is not crucial so long as it is compatible with the reagents and overall methods of the invention, maintains the activity of the sample and is nondiffusable. Particular methods of binding include the use of antibodies (which do not sterically block either the ligand binding site or activation sequence when the protein is bound to the support), direct binding to "sticky" or ionic supports, chemical crosslinking, the synthesis of the protein or agent on the surface, etc. Following binding of the sample, excess unbound material is removed by washing. The sample receiving areas may then be blocked through incubation with bovine serum albumin (BSA), casein or other innocuous protein or other moiety. [00157] The chemical entities of the invention may be used on their own to inhibit the activity of a mitotic kinesin. In some embodiments, at least one chemical entity of the invention is combined with a mitotic kinesin and the activity of the mitotic kinesin is assayed. Kinesin activity is known in the art and includes one or more of the following: the ability to affect ATP hydrolysis; microtubule binding; gliding and polymerization/depolymerization (effects on microtubule dynamics); binding to other proteins of the spindle; binding to proteins involved in cell-cycle control; serving as a substrate to other enzymes, such as kinases or proteases: and specific kinesin cellular activities such as spindle pole separation.
[00158] Methods of performing motility assays are well known to those of skill in the art. (See e.g., Hall, et al. (1996), Biophys. J., 71 : 3467-3476, Turner et al., 1996, AnaL Biochem. 242 (l):20-5; Gittes et al., 1996, Biophys. J. 70(1): 418-29; Shirakawa et al., 1995, J. Exp. BioL 198: 1809-15; Winkelmann et al., 1995, Biophys. J. 68: 2444-53; Winkelmann et al., 1995, Biophys. J. 68: 72S.)
[00159] Methods known in the art for determining ATPase hydrolysis activity also can be used. Suitably, solution based assays are utilized. U.S. Patent 6,410,254, hereby incoφorated by reference in its entirety, describes such assays. Alternatively, conventional methods are used. For example, Pj release from kinesin (and more particularly, the motor domain of a mitotic kinesin) can be quantified, In some embodiments, the ATPase hydrolysis activity assay utilizes 0,3 M PCA (perchloric acid) and malachite green reagent (8.27 mM sodium molybdate II, 0.33 mM malachite green oxalate, and 0.8 mM Triton X-l 00). To perform the assay, 10 μL of the reaction mixture is quenched in 90 μL of cold 0.3 M PCA. Phosphate standards are used so data can be converted to mM inorganic phosphate released. When all reactions and standards have been quenched in PCA, 100 μL of malachite green reagent is added to the relevant wells in e.g., a microtiter plate. The mixture is developed for 10-1 minutes and the plate is read at an absorbance of 650 nm. If phosphate standards were used, absorbance readings can be converted to mM P, and plotted over time. Additionally, ATPase assays known in the art include the luciferase assay.
[00160] ATPase activity of kinesin motor domains also can be used to monitor the effects of agents and are well known to those skilled in the art. In some embodiments ATPase assays of kinesin are performed in the absence of microtubules. In some embodiments, the ATPase assays are performed in the presence of microtubules. Different types of agents can be detected in the above assays. In some embodiments, the effect of an agent is independent of the concentration of microtubules and ATP. In some embodiments, the effect of the agents on kinesin ATPase can be decreased by increasing the concentrations of ATP, microtubules or both. In some embodiments, the effect of the agent is increased by increasing concentrations of ATP, microtubules or both.
[00161] Chemical entities that inhibit the biochemical activity of a mitotic kinesin in vitro may then be screened in vivo. In vivo screening methods include assays of cell cycle distribution, cell viability, or the presence, morphology, activity, distribution, or number of mitotic spindles. Methods for monitoring cell cycle distribution of a cell population, for example, by flow cytometiy, are well known to those skilled in the art, as are methods for determining cell viability. See for example, U.S. Patent 6,437,115, hereby incoφorated by reference in its entirety. Microscopic methods for monitoring spindle formation and malformation are well known to those of skill in the art (see, e.g., Whitehead and Rattner (1998), J. Cell Sci. 111:2551-61; Galgio et al, (1996) J. Cell Biol,, 135:399-414), each incoiporated herein by reference in its entirety.
[00162] The chemical entities of the invention inhibit one or more mitotic kinesins.
One measure of inhibition is IC50, defined as the concentration of the chemical entity at which the activity of the mitotic kinesin is decreased by fifty percent relative to a control. In some embodiments, the at least one chemical entity has an IC50 of less than about 1 mM, In some embodiments, the at least one chemical entity has an IC50 of less than about 100 μM. In some embodiments, the at least one chemical entity has an IC50 of less than about 10 μM. In some embodiments, the at least one chemical entity has an IC50 of less than about 1 μM. In some embodiments, the at least one chemical entity has an IC50 of less than about 100 nM. In some embodiments, the at least one chemical entity has an IC50 of less than about 10 nM. Measurement of IC50 is done using an ATPase assay such as described herein. [00163] Another measure of inhibition is Kj. For chemical entities with IC5 S less than
1 μM, the K, or I j is defined as the dissociation rate constant for the interaction of the compounds described herein, with a mitotic kinesin. In some embodiments, the at least one chemical entity has a K, of less than about 100 μM, In some embodiments, the at least one chemical entity has a K, of less than about 10 μM. In some embodiments, the at least one chemical entity has a K, of less than about 1 μM. In some embodiments, the at least one chemical entity has a K, of less than about 100 nM. In some embodiments, the at least one chemical entity has a Kj of less than about 10 nM.
[00164] The K, for a chemical entity is detennined from the IC50 based on three assumptions and the Michaelis-Menten equation. First, only one compound molecule binds to the enzyme and there is no cooperativity, Second, the concentrations of active enzyme and the compound tested are known (i.e., there are no significant amounts of impurities or inactive forms in the preparations). Third, the enzymatic rate of the enzyme-inhibitor complex is zero. The rate (i.e., compound concentration) data are fitted to the equation:
V ~ VmaxE0
Figure imgf000118_0001
where V is the observed rate, Vmaλ is the rate of the free enzyme, lo is the inhibitor concentration, Eo is the enzyme concentration, and Kj is the dissociation constant of the enzyme-inhibitor complex.
[00165] Another measure of inhibition is GI50, defined as the concentration of the chemical entity that results in a decrease in the rate of cell growth by fifty percent. In some embodiments, the at least one chemical entity has a GI50 of less than about 1 mM. In some embodiments, the at least one chemical entity has a GI50 of less than about 20 μM. In some embodiments, the at least one chemical entity has a GI50 of less than about 10 μM. In some embodiments, the at least one chemical entity has a GI50 of less than about 1 μM, In some embodiments, the at least one chemical entity has a GI50 of less than about 100 nM. In some embodiments, the at least one chemical entity has a GI50 of less than about 10 nM. Measurement of GI50 is done using a cell proliferation assay such as described herein. Chemical entities of this class were found to inhibit cell proliferation. [00166] In vitro potency of small molecule inhibitors is determined, for example, by assaying human ovarian cancer cells (SKOV3) for viability following a 72-hour exposure to a 9-point dilution series of compound. Cell viability is determined by measuring the absorbance of formazon, a product formed by the bioreduction of MTS/PMS, a commercially available reagent. Each point on the dose-response curve is calculated as a percent of untreated control cells at 72 hours minus background absoφtion (complete cell kill). [00167] Anti-proliferative compounds that have been successfully applied in the clinic to treatment of cancer (cancer chemotherapeutics) have GIso's that vary greatly. For example, in A549 cells, paclitaxel GI50 is 4 nM, doxorubicin is 63 nM, 5-fluorouracil is 1 μM, and hydroxyurea is 500 μM (data provided by National Cancer Institute, Developmental Therapeutic Program, http://dtp.nci.nih.gov/). Therefore, compounds that inhibit cellular proliferation, iπespective of the concentration demonstrating inhibition, have potential clinical usefulness.
[00168] To employ the chemical entities of the invention in a method of screening for compounds that bind to a mitotic kinesin, the mitotic kinesin is bound to a support, and a compound of the invention is added to the assay. Alternatively, the chemical entity of the invention is bound to the support and a mitotic kinesin is added. Classes of compounds among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells. A wide variety of assays may be used for this puφose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, ftmctional assays (phosphorylation assays, etc.) and the like.
[00169] The determination of the binding of the chemical entities of the invention to a mitotic kinesin may be done in a number of ways. In some embodiments, the chemical entity is labeled, for example, with a fluorescent or radioactive moiety, and binding is determined directly. For example, this may be done by attaching all or a portion of a mitotic kinesin to a solid support, adding a labeled test compound (for example a chemical entity of the invention in which at least one atom has been replaced by a detectable isotope), washing off excess reagent, and determining whether the amount of the label is that present on the solid support. [00170] By "labeled" herein is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, etc. Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin etc. For the specific binding members, the complementary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above. The label can directly or indirectly provide a detectable signal.
[00171] In some embodiments, only one of the components is labeled. For example, the kinesin proteins may be labeled at tyrosine positions using 125I, or with fluorophores. Alternatively, more than one component maybe labeled with different labels; using l25I for the proteins, for example, and a fluorophor for the antimitotic agents. [00172] The chemical entities of the invention may also be used as competitors to screen for additional drug candidates. "Candidate agent" or "drug candidate" or grammatical equivalents as used herein describe any molecule, e.g., protein, oligopeptide, small organic molecule, polysaccharide, polynucleotide, etc., to be tested for bioactivity, They may be capable of directly or indirectly altering the cellular proliferation phenotype or the expression of a cellular proliferation sequence, including both nucleic acid sequences and protein sequences. In other cases, alteration of cellular proliferation protein binding and/or activity is screened. Screens of this sort may be performed either in the presence or absence of microtubules. In the case where protein binding or activity is screened, particular embodiments exclude molecules already known to bind to that particular protein, for example, polymer structures such as microtubules, and energy sources such as ATP. Particular embodiments of assays herein include candidate agents which do not bind the cellular proliferation protein in its endogenous native state termed herein as "exogenous" agents. In some embodiments, exogenous agents further exclude antibodies to the mitotic kinesin,
[00173] Candidate agents can encompass numerous chemical classes, though typically they are small organic compounds having a molecular weight of more than 100 and less than about 2,500 daltons. Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding and lipophilic binding, and typically include at least an amine, carbonyl-, hydroxyl-, ether, or carboxyl group, generally at least two of the functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines. pyrimidines, derivatives, structural analogs or combinations thereof.
[00174] Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means. Known phaimacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, and/or amidification to produce structural analogs. [00175] Competitive screening assays may be done by combining a mitotic kinesin and a d g candidate in a first sample. A second sample comprises at least one chemical entity of the present invention, a mitotic kinesin and a drug candidate. This may be performed in either the presence or absence of microtubules. The binding of the dmg candidate is determined for both samples, and a change, or difference in binding between the two samples indicates the presence of a dmg candidate capable of binding to a mitotic kinesin and potentially inhibiting its activity. That is, if the binding of the dmg candidate is different in the second sample relative to the first sample, the dmg candidate is capable of binding to a mitotic kinesin.
[00176] In some embodiments, the binding of the candidate agent to a mitotic kinesin is determined through the use of competitive binding assays. In some embodiments, the competitor is a binding moiety known to bind to the mitotic kinesin, such as an antibody, peptide, binding partner, ligand, etc. Under certain circumstances, there may be competitive binding as between the candidate agent and the binding moiety, with the binding moiety displacing the candidate agent.
[00177] In some embodiments, the candidate agent is labeled. Either the candidate agent, or the competitor, or both, is added first to the mitotic kinesin for a time sufficient to allow binding, if present. Incubations may be performed at any temperature which facilitates optimal activity, typically between 4 and 40°C,
[00178] Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high throughput screening. Typically between 0.1 and 1 hour will be sufficient. Excess reagent is generally removed or washed away. The second component is then added, and the presence or absence of the labeled component is followed, to indicate binding,
[00179] In some embodiments, the competitor is added first, followed by the candidate agent. Displacement of the competitor is an indication the candidate agent is binding to the mitotic kinesin and thus is capable of binding to, and potentially inhibiting, the activity of the mitotic kinesin. In some embodiments, either component can be labeled. Thus, for example, if the competitor is labeled, the presence of label in the wash solution indicates displacement by the agent. Alternatively, if the candidate agent is labeled, the presence of the label on the support indicates displacement.
[00180] In some embodiments, the candidate agent is added first, with incubation and washing, followed by the competitor. The absence of binding by the competitor may indicate the candidate agent is bound to the mitotic kinesin with a higher affinity, Thus, if the candidate agent is labeled, the presence of the label on the support, coupled with a lack of competitor binding, may indicate the candidate agent is capable of binding to the mitotic kinesin.
[00181] Inhibition is tested by screening for candidate agents capable of inhibiting the activity of a mitotic kinesin comprising the steps of combining a candidate agent with a mitotic kinesin as above, and determining an alteration in the biological activity of the mitotic kinesin. Thus, in some embodiments, the candidate agent should both bind to the mitotic kinesin (although this may not be necessary), and alter its biological or biochemical activity as defined herein. The methods include both in vitro screening methods and in vivo screening of cells for alterations in cell cycle distribution, cell viability, or for the presence, moφohology, activity, distribution, or amount of mitotic spindles, as are generally outlined above.
[00182] Alternatively, differential screening may be used to identify dmg candidates that bind to the native mitotic kinesin but cannot bind to a modified mitotic kinesin. [00183] Positive controls and negative controls may be used in the assays. Suitably all control and test samples are performed in at least triplicate to obtain statistically significant results. Incubation of all samples is for a time sufficient for the binding of the agent to the protein. Following incubation, all samples are washed free of non-specifically bound material and the amount of bound, generally labeled agent determined. For example, where a radiolabel is employed, the samples may be counted in a scintillation counter to determine the amount of bound compound.
[00184] A variety of other reagents may be included in the screening assays. These include reagents like salts, neutral proteins, e.g., albumin, detergents, etc which may be used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions, Also reagents that otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc., may be used. The mixture of components may be added in any order that provides for the requisite binding. [00185] Accordingly, the chemical entities of the invention are administered to cells.
By "administered" herein is meant administration of a therapeutically effective dose of at least one chemical entity of the invention to a cell either in cell culture or in a patient. By "therapeutically effective dose" herein is meant a dose that produces the effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for systemic versus localized delivery, age. body weight, general health, sex, diet, time of administration, dmg interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art. By "cells" herein is meant any cell in which mitosis or meiosis can be altered.
[00186] A "patient" for the puφoses of the present invention includes both humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In some embodiments, the patient is a mammal, and more particularly, the patient is human.
[00187] Chemical entities of the invention having the desired phaimacological activity may be administered, in some embodiments, as a pharmaceutically acceptable composition comprising an pharmaceutical excipient, to a patient, as described herein. Depending upon the manner of introduction, the chemical entities may be formulated in a variety of ways as discussed below. The concentration of the at least one chemical entity in the foπnulation may vary from about 0,1-100 wt.%.
[00188] The agents may be administered alone or in combination with other treatments, i.e., radiation, or other chemotherapeutic agents such as the taxane class of agents that appear to act on microtubule formation or the camptothecin class of topoisomerase I inhibitors. When used, other chemotherapeutic agents may be administered before, concurrently, or after administration of at least one chemical entity of the present invention. In one aspect of the invention, at least one chemical entity of the present invention is co- administered with one or more other chemotherapeutic agents. By "co-administer" it is meant that the at least one chemical entity is administered to a patient such that the at least one chemical entity as well as the co-administered compound may be found in the patient's bloodstream at the same time, regardless when the compounds are actually administered, including simultaneously.
[00189] The administration of the chemical entities of the present invention can be done in a variety of ways, including, but not limited to, orally, subcutaneously, intravenously, intranasally, transdermally, intrapeiitoneally, intramuscularly, intrapulmonary, vaginally, rectally, or intraocularly. In some instances, for example, in the treatment of wounds and inflammation, the compound or composition may be directly applied as a solution or spray. [00190] Pharmaceutical dosage forms include at least one chemical entity described herein and one or more pharmaceutical excipients. As is known in the ait, pharmaceutical excipients are secondaiy ingredients which function to enable or enhance the delivery of a dmg or medicine in a variety of dosage forms (e.g.: oral foπns such as tablets, capsules, and liquids; topical foπns such as dermal, opthalmic, and otic forms; suppositories; injectables; respiratory forms and the like). Phaπnaceutical excipients include inert or inactive ingredients, synergists or chemicals that substantively contribute to the medicinal effects of the active ingredient. For example, pharmaceutical excipients may function to improve flow characteristics, product uniformity, stability, taste, or appearance, to ease handling and administration of dose, for convenience of use, or to control bioavailability. While phaπnaceutical excipients are commonly described as being inert or inactive, it is appreciated in the art that there is a relationship between the properties of the pharmaceutical excipients and the dosage forms containing them.
[00191] Pharmaceutical excipients suitable for use as earners or diluents are well known in the art, and may be used in a variety of formulations. See, e.g., Remington's Phaπnaceutical Sciences, 18th Edition, A. R. Gennaro, Editor, Mack Publishing Company (1990); Remington: The Science and Practice of Pharmacy, 20th Edition, A. R. Gennaro, Editor, Lippincott Williams & Wilkins (2000); Handbook of Pharmaceutical Excipients, 3rd Edition, A. H. Kibbe, Editor, American Pharmaceutical Association, and Pharmaceutical Press (2000); and Handbook of Pharmaceutical Additives, compiled by Michael and Irene Ash,Gower (1995), each of which is incoφorated herein by reference for all puφoses. [00192] Oral solid dosage forms such as tablets will typically comprise one or more pharmaceutical excipients, which may for example help impart satisfactory processing and compression characteristics, or provide additional desirable physical characteristics to the tablet. Such pharmaceutical excipients may be selected from diluents, binders, glidants, lubricants, disintegrants, colors, flavors, sweetening agents, polymers, waxes or other solubility-retarding materials.
[00193] Compositions for intravenous administration will generally comprise intravenous fluids, i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily carried by the circulatory system and assimilated. Such fluids are prepared with water for injection USP.
[00194] Dosage forms for parenteral administration will generally comprise fluids, particularly intravenous fluids, i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily earned by the circulatory system and assimilated. Such fluids are typically prepared with water for injection USP. Fluids used commonly for intravenous (IV) use are disclosed in Remington, The Science and Practice of Pharmacy [full citation previously provided], and include: • alcohol, e.g., 5% alcohol (e.g., in dextrose and water ("D/W") or D/W in noπnal saline solution ("NSS"), including in 5% dextrose and water ("D5/W"), or D5/ΛV in NSS); • synthetic amino acid such as Aminosyn, FreAmine, Travasol, e.g., 3.5 or 7; 8,5; 3.5, 5.5 or 8.5 % respectively; ammonium chloride e.g., 2.14%; dextran 40, in NSS e.g., 10% or in D5/W e.g., 10%; dextran 70, in NSS e.g., 6% or in D5/W e.g., 6%; dextrose (glucose, D5/W) e.g., 2.5-50%; dextrose and sodium chloride e.g., 5-20% dextrose and 0,22-0.9% NaCl; lactated Ringer's (Hartmann's) e.g., NaCl 0.6%, KC1 0.03%, CaCl2 0.02%; lactate 0.3%; mannitol e.g., 5%, optionally in combination with dextrose e.g., 10% or NaCl e.g., 15 or 20%; multiple electrolyte solutions with varying combinations of electrolytes, dextrose, fructose, invert sugar Ringer's e.g., NaCl 0,86%, KCl 0.03%, CaCl2 0.033%; sodium bicarbonate e.g., 5%; • sodium chloride e.g., 0.45, 0.9, 3, or 5%; • sodium lactate e.g., 1/6 M; and • sterile water for injection
The pH of such IV fluids may vary, and will typically be fi™ 3.5 to 8 as known in the art. [00195] The chemical entityies of the invention can be administered alone or in combination with other treatments, i.e., radiation, or other therapeutic agents, such as the taxane class of agents that appear to act on microtubule foπnation or the camptothecin class of topoisomerase I inhibitors. When so-used, other therapeutic agents can be administered before, concurrently (whether in separate dosage forms or in a combined dosage form), or after administration of an active agent of the present invention.
[00196] The following examples serve to more fully describe the manner of using the above-described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the t e scope of this invention, but rather are presented for illustrative puφoses. All publications, including but not limited to patents and patent applications, cited in this specification are herein incoφorated by reference as if each individual publication were specifically and individually indicated to be incoφorated by reference herein as though fully set forth.
EXAMPLES
[00197] The following examples serve to more fully describe the manner of using the above-described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the tme scope of this invention, but rather are presented for illustrative puφoses. All references cited herein are incoφorated by reference in their entirety.
Example 1
Figure imgf000127_0001
[00198] To a solution of 4-isopropoxylbenzoic acid 1 (25 g, 140 mmol) in DMF
(150mL) was added NCS (24 g, 182 mmol). The reaction mixture was stirred overnight. H2O (500mL) was added to the reaction mixture. The precipitate was collected and washed with water, and dried in vacuo to give 2 (26.4 g, 88 %) as a white solid, which was used in the next step without further purification. LRMS (M+H ) m/z 213,0. [00199] To a solution of 2 (20 g, 93 mmol) in DCM were added pentafluorotrifluoroacetate (20 mL, 112 mmol) and triethvlamine (17 mL, 112 mmol) at 0 °C. The reaction mixture was stiπed for 1 h. The solution was concentrated and the mixture purified by flash column chromatography (100% DCM) to give 3 (35 g, quant.) as a white solid.
[00200] To a solution of 3 in DMF (0.2 M) were added amino acid (1.2 equiv.) and N,
N-diisopropylethylamine (3 equiv.). The reaction was monitored by LC/MS. After completion, methylamine (2 M in THF, 1.5 equiv.) and HBTU (1.5 equiv.) were added to the reaction solution. The reaction mixture was stirred for 4 h. The product was purified by either HPLC or flash column chromatography to give 4.
Example 2
Figure imgf000128_0001
1a
[00201] To a solution of H-Phe(4-Br)-OH (2, 2.5 g, 10 mmol) in DMF (20 mL) were added 3 (4.7 g, 12 mmol) and diisopropylethylamine (5.4 mL, 30 mmol) at room temperature. The reaction mixture was monitored by LC/MS. After completion, methylamine (2M in THF, 7,7 mL, 15 mmol) and HBTU (5.8 g, 15 mmol) were added to the reaction solution. The reaction mixture was stirred for 2 days. The mixture was filtered, and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 4 (2,3 g, 50%). LRMS (M+H+) m/z 455.0.
[00202] To a suspension of 4 (71 mg, 0.16 mmol) in dioxane (1 mL) were added piperazine (1 mg, 0.19 mmol), palladium (II) acetate (4 mg, 0.016 mmol), dicyclohexylphosphino-2'-(.Y '-dimethylamino)-biphenyl (6 mg, 0.016 mmol), and cesium carbonate (104 mg, 0.32mmol). The resulting mixture was stirred for 36 hours at 110 °C. The reaction mixture was diluted with EtOAc. The organic layer was washed with saturated NaHCO3 (20mL) and brine, dried over Na2SO , and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give la (6 mg, 8%). LRMS (M+FT) m/z 459.2.
Example 3
Figure imgf000129_0001
1b
[00203] To a solution of H-Tyr-NH2 HCI (2, 830 mg, 3.8 mmol) in DMF (5 mL) were added 3 (1.8 g, 4.5 mmol) and diisopropylethylamine (3.4 mL, 19 mmol) at room temperature. The reaction was stiπed for 20 hours and filtered after adding water. The wliite precipitate was recrystallized in DCM and methanol to give 4 as λvhite crystals (1.120 g, 78%). LRMS (M+H+) m/z 377.1.
[00204] To a solution of 4 (50 mg, 0.13 mmol) in DMF (1 mL) were added (s)-(+)-3- bromo-2-methyl-l-propanol (0.083 mL, 0.8 mmol) and potassium carbonate (110 mg, 0.8 mmol). The resulting mixture was stirred for 15 hours at 50 °C. The mixture was filtered, and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H O to give lb (30 mg, 51 %). LRMS (M+H+) m/z 449.1.
Example 4
Figure imgf000130_0001
Figure imgf000130_0002
Figure imgf000130_0003
1c
[00205] To a solution of H-Tyr-OBut (2, 1.9 g, 8 mmol) in DMF (50 mL) were added 3
(2.4 g, 6.2 mmol) and diisopropylethylamine (3.3 mL, 19 mmol) at room temperature. The reaction was stiπed for 2 hours. The resulting solution was diluted with EtOAc (200 mL) and washed with saturated NaHC03 (50 mL). The organic layer was separated, washed with brine, dried over Na S04, and concentrated to give a yellow solid. To a solution of the yellow solid in dichloromethane (10 mL) was added trifluoroacetic acid (30 mL). The mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was dried in vacuo to give 4 (3,1 g), which was used in the next step without further purification. LRMS (M-H+) m/z 376.1.
[00206] To a solution of 4 (3.1 g, 8 mmol) in DMF (25 mL) was added glycinamide hydrochloride (1.1 g, 9.6 mmol), diisopropylethylamine (7 mL, 40 mmol), and HBTU (3.6 g, 9.6 mmol). The reaction mixture was stiπed for 15 hours, after which solution was diluted with ethyl acetate and washed with saturated NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO , and concentrated. The resulting cmde was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 5 (38 mg, 35%). LRMS (M+H"1) m/z 434.1.
[00207] To a solution of 5 (100 mg, 0.23 mmol) in DMF (1 mL) were added cyclopropylmethyl bromide (0.1S mL, 1.S4 mmol) and potassium carbonate (317 mg, 2.3 mmol). The resulting mixture was stiπed for 10 hours at 80 °C. The mixture was filtered, and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H2O to give lc (36 mg, 34%). LRMS (M+H+) m/z 488.1.
Example 5
Figure imgf000131_0001
4 1d
[00208] To a solution of 4 (80 mg, 0.2 mmol) in DMF (1 mL) were added (±)-3- bromo-l -phenyl-2-pyrrolidinone (250 mg, 1 mmol) and potassium carbonate (235 mg, 1.7 mmol), The resulting mixture was stiπed for 10 hours at 110 °C. The mixture was filtered, and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H20 to give 5 (38 mg, 35%), LRMS (M+H+) m/z 536.1.
Example 6
Figure imgf000131_0002
4 1f
[00209] To a solution of 4 (70 mg, 0, 19 mmol) in DMF (1 mL) were added 3-
(hydroxymethyl) pyridine (0.023 mL, 0,23 mmol), triphenylphosphine (100 mg, 0.38 mmol), and diisopropylazodicarboxylate (0.055 mL, 0.38 mmol). The resulting mixture was stirred for 20 hours at room temperature, The reaction solution was concentrated and purified via flash column chromatography using a mixture of ethyl acetate and hexane as eluent to give lf (22 mg, 25%). LRMS (M+H*) m/z 468.2.
Example 7
Figure imgf000132_0001
4 1g
[00210] To a solution of 4 (50 mg, 0.12 mmol) in toluene (2 L) was added 2-
(fluorophenyl) boronic acid (20 mg, 0.14 mmol), tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.04 mmol), and 2M sodium carbonate (0.18 mL, 0.36 mmol). The reaction mixture was stirred for 90 min at 100 °C. The resulting solution was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 5 (22 mg, 40%). LRMS (M+H+) m/z 469.2.
Example 8
Figure imgf000132_0002
4 1 h
[00211] To a solution of 4 (45 mg, 0.1 mmol) in DMF (1 mL) w ere added bis(pinacolate) diboron (30 mg, 0.12 mmol), l,l'-bis(diphenylphosphino)feπocene- palladium(II) dichloride dichloromethane complex (17 mg, 0.02 mmol), and potassium acetate (39 mg, 0,4 mmol). The reaction mixture was stirred for 1 hour at 80 °C. The resulting mixture was added 4-bromo-3,5-dimethylisoxazole (35 mg, 0.2 mmol) and 2M sodium carbonate (0.4 mL, 0.8 mmol). The mixture was stirred at 80 °C for 90 min. The resulting residue was filtered, and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H2O to give lh (23 mg, 49%). LRMS (M+H ) m/z 470.1. Example 9
Figure imgf000133_0001
4 1i
[00212] To a solution of 4 (62 mg, 0.14 mmol) in DMF (1 mL) was added bis(pinacolate) diboron (42mg, 0.16 mmol), l,r-bis(diphenylphosphino)ferrocene- palladium(II) dichloride dichloromethane complex (34 mg, 0.04 mmol), and potassium acetate (54 mg, 0.55 mmol). The reaction mixture was stirred for 1 hour at 80 °C. The resulting mixture was added N-methyl-2-bromobenzimidazole (58 mg, 0.27 mmol) and 2M sodium carbonate (0.54 mL, 1.08 mmol). The mixture was stiπed at 80 °C for 60 min. The resulting solution was diluted with ethylacetate (20mL), and washed with saturated NaHCO3 (20 mL). The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give li (44 mg, 64%). LRMS (M+H^) m/z 505,1.
Example 10
Figure imgf000133_0002
[00213] To a solution of 4 (50 mg, 0.13 mmol) in DMF (1 mL) were added bis(pinacolate) diboron (34 mg, 0.13 mmol), l,r-bιs(diphenylphosphino)ferrocene- palladium(II) dichloride dichloromethane complex (27 mg, 0.03 mmol), and potassium acetate (43 mg, 0.44 mmol). The reaction mixture was stiπed for 1 hour at 80 °C. To the resulting mixture was added 3-bromothiophene-2-carbonitrile (41 mg, 0.22 mmol) and 2M sodium carbonate (0.44 mL, 0.88 mmol). The mixture was stirred at 80 °C for 90 min, The resulting residue was filtered, and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 5 (20 mg, 37%). LRMS (M+H*) m/z 482.1.
Example 11
Figure imgf000134_0001
4 1 k
[00214] To a solution of 4 (85 mg, 0.2 mmol) in toluene (2 mL) was added l-/-butyl- l,3-dihydro-imidazol-2-one (53 mg, 0.4 mmol), copper(I) iodide (18 mg, 0,1 mmol), trans- 1 ,2-diamino-cyclohexane (1 1 mg, 0.1 mmol), and cesium carbonate (124 mg, 0.4 mmol). The reaction mixture was stiπed for 4 hours at 100 °C. The mixture was filtered, and the filtrate was concentrated, The resulting residue was filtered, and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H20 to give Ik (27 mg, 28%). LRMS (M+H+) m/z 513.1 ,
Example 12
Figure imgf000134_0002
4 11
[00215] To a solution of 4 (100 mg, 0,2 mmol) in dioxane (2 mL) was added benzimidazole (39 mg, 0.33 mmol), copper (I) iodide (8.4 mg, 0,04 mmol), 1,10- phenanthrohne (16 mg, 0.1 mmol), and cesium carbonate (144 mg, 0,44 mmol). The reaction mixture was stirred for 15 hours at 100 °C. The mixture was filtered, and the filtrate was concentrated. The resulting residue was filtered, and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 11 (5,7 mg, 6 %). LRMS (M+H4) m/z 491.1 ,
Example 13
Figure imgf000135_0001
4 1m
[00216] To a solution of 4 (60 mg, 0.16 mmol) in toluene (1 mL) was added 2- chlorobenzimidazole (50 mg, 0.32 mmol), copper(I) iodide (9 mg, 0.05), and cesium carbonate (105 mg, 0,32 mmol). The reaction mixture was stirred for 28 hours at 110 °C. The mixture was filtered, and the filtrate was purified on RP-HPLC using a mixture of acetonitπle and H2O to give lm (8 mg, 10%). LRMS (M+H+) m/z 493.0.
Example 14
Figure imgf000135_0002
4 1 n
[00217] To a solution of 4 (50 mg, 0.1 mmol) in toluene (1 mL) was added phenol (21 mg, 0.2 mmol), copper(I) iodide (6 mg, 0.03 mmol), and cesium carbonate (72 mg, 0.2 mmol). The reaction mixture was stiπed for 5 hours at 115 °C. The mixture was filtered, and the filtrate was concentrated, The resulting residue was purified via flash column chromatography using a mixture of ethyl acetate and hexane as eluent to give In (23 mg, 45%). LRMS (M+H+) nvz' 467.1.
Examples 15
Figure imgf000135_0003
Figure imgf000136_0001
[00218] To a solution of 1 (2.3 g, 12.6 mmol) in DMF (30 mL) were added 2 (4.0 g,
10.5 mmol) and N, N-diisopropylethylamine (5.2 mL, 30 mmol). The reaction was monitored by LC/MS. The resulting solution was used in the next step without further purification. LRMS (M+H+) w/~ 377.1.
[00219] To a solution of cmde 3 in DMF (6 mL, ~ 2mmol) were added glycinamide
HCI (330 mg, 3 mmol), HBTU (1.14 g, 3 mmol) and N, N-diisopropylethylamine (522 μL, 3 mmol). The reaction was stirred overnight. The resulting crude product was purified via RP- HPLC using a mixture of acetonitrile and H O to give 4 (600 mg, 69% from 2), LRMS (U+X) m/z 433.1.
Examples 16
Figure imgf000136_0002
Figure imgf000136_0003
[00220] To a solution of crude 3 in DMF (15 mL, - 5.25 mmol) were added methylamine (2 M in THF, 4 mL, 8 mmol), and HBTU (3 g, 7.9 mmol). The reaction was stirred overnight. The mixture was diluted with ethyl acetate (200 mL), The organic layer was washed with H20, brine, dried over sodium sulfate, and concentrated. The resulting crude 5 was used in the next step without further purification. LRMS (M+H4) m/z 390.1. [00221] To a solution of crude 5 (75 mg, ~ 0.2 mmol) in DCM (2 mL) were added benzoyl chloride (23 μL, 0.2 mmol) and N, N-diisopropylethylamine (35 μL, 0.2 mmol). The reaction mixture was stined overnight. The solution was concentrated and purified on RP- HPLC using a mixture of acetonitrile and H2O to give 6 (36 mg, 40 % from 2). LRMS (M+lT) m/z 494.1
Examples 17
Figure imgf000137_0001
[00222] To a solution of 5 (75 mg, ~ 0.2 mmol) in DCM (2 mL) was added phenyl isocyanate (26 μL, 0.24 mmol). The reaction mixture was stiπed overnight. The resulting solution was concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 7 (40 mg, 39 % from 2). LRMS (M+H+) m/z 509.1.
Example 18
Figure imgf000137_0002
[00223] To a solution of 5 (75 mg, 0.19 mmol) in DCM (3 mL) were added isobutyl chloroformate (38 μL, 0.29 mmol) and N, N-diisopropylethylamine (50 μL, 0.29 mmol). The reaction mixture was stiπed overnight. The resulting solution was concentrated and purified on RP-HPLC using a mixture of acetonitrile and H20 to give 8 (45 mg, 48%). LRMS (M+H ) m/z 490.1. Example 19
Figure imgf000138_0001
[00224] To a solution of 5 (75 mg, 0.19 mmol) in DCM (5 mL) were added dimethylsulfamoyl chloride (30 μL, 0.29 mmol), N, N-diisopropylethylamine (50 μL, 0.29 mmol) and DMAP (50 mg, 0.4 mmol). The reaction mixture was stiπed overnight. The reaction mixture was then heated to 30 °C and stirring continued for 8 h. The resulting solution was concentrated and purified on RP-HPLC using a mixture of acetonitrile and H20 to give 9 (30 mg, 32%). LRMS (M+H+) m/z 497.1.
Example 20
Figure imgf000138_0002
Figure imgf000138_0003
Figure imgf000139_0001
Figure imgf000139_0002
Figure imgf000139_0003
Figure imgf000139_0004
[00225] To a solution of H-Phe(4-COOrBu)-OH (5.8 g, 22 mmol) in ethyl acetate (60 mL) and water (20 mL) were added platinum (IV) oxide (400 mg, 1.8 mmol) and acetic acid (50 mL). The reaction mixture was stiπed under a stream of H (60psi) for 20 hrs. The catalyst was removed by filtration through a PTFE (0.45 μm) filter and the solvent evaporated to give 2 (5.9 g), which was used in the next step without further purification. LRMS (M+H*) m/z 212 A.
[00226] To a solution of 2 (6,9 g, 18 mmol) in DMF (30 mL) were added 3 (5,9 g, 21.8 mmol) and N, N-diisopropylethylamine (9.5 mL, 54.3 mmol). The reaction was monitored by LC/MS. After completion, 2M methylamine in THF (13,6 mL, 27 mmol), HOBt (4 g, 27 mmol), and HBTU (10 g, 27 mmol) were added to the reaction solution. The reaction was stirred for 4 hours. The mixture was diluted with ethyl acetate (60 mL) and washed with saturated ΝaHCO (20 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The resulting cmde product was purified via flash column chromatography using a mixture of ethyl acetate and hexane as eluent to give 4 (cis isomer 808 mg, 1.68 mmol, trans isomer 300mg, 0.63 mmol). LRMS (M+H+) m/z 481.1.
[00227] To a solution of 4 (290 mg, 0.6 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5 mL). The resulting solution was stiπed at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified via flash column chromatography using a mixture of 99% ethyl acetate and 1 % acetic acid as eluent to give 5 as a white solid (140 mg, 55%). LRMS (M+H+) m/z 425.1.
[00228] To a solution of 5 (330 mg, 0.7 mmol) in DMSO (5 mL) were added ammonium chloride (83 mg, 1.5 mmol), diisopropylethylamine (0.27 mL, 1.5 mmol), and HBTU (580 mg, 1.5 mmol). The resulting solution was stirred at room temperature for 15 hours. Additional ammonium chloride (37 mg, 0.7 mmol), diisopropylethylamine (0.12 mL, 0.7 mmol), and HBTU (266 mg, 0.7 mmol) were added. Stirring was continued for additional 5 hours, and the mixture was diluted with ethyl acetate (50 mL) and washed with saturated NaHCO3 (20 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to yield slightly yellow cmde. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6 (128 mg, 30%). LRMS (M+H+) m/z 424.1.
[00229] To a solution of 6 (94 mg, 0.2 mmol) in DMF (2 mL) was added cyanuric chloride (45 mg, 0.2 mmol) at 0 °C, and the reaction micxture was stirred under nitrogen. After 1 hour, the reaction solution was concentrated to give 7 (79 mg), which was used in the next step without further purification, LRMS (M+H+) m/z 406.1.
[00230] To a solution of 7 (17 mg, 0.04 mmol) in methanol (2 mL) was stirred under a stream of HCI for 15 min. A stream of nitrogen λvas then bubbled through the reaction mixture, After 1 hour, the reaction solution was concentrated to give 8, which was used in the next step without further purification. LRMS (M+H ) m/z 438.1.
[00231] To a solution of cmde 8 (17 mg, -0,04 mmol) in acetic acid (2 mL) was added σ-phenylenediamine(50 mg, 0.46 mmol), and the resulting solution was stiπed at SO °C for 1 h. The reaction mixture was concentrated and purified via preparative thin layer chromatography using 5% methanol in dichloromethane as eluent to give a white solid. The solid was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 9 (9 mg, 45%). LRMS (M+H+) m/z 497.1.
Example 21
Figure imgf000141_0001
[00232] To a solution of 5 (50 mg, 0.12 mmol) in DMF ( 1 mL) were added benzvlamine (16 mg, 0.14 mmol) and HATU (57 mg, 0.14 mmol). The reaction mixture was stiired at room temperature for 3 hours. The resulting solution was filtered and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H20 to give 6 (16 mg, 26%). LRMS (M+H+) m/z 514.1 ,
Examples 22-24
Figure imgf000141_0002
Figure imgf000142_0001
Figure imgf000142_0002
Figure imgf000142_0003
[00233] To a solution of H-Phe(4-NHBoc)-OH (4.8 g, 17, 1 mmol) in ethanol (60 mL), methanol (20 mL), acetic acid (60 mL), and water (30 mL) was added platinum (IV) oxide (360 mg, 1.6 mmol), The reaction mixture was stirred under a stream of H2 (45 psi) for 20 hrs. The catalyst was removed by filtration through a PTFE (0,45 μm) filter and the solvent evaporated to give 2 (5 g), which was used in the next step without further purification. LRMS (M+H+) m/z 2S7.1.
[00234] To a solution of cmde 2 (3.2 g, 11.2 mmol) in DMF (20 mL) were added 3
(3.8 g, 10 mmol) and N, N-diisopropylethylamine (5.2 mL, 30 mmol). The reaction was monitored by LC/MS. After completion, methylamine (2 M in THF, 7.5 mL, 15 mmol), and HBTU (5.7 g, 15 mmol) were added to the reaction solution. The reaction was stiπed overnight. The mixture was diluted with ethyl acetate (60 mL) and washed with saturated ΝaHCO3 (20 mL). The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The resulting cmde was purified via RP-HPLC using a mixture of acetonitrile and H2O to give 4 (1 ,0 g, 18% from 1), LRMS (M+H+) m/z 496.1. [00235] To a solution of 4 (1.0 g, 2,0 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (8 mL), The resulting solution was stiπed at room temperature for 4 hous and then concentrated under reduced pressure. The residue was purified via RP-HPLC using a mixture of acetonitrile and H2O to give 5 (820 mg, 79%). LRMS (M+H+) m/z 396.1. [00236] To a solution of 5 (75 mg, 0, 16 mmol) in THF (3 mL) were added 4- fluorobenzoyl chloride (28 μL, 0.23 mmol) and N, N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred overnight. The resulting solution was concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6 (65 mg, 78%),
Figure imgf000143_0001
[00237] To a solution of 5 (75 mg, 0.1 mmol) in THF (3 mL) were added isobutyl chlorofoπnate (30 μL, 0.23 mmol) and N, N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stiπed overnight. The resulting solution was concentrated and purified on RP-HPLC using a mixmre of acetonitrile and H2O to give 7 (62 mg, 78%). LRMS (M+H1) m/z 496.1 ,
Figure imgf000143_0002
[00238] To a solution of 5 (75 mg, 0.16 mmol) in THF (3 mL) was added terr-butyl isocyanate (26 μL, 0.23 mmol) and N, N-diisopropylethylamine (100 μL, 0,57 mmol), The reaction mixture was stiπed overnight, The resulting solution was concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 7 (55 mg, 69%). LRMS (M+H+) m/z 495.1. Example 25
Figure imgf000144_0001
[00239] To a solution of Boc-L-serine-beta-lactone 28 (200mg, 1.07 mmol) in acetonitrile (5 mL) was added 29 (154 mg, 1.07 mmol). The mixture was stiπed at 56 °C ovemight. Concentrated under reduced pressure to give 30.
[00240] Cmde 30 was redissolved in DMF (lmL) treated with methylamine (2 M in
THF) (0.54 mL, 1.08 mmol) and HBTU (404 mg, 1.07 mmol). The mixture was stiπed for 1 hour, after which it was filtered, and the filtrate purified on reverse phase HPLC (CI 8) using a mixture of acetonitrile and H20 to give 31 (50.0 g, 14%).
[00241] To a solution of 31 (50.0 g, 0.145 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature. The reaction mixture was stirred for 20 min. The solvents were evaporated under reduced pressure and the residue re-suspended in DMF (100 mL) followed by the addition of 6 (66.3 mg, 0.174 mmol) and diisopropylethylamine (51 uL, 0.290 mmol) at room temperature. The reaction mixture was stirred for 1 hour, then concentrated under reduced pressure, and the residue purified on a flash silica gel soumn (hexane: EtOAc, 1 :1) to give 32 (50.0 mg, 78.2%). LCMS (M+H*) m/z 441.1. Example 26
Figure imgf000145_0001
40 41
[00242] To a solution of 40 (50.0 g, 0.0S74 mmol) in water (1 mL) and methanol (1 mL) were added sodium EDTA (88.1 mg, 0.262 mmol) and Hg(OAc), (83.7 mg, 0.262 nunol). The reaction mixture was stirred at 100 °C for 1 h and then concentrated under reduced pressure. The residue was purified on a flash silica gel column (DCM:MeOH, 10:1) to give 41 (29.6 mg, 71%). LCMS (M+H+) m'z 472,4.
Example 27
Figure imgf000145_0002
[00243] To a stirring solution of 51 (1.0 g, 8.76 mmol) in DMF (20 mL) were added 6
(3.34 g, 8.76 mmol) and diisopropylethylamine (2.30 mL, 13.1 mmol) at room temperature. The reaction mixture was monitored by reverse phase HPLC/MS. After completion, 2 M methylamine in THF (8.80 mL, 17.5 mmol) and HBTU (4.97 g, 13.1 mmol) were added to the reaction solution. After stirring for 1 hour, the reaction mixture was concentrated and purified on a flash silica gel column (hexane: EtOAc, 1 :1) to give 53 (1.0 g, 35.3%), [00244] To a solution of 53 (1.0 g, 3.09 mmol) in ethanol (20 mL) were added triethylamine (0.517 mL, 3.71 mmol) and hydroxyamine hydrocMoride (258 mg, 3.71 mmol). After stimng at reflux for 24 hours, the solvents were evaporated under reduced pressure. The residue was purified on reverse phase HPLC (CIS) using a mixture of acetonitrile and H2O to give 54 (280 mg, 25%).
[00245] To a stiπ-ed solution of 54 (280 mg, 0.7S5 mmol) in THF (50 mL) were added diisopropylethylamine (164 uL, 0.942 mmol) and benzoyl chloride (100 uL, 0.864 mmol) at room temperature. After stirring for 30 min, the reaction mixture was concentrated, the esidue was dissolved in HOAc (100 mL), and the mixture was stiπed at reflux for 5 hours. The solvents were removed under reduced pressure, and the residue was purified on a flash silica gel column (hexane: EtOAc, 1 :1) to give 56 (49 mg, 14.1%). LCMS (M+H+) m/z 443.1.
Example 28
Figure imgf000146_0001
[00246] To a solution of 57 (3.0 g, 10.4 mmol) in DMF (50 mL) were added 58 (1.69 g, 12.4 mmol) and HBTU (5.92 g, 15.6 mmol). The reaction mixture was monitored by reverse phase HPLC/MS. After stirring 5 hours, the solvents were evaporated under reduced pressure and the residue purified on a flash silica gel column (hexane:EtOAc, 1 :1) to give 59 (3.50 g, 82%). [00247] To a solution of 59 (200 mg, 0.491 mmol) in toluene (5 mL) was added
Lawesson's Reagent (109 mg, 0.270 mmol), After stirring at 100 °C for 30 min, the solvents were evaporated under reduced pressure. The residue was purified on a flash silica gel column (hexane: EtOAc, 1 :1) to give 60 (160 mg, 80%).
[00248] To a solution of 60 (150 mg, 0,431 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature. The reaction mixture was stirred for 2 hours. The solvents were evaporated under reduced pressure, and the residue 61 (121 mg, 100%) was dried under vacuum overnight.
[00249] To a stiπ-ed solution of 61 (0,395 mmol) in DMF (5 mL) were added 6 (180 mg, 0.473 mmol) and diisopropylethylamine (138 uL, 0.790 mmol) at room temperature. The reaction mixture was monitored by HP LC/MS. After completion, 2 M methylamine in THF (395 uL, 0.790 mmol) and HBTU (225 mg, 0.593 mmol) were added to the reaction solution. The reaction mixture was stiπed for 30 min, after which the mixture was filtered, and the filtrate purified by reverse phase HPLC (CI 8) using a mixture of acetonitrile and H2O to give 62 (70.0 mg, 38.6%). LCMS (M+H+) m/z 459.0.
Example 29
Figure imgf000147_0001
Figure imgf000147_0002
[00250] A solution of the nitrile 1 (640 mg, 1.6 mmol) and MeOH (25 mL) at 0 °C was saturated with HCI gas. The reaction vessel was allowed to warm to 23 °C. After 2 h at 23 °C the reaction solution was concentrated in vacuo and the resulting residue 2 was used without further purification.
[00251] A solution of cmde imidate 2 (50 mg, 0.12 mmol), 2-amino-3-methyl- propanol (36 mg, 0.35 mmol), and THF (1 mL) was stirred at 80 °C for 30 min. The reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in EtOAc (10 mL) and washed with 1 N NaOH (5 mL) and brine (5 mL). The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 100% EtOAc) to yield 25 mg (43%>) of the oxazole 3. LRMS (M+U+) m/z 486.3.
Figure imgf000148_0001
[00252] A solution of cmde imidate 2 (50 mg, 0.12 mmol), phenylene diamine (36 mg,
0.32 mmol), and acetic acid (1 mL) was stin-ed at 80 °C for 30 min. The reaction mixture was then concentrated in vacuo, and the resulting residue was dissolved in EtOAc (10 mL) and washed with 1 N NaOH (5 mL) and brine (5 mL). The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1:3 hexanes :EtO Ac) to yield 20 mg (34%) of the benzimidazole 3. LRMS (M+H+) / 491.2.
Figure imgf000148_0002
Figure imgf000149_0001
A solution of bromide 4 (500 mg, 1.1 mmol), 4-methyl-l-pentyn-3-ol (0.15 mL, 1.32 mmol), bis(triphenylphosphine)palladium(II) chloride (390 mg, 0.55 mmol), copper iodide (52 mg, 0,28 mmol), triethylamine (5 mL), and DMF (10 mL) was stiπed at 100 °C for 3 hours. The reaction mixture then concentrated in vacuo and the resulting residue was dissolved in EtOAc (50 mL) and washed with 0.1 N HCI (3 x 20 mL) and bnne (20 mL). The organic layer was dried (MgS04), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :1 hexanes:EtOAc) to yield 200 mg (42%) of the acetylene 5. LRMS (M+H^ m/z 471.2.
[00253] A solution of alcohol 5 (50 mg, 0, 12 mmol), Dess-Martin periodinane (90 mg,
0.21 mmol), and CH2C12 (3 mL) was stin-ed at 23 °C for 2 hours. The reaction mixture was diluted in EtOAc (20 mL). and washed with saturated aqueous NaHC03 (10 mL) and brine (20 mL). The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The resulting residue was used directly.
[00254] A solution of cmde ketone 6 (30 mg, 0.06 mmol), hydrazine (0.13 mL, 1.0 M in THF), and DMF (1 mL) was stirred at 23 °C for 12 hours. The reaction mixture was then diluted in EtOAc (10 mL), and washed with 0, 1 N HCI (5 mL) and brine (5 mL). The organic layer was dried (MgS0 ), filtered, and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (C18. acetonitrile/water) to yield 5 mg (18%) of the pyrazine 7. LRMS (M+H+) m/z 483.2
Example 32
Figure imgf000150_0001
Figure imgf000150_0002
Figure imgf000150_0003
[00255] A solution of bromide 4 (500 mg, 1.1 mmol), bis(pinacolote)diboron (420 mg,
1,65 mmol), potassium acetate (433 mg, 4.4 mmol), [l,l'-bis(diphenylphosphino) ferrocene]- dichloropalladium(II) (1 SO mg, 0.22 mmol), and DMF (5 mL) was stiπed at 80 °C for 3 min. Bromide 9 (366 mg, 4.65 mmol) and Na2CO3 (4.4 mL, 2.0 M in H20) were then added and the mixture stirred at 80 °C for 2 hours. The reaction mixture was then diluted in EtOAc (50 mL), the layers were separated, and the organic layer was washed with 0.1 N HCI (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (CI S, acetonitrile/water) to yield 165 mg (28%) of the thiazole 10. LRMS (M+H+) m/z 531.2.
[00256] A solution of ester 10 (165 mg, 0.31 mmol), potassium hydroxide (35 mg, 0.62 mmol), H2O (1 mL), MeOH (1 mL), and THF (2 mL) was stirred at 50 °C for 2 hours. The reaction mixture then diluted with EtOAc (20 mL), and washed with 1 N HCI (5 mL) and brine (10 mL). The organic layer was dried (MgS04), filtered, and concentrated in vacuo, and the resulting residue was used directly.
[00257] A solution of acid 11 (140 mg, 0,28 mmol), pentafluorophenol trifluoroacetate
12 (96 μL, 0.56 mmol), triethylamine (77 μL, 0.56 mmol), and DMF (4 mL) was stirred at 23 °C for 2 hours. The reaction mixture was then diluted with EtOAc (20 mL), and washed with 1 N HCI (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chi-omatography (silica gel, 1 :1 hexanes:EtOAc) to yield 80 mg of the ester 13. [00258] A solution of ester 13 (20 mg, 0.03 mmol), isopropyl amine (5 μL, 0.06 mmol), and THF (1 mL) was stiπed at 23 °C for 12 hours. The reaction mixture λvas then diluted with EtOAc (20 mL), and washed with 1 N HCI (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (10 mL). The organic layer was dried (MgS04), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chi-omatography (silica gel, 1 :3 hexanes: EtOAc) to yield 9 mg (55%) of the amide 14. LRMS (M+H+) m/z 543.2.
Figure imgf000151_0001
Figure imgf000152_0001
[00259] A solution of imidate 2 (1.6 g, 4.0 mmol) and 2.0 M NH3 in MeOH (10 mL) was stiπed at 23 °C for 12 hr. The reaction mixture was then concentrated in vacuo and the resulting residue was punfied by flash column chromatography (silica gel, 1 :10 CH2Cl2:MeOH) to yield 1.3 g (78%) of the amidine 17. LRMS (M+H+) m/z All .2 [00260] A solution of amidine 17 (50 mg, 0.12 mmol), methyl isobutyrylacetate (17 μL, 0.12 mmol), and NaOMe (0.5 M in MeOH, 0,72 mL) was stilted at 120 °C for 1 hr. The reaction mixture was then concentrated in vacuo and the resulting residue purified by reverse phase HPLC (CIS, acetonitrile/water) to yield 10 mg (16%) of the pyrimidine 18. LRMS (U+\X) m/∑ 5l \ 2.
Figure imgf000152_0002
[00261] A solution of bromide 4 (l .0 g, 2.20 mol), dichlorobis(triphenylphosphine)palladium(II) (154 mg, 0.220 mol), tributyl(l-ethoxyvinyl)tin (1.49 ml, 4.41 mmol), and toluene (15 mL) under N2 was stiπed at 100 °C for 6 hours. Upon completion, as monitored by LCMS, the reaction mixture was cooled, filtered through Celite, and concentrated in vacuo, The resulting residue was purified by flash column chromatography (silica gel, 2:1 :0.1 EtOAc: hexanes: triethylamine) to give 540 mg (55%) of styrene 19. LRMS (M+H+) m/z 445.2.
[00262] A solution of compound 19 (540 mg, 1.21.mmol), THF:H2O (3:1, 12 mL), and
N-bromo-succinirnide (216 mg, 1 ,21 mmol) was stiπed at 23 °C for 15 min. The reaction mixture was then concentrated in vacuo and the cmde residue diluted with EtOAc (30 mL), washed with brine (10 mL), and concentrated in vacuo. The resulting residue was purified by flash column chro atogi-aphy (silica gel, 1 :1 EtOAc:hexanes) to give 210 mg (35%») of bro oketone 20. LRMS (M+H+) m/z 495.1.
[00263] A solution of bromoketone 20 (210 mg, 0.42 mmol), K C03 ( 174 mg 1.26 mmol), tert-butylcarbamidine hydrochlonde (115 mg, 0.84 mmol), and DMF (4 mL) was stiπed at 23 °C under N for 18 hours. The reaction mixture was concentrated under high vacuum (0.1 mm Hg), and the resulting residue was purified by column chromatography (silica gel, 4: 1 EtOAc :hexanes) to give 50 mg (24%) of imidazole 21. LRMS (M+H+) /z 497.2.
Example 35
Figure imgf000153_0001
20 22
[00264] A solution of bromoketone 20 (25 mg, 0.05 mmol), K2CO3 (14 mg 0.1 mmol), acetamide (6 mg, 0.1 mmol), and DMF (1 mL) was stirred at 100 °C for 4 hours. The reaction mixture was diluted with EtOAc (1 mL), washed with brine (3 x 10 mL), and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 2:1 EtOAc:hexanes) to give 5 mg (22%) of oxazole 22, LRMS (M+H+) m/z 446.2.
Example 36
Figure imgf000154_0001
20 23
[00265] A solution of bromoketone 20 (25 mg, 0,05 mmol), K2CO3 (14 mg 0.1 mmol), cyanothioacetamide (10 mg, 0.1 mmol), and DMF (1 mL) was stiπed at 100 °C for 4 hours. The reaction mixture was diluted with EtOAc (15 mL), washed with brine (3 x 10 mL), and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (CI 8, acetonitrile/water) to give 5 mg (20%) of thiazole 23. LRMS (M+H+) m/z 497,2.
Example 37
Figure imgf000154_0002
20 24
[00266] A solution of bromoketone 20 (30 mg, 0.06 mmol), K2CO3 (25 mg 0.18 mmol), phenylthiourea (IS mg, 0.12 mmol), and DMF (1 mL) was stiπed at 100 °C for 4 hours. The reaction mixture was diluted with EtOAc (15 mL), washed with brine (3 x 10 mL), and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (CIS, acetonitrile/water) to give 10 mg (30%) of aminothiazole 24. LRMS (M+H"") m/z 549.2.
Example 38
Figure imgf000154_0003
25 26
Figure imgf000155_0001
27
[00267] A solution of aniline 25 (100 mg, 0,25 mmol), concentrated HCI (1 mL), and
AcOH (1 mL) was cooled to -5 °C. NaN02 (20 mg, 0.29 mmol) was then added slowly to the solution over 1 min. The reaction solution was stiπed at -5 °C for 45 min to provide a solution of the diazonium salt.
[00268] In another reaction vessel, SO2 was bubbled through a solution of AcOH (1 mL) and copper(I)chloride (6 mg, 0.06 mmol) until a blue-green color persisted. The diazonium solution was then added slowly over I min to the SO2/CuCl solution, The internal temperature of the reaction solution was stilted below 30 °C. The resulting reaction mixture was then poured into cold H O (10 mL), extracted λvith diethyl ether (3 x 10 mL), and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The cmde sulfonyl chlonde 26 was used without further purification.
[00269] A solution of sulfonyl chloride 26 (74 mg, 0.16 mmol), diisopropyl ethylamine
(81 mL, 0.16 mmol), benzyl amine (17 mL, 0.16 mmol) and THF (1 mL) was stirred at 23 °C for IS hours. . The reaction mixture was diluted with EtOAc (15 mL), washed with brine (3 x 10 mL), and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 1 :1 EtOAc:hexanes) to give 25 mg (29%) of sulfonamide 27. LRMS (M+H+) m/z 544.2
Example 39
Figure imgf000155_0002
Figure imgf000156_0001
[00270] A solution of amino acid 64 (2.20 g, 8.27 mmol), pentafluorophenyl ester 28
(3.0 g, 7.88 mmol), diisopropylethylamine (5.5 mL, 31.5 mmol), and DMF (30 mL) was stirred at 23 °C. After 18 hours, H2NMe (2.0 M in THF, 3.94 mL), O-benzotriazole- N,N,N',N'-tetramethyl-uiOnium-hexafluoiO-phosphate (HBTU, 6.0 g, 15.76 mmol) was added. After 4 hours, the reaction solution was dissolved in EtOAc (200 mL), washed with brine (3 x 200 mL), and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 2: 1 EtOAc:hexanes) to give 3.5 g (93%) of amide 30. LRMS (M+H+) /z 475.2.
[00271] A solution of ester 66 (3.5 g, 7.36 mmol), TFA:H2O (97.5:2.5, 10 mL), and
CH2C1 (10 mL) was stiπed at 23 °C for 3 hrs, The reaction solution was concentrated in vacuo, and the resulting residue was placed under high vacuum for 2 hours and then used without further purification.
[00272] A solution of acid 67 (4,7 g, 11.2 mmol), pentafluorophenol trifluoroacetate 12
(3.86 mL, 22.4 mmol), triethylamine (4.7 L, 33.6 mmol), and DMF (25 mL) was stiπed at 23 °C for 18 hours. The reaction mixture was then diluted with EtOAc (200 mL), and washed with 1 N HCI (50 mL), saturated aqueous NaHC03 (50 L) and brine (100 mL). The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 2:1 hexanes: EtOAc) to yield 1.1 g (17%)of the ester 68. [00273] A solution of ester 68 (20 mg, 0.03 mmol), benzyl amine (6 μL, 0,05 mmol), and THF (0.5 mL) was stiπed at 23 °C for 18 hours. The reaction mixture was then diluted with EtOAc (10 mL), and washed with 1 N HCI (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried (MgS04), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (CI S, acetonitrile/water) to yield 13 mg (85%) of the amide 14. LRMS (M+H+) m/z 508.2.
Example 40
Figure imgf000157_0001
[00274] A solution of ester 66 (50 mg, 0.1 mmol), LiAlH4 (1.0 M in THF, 0.21 mL), and THF (1 mL) was stirred at 23 °C for 2 hours. The reaction mixture was quenched with MeOH (1 mL), then diluted with EtOAc (10 mL), washed with 1 N HCI (5 mL), and brine (5 mL), The organic layer was dried (MgSO^), filtered, and the filtrate was concentrated in vacuo. The resulting residue was punfied by reverse phase HPLC (C18, acetonitrile/water) to yield 2 mg (5%) of the alcohol 70. LRMS (M+H^ m/z 405.2.
Example 41
Figure imgf000157_0002
Figure imgf000158_0001
[00275] A solution of nitrile 71 (108 mg, 0,27 mmol), LiAlH4 (1.0 M in THF, 0.1 mL), and THF (2 mL) was stiπed at 23 °C for 2 hours. The reaction mixture was quenched with MeOH (1 mL), then diluted with EtOAc (10 mL), washed with 1 N HCI (5 mL), and brine (5 mL). The organic layer was dried (MgSO ), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (CIS, acetonitrile/water) to yield 30 mg (28%) of the amine 72. LRMS (M+H+) m/z 404.2.
[00276] A solution of amine 72 (10 mg, 0.02 mmol), benzoyl chloride (3.2 μL, 0.03 mmol), triethylamine (50 μL, 0.36 mmol), and CH2C12 (0.5 mL) was stirred at 23 °C for 2 hours. The reaction mixture was then diluted with EtOAc (15 mL), and washed with 1 N HCI (2 mL), saturated aqueous NaHCO3 (2 L) and brine (5 mL). The organic layer was dried (MgS04), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 2:1 hexanes : EtOAc) to yield 5 mg (49%)of the amide 73. LRMS (M+H4) m/z 508.2.
Example 42
Figure imgf000158_0002
Figure imgf000159_0001
[00277] A solution of nitrile 71 (300 mg, 0.75 mmol), hydroxylamine hydrochloride
(156 mg, 2.25 mmol), K2CO3 (726 mg, 5.25 mmol), and EtOH (10 mL) was stiπed at 80 °C for 18 hours. The reaction mixture was concentrated in vacuo. The resulting residue was diluted with EtOAc (15 mL) and washed with brine (5 mL), The organic layer was dried (MgSO ), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :20 MeOH:EtOAc) to yield 80 mg (25%) of the hydroxyamidine 74, LRMS (M+H+) m/z 433.2.
[00278] A solution of hydroxyamidine 74 (20 mg, 0.05 mmol), carbonyldiimidazole
(CDI, 15 mg, 0.09 mmol), triethylamine (13 μL, 0.09 mmol), and DMF (1 mL) was stilted at 100 °C for 2 hours. The resulting residue was diluted with EtOAc (15 mL) and washed with brine (3 x 5 mL). The organic layer was dried (MgS0 ), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :20 MeOH:EtOAc) to yield 10 mg (44%) of the oxadiazolone 75. LRMS (M+H+) m/z 459.2.
Example 43
Figure imgf000159_0002
[00279] A solution of hydroxyamidine 74 (20 mg, 0.05 mmol), triethylamine (13 μL,
0.09 mmol), acetic anhydride (0.5 mL), and DMF (0.5 mL) was stiπed at 100 °C for 2 hours. The resulting residue was diluted with EtOAc (15 mL) and washed with brine (3 x 5 mL). The organic layer was dried (MgSO ), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :20
15S MeOH:EtOAc) to yield 13 mg (57%) of the oxadiazole 75. LRMS (M+H^ m/z 457.2.
Figure imgf000160_0001
[00280] To a solution of 63 (lOO.mg, 0.367 mmol) in DCM (10 mL) were added benzoic chloride 64 (93.8 uL, 0.808 mmol) and diisopropylethylamine (192 uL, 1.10 mmol). After stirring for 10 min, 2 M methylamine in THF (550 uL, 1.10 mmol) was added to the reaction solution. The reaction mixmre was stiπed for 30 min and concentrated. The residue was purified on a flash silica gel column (hexane:EtOAc, 1 : 1 ) to give 66 (100 mg, 70%). [00281] To a solution of 66 (100 mg, 0.257 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature. The reaction mixture was stilted for 100 min. The solvents were evaporated under reduced pressure, and the residue dried under high vacuum overnight. The residue was dissohed in DMF (2 mL) and then stirred with 6 (117 mg, 0.308 mmol) and diisopropylethylamine (90.0 uL, 0.515 mmol) at room temperature. The reaction mixture was monitored by reverse phase HPLC/MS. The reaction mixture was stiπed for 30 min, after which it was filtered, and the filtrate purified by reverse phase HPLC (CIS) using a mixture of acetonitrile and H2O to give 67 (100 mg, 52.9%). LCMS (M+H+) m/z 486,2.
Example 45
Figure imgf000161_0001
[00282] To a solution of 68 (500 mg, 1.23 mmol) in DCM (10 mL) was added TFA (10 mL) at room temperature. The reaction mixture was stined for 10 min, and then the solvents were evaporated under reduced pressure. The resulting residue (~1.23 mmol) was resuspended in DMF (50 mL) to which was added 6 (562 mg, 1.4S mmol) and diisopropylethylamine (429 uL, 2.46 mmol) at room temperature. The reaction mixture was monitored by reverse phase HPLC/MS. After starting material was no longer observed, 2 M methylamine in THF (1.23 mL, 2.46 mmol) and HBTLT (702 mg, 1.85 mmol) were added to the solution. After stirring for 30 min, the solvents were evaporated under reduced pressure and the residue purified on a flash silica gel column (hexane:EtOAc, 1 : 1) to give 69 (450 g, 71%). LCMS (M+H+) m/z 516.2.
[00283] 69 (400 mg, 0.775 mmol) was dissolved in HBr/HOAc solution (10 mL). After stirring for 10 min, the solvents were removed. The residue was dissolved in sodium bicarbonate solution (50 mL), and extracted with DCM (50 mL) three times. The combined DCM layers were dried over sodium sulfate and filtered, and the filtrate concentrated under reduced pressure to give 70 (285 mg, 96%).
[00284] To a solution of 70 (82,5 g, 0.216 mmol) in DMF (2 mL) were added benzyl bromide (30,8 uL, 0.259 mmol) and diisopropylethylamine (75.3 uL, 0.432 mmol). The reaction mixture was monitored by reverse phase HPLC/MS. After stirring for 2 hours, the mixture was filtered and the filtrate purified by reverse phase HPLC (CIS) using a mixture of acetonitrile and H2O to give 71 (183 mg, 90%), LCMS (M+H4) m/z 472.1. [00285] To a solution of 71 (128 mg, 0.271 mmol) in water (1 mL) and methanol (1 mL) were added sodium EDTA (273 mg, 0.814 mmol), HOAc (20 uL) and Hg(OAc)2 (259 mg, 0.814 mmol). The reaction mixture was stirred at 100 °C for 8 h, after which the solvents were evaporated under reduced pressure. The residue was re-dissolved in DMF (2 mL) and filtered, and the filtrate was purified by reverse phase HPLC (CIS) using a mixture of acetonitrile and H2O to give 72 (37.6 mg, 28.5%). LCMS (M+H*) m/z 486,1.
Example 46
BocH
Figure imgf000162_0001
[00286] To a solution of 42 (1.0 g, 3.24 mmol) in methanol/water (2/1, 20 mL) was added sodium bicarbonate (327 mg, 3.24 mmol). While stirring over an ice-bath, bromine (200 uL, 3.89 mmol) was added dropwise into the reaction mixture. The reaction mixture was monitored by reverse phase HPLC/MS. After starting material was no longer observed, the solvents were evaporated under reduced pressure. The residue was dissolved in water (100 mL), and extracted with DCM (50 mL) three times, The combined DCM layers were dried over sodium sulfate, the mixture was filtered, and the filtrate was concentrated to give 43. [00287] To a solution of crude 43 (3.24 mmol) in methanol (50 mL) were added diisopropylethylamine (1.14 mL, 6.48 mmol) and benzyl thioamide 44 (445 mg, 3.24 mmol). After stirring at reflux for 24 hours, the solvents were evaporated under reduced pressure. The residue was purified by reversed phase HPLC (CIS) using a mixture of acetonitrile and H2O to give 45 (200 mg, 18%).
[00288] To a solution, of 45 (150 mg, 0.431 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature. The reaction mixmre was stirred for 10 min. Then the solvents were evaporated under reduced pressure, and the residue 46 (107 mg, 100%) was dried under high vacuum overnight.
[00289] To a stirred solution of 46 (0.431 mmol) in DMF (20 mL) were added 6 (197 mg, 0.517 mmol) and diisopropylethylamine (150 uL, 0.862 mmol) at room temperature. The reaction mixture was monitored by reverse phase HPLC/MS, After starting material was no longer observed, 2 M methylamine in THF (0.431 mL, 0.862 mmol) and HBTU (245 mg, 0.647 mmol) were added to the solution. The reaction mixture was stirred for 30 min, after which the mixture was filtered, and the filtrate purified by reversed phase HPLC (C18) using a mixmre of acetonitrile and H O to give 47 (80.0 mg, 40.5% ). LCMS (M+H+) /z 45S.1. [00290] The same procedures applied to 47 were used for making 50 (5S.3 mg). LCMS
Figure imgf000163_0001
Example 47
Boc' ."
Figure imgf000164_0001
Figure imgf000164_0002
[00291] To a stiπed solution of Boc- -biphenylalanine 9 (3.0 g, 8.79 mmol) in THF
(200 mL) over ice bath was added LAH (1.0 M in THF, 17.6 mL, 17.6 mmol). After stirring for 2 hours, the reaction was quenched with MeOH (lOmL) followed by NaOH solution (17.6 mL, 35.1 mmol). The mixmre was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was dissolved in water (200 mL) and extracted by DCM (200 mL) three times, The combined DCM layers were dried (Na2S0 ), filtered, and concentrated under reduced pressure to give 10 (2,85g, 9S%).
[00292] To a stiπ-ed solution of 10 (2.85 g, 8.70 mmol) in THF (250 mL) were added
11 (1.54g, 10.4 mmol) and triphenylphosphine (2.51g, 9.57 mmol). DEAD (1.49 mL, 9.57 mmol) was then added dropwise and the reaction stiπed for 30 min. concentrated in vacuo, and the residue was purified on a flash silica gel column (hexane:EtOAc, 6:1) to obtain the product 12 (2,0g, 50%).
[00293] To a solution of 12 (2,0 g, 4.38 mmol) in DCM (50 mL) was added TFA (50 mL) at room temperature. The reaction mixture was stirred for 20 min and then concentrated in vacuo to give 13 (1.56 g 100%), [00294] To a solution of 13 in DMF (100 mL) were added 6 (2.0 g, 5.26 mmol) and diisopropylethylamine (1.53 mL, 8.76 mmol) at room temperature. The reaction mixture was stirred overnight. The solvents were evaporated under reduced pressure and the residue purified over silica gel (hexane:EtOAc = 2:1) to give 14 (1.5 g, 61.9%). LRMS (M+H*) X 553.1.
[00295] To a solution of 14 (1.5 g, 2.71 mmol) in methanol (20 mL) was added hydrazine hydrate (0.845 mL, 27.1 mmol). The reaction mixture was stiπed at 50 °C for 5 h, and then cooled to room temperature. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give 15 (1.0g, 87.2%). LCMS (M+H+) m/z 423.1.
Example 48
Figure imgf000165_0001
[00296] To a solution of 15 (20.0 mg, 0.0473 mmol) in DCM (10 mL) were added diisopropylethylamine (24.7 uL, 0.142 mmol) and acetyl chloride (5.0 uL, 0.0709 mmol). The reaction mixture was stiπed for 10 min, then concentrated under reduced pressure and purified on reverse phase HPLC (CIS) using a mixture of acetonitrile and H20 to give 16 (8.0 mg, 36.4%). LCMS (M+H+) m/z 465.2. [00297] To a solution of 15 (60.0 mg, 0.142 mmol) in DCM (2 mL) were added diisopropylethylamine (49.5 uL, 0.282 mmol), 17 (32.2 mg, 0.170 mmol) and HBTU (80.8 mg, 0.213 mmol). The reaction mixture was stiπed for 10 min and then concentrated under reduced pressure. The resulting residue was dissolved in DCM (1 mL) and TFA (1 mL) and stiπed for 10 min. concentrated under reduced pressure and the product purified on reverse phase HPLC (CIS) using a mixture of acetonitrile and H2O to give 19 (25.0 mg, 35.6%), LGMS (M+H+) m/z 494.2.
[00298] To a solution of 15 (35,0 mg, 0.0S28 mmol) in DCM (2 mL) were added diisopropylethylamine (28.8 uL, 0,166 mmol) and methanosulfonyl chloride (9.64 uL, 0.124 mmol), The reaction mixture was stilted for 10 min, then concentrated under reduced , pressure and product purified on reverse phase HPLC (CIS) using a mixture of acetonitrile and H20 to give 20 (25.0 mg, 60.3%). LCMS (M+H+) m/z 501.2. [00299] To a solution of 15 (60.0 mg, 0.142 mmol) in DCM (2 mL) were added diisopropylethylamine (49,5 uL, 0.2S2 mmol) and trimethylsiliylisocyanide (1 .6 mg, 0.170 mmol), The reaction mixture was stin-ed for 10 min, then concentrated under reduced pressure and the product purified on reverse phase HPLC (C18) using a mixture of acetonitrile and H2O to give 21 (20,6 mg, 31.1%). LCMS (M+H*) m/z 466.1. [00300] To a solution of 15 (60.0 mg, 0.142 mmol) in DCM (2 mL) were added diisopropylethylamine (49.5 uL, 0.2S2 mmol) and methyl chloro fonnate (13.1 uL, 0.170 mmol). The reaction mixture was stin-ed for 10 min, then concentrated under reduced pressure and the residue purified on reverse phase HPLC (CI S) using a mixture of acetonitrile and H20 to give 22 (19.9 mg, 29.1%). LCMS (M+H+) m/z 481.1.
Example 49
Figure imgf000167_0001
[00301] A solution of 4-bromobenzaldehyde (14.8 g. SO mmol) and ammonium acetate
(14.0 g, 180 mmol) in nitroethane (50.0 g) was heated to reflux for 8 hours. It was then cooled to room temperature, partitioned between dichloromethane (150 mL) and water (30 mL). The phases were separated; after which the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was passed down a plug silica gel column (ethyl acetate/hexane as eluent) followed by recrystallization from methanol to yield intermediate 2 (9.8 g, 51%), which was determined to be pure enough for use in subsequent transformations (LC/MS (LRMS (M+H^) m/z: 240.97).
[00302] To a 0 °C solution of sodium borohydride (4.6 g, 124 mmol) in tetrahydrofuran
(100 mL) was added borane-tetrahydrofuran complex (150 mL, 150 mmol, 1.0 M). The resulting solution was then stirred at room temperature for an additional 15 minutes, Intermediate 2 (6.5 g, 27 mmol) in tetrahydrofuran (30 mL) was added dropwise, and the resulting solution was refluxed for 4 hours. It was cooled to room temperature and the reaction quenched with water and extracted with dichloromethane (3 x 80 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo, and the residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide intermediate 3 (5.2 g, 90%), which was characterized by LC/MS (LRMS (M+H+) m/z: 213.02).
[00303] A 0 °C solution of amine 3 (4.0 g, 16 mmol) in ethyl acetate (30 mL) was saturated with hydrochloric acid (gas). The resulting salt was collected by filtration and dried in vacuo.
[00304] I-N-Acetylleucine sodium salt (8.0 mmol) (prepared by addition of 1 N sodium hydroxide solution to a suspension of Z-N-acetylleucine (1.39 g, 8,0 mmol) in 5 mL of water until pH = 7) was added slowly to a stiπed solution of the aforementioned 3 hydrochloride salt in water (10 mL). Crystals formed overnight and were removed by filtration, washed with a small amount of cold water, and recrystallized from absolute methanol. The crystalline 4a salt was collected and dried in vacuo.
[00305] The mother liquors, which were rich in (S)-3, were combined, made strongly alkaline with 5 N sodium hydroxide solution, and washed three times with diethyl ether. The combined organic layers were washed with water and dried over sodium sulfate. After removal of sodium sulfate, hydrochloric acid was passed through the solution until the precipitation of hydrochloride salt was complete. The same procedure as above was applied with D-N-acetylleucine salt. The crystalline 4b salt was collected and dried in vacuo. [00306] The diastereomeric salt of each enantiomer was partitioned between 20 mL of water, made strongly alkaline with 5 N sodium hydroxide solutions, and extracted with diethyl ether. The combined organic layers were washed with water and dried over sodium sulfate. The soh'ents were removed, and both products were deteπnined to be pure enough for use in subsequent transformations (4a: 1.3 g, 32%; 4b: 0.9g, 22%) (Η-NMR and LC/MS (LRMS (M+H+) m/z: 213,02)). Capillary electrophoresis indicated > 98% ee. [00307] To a room temperature solution of amine 4a (111 mg, 0.52 mmol) in dimethylfoπnamide (5 mL) was added diisopropylethylamine (99 μl, 0.57 mmol). The resulting solution was stirred for 5 minutes and intermediate 5 (217 mg, 0,57 mmol) was added, The reaction mixture was stiπed under an atmosphere of nitrogen for 30 minutes and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (20 mL) and aqueous citric acid solution (20 mL, 10%>). The layers were separated, and the organic phase was washed with aqueous citric acid solution (20 mL, 10%) and aqueous potassium hydroxide solution (2 x 20 mL, 0.1 M). It was then dried over sodium sulfate and concentration in vacuo to yield 6 (212 mg, 100%), which was determined to be pure enough for use in subsequent transformations (LRMS (M+H+) /z: 410.1).
[00308] To a room temperature solution of bromide 6 (212 mg, 0.53 mmol) in dioxane
(10 mL) were added rrα/7s-dichlorobis(triphenylphosphine)palladiurn(H) (37 mg, 10 mol %) and 1 -ethoxyvinyltri-n-butyltin (481 mg, 1.33 mmol), successively. The resulting solution was heated to 100°C for 4 hours. It was cooled to room temperature and the solvents were removed in vacuo. The residue was then purified by flash chromatography (silica gel, ethyl acetate plus 5% triethylamine) to provide intermediate 7 (250 mg) which was unstable and determined to be pure enough for use in subsequent transformations LC/MS (LRMS (M+H+) m/z: 402.8),
[00309] Intermediate 7 in tetrahydrofuran ( 10 mL) and water (3 mL) was stirred with
N- bromosuccinimide (190 mg, 1.1 mmol) at 50 °C for 2 hours. The solvents were removed in vacuo. and the resulting residue was partitioned between water (10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide intermediate 8 (55 mg, 23%), which was characterized by LC/MS (LRMS (M+H+) m/z: 452,1),
[00310] To a room temperature solution of intermediate 9 (55 mg, 0.12 mmol) in dimethylformamide (3 mL) was added potassium carbonate (34 mg, 0.24 mmol) and tert- butylcarbamidine (31 mg, 0.30 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at 50 °C for 1.5 hours. It was cooled to room temperature and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (15 mL) and water (15 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was then purified by flash chi-omatography (silica gel, hexane/ethyl acetate) to provide 9 (35 mg, 67%), which was characterized by Η ΝMR and LC/MS (LRMS
Figure imgf000169_0001
Example 50
BocHN
Figure imgf000170_0001
Figure imgf000170_0002
1. triphosgene, 2. MeNHCMe3
Figure imgf000170_0003
Figure imgf000170_0004
[00311] To a room temperature solution of acid 1 (2.98 g, 9.2 mmol) in methanol (15 mL) was added dropwise a solution of TMS diazomethane in hexanes (9.2 mL, 18.4 mmol, 2.0 M). The resulting yellow solution was stilted at ambient temperature for 30 minutes, and the solvents were removed in vacuo. The residual viscous oil 2 (3.10 g, 9.2 mmol) was dried and detennined to be pure enough for use in subsequent transformations (LC/MS (LRMS {U+\X) m/z: 339.10)).
[00312] A mixture of intermediate 2 (3.10 g, 9.2 mmol) and palladium on carbon (310 mg) in methanol (30 mL) was stirred under hydrogen at room temperature for 2 hours. It was then filtered through Celite and concentrated to provide aniline 3 (2.47 g, 8.0 mmol) as a viscous oil, which was dried and determined to be pure enough for use in subsequent transformations (LC/MS (LRMS (M+H+) m/z: 309.20)).
[00313] To a room temperature solution of aniline 3 (2.47 g, 8.0 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL). The resulting solution was stiπed for 45 minutes, and the solvents were removed in vacuo. The residue was partitioned between dichloromethane (75 mL) and saturated aqueous sodium bicarbonate solution (25 mL), and the layers were separated. The aqueous phase was saturated with sodium chloride and extracted with dichloromethane (3 x 75 mL) and tetrahydrofuran (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 4 (1.30 g, 63 mmol) as a viscous oil, which was characterized by LC/MS (LRMS (MH) m/z: 209.30).
[00314] A solution of amine 4 (1.30 g, 6,25 mmol) in dimethylformamide (20 mL) was stiπed with diisopropylethylamine (3.27 ml, 18.80 mmol) at room temperature for 5 minutes, followed by the addition of intermediate 5 (2.38 g, 6.25 mmol). The reaction mixture was stirred for additional 30 minutes, and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (50 L) and water (50 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide 6 (1.47 g, 58%) as a foamy white solid, which was characterized by (LC/MS (LRMS (M+H+) m z: 405.15). [00315] To a room temperature solution of aniline 6 (131 mg, 0.32 mmol) in tetrahydrofuran (5 mL) were added diisopropylethylamine (85 μL, 0.48 mmol), 4- (dimethylamino)pyridine (15 mg, 0.12 mmol), and di-/ert-butyldicarbonate (85 mg, 0.39 mmol). The resulting solution was stilted overnight and then diluted with ethyl acetate (20 mL), washed with aqueous hydrochloric acid solution (2 x 15 mL, 0,1 M) and dried over sodium sulfate. Removal of solvents yielded carbamate 7 (139 mg, 8S%>) as a glassy solid, which was detennined to be pure enough for use in subsequent transformations (LC/MS (LRMS (M+Yf) m/z: 505.10).
[00316] To a room temperature solution of carbamate 7 (139 mg, 0.28 mmol) in methanol (2 mL) and tetrahydiOfuran (2 mL) was added sodium borohydride (261 mg, 6.9 mmol). The resulting mixture was stirred for 2 hours, after which the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (15 mL) and water (15 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by reverse-phase HPLC using a mobile phase gradient consisting of acetonitrile and water. The pure product 8 (47 mg, 36%) was isolated and characterized by Η-NMR and LC/MS (LRMS (M+H*) m/z: 477.20).
[00317] To a 0 °C solution of triphosgene (37 mg, 0.13 mmol) in tetrahydrofuran (15 mL) was added dropwise a solution of 6 (145 mg, 0.36 mmol) and diisopropylethylamine (130 μL, 0.75 mmol) in tetrahydrofuran (5 mL). The resulting mixture was kept under an atmosphere of nitrogen at the same temperature for 30 minutes and quenched with methyl- terr-butylamine (215 μL, 1.80 mmol), The reaction mixture was stirred for an additional 30 minutes followed by removal of the solvents in vacuo. The residue was partitioned between ethyl acetate (15 mL) and aqueous hydrochloric acid solution (15 mL, 0.1 M), the layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to yield urea 9 (152 mg, 0.29 mmol) as a glassy solid, which was determined to be pure enough for use in subsequent transfoπnations (LC/MS (LRMS (M+H+) m'z: 518.2), [00318] To a room temperature solution of urea 9 (150 mg, 0.29 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added sodium borohydride (260 mg, 6.90 mmol). The resulting mixture was stiπed under an atmosphere of nitrogen at room temperature for 2 hours. The solvents were removed and the residue was partitioned between ethyl acetate (15 mL) and water (15 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by reverse-phase HPLC using a mobile phase gradient consisting of acetonitrile and water. The pure product 10 (4 mg, 28%) was isolated and characterized by Η-NMR and LC/MS (LRMS (M+H+) m/z; 490.1).
Example 51
BocHN . C0 H
Figure imgf000173_0001
BocHN BocHN
Figure imgf000173_0003
Figure imgf000173_0002
BocHN NHjOAc HCONH-., I 30 °C
Figure imgf000173_0004
Figure imgf000173_0005
Me 10
[00319] To a solution of carboxylic acid 1 (10.0 g, 28 mmol) in anhydrous diethyl ether
(200 mL) at 0 °C was added dropwise a solution of lithium aluminum hydride in tetrahydrofuran (40 mL, 40 mmol, 1 M). The resulting solution was then stirred for an additional 2 hours at the same temperature. It was carefully quenched with water (2.5 mL), aqueous sodium hydroxide (2.5 mL, IM) and water (3,0 mL). The solution was then dried over sodium sulfate and removal of the solvents yielded intermediate 2 (9.2 g, 96%), which was determined to be pure enough for use in subsequent transformations (Η-NMR and LC/MS (LRMS (M+H+) m/z: 344.08)).
[00320] To a room temperature solution of inteπnediate 2 in anhydrous dioxane (200 mL) were added triethylamine (6 mL, 40 mmol) and ?e/7-butyldimethylsilyltrifluoro methanesulfonate (S.6 g, 32 mmol). The resulting solution was then stirred overnight and quenched with saturated aqueous sodium bicarbonate solution. It was extracted with dichloromethane (3 x 100 mL), and the combined organic layers were dried over sodium sulfate and concentrate in vacuo. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide intermediate 3 (9.2 g, 72% overall), which was characterized by LC/MS (LRMS (M+H*) m/z: 458.1 ).
[00321] To a room temperature solution of bromide 3 (6.0 g, 13 mmol) in dioxane (100 mL) were added rra«.s-dichlorobis(triphenylphosphine)palladium(II) (500 mg) and 1- ethoxyvinyltri-n-butyltin (12,3 g, 34 mmol), successively. The resulting solution was heated to 100°C for 4 hours. Removal of the solvents in vacuo was followed by purification by flash chromatography (silica gel, hexane/ethyl acetate plus 5% triethylamine) to provide intermediate 4 (5.4 g) which was characterized by LC/MS (LRMS (M+H^ m/z: 450.30). The product was found to be unstable and used immediately in subsequent transformations. [00322] Inteπnediate 4 in methanol (100 mL) and water (50 mL) was stirred with N- bromosuccinimide (5.9 g, 33 mmol) at 50°C for 4 hours, The solvents were removed in vacuo, and the resulting residue extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrate in vacuo. The residue was then purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide intermediate 5 (4.5 g, 69% overall), which was characterized by LC/MS (LRMS (M+H+) m/z: 500.54). [00323] Under a nitrogen atmosphere, a pressure-equalizing dropping funnel charged with the bromomethyl ketone 5 (2.5 g, 5.0 mmol) in dichloromethane (40 mL) was attached to a 150-mL flask which contains a solution of methylamine (15 mL, 30 mmol, 1 M in THF). The flask was cooled to 0 °C, and the bromide solution was added dropwise over 2 hours. The resulting solution was stilted for one more hour, after which triethylamine (1 mL) and a solution of trimethylacetyl chloride (4.8 mL, 40 mmol) in dichloromethane (10 mL) were added. The resulting mixture was stirred for another 2 hours and then quenched with saturated sodium bicarbonate solution. The mixmre was extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (silica gel, ethyl acetate/hexane) provided ester 6 (1 ,3 g, 49%> overall), which was characterized by Η-ΝMR and LC/MS analysis (LRMS (M+H*) m/z: 535.35).
[00324] A solution of 6 (1 ,3 g, 2.6 mmol) in an excess of ammonium acetate in formamide (10 mL) was heated to 130 °C under a nitrogen atmosphere for 3 hours, The resulting mixture was cooled to room temperature, partitioned between water and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) providing imidazole 7 (0.8 g, 60%), which was characterized by Η- ΝMR and LC/MS analysis (LRMS (M+H+) m/z: 516.35). [00325] A solution of 7 (800 mg, 1.55 mmol) in tetrahydrofuran (10 mL) was stirred with hydrogen chloride in 1,4-dioxane (10 mL, 4.0 M) at room temperature for one hour. The solvents were removed in vacuo, and the residue was dried under high vacuum overnight to yield inteπnediate 8 (600 mg), which was deteπnined to be pure enough for the next transformation (Η-NMR and LC/MS (LRMS (M+H ) m/z 302.22)). [00326] To a room temperature solution of amine 8 (60 mg, 0.02 mmol) in dimethylformamide (3 mL) was added diisopropylethylamine (53 μl, 0.30 mmol) and the resulting solution stirred at room temperature for 5 minutes. Iintermediate 9 (23 mg, 0.06 ltimol) was then added, and the reaction mixture was stiπed under an atmosphere of nitrogen for 30 minutes. The solvents were removed in vacuo, and the residue purified by flash chromatography (silica gel, ethanol/dichloromethane) to provide 10 (25 mg, 26%>) as a glassy solid, which was characterized by Η NMR and LC/MS (LRMS (M+H+) m/z; 489.28).
Example 52
BocHN BocHN .CH2OH NaBH., NH,OH HCI THF/MeOH NaOMe/MeOH, 50 CC
Figure imgf000175_0001
Figure imgf000175_0002
[00327] To a room temperature solution of 1 (4,96 g, 17 mmol) in methanol ( 15 mL) was added dropwise a solution of TMS diazomethane in hexanes (17.0 mL, 34 mmol, 2 M). The resulting yellow solution was stirred at ambient temperature for 30 minutes. The solvents were removed in vacuo, and the viscous oil 2 (5.19 g, 17 mmol) was dried under high vacuum and determined to be pure enough for use in subsequent transfonnations (LC/MS (LRMS (M+H ) m/z: 305.3)). [00328] Intermediate 2 (5.19 g, 17 mmol) was stirred with sodium borohydride (3.23 g,
85 mmol) in methanol (50 mL) and tetrahydrofuran (50 mL) at room temperature for 2 hours. The solvents were removed in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous phase was extracted λvith ethyl acetate (3 x 50 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to yield 3 (4,71 g, 17 mmol) as a white solid, which was detennined to be pure enough for use in subsequent transformations LC/MS (LRMS (M+H*) m/z: 277.3). Nitrile 3 (1,92 g, 6,9 mmol) was stined with sodium methoxide in methanol (27,7 mL, 13,9 mmol, 0.5 M) and hydroxylamine hydrochloride (964 mg, 13.9 mmol) under an atmosphere of nitrogen at 50 °C for 2 hours, It was then cooled to room temperature and the solvents were removed in vacuo. The residue was partitioned between saturated aqueous ammonium chloride solution (30 mL) and ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo, and the residue'was purified by flash chromatography (silica gel, hexane/ethyl acetate) to yield intermediate 4 (1.08 g, 51%), which was characterized by Η NMR and LC/MS (LRMS (M+H+) m/z: 310.2). [00329] To a room temperature solution of 4 (1 ,08 g, 3.5 mmol) in methanol (30 mL) was added Raney nickel (200 mg) and acetic acid (1 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 2 hours. It was filtered through Celite and concentrated in vacuo to provide 5 (1.02 g, 100%) as a white solid, which was determined to be pure enough for use in subsequent transfoimations (LC/MS (LRMS (M+H+) m/z: 294.3)).
[00330] To a room temperature solution of amidine 5 (304 mg, 1.0 mmol) in anhydrous ethanol (15 mL) was added l,8-diazabicyclo[5.4,0]undec-7-ene (622 μL, 4.2 mmol) and 3-bromo-l,l ,l-trifluoro-2-butanone (424 mg, 2,1 mmol). The resulting mixture was stirred under an atmosphere of nitrogen at 115 °C for 30 minutes. It was then cooled to room temperature and the solvents removed in vacuo. The residue was purified by reverse- phase HPLC using a mobile phase gradient consisting of acetonitrile and water. Compound 6 (76 mg, 20%) was isolated and characterized by Η NMR and LC/MS (LRMS (M+H*) m/z 400.1).
[00331] A solution of 6 (76 mg, 0.2 mmol) in dichloromethane (2 mL) was stirred with trifluoroacetic acid (2 mL) at room temperature for 45 minutes. The solvents were removed in vacuo to provide 7 (57 mg, 100%), which was deteπnined to be pure enough for use in subsequent transformations (LC/MS (LRMS (M+H*) m/z: 300.3)). [00332] To a room temperature solution of amine 7 (25 mg, 0.08 mmol) in dimethylformamide (3 mL) was added diisopropylethylamine (87 μl, 0,50 mmol). The resulting solution was stin-ed at room temperature for 5 minutes and intermediate 8 (32 mg, 0.08 mmol) was added. The reaction mixture was stiπed under an atmosphere of nitrogen at room temperature for 30 minutes, and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (5 mL) and water (5 mL), after which the layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate) to provide 9 (7 mg, 18%) as a glassy solid, which was characterized by Η NMR and LC/MS (LRMS (M+H ) m/z: 496.4).
Example 53 BocHN NHjOAc HCONH„ 130 °
Figure imgf000177_0001
Figure imgf000177_0002
[00333] To a room temperature solution of aniline 1 (500 mg, 1.3 mmol) in dimethylformamide (3 mL) were added potassium carbonate (1.5 g) and 1 -bromopinacolone (500 mg, 2,8 mmol). The reaction mixture was stirred at 50 °C for 4 hours, and the solvents were removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (15 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate) to provide 2 (320 mg, 51%), which was characterized by Η NMR and LCMS (LRMS (M+H+) m/z: 479.74). [00334] To a room temperature solution of 2 (307 mg, 0.64 mmol) in triethyl orthoformate (20 mL) was added concentrated aqueous HCI (25 μL). The resulting mixture was stiπed at 90 °C for 3 hours and then cooled to room temperature. The solvents were removed in vacuo and the residue partitioned between water (15 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer washed with water (3 x 20 mL) and brine (3 x 20 mL), and dried over sodium sulfate. Removal of the solvents yielded intermediate 3 (326 mg, 100%) as a viscous oil, which was characterized by LC/MS (LRMS (M+H+) w/r: 507.1).
[00335] Intermediate 3 (207 mg, 0.41 mmol) was stined with ammonium acetate (1.57 g, 20.40 mmol) in formamide under an atmosphere of nitrogen at 130 °C for 4.5 hours. The resulting solution was cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (10 mL), The layers were separated, the organic layer was washed with water (4 x 10 mL) and brine (20 mL) and dried over sodium sulfate. The solvents were removed in vacuo, and the residue was purified by reverse-phase HPLC using a mobile phase gradient consisting of acetonitrile and water to yield imidazole 4 (159 mg, 80%), which was' isolated and characterized by Η NMR and LC/MS (LRMS (M+H* m/z: 488.2). [00336] To a room temperature solution of 4 (159 mg, 0,33 mmol) in dichloromethane
(4 mL) was added trifluoroacetic acid (4 mL), and the resulting solution stiπed at room temperature overnight. The solvents were removed in vacuo provide amine 5 (89 mg) as a glassy solid, which was determined to be pure enough for use in subsequent transformations LC/MS (LRMS (M+H+) m/z: 274.1).
[00337] Crude amine 5 (72 mg, 0.26 mmol) was stined with diisopropylethylamine
(197 μl, 1 ,1 mmol) in dimethylfonnamide (3 mL) at room temperature for 5 minutes, after which intermediate 6 (100 mg, 0.26 mmol) was added. The resulting mixture was stiπed for another 30 minutes and the solvents removed in vacuo. The crude residue was purified by reverse-phase HPLC using a mobile phase gradient consisting of acetonitrile and water to give compound 7 (10 mg, 8%) as a glassy solid, which was characterized by Η NMR and LC/MS (LRMS (M+H*) m/z; 470.2). Example 54
Figure imgf000179_0001
H,, AcOH/MeOH (MeO),SO, Raney Ni K,CO,, DMF
Figure imgf000179_0002
Figure imgf000179_0003
[00338] To a room temperature solution of alcohol 1 (2.59 g, 9.4 mmol) in benzene (50 L) was added 2,2-dimethoxypropane (1.75 mL, 14.1 mmol) and -toluenesulfonic acid (179 mg, 0.94 mmol). The resulting solution was stiπed under an atmosphere of nitrogen at 110 °C for 1,5 hours. The solvents were removed in vacuo, and the residue purified using flash chromatography (silica gel, ethyl acetate/hexanes) to provide 2 (765 mg, 27%), which was characterized using LC/MS (LRMS (M+H+) m/z: 317.4).
[00339] Nitrile 2 (765 mg, 2.4 mmol) was stirred with sodium methoxide in methanol
(10.0 mL, 5,0 mmol, 0.5 M) and hydroxylamine hydrochloride (336 mg, 4.8 mmol) under an atmosphere of nitrogen at 50 C for 2 hours. It was then cooled to room temperature and the solvents removed in vacuo. The residue was partitioned between saturated aqueous ammonium chloride solution (30 mL) and ethyl acetate (30 mL), the layers were separated, and the aqueous phase extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to yield intermediate 3 (314 mg, 38%), which was characterized by Η NMR and LC/MS (LRMS (M+H+) m/z: 350.1). [00340] To a room temperature solution of 3 (314 mg, 0,9 mmol) in methanol (15 mL) was added Raney nickel (50 mg) and acetic acid (300 μL), The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 2 hours. It was filtered through Celite and concentrated in vacuo to provide 4 (275 mg, 0.83 mmol) as a white solid, which was detennined to be pure enough for use in subsequent transformations (LC/MS (LRMS (M+Yf) m/z: 414.1)).
[00341] To a room temperature solution of amidine 4 (138 mg, 0.4 mmol) in anhydrous ethanol (15 mL) was added l,8-diazabicyclo[5.4,0]undec-7-ene (622 μL, 4.2 mmol) and l-bromopinacolone (84 μL, 0.6 mmol). The resulting mixture was stirred under an atmosphere of nitrogen at 115 °C for 30 minutes. It was then cooled to room temperature and the solvents removed in vacuo. The residue was purified by reverse-phase HPLC using a mobile phase gradient consisting of acetonitrile and water to give compound 5 (29 mg, 17%), which was characterized using Η NMR and LC/MS (LRMS (M+H*) m/z: 414.1). [00342] To a room temperature solution of imidazole 5 (29 mg, 0.07 mmol) in anhydrous dimethylformamide (5 mL) were added potassium carbonate (39 mg, 0.28 mmol) and dimethylsulfate (133 μL, 1.40 mmol). The resulting mixture was stiπed under an atmosphere of nitrogen at 50 °C for 24 hours, after which the solvents were removed in vacuo. The residue was purified using flash chromatography (silica gel, ethyl acetate/hexanes) to provide 6 (15 mg, 43%) as a glassy solid, which was characterized by Η NMR and LC/MS (LRMS (M+H+) m/z: 428.3).
[00343] A solution of 6 (15 mg, 0.04 mmol) in anhydrous methanol (3 mL) and water
(300 μL) was stined with DOWEX 50WX8-400 ion-exchange resin (100 mg) at room temperature for 16 hours. The resin was removed by filtration and rinsed with triethylamine (3 mL). The solvents were removed under high vacuum to provide 7 (12 mg, 0.04 mmol), which was deteπnined to be sufficiently pure for the next transformation (LRMS (M+H+) m/z: 288.2),
[00344] To a room temperature solution of amine 7 (12 mg, 0.04 mmol) in dimethylfonnamide (3 mL) was added diisopropylethylamine (20 μl, 0.10 mmol). The resulting solution was stilted at room temperature for 5 minutes, after which intermediate 8 (16 mg, 0.04 mmol) was added. The reaction mixture was stirred for another 30 minutes. The solvents were removed in vacuo and the residue purified by flash chromatography (silica gel, methanol/ dichloromethane) to provide 9 (10 mg, 50%) as a glassy solid, which was characterized by Η NMR and LC/MS (LRMS (M+H4) m/z: 484.2).
Example 55
Figure imgf000181_0001
Figure imgf000181_0002
1e
[00345] To a solution of Boc-L-β-homotyrosine(OBzl) (5 g, 13 mmol) in methanol
(200 mL) was added trimethylsilyldiazomethane (2 M in hexanes, 40 mL, 78 mmol) dropwisely. The reagent was continuously added if necessary until bubbling ceased. The mixture was concentrated to give 2 (5.5 g), which was used in the next step without further purification, LRMS (M+H m/z 300.3.
[00346] To a solution of 2 (5.5 g, 13.76 mmol) in THF (100 mL) was added LAH (1 M in THF, 13.7 mL, 13,7 mmol) at 0 °C. The resulting solution was stiπed for 2 hours, and methanol (-20 mL) was added to quench the reaction. The solvents were then evaporated to obtain the yellowish solid which was diluted in ethyl acetate and washed in saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO and concentrated under reduced pressure. The residue was purified via flush column chromatography using a mixture of ethyl acetate and hexanes as eluent to give 3 as a white solid (3.5 g, 70%). LRMS (M+H+) m/z 394.4.
[00347] A solution of 3 (1.9 g, 5 mmol) in M . A (40 mL) was stiπed under a stream of H2 (50 psi) in the presence of 10% Pd/C (200 mg) for 30 h. The catalyst was removed by filtration through a PTFE (0.45 μm) filter and the solvent evaporated to give a white solid (1.5 g), which was stirred in the mixture of TFA (1 mL) and DCM (9 mL) for 2 hours. The resulting solution was concentrated and used in the next step without further purification.
Figure imgf000182_0001
[00348] To a solution of 4 (926 mg, 5 mmol) in THF ( 10 mL) were added 5 (950 mg,
2,6 mmol) and N, N-diisopropylethylamine (4.5 L, 25.5 mmol). The reaction was stiπed at room temperature for 10 hours. The mixture was concentrated and dried on high vacuum. The resulting crude product was purified via flash column chromatography using ethyl acetate as eluent to give 6 (710 mg, 74 %). LRMS (M+H"1 m/z 370.4. [00349] To a solution of 6 (70 mg, 0.2 mmol) in DMF (1 mL) was added 4- fluorobenzyl bromide (0.15 mL, 1.2 mmol) and potassium carbonate (1 6 mg, 1.2 mmol). The resulting mixture was stiπed for 1 hours at room temperature. The mixture was filtered, and the filtrate was purified on RP-HPLC using a mixmre of acetonitrile and H2O to give le (35 mg, 37%). LRMS (M+H4) m/z 477.5.
Figure imgf000182_0002
[00350] A solution of imidate 15 (20 mg, 0.05 mmol), pivalic acid hydrazide (9 mg,
0.08 mmol), and acetic acid (1 mL) was stiπed at SO °C for 1 hr. The reaction mixture was then concentrated in vacuo and the resulting residue purified by reverse phase HPLC (C18, acetonitrile/water) to yield 10 mg (43%) of the tetrazole 16. LRMS (M+H"1") m/z All .2. Example 57
Figure imgf000183_0001
[00351] A solution of pentafluorophenyl ester 28 (1 ,0g, 2.62 mmol), amine 29 (0.49 mL, 3.15 mmol), and THF (10 mL) was stirred at 23 °C for 4 hours. The reaction solution was concentrated in vacuo, and the resulting residue was purified by column chiOmatography (silica gel, 1 :1 EtOAc :hexanes) to give 1.1 g (88%) of amide 30. LRMS (M+H+) m/z 396.1. [00352] A solution of bromide 30 (200 mg, 0.51 mol), dichlorobis(triphenylphosphine) palladium(II) (35 mg, 0.05 mol), tributyl(l-ethoxyvinyl)tin (0.34 ml, 1.0 mmol), and toluene (2 mL) under N was stiπed at 100 °C for 4 hours. Upon completion, as monitored by LCMS, the reaction mixture was cooled, filtered through cotton, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :4:0.1 EtOAc: hexanes: triethylamine) to give 100 mg (52%) of styrene 31. LRMS (M+H+) m/z 388.2, [00353] A solution of compound 31 (100 mg, 0.25.mmol), THF:H2O (3: 1, 4 mL), and
N-bromo-succinimide (46 mg, 0.25 mmol) was stiπed at 23 °C for 15 min. The reaction mixture was then concentrated in vacuo, and the crude residue was diluted with EtOAc (30 mL), washed with brine (10 mL), and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 4:1 EtOAc:hexanes) to give 50 mg (46%) of bromoketone 32. LRMS (M+H+) m/z 438.1. [00354] A solution of bromoketone 32 (50 mg, 0.11 mmol), K2CO3 (47 mg 0.34 mmol), /er/-butylearbamidine hydrochloride (21 mg, 0.23 mmol), and DMF (2 mL) was stirred at 23 °C under N for 18 hours. The reaction mixture was concentrated in vacuo under high vacuum (0.1 mm Hg), and the resulting residue was purified by column chromatography (silica gel, 2: 1 EtOAc:hexanes) to give 35 mg (72%) of imidazole 34. LRMS (M+H+) m/z 440.2.
Example 58 BocHN
Figure imgf000184_0001
34 35
Figure imgf000184_0002
38 39
Figure imgf000184_0003
39 40 41
Figure imgf000185_0001
42 [00355] Chloroform (20 mL) was added slowly over 2 hours to a solution of Boc- tyrosine (20 g, 71 mmol) and 10% NaOH in H2O (400 mL) at 85 °C, After a total of 4 hours, the reaction solution was acidified with 3 N HCI (200 mL) and extracted with EtOAc (3 x 150 mL). The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chiOmatography (silica gel, 1 :1 :0.1 hexanes: EtOAc: AcOH) to yield 6.3 g of a mixture of aldehyde 35 and some recovered 34. [00356] A solution of aldehyde 35 (contaminated with 34, 6.3 g, 20 mmol), K2CO3 (5.8 g, 42 mmol), benzyl bromide (5.0 mL, 42 mmol), and DMF (100 mL) was stiπed at 23 °C for 18 hours. The reaction mixture was diluted with EtOAc (200 mL), and washed with 1 N HCL (3 x 200 L) and brine (3 x 200 mL), The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 1 :4 EtOAc :hexanes) to give 2.2 g (22%) of ester 36. LRMS (M+H+) m/z 490.2. [00357] A solution of aldyhyde 36 (570 mg, 1.16 mmol), KMnO4 (368 mg, 2.32 mmol), dioxane (3 mL), and H2O (1 mL) was stirred at 23 °C for 3 hours. The reaction mixture was concentrated in vacuo and the resulting residue λvas purified by column chromatography (silica gel, 1 :1 EtOAc:hexanes) to give 350 mg (60%) of acid 37. LRMS (M+H+) m/z 506.2.
[00358] A solution of acid 37 (1 15 mg, 0.23 mmol), dimethyl amine (0.23 mL, 2.0 M in THF), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg, 0.34 mmol), diisopropyl ethyl amine (0.12 mL, 0.68 mmol), and CH2C12 (1 mL) was stin-ed at 23 °C for 4 hours. The reaction mixture was then diluted with EtOAc (10 mL), and washed with 1 N HCI (5 mL) and brine (5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :1 hexanes:EtOAc) to yield 60 mg (49%) of the amide 38. LRMS (M+H+) m/z 533.3. [00359] A solution of amide 38 (60 mg, 0.11 mmol), TFA:H20 (97.5:2.5, 1 L) and
CH2C12 (1 mL) was stirred at 23 °C for 30 min. The reaction solution was concentrated in vacuo, and the resulting residue was placed under high vacuum for 2 hours and then used without further purification.
[00360] A solution of amine 39 (69 mg, 0.16 mmol), pentafluorophenol ester 40 (71 mg. 0.19 mmol), diisopropylethylamine (S3 μL, 0.68 mmol), and DMF (1 mL) was stilted at 23 °C for 4 hours. The reaction mixture was then diluted with EtOAc (10 mL), and washed with 1 N HCI (5 mL) and brine (5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :1 hexanes :EtO Ac) to yield 60 mg (60%) of the ester amide 41. LRMS (M+H"1") m/z 620.3.
[00361] A solution of ester 41 (50 mg, 0.08 mmol), NaBH4 (30 mg, 0.81 mmol), THF
(0.5 L), and MeOH (0.5 mL) was stiπed at 23 °C for 2 hours. The reaction mixture was then diluted with EtOAc (10 mL), and washed with 1 N HCI (5 mL) and brine (5 mL). The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chi-omatography (silica gel, 1:50 MeOH:EtOAc) to yield 31 mg (75%) of the alcohol 42. LRMS (M+H+) m/z 516.3.
Example 59
BocHN
Figure imgf000186_0001
43 44
Figure imgf000186_0002
45 46
Figure imgf000186_0003
46 40 47
[00362] A solution of acid 43 (300 mg, 1.0 mmol), K CO3 (276 mg, 2.0 mmol), benzyl bromide (0.24 mL, 2,0 mmol), and DMF (4 mL) was stiπed at 23 °C for 18 hours. The reaction mixture was diluted with EtOAc (30 mL), and washed with 1 N HCI (10 mL) and brine (3 x 15 mL). The organic layer was dried (MgS0 ), filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, 1 :3 EtOAc:hexanes) to give 400 mg (83%) of ester 44, LRMS (M+H ") m/z 480.2. [00363] A solution of ester 44 (100 mg, 0.21 mmol), NaBH4 (24 mg, 0,63 mmol), THF
(1 mL), and MeOH (1 mL) was stiπ-ed at 23 °C for 18 hours. The reaction mixture was then diluted with EtOAc (10 mL), washed with 1 N HCI (5 mL), and brine (5 mL), The organic layer was dried (MgS04), filtered, and concentrated in vacuo. The resulting residue was used without further purification.
[00364] A solution of alcohol 45 (100 mg, 0.27 mmol) and TFA:H2O (97.5:2.5, 1 mL) was stiπed at 23 °C for 30 min. The reaction solution was concentrated in vacuo, and the resulting residue was placed under high vacuum for 2 hours and then used without further purification.
[00365] A solution of amine 46 (40 mg, 0.15 mmol), pentafluorophenyl ester 40 (43 mg, 0.12 mmol), triethylamine (51 μL, 0.29 mmol), and DMF (0.6 mL) was stiπed at 23 °C for 4 hours. The reaction mixture was then diluted with EtOAc (10 mL), and washed with 1 N HCI (5 mL) and brine (5 mL). The organic layer was dried (MgS0 ), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :2 hexanes: EtOAc) to yield 30 mg (43%) of the ester amide 47. LRMS (M+H+) m/z 463.2.
Example 60
BocHN
Figure imgf000187_0001
36 48
Figure imgf000187_0002
o 49 50
Figure imgf000188_0001
Figure imgf000188_0002
52 [00366] A solution of aldehyde 36 (300 mg, 0.6 mmol), dimethyl hydrazine (47 μL, 0.6 mmol), and MeOH (2.5 mL) was stirred at 0 °C for 2 hours, then allowed to warm to 23 °C and stirred for an additional 15 hours. The reaction solution was concentrated in vacuo and the resulting residue was used without further purification.
[00367] To a -5DC solution of crude hydrazone 48 (325 mg, 0.6 mmol) and CHC13 (2 mL) was added dropwise a solution of w-chloroperoxybenzoic acid (212 mg, 1.23 mmol) and CHC1 (2 mL), The reaction solution was allowed to warm to 23 °C and was stiπed for 2 days. The reaction mixture was then diluted with EtOAc (10 mL), and washed with saturated aqueous NaHC03 (5 mL) and brine (5 mL). The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :2 hexanes :EtO Ac) to yield 100 mg (34%) of the nitrile 49, LRMS (M+H+) m/z 487.2.
[00368] A solution of nitrile 49 (60 mg, 0.27 mmol) and TFA:H:O (97,5:2.5, 2 mL) was stiπed at 23 °C for 30 min. The reaction solution was concentrated in vacuo, and the resulting residue was placed under high vacuum for 2 hours and then used without further purification.
[00369] A solution of amine 50 (100 mg, 0.25 mmol), pentafluorophenyl ester 40 (85 mg, 0.22 mmol), triethylamine (96 μL, 0.74 mmol), and DMF (1 mL) was stiπed at 23 °C for
1S7 4 hours. The reaction mixture then diluted with EtOAc (10 mL), and washed with 1 N HCI (5 mL) and brine (5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 : 1 hexanes:EtOAc) to yield 60 mg (42%) of 51. LRMS (M+H > m/z 574.2. [00370] A solution of ester 51 (60 mg, 0.1 mmol), NaBH4 (12 mg, 0.3 mmol), THF (1 mL), and MeOH (1 mL) was maintained at 23 °C for 18 hrs. The reaction mixture then diluted with EtOAc (10 mL), washed with 1 N HCI (5 mL), and brine (5 mL). The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The resulting residue was purified by flash column chiOmatography (silica gel, 1 :2 hexanes: EtOAc) to yield 30 mg (64%) of the alcohol 52. LRMS (M+H+) m/z 470.2.
Example 61
Figure imgf000189_0001
55 56
Figure imgf000189_0002
58 57
[00371] A solution of amide 55 (1.6 g, 4.38 mmol) and diethylaniline 56 (5 mL) was maintained at 240 C for 18 hrs. The reaction solution was cooled to 23 °C, diluted with EtOAc (30 mL), and washed with 1 N HCI (3 x 50 mL) and brine (2 x 50 mL). The organic layer was dried (MgSO ), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 2:1 hexanes:EtOAc) to yield 1 g (63%) of the phenol 56. LRMS (M+H+) m/z 365.2. [00372] A solution of phenol 56 (700 mg, 1.92 mmol), Cs2CO3 (1.25 mg, 3,84 mmol), benzyl bromide (0.46 mL, 3.84 mmol), and DMF (10 mL) was maintained at 50 °C for 2 hrs. . The reaction mixture was diluted with EtOAc (30 mL), washed with 1 N HCL (20 mL) and brine (3 x 30 mL). The organic layer was dried (MgS0 ), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 1 :3 EtOAc:hexanes) to give 500 mg (57%) of amide 57. LRMS (M+H+) m/z 455.2. [00373] A solution of amide 57 (150 mg, 0.33 mmol), osmium tetroxide (8 mg, 0.03 mmol), N-methylmorpholine-N-oxide (182 mg, 1.55 mmol), pyridine (2.4 μL, 0.03 mmol), THF (2 mL) and H2O (2 mL) was maintained at 23 °C, After 2 hrs, Celite (1 g), NaHSO3 (1 g) and EtOAc (20 mL) were added and the resulting mixture was stirred. After 30 mins, the reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The . resulting residue was purified by flach column chromatography (silica gel, 3: 1 EtOAc:hexanes) to give 100 mg (62%) of diol 58. LRMS (M+H"") m/z 489.2. [00374] A solution of diol 58 (52 mg, 0.1 1 mmol), Pb(OAc)4, and CH2C12 (2 mL) was maintained at 23 C for 30 mins, The reaction mixture was then filtered through a plug of Celite and the filtrate was concentrated to provide the aldehyde as a colorless oil. [00375] A solution of the cmde aldehyde (-50 mg, ~0.1 1 mmol), NaBH (24 mg, 0.63 mmol), THF (1 mL), and MeOH (1 mL) was maintained at 23 °C for 30 nims. The reaction mixture then diluted with EtOAc (10 mL), washed with 1 N HCI (5 mL), and brine (5 mL). The organic layer was dried (MgS0 ), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 2:1 EtOAc:hexanes) to give 20 mg (40%) of alcohol 59. LRMS (M+H+) m/z 459.2.
Example 62 BocHN
Figure imgf000190_0002
Figure imgf000190_0001
60 61
Figure imgf000191_0001
63 40
[00376] A solution of styrene 60 (190 mg, 0.54 mmol), borane-THF (1.0 M, 0.54 mL) was maintained at 23 °C for 2 hrs. An additional amount of borane-THF (0.54 mL) was then added. After another 2 hrs, an third portion (0.54 mL) was added. The reaction solution was maintained for 18 hrs, cooled to 0 °C, then 3 N NaOH (0.5 mL) and H202 (0.5 mL) was added. After 2 hrs at 23 °C, the reaction mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried (MgSO ), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 2:1 EtOAc :hexanes) to give 150 mg (75%) of alcohol 61. LRMS (M+H+) m/z 372.2.
[00377] A solution of alcohol 61 (120 mg, 0.32 mmol), TFA:H20 (97.5:2.5, 4 mL) was maintained at 23 °C for 30 mins. The reaction solution was concentrated in vacuo, and the resulting residue was placed under high vacuum for 2 hours and then used without further purification.
[00378] A solution of the above amine 62 (50 mg, 0.18 mmol), pentafluorophenol ester
40 (82 mg, 0.22 mmol), triethylamine (96 μL, 0.55 mmol), and DMF (1 mL) was maintained at 23 °C for 2 hrs. The reaction mixture then diluted with EtOAc (10 mL), washed with 1 N HCI (5 mL), and brine (5 mL). The organic layer was dried (MgSO ), filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (CIS, acetonitrile/water) to yield 6 mg (7%) of the amide 63. LRMS (M+H+) m/z 459.2.
Example 63
Figure imgf000192_0001
[00379] To a solution of 10 ( 1.15 g, 2.71 mmol) in DCM (100 mL) was added Dess-
Martin periodinane (2.30 g, 5,42 mmol). The reaction mixture was stilted for 1 h, after which the DCM solution was washed by sodium thiosulfate solution and sodium bicarbonate solution, and dried over sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to give 23 (l.Og, 87%).
[00380] To a solution of 23 (30.0 mg, 0.071 1 mmol) in DCM (2 mL) were added diisopropylethylamine (37.0 uL, 0.213 mmol), 24 (12.9 uL, 0,213 mmol) and sodium triacetoxyborohydride (20,0 mg, 0.142 mmol). The reaction mixture was stiπed overnight, and then concentrated under reduced pressure. The residue was purified on reverse phase HPLC (CI 8) using a mixture of acetonitrile and H2O to give 25 (5.6 mg, 16.9%). LRMS (M+H+) m/z 467.4.
[00381] To a solution of 23 (50,0 mg, 0.119 mmol) in methanol (2 mL) were added diisopropylethylamine (62,0 uL, 0.356 mmol), 26 (31.1 uL, 0.356 mmol) and sodium cyanoborohydride (22,4 mg, 0.356 mmol). The reaction mixture was stirred for overnight, then concentrated under reduced pressure and the residue purified on reverse phase HPLC (C18) using a mixture of acetonitrile and H2O to give 27 (31.0 mg, 22.9%). LRMS (M+H+) m/z 518,5. Example 64
Figure imgf000193_0001
Figure imgf000193_0002
Figure imgf000193_0003
[00382] To a solution of 1 (1.0 g, 4.66 mmol) in MeOH (10.0 mL) was added
SOCl2 (0.68 mL, 9.32 mmol). After stimng overnight at ambient temperature, the solution was concentrated in vacuo and taken on without purification.
[00383] To a solution of 2 (-1.065 g crude, 4.66 mmol) in EtOH (1.5 mL) was added
N2H »H20 (1.13 mL, 23.3 mmol). The reaction mixture was heated to reflux and stirred for 3 h. Upon cooling, the solution was treated with H2O. extracted with trice with EtOAc, dried over MgS0 , filtered, and concentrated. Recrystallization from CH2C1 yielded l .Olg 3 as white crystals; 95% yield, 2 steps.
[00384] To a solution of 3 (0.477 g, 2.09 mmol) in THF (S.O mL) was added carbonyldiimidazole (0.379 g, 2.29 mmol). The reaction mixture was heated to reflux and stirred for 1.5 h. Upon cooling, the solution was concentrated in vacuo and purified via flash column cliromatography (10-40% EtOAc/Hex) to yield 0.515 g 4 as a white solid; 97% yield, [00385] To a solution of 4 (1.0 equiv.; typically 0.3-1.0 mmol) in CH3CN (2.0 mL) was added the electrophile (1.1 equiv.) and K2CO3 (1.1 equiv.). The reaction mixture was heated to 80 °C under microwave inadiation for 30 min followed by filtration and concentration in vacuo, The product can be taken on without purification or purified via flash column cluomatography (typically 10-40% EtOAc/Hex) to afford 5 in generally >90% yield. [00386] To 5 (1.0 equiv.; typically 0.3-1 ,0 mmol) was added methylamine (2.0 M solution in THF, 10.0 equiv.). The reaction mixture was heated to 100 °C under microwave iitadiation for 4 h followed by concentration in vacuo. The product was purified via flash column chromatography (typically 40-80% EtOAc/Hex) to afford 6 in generally 70-85% yield.
Example 65
Figure imgf000194_0001
NaN DMF
Figure imgf000194_0002
[00387] To a stirred solution of 2-aminoacetonitrile bisulfate (2.9 g, 0.013 mmol) in
DCM (50 mL) was added benzophenone (3.48 mL, 0.0208 mmol) followed by DIEA (4.53 mL, 0.026 mmol). After stirring 18 h, the DCM solution was washed with water (50 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on a flash silica gel column (hexanes:EtOAc, 1 :1) to give 3 (2.40g, 82%).
[00388] Lithium bis(trimethylsilyl)amide (1 M solution in THF) was slowly added to a stiπed solution of 3 (1.2g, 0.00545 mol) and -phenylbenzyl bromide (l.OSg, 0.00436 mol) in THF (50 mL) over an acetone-dry ice bath under a nitrogen atmosphere. After lhour, the reaction was quenched by adding methanol, and the solvent was evaporated under reduced pressure. The residue was purified on a flash silica gel column (hexanes:EtOAc, 1 : 1 ) to obtain 4. 4 was re-suspended in EtOAc (100 mL) and treated with concentrated HCI (5 mL). After stirring for 1 hour, the solvents were evaporated under reduced pressure, and the resulting solid 5 was washed with ethyl ether (50 mL) three times and dried under vacuum (0.39 g, 32.1%).
[00389] To a solution of 5 (0.39 g, 1.75 mmol) in DMF (10 mL) were added 6 (0.S01 g, 2.11 mmol) and diisopropylethylamine (0.61 mL, 3.50 mmol) at room temperature, The reaction mixture was stirred overnight. The soh'ents were then evaporated under reduced pressure, and the residue purified on a flash silica gel column (hexane: EtOAc, 3:1) to give 7 (0.40g, 54,5% ). LCMS (M+H+) nvz 419.1.
[00390] To a solution of 7 (50 mg, 0.119mmol) in DMF (2 mL) were added sodium azide (15.5 mg, 0.239 mmol) and ammonium chloride (12.8 mg, 0.23Smmol). The mixture was stilted at 80 °C overnight and then filtered. The filtrate was purified on reverse phase HPLC (C18) using a mixture of acetonitrile and H2O to give 8 (6.40 mg, 11.6 %). LCMS (M+H^ m/z 462.4.
Example 66
Scheme A:
Figure imgf000195_0001
19 A Methyl 3-cyano-4-[(l -methylethyl)oxy]benzoate:
Figure imgf000196_0001
[00391] To a solution of methyl 3-cyano-4-hydroxybenzoate (82 g, 463 mmol; J. Med.
Chem, 2002, 45, 5769) in dimethylfoπnamide (800 mL) was added 2-iodopropane (93 mL, 926 mmol) and potassium carbonate (190 g, 1.4 mol). The resulting mixture was heated at 50 °C for 16 h, at which time it was allowed to cool to room temperature. The reaction was filtered and the mother liquor diluted with 0.5 N sodium hydroxide (1 L). The resulting mixture was extracted with ether (2 x 1 L) and the organics washed with 1 N HCI (1 L) and brine (700 mL), dried (MgSO ) and concentrated to give 100 g (—100%) of methyl 3-cyano-4- [(l-methylethyl)oxy]benzoate as a yellow solid.
3-Cyano-4-[(l-methylethyl)oxy]benzoic acid:
Figure imgf000196_0002
[00392] To a cooled (0 °C) solution of methyl 3-cyano-4-[(l-methylethyl)oxy]benzoate
(100 g, 463 mmol) in tetrahydrofuran (500 mL) was added 10%) potassium hydroxide (500 mL). The resulting solution was allowed to warm to room temperature and maintained for 16 h, at which time it was concentrated to remove the tetrahydrofuran. The residue was diluted with water (500 mL) and washed with ether (2 x 500 mL). The aqueous layer was then acidified with 3 N HCI and stood for 2 h. The solids were collected by filtration and washed several times with water, then dissolved in methylene chloride (1 L). The mostly homogeneous mixture was filtered through Celite and concentrated to a minimal volume of methylene chloride. Collection of the solids by filtration gave 82 g (87%) of 3-cyano-4-[(l- methylethyl)oxy]benzoic acid as a white solid.
Scheme B:
Figure imgf000197_0001
Reagents and Conditions: a) 4N HCl/dioxane, rt; b) HBTU, /-Pr2NEt, DMF, rt; c) 1- ethoxyvinyltri-n-butyltin, PdCl2(PPh3)2, dioxane, 100 °C; d) NBS, THF/H20 (3:1), rt; e) 2- amino-3-picoline, NaHC0 , z-PrOH, 80 °C .
(3S)-3-Amino-4-(4-bromophenyl)- 1 -butanol hydrochloride. HCI H,N, /^ ,OH
Figure imgf000197_0002
[00393] 1,1 -Dimethylethyl {(15)-l-[(4-bromophenyl)methyl]-3- hydroxypropyl} carbamate (4.4 g, 12.8 mmol) was dissolved in 4N HCl/dioxane (20 mL). After 2 h, the reaction mixture was concentrated in vacuo to give 3.69 g (94%) of the title compound as a white solid. LC/MS (ES) nv'e 244.0 (M + H)+.
Λr-{(lS)-l-[(4-Bromophenyl)methyl]-3-hydroxypropyl}-3-cyano-4-[(l- methylethyl)oxy]benzamide.
Figure imgf000197_0003
[00394] To a suspension of (31S)-3-Amino-4-(4-bromophenyl)-l -butanol hydrochloride
(1.80 g, 6.42 mmol) in dry DMF (32 mL) was added N,N-diisopropylethyl amine (2.49 g, 19.3 mmol) and the resultant clear solution was stirred for 3 min. 3-Cyano-4-[(l- methylethyl)oxy]benzoic acid (1,45 g, 7.06 mmol) and HBTU (2.68 g, 7.06 mmol) were added and the reaction was stiπed at rt under nitrogen. After 1.5 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 X 30 mL), The extracts were dried (Na SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chi-omatography (75% EtOAc/hexanes) to give 2.1 S g (78%) of the title compound as a white solid. LC/MS (ES) m/e 431.2 (M + H)+.
N-((lS)-l-{[4-(Bromoacetyl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(l- methylethyl)oxy]benzamide.
Figure imgf000198_0001
[00395] A flask, dried with a heat gun under argon purge, was charged with N-{(1S)-1-
[(4-biOmophenyl)methyl]-3-hydroxypropyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide (1.0 g, 2,32 mol), dichlorobis(triphenylphosphine)-palladium(II) (81 mg, 0,116 mol), tributyl(l- ethoxyviny])tin (1.68 g, 4.64 mmol), and 1,4-dioxane (15 mL). The mixture was stirred at 100 °C for 2 hours under argon. Upon completion, as monitored by LCMS, the reaction was concentrated under reduced pressure and the residue was purified immediately on deactivated silica gel (65% EtOAc/hexanes with 5% triethylamine) to give 720 mg (1.70 mmol) of enol ether intennediate as a colorless foam which was immediately dissolved in THF:H2O (3:1, IS mL) and treated with N-bromosuccinimide (3 IS mg, 1.79 mmol). After 15 min at rt, the reaction mixture was concentrated under reduced pressure and the crude residue was diluted with EtOAc (30 mL), washed with brine (10 mL) and water (10 mL) and concentrated under reduced pressure. The residue was purified by silica gel chi-omatography (80% EtOAc/hexanes) to give 651 mg (59%) ofN-((lό> l -{[4-(bromoacetyl)phenyl]methyl}-3- hydroxypropyl)-3-cyano-4-[(l -methylethyl)oxy]benzamide as a white tacky solid, LC/MS (ES) nVe 473.2 (M + H)+.
3-Cyano-N-((lS)-3-hydroxy-l-{[4-(8-methylimidazo[l,2-α]pyridin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide.
Figure imgf000198_0002
[00396] To a solution of N-((lS)-l-{[4-(bromoacetyl)phenyl]methyl}-3- hydroxypropyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide (300 mg, 0.634 mmol) in i-PrOH (6 mL) was added 2-amino-3-picoline (Aldrich, 69 mg, 0.634 mmol) followed by solid NaHCO3 (64 mg, 0.761 mmol). The resultant suspension was heated to 80 °C, After 7 h, a majority of the i-PrOH was removed under reduced pressure and the residue was dissolved in 3% MeOH/EtOAc (30 mL) and washed with water (10 mL) and brine (10 mL), The combined aqueous layers were extracted with 3% MeOH/EtOAc (30 mL) and the combined extracts were dried (Na2SO ), filtered and concentrated under reduced pressure, The residue was purified by reverse phase HPLC (MeCN/H20 with 0.1 % TFA) and the clean fractions were adjusted to pH ~8 with saturated aqueous NaHCO3 and extracted with 3% MeOH/EtOAc (3 X 30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 215 mg (70%) of the title compound as a pale yellow solid. LC/MS (ES) m/e 4S3.2 (M + H)+.
Scheme C:
Figure imgf000199_0001
enantiomer A enantiomer B
1 -(2-amino-3-pyridinyl)ethanol:
Figure imgf000199_0002
[00397] To a diy flask (dried with a heat gun under argon purge) was added dry THF
(400 mL) and MeLi-LiBr (137 mL of a 1.5M solution in Et O, 204.9 mmol) via cannula. This solution was cooled to -7S °C when a solution of 2-aminopyridine-3-carboxaldehyde (10.0 g, 82.0 mmol) in THF (150 mL) was added dropwise via a pressure equalizing addition funnel over ~45 with vigorous stirring (exotherm observed, orange color persisted). Upon complete addition, the solution was allowed to stir for 1 hour at -7S °C, at which time TLC (KMnO stain with heat) indicated that most of the starting material had been converted to product. The reaction was quenched very carefully with water (200 mL; dropwise initially), diluted with EtOAc (200 mL) and allowed to warm to rt. The layers were separated and the aqueous layer was extracted with 3% MeOH in EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Analogix; 0 to 5% MeOH in EtOAc) to give 7.78 g (68%) of the desired racemic product as a yellow oil that solidified under high vac over several days. This material was separated into its respective enantiomers (>98% ee) by SFC with a chiralcel OD-H (20x250mm) column (10% EtOH/0.1% isopropylamine in heptane/0.1% isopropylamine).
Scheme D:
Figure imgf000200_0001
NaHCOj. lPA
Figure imgf000200_0002
Figure imgf000200_0003
1 , 1 -Dimethylethyl [( 1 S)- 1 -( {4-[ 1 -(ethyloxy)ethenyl]phenyl}methyl)-3- hydroxypropyl]carbamate:
Figure imgf000200_0004
[00398] To a solution of 1 ,1 -dimethylethyl {(lS)-l-[(4-bromophenyl)methyl]-3- hydroxypropyl} carbamate (20 g, 58 mmol) in dioxane (500 mL) was added tributylfl- (ethyloxy)ethenyl]stannane (39 mL, 116 mmol) and PdCl (PPh3)2. The resulting solution was heated at 100 °C for 5 h. The reaction was then concentrated and the residue purified by flash chromatography (47.5%> EtOAc, 47,5% hexanes, 5% triethylamine) to give 15 g (77%) of 1,1- dimethylethyl [(lS)-l-({4-[l-(ethyloxy)ethenyl]phenyl}methyl)-3-h}'droxypropyl]carbamate as a brown solid.
1 , 1 -Dimethylethyl (( 1 S)- 1 - { [4-(bromoacetyl)phenyl]methyl } -3 -hydroxypropyl)carbamate:
Figure imgf000201_0001
[00399] To a cooled (0 °C) solution of 1 , 1 -dimethylethyl [(lS)-l-({4-[l-
(ethyloxy)ethenyl]phenyl}methyl)-3 -hydroxypropyl] carbamate (15 g, 44 mmol) in tetrahydrofuran (450 mL) and water (150 mL) was added N-bromosuccinamide. The resulting solution was allowed to wann to room temperature and maintained for 90 minutes. The reaction was then concentrated and diluted with ethyl acetate (1 L). The resulting solution was washed with water (1 L) and bnne (500 mL), dried (MgSO ) and concentrated to give 19.5 g (-100%) of 1,1 -dimethylethyl ((lS)-l-{[4-(bromoacetyl)phenyl]methyl}-3- hydroxypropyDcarbamate as a slightly yellow solid. ESMS [M+H]+: 386.2.
1 , 1 -Dimethylethyl [( 1 S)-3-hydroxy- 1 -( {4-[8-(l -hydroxyethyl)imidazo[ 1 ,2-c/]pyridin-2- yl]phenyl)methyl)propyl] carbamate
Figure imgf000201_0002
[00400] A mixture of 1,1 -dimethylethyl ((lS)-l-{[4-(bromoacetyl)phenyl]methyl}-3- hydroxypiOpyl)carbamate (1.00 g, 2.59 mmol), l-(2-amino-3-pyridinyl)ethanol (0.358 g, 2.59 mmol), and solid sodium bicarbonate (0.272 g, 3.24 mmol) in isopropanol (25 mL) was heated at reflux for 3.5 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried (Νa2S0 ), and concentrated. The resulting pale yellow solid was used in the next reaction without further purification. MS(ES+) m/e 426 [M+H]+.
3 -Chloro-N- [( 1 S)-3 -hydroxy- 1 -( {4- [ 8 -( 1 -hydroxyethyl)imidazo [ 1 ,2-β]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide
Ϊ00
Figure imgf000202_0001
[00401] A mixture of 1,1 -dimethylethyl [(15)-3-hydroxy-l-({4-[8-(l- hydiOxyethyl)imidazo[l,2-α]pyridin-2-yl]phenyl}methyl)propyl]carbamate (1.08 g. 2.54 mmol) and 4M HCI in 1,4-dioxane (8.0 mL, 32 mmol) was stirred at room temperature for 30 minutes. The reaction was concentrated to dryness ,redissolved in DMF (25 mL), and to this solution was added N,N-diisopropylethylamine (1.64 g, 12.7 mmol) and pentafluorophenyl 3-chloro-4 [(l-methylethyl)oxy]benzoate (0.963 g, 2.54 mmol). The mixture was stilted for 3.0 h at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water and saturated sodium chloride, dried (Νa2SO ), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2% MeOH:EtOAc) to give the title compound (0.7 g, 53%) as a pale yellow powder. MS(ES+) m e 522 [M+H]+.
Scheme E:
ide
Figure imgf000203_0001
Figure imgf000203_0002
NaHCOj, IPA 100 'C
Figure imgf000203_0003
Figure imgf000203_0004
1 , 1 -Dimethylethyl [( 1 S)-2-(4-bromophenyl)- 1 -(hydroxymethyl)ethyl]carbamate:
Figure imgf000203_0005
[00402] To a solution of 4-bromo-N-{[(l ,1 -dimethylethyl)oxy] carbonyl }-L- phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0 °C was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stiπed for an additional 2 h at 0 °C, The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stiπed at RT for half an hour. Lithium aluminium salts crashed out of solution which were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%).
ESMS [M+H]+: 331.2.
1,1 -Dimethylethyl {(lS)-2-(4-bromophenyl)-l-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]ethyl}carbamate:
Figure imgf000204_0001
[00403] To a solution of 1 ,1 -dimethylethyl [(lS)-2-(4-bromophenyl)-l -
(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0 °C was added dropwise diisopropyl azodi carboxyl ate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to wai to RT over 5h, The reaction was then concentrated in vacuo and product was tritarated out of solution usingl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3 x 100 mL), and dried to afford the title product as a white solid (57%).
ESMS [M+H]+: 460.4.
1 ,1 -Dimethylethyl {(15)-2-[4-(bromoacetyl)phenyl]-l -[(l,3-dioxo-l ,3-dihydro-2H-isoindol- 2-yl)methyl]ethyl}carbamate:
Figure imgf000204_0002
[00404] A solution of 1,1 -dimethyl ethyl {(lS)-2-(4-bromophenyl)-l-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (21.7 mmol), 1-ethoxyvinyltri-n-butylin (43.5 mmol), and /ra/?s--dichlorobis(triphenylphospine)palladιum(II) (5 mol%) were stiπed in anhydrous dioxane (300 mL) at 100 °C for 3h. The reaction was then concentrated in vacuo and redissolved in a solution of tetrahydrofuran and water (3:1, 400mL) and treated with N- bromosuccinimide (108.8 mmol) and stined at RT for half an hour. The reaction solution was then concentrated to dryness and redissolved in ethyl acetate (150 mL) and precipate formed upon addition of hexanes (350 mL). The precipitate was filtered and dried to afford the title product as yellow solid (71%). ESMS [M+Η]+: 502.4. l,l-Dimethylethyl [(lS)-2-(l ,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-l-({4-[8-(l- hydroxyethyl)imidazo[l,2-β]pyridin-2-yl]phenyl}methyl)ethyl]carbamate:
Figure imgf000205_0001
[00405] A mixture of l!l-dimethylethyl{(lS)-2-{4-(biOinoacetyl)phenyl]-l-[(l,3- dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), l-(2- amino-3-pyτidinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4,72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na2S04), and concentrated to give the title compound (1.79 g, S7%) as a light pink solid. MS(ES+) m/e 541 [M+Η]+.
3-Chloro-N-[(lS)-2-(l,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)-l-({4-[8-(l- hydroxyethyl)imidazo[l,2-Λ]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l - methylethyl)oxy]benzamide:
Figure imgf000205_0002
[00406] A mixture of 1,1 -dimethylethyl [(15)-2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-fl]pyridin-2-yl]phenyl}methyl)ethyl]carbamate (1.79 g, 3.31 mmol) and 4M ΗC1 in 1,4-dioxane (20 mL, 80 mmol) was stirred at room temperature for 45 minutes. The reaction was concentrated to dryness ,redissolved in DMF (30 mL), and to this solution was added N,N-diisopropylethylamine (2.14 g, 16,55 mmol) and pentafluorophenyl 3-chloro-4 [(l-methylethyl)oxy]benzoate (1.36 g, 3.31 mmol). The mixture was stirred overnight at room temperature, diluted with water, and extracted into ethyl acetate. The extracts were washed with water, dried (Na SO ), and concentrated in vacuo to give the title compound (2.10 g, 100%) as a tan solid. MS(ES+) m/e 637 [M+H]+.
N-[(lS)-2-Amino-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-α]p>tidin-2- yl]phenyl}methyl)eth)'l]-3-chloro-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000206_0001
[00407] A mixture of 3-chloro-N-[(lS)-2-(l,3-dioxo-l ,3-dihydro-2N-isoindol-2-yl)-l-
({4-[8-(l -hydiOxyethyl)imidazo[l,2-β]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l- methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57°C ovemight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound(1.67 g, 100%) as a pale yellow powder. MS(ES+) m/e 507 [M+H]+.
3-Chloro-N-[(15)-2-[(7VN-dimethylglycyl)amino]-l-({4-[8-(l-hydroxyethyl)imidazo[l ,2- «]pyitdin-2-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000206_0002
[00408] A mixture ofN-[(lS)-2-amino-l-({4-[S-(l-hydroxyethyl)imidazo[l,2- α]pyridin-2-yl]phenyl)methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide (0.912 g, 1 ,80 mmol), EDCI (0.69 g, 3,6 mmol), NN-diisopropylethylamine (0.466 g, 3,6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Νa2S0 ), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH2Cl2) to give the title compound ( 0.515 g, 48%) as a pale yellow solid. MS(ES+) m/e 592 [M+H]+.
1 ,1 -Dimethylethyl {(15)-2-[4-(8-bromoimidazo[l ,2-α]p)'ridin-2-yl)phenyl]-l-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2 yl)methyl]ethyl) carbamate:
Figure imgf000207_0001
[00409] A solution of 1,1 -dimethyl ethyl {(lS)-2-[4-(bromoacetyl)phenyl]-l-[(l ,3- dioxo-1, 3 -dihydro-2H-isoindol-2-yl)methyl]ethyl} carbamate (6.9 mmol), 3-bromo-2- pyridinamine (S.4 mmol), and sodium bicarbonate (10.4 mmol) in isopropanol (70 mL) were stilted at 80 °C for IS h. The reaction was then cooled to RT and a precipitate formed which was filtered, washed with cold hexanes (3 x 100 mL), and dried to afford the title compound as light gray solid (72%). ESMS [M+Η]+: 576.2.
1 , 1 -Dimethylethyl ((1 S)-2-( 1 ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)-l - {[4-(S- methylimidazo[l ,2-α]pyιtdin-2-yl)phenyl]methyl}ethyl)carbamate:
Figure imgf000207_0002
[00410] Following the procedure described above with 3-methyl-2-pyridinamine, instead of 3-bromo-2-pyridinamine, provided the title product as a light pink solid. ESMS [M+H]+: 511.0.
N-{(l1S)-2-[4-(8-Bromoimidazo[l,2-α]p)τidin-2-yl)phenyl]-l-[(l ,3-dioxo-l,3-dihydro-2N- isoindol-2-yl)methyl]ethyl}-3-chloro-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000208_0001
[00411] A solution of 1,1 -dimethylethyl {(15)-2-[4-(8-bromoimidazo[l,2-a]pyridin-2- yl)phenyl]-l-[(l ,3-dioxo-l,3-dihydro-2H-isoindol-2 yl)methyl]ethyl} carbamate (3.5 mmol) and hydrogen chloride in 1 ,4- dioxane (20 mL, 4.0M) stin-ed for lh at RT. The reaction was concentrated to dryness and redissolved in NN-dimethylformamide (35 mL). Added to the solution was diisopropylethylamine (10.5 mmol) and pentafluorophenyl 3-chloro-4-[(l- methylethyl)oxy]benzoate (3.S mmol), which was stilted at RT for half an hour. The reaction was dissolved in ethyl acetate (80 mL) and washed with water (3 x 50 mL) and brine (1 x 50 mL). To the separated organic layer was added hexanes (150 mL) upon which a. precipitate was formed, filtered, and dried to afford the title compound as an off white solid (65%). ESMS [M+Hf: 672.2.
3-ChloiO-N-((lS)-2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)-l-{[4-(8-methylimidazo[l,2- α]p)ridin-2-yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000208_0002
[00412] Following the procedure described above with 1,1 -dimethyl ethyl ((lS)-2-(l,3- dioxo-l ,3-dihydro-2H-isoindol-2-yl)-l-{[4-(S-methylimidazo[l,2-α]p)tidin-2- yl)phenyl]methyl}ethyl)carbamate provided the title product as an off white solid. ESMS [M+Η]+: 608.2.
N-((lS)-2-Amino-l-{[4-(8-bromoimidazo[l,2-rt]p)τidin-2-yl)phenyl]methyl}ethyl)-3-chloro- 4-[(l-methylethyl)oxy]benzamide:
07
Figure imgf000209_0001
[00413] To a solution ofN-{(lS)-2-[4-(8-bromoimidazo[l,2-α]pyridin-2-yl)phenyl]-l-
[(l,3-dioxo-l,3-dihydiO-2H-isoindol-2-yl)methyl]ethyl}-3-chloro-4-[(l- methylethyl)oxy]benzamide (1.5 mmol) in ethanol (10 mL) was added hydrazine monohydrate (7.6 mmol). The reaction stirred for 18h at 50 °C upon which a white precipitate foπned and filtered. The filtrate was concentrated in vacuo. The resultant light yellow solid was used directly in the next reaction Avithout further purification. ESMS [M+H]+: 533.2
Λr-((lS)-2-Amino-l-{[4-(S-methylimidazo[l,2-Λ]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro- 4-[(l-methylethyl)oxy]benzamide:
Figure imgf000209_0002
[00414] Following the procedure described above with 3-chloro-N-((lS)-2-(l ,3-dioxo- l ,3-dihydro-2N-isoindol-2-yl)-l-{[4-(8-methylimidazo[l ,2-α]pyridin-2- yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide provided the title product as an off white solid. ESMS [M+H]+: 478.2.
N-((lS)-2-(D-Alanylamino)-l-{[4-(8-bromoimidazo[l,2-α]pyridin-2-yl)phenyl]methyl)ethyl)- 3-chloro-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000210_0001
[00415] A solution of N-((lS)-2-amino-l-{[4-(8-bromoimidazo[l,2-<3]pyridin-2- yl)phenyl]methyl}ethyl)-3-chloro-4-[(l-methylethyl)oxy]benzamide (0.2S mmol), N-{[(1,1- dimethylethyl)oxy]carbonyl}-D-alanine (0.56 mmol), EDCI (0,56 mmol), and TEA (1.12 mmol) stined in methylene chloride (2 mL) at RT for 18 h. The reaction was then treated with 4 M HCI in 1,4-dioxane (2mL) and stirred at RT for 1 h and concentrated in vacuo, redissolved in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate solution (1 x 10 mL) , The organic layer was concentrated in vacuo. Purification of the residue by Gilson reverse phase HPLC afforded the title product as a white solid (25%). ESMS [M+H]+: 613.2.
3-Cliloro-N-((15)-2-[(2-methylalanyl)amino]-l -{[4-(S-methylimidazo[1.2-a]pyridin-2- yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000210_0002
[00416] Following the procedure described above with N-((lS)-2-amino-l-{[4-(8- methylimidazo[l,2-α]pyridin-2-yl)phenyl]methyl)ethyl)-3-chloro-4-[(l- methylethyl)oxy]benzamide and N-{[(l,l-dimethylethyl)oxy]carbonyl}-2-methylalanine provided the title product as a white solid. ESMS [M+H]+: 563.2.
3-Chloro-N-((15)-2-[(N -dimethylglycyl)amino]-l-{[4-(8-methylimidazo[l,2-α]pyridin-2- yl)phenyl]methyl) ethyl)-4-[(l -methylethyl)oxy]benzamide:
Figure imgf000211_0001
[00417] Following the procedure described above with N-((lS)-2-amino-l-{[4-(8- methylimidazo[l,2- ]pytidin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(l- methylethyl)oxy]benzamide and NN-dimethylglycine provided the title product as a white solid. ESMS [M+H]+: 563.2.
Scheme F:
Figure imgf000211_0002
2-Bromo-l-(4-iodophenyl)ethanone:
Figure imgf000211_0003
[00418] A solution of l-(4-iodophenyl)ethanone (55.9 mmol) in dioxane (160 mL) was cooled to 10 °C. Bromine (1.1 equiv, 61.6 mmol) was added dropwise to the reaction mixture. After 10 min, the cooling bath was removed and the reaction mixture was stirred at room temperature. After 1.5 h, the reaction mixture was concentrated in vacuo, poured into water (100 mL), and extracted with (3 x 100 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to a tan solid (18.2 g) which was used directly in the next step,
2-(4-Iodophenyl)-8-methylimidazo[l,2-α]pyridine:
Figure imgf000211_0004
[00419] A mixture of crude 2-bromo-l-(4-iodophenyl)ethanone (18.2 g), 2-amino-3- picoline (1.1 equiv, 61 ,6 mmol), and sodium bicarbonate (1.3 equiv, 72.8 mmol) in isopropanol (160 mL) was heated at SO °C for 16 h. After concentrating the reaction mixture in vacuo, water (100 mL) was added and the resultant tan slurry was filtered, rinsing with water (2 x 50 mL). The brown solid was recrystallized fi-om hot isopropanol and further dried in vacuo to provide the title product as a brown solid (13.2 g, 11%). ESMS [M+H]+: 335.0.
Scheme G:
Figure imgf000212_0001
4-(4-BiOinophenyl)-N,l-dimethyl-Λ/-(methyloxy)-lH-imidazole-2-carboxamide:
[00420] To a solution of ethyl 4-(4-bromophenyl)-l-methyl-lH-imidazole-2- carboxylate (1.66 g, 5.37 mmol) in MeOΗ (38 mL) was added IN ΝaOΗ solution (19 mL). The reaction turned cloudy white and was stilted at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and pumped under high vacuum overnight to give the sodium salt of 4-(4-bromophenyl)-l -methyl- lH-imidazole-2-carboxylic acid as a white solid. The sodium salt of 4-(4-bromophenyl)-l-methyl-lH-imidazole-2-carboxylic acid was dissolved in anhydrous CΗ2C12 (40 mL) under nitrogen at -15°C (ice/methanol bath) and Ν- methylmorpholine (1.1 equiv, 5,91 mmol) was added followed by isobutyl chloroformate (1 ,1 equiv, 5.91 mmol). The reaction mixture was stined at -15°C for 15 minutes and then Ν,O- dimethylhydroxylamine hydrochloride (1,0 equiv, 5.37 mmol) was added. The reaction was allowed to warm to room temperature and was stirred for 17 hours. The reaction was quenched with H 0 (lOmL). The product was extracted using EtOAc (3 x 30 mL) and the combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica gel chi-omatography (Analogix IF280, 20-100%
EtOAc/hexanes) afforded the title compound as a tan solid (32%). ESMS [M+H]+: 324.2. Scheme H:
Figure imgf000213_0001
1 , 1 -Dimethylethyl (4Λ)-4-( {[(1 , 1 -dimethylethyl)oxy]carbonyl } amino)-5-hydroxypentanoate:
Figure imgf000213_0002
[00421] Triethylamine (1 1.49 mL, 82.4 mmol) and ethyl chlorofoπnate (8.27 mL, 86.5 mmol) were added successively by syringe to N-t-BOC-D-glutamic acid 5-/er/-butyl ester (25 g, 82.4 mmol) in THF (588 mL) at <0 °C (ice-salt bath). After stirring in the cold bath for 40 min, solids were filtered and were washed with THF (150 mL). The filtrate was transfeπed to a 250-mL addition funnel and added to a solution of sodium borohydride (8,42 g, 222.5 mmol) in H2O (114 mL) at 0 °C over 1 hour. The reaction mixture was maintained at 0 °C for 1.5 h and then stined for 16 h (0°C to room temperature). After the bulk of solvents were removed by rotary evaporation, the concentrate was quenched with ice water (50 mL) and 1 Ν HCI (50 mL). After extraction with EtOAc (4 x 100 mL), the extracts were washed with lOOmL: 0.5 M citric acid, saturated ΝaHCO3, H2O, and brine and concentrated in vacuo to give the title compound, which was used directly in the next step. ESMS [M+H]+ = 290.4, [2M+H]+ = 579.4. (Literature prep: J. Med. Chem, 1999, 42(1), 95-108 for other isomer).
1 ,1 -dimethylethyl (AR)-A-( {[(1 ,1 -dimethylethyl)oxy]carbonyl}amino)-5-iodopentanoate:
Figure imgf000214_0001
[00422] To a solution of crude 1,1 -dimethyl ethyl (4R)-4-({[(l ,l- dimethylethyl)oxy]carbonyl}amino)-5-hydroxypentanoate (23.8 g, 82.4 mmol), triphenylphosphine (32.42 g, 123.6 mmol) and imidazole (8.41 g, 123.6 mmol) in 515 mL anhydrous CH2C12 under N2 at 0°C was added iodine over 15 min portionwise. The ice bath was removed and the reaction was allowed to wann to room temperature and stirred over 30 minutes. The reaction was quenched with 200 mL H20. The aqueous layer was extracted with diethyl ether (2 x 150 mL). The combined organic layers were washed with sat. aq. Na2SO3 solution (2 x 25 mL) and brine (25 mL), dried over MgS04, and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF280, 5% - 50% EtOAc/Hex) afforded the title compound as a white solid (25.34 g, 77%). ESMS [M+H]+ = 400.4.
l,l-dimethylethyl (4i?)-4-({[(l,l-dimethylethyl)oxy]carbonyl}amino)-5-[4-(8- methylimidazo[ 1 ,2-«]pyridin-2-yl)phenyl]pentanoate:
Figure imgf000214_0002
[00423] A flask containing zinc dust (6.0 equiv, 325 mesh, Strem) was heated with a heat gun while evacuating and filling with nitrogen (3 times). Under nitrogen, degassed DMF (14 mL) was added via syringe followed by 1 ,2-dibromoethane (0.35 equiv). The grey reaction mixture was stiπed in an oil bath at 100°C for 15 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.25 equiv) was added to the mixture via syringe and the reaction was stirred at room temperature for 30 minutes. A solution of 1 ,1 -dimethylethyl (AR)-A-({ [(1,1 -dimethyl ethyl)oxy] carbonyl} amino)- 5 -iodopentanoate (2,0 g, 1,2 equiv) in degassed DMF (14 mL) was added to the reaction mixture via cannula. The flask containing the solution was rinsed with degassed DMF (4 mL) and cannulated into the reaction mixture. The reaction was stined at room temperature for 1 hour. Then, tris(dibenzylideneacetone)dipalladium (0) (2.5 mol%), tri-otolylphosphine (10 mol%) and 2- (4-iodophenyl)-S-methylimidazo[l ,2-α]pyridine (1.4 g, 1.0 equiv) were added througli the top all at once. The reaction mixture was stirred at room temperature for 17 hours. The reaction was diluted with EtOAc (40 mL) and filtered through Celite®. The filtrate was washed with H2O (20 mL) and brine (20 mL), and the organic layer was dried oyer MgSO and concentrated in vacuo. Purification by silica gel chiOinatography (Analogix IF280, 5-90% EtOAc/hexanes) afforded the title compound as a white solid (90%). ESMS [M+H]+ = 480.4.
1 , 1 -dimethylethyl (AR)-4-( {[(1 , 1 -dimethylethyl)oχ ]carbonyl} amino)-5-[4-(l -methyl-2- {[methyl(methyloxy)amino]carbonyl}-l//-imidazol-4-yl)phenyl]pentanoate:
Figure imgf000215_0001
[00424] Following the procedure described above using 4-(4-bromophenyl)-Nl- dimethyl-N-(methyloxy)-lH-imidazole-2-carboxamide provided the title compound as a solid (82%). ESMS [M+Η]+ = 517.2.
(4Λ)-4-[({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(8- methylimidazo[l ,2-α]pyridin-2-yl)phenyl]pentanoιc acid:
Figure imgf000215_0002
[00425] To a solution of 1,1 -dimethylethyl (4Λ)-4-({[(l,l- dimethylethyl)oxy]carbonyl) amino)-5-[4-(8-methylimidazo[l,2-β]p)tidin-2- yl)phenyl]pentanoate (1.35 g, 2,82 mmol) in CH C12 (14 mL) was added trifluoroacetic acid (10 mL) followed by triethylsilane (2.5 equiv, 7.04 mmol), The reaction was stirred for 45 minutes at room temperature and then concentrated in vacuo. DMF (35 mL) was added to the residue followed by diisopropylamine (14.7 mL, 84.51 mmol) under nitrogen. The reaction was stilted for 5 minutes and pentafluorophenyl 3 -chloro-4-[(l -methyl ethyl)oxy]benzoate (1.1 equiv, 3.10 mmol) was added. The reaction was stirred for 45 minutes and then concentrated in vacuo. Ethyl acetate (50mL) was added to the residue and it was washed with H2O (30 mL), The aqueous layer was extracted with EtOAc (20 mL) and the combined organic layers were dried over MgSOα and concentrated in vacuo. Purification by silica gel chi-omatography (Analogix IF280, 25-100% EtOAc/hexanes) provided the title compound as a white foamy solid (61%). ESMS [M+H]+ = 520,2.
(4Λ)-4-[({3-chloro-4-[(l-methylethyl)oxy]phenyl)carbonyl)amino]-5-[4-(l-methyl-2- {[methyl(methyloxy)amino]carbonyl}-lH-imidazol-4-yl)phenyl]pentanoic acid:
Figure imgf000216_0001
[00426] Following the procedure described above with 1 , 1 -dimethylethyl (4R)-4-
({[(l,l-dimethylethyl)oxy]carbonyl}amino)-5-[4-(l -methyl-2-
{[methyl(methyloxy)amino]carbonyl}-lH-imidazol-4-yl)phenyl]pentanoate and foregoing purification provided the title compound as a solid. ESMS [M+Η]+ = 557.2,
(4R)-5-[4-(2-acetyl-l-methyl-lH-imidazol-4-yl)phenyl]-4-[({3-chloro-4-[(l- methylethyl)oxy]phenyl}carbonyl)amino]pentanoic acid:
Figure imgf000216_0002
[00427] To a solution of crude (4 ?)-4-[({3-chloro-4-[(l - methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(l-methyl-2-
{[methyl(methyloxy)amino]carbonyl}-lH-imidazol-4-yl)phenyl]pentanoic acid (3, IS mmol) in anhydrous THF (16 mL) under nitrogen at 0°C was added methylmagnesium bromide (10,6 mL, 10 equiv, 3.0 M in ether) dropwise by syi-inge. Tl e reaction was stirred for 30 minutes at 0°C and then carefully quenched with sat. aq. NH C1 solution (10 mL), followed by IN HCI solution (60 mL) such that the pH of the aqueous layer -5.5, The product was extracted with EtOAc (4 x 40 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound, which was used directly in the next reaction. ESMS [M+H]+ = 512.4.
N-((lΛ)-4-Amιno-l-{[4-(S-ιnethylimidazo[l,2-α]p>tidin-2-yl)phenyl]methyl)-4-oxobutyl)-3- chloro-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000217_0001
[00428] To a solution of .(47?)-4-[({3-chloro-4-[(l- methyleth}'l)oxy]phenyl)carbonyl)amino]-5-[4-(8-methylimidazo[l,2-6ϊ]pyridin-2- yl)phenyl]pentanoic acid (900 mg, 1.73 mmol) in anhydrous THF (12.4 mL) at 0°C under nitrogen was added triethylamine (242 uL, 1.73 mmol) followed by ethyl chloroformate (174 uL, 1.82 mmol). The reaction was stiπed for 40 mins at 0°C and then the solids were filtered and washed with 5 mL THF. The filtrate was added to a flask containing ΝH OH (5 mL) at room temperature and the reaction mixture was stilted for 1 hour. The product was extracted from the reaction mixture with EtOAc (50mL). The aqueous layer was extracted with EtOAc (20 mL) and then acidified with IN HCI solution (30 mL) and re-extracted with EtOAc (10 mL). The combined organic layers were dried over MgSO and concentrated in vacuo to give a white solid. Purification by recrystallization from hot isopropanol afforded the title compound as a white solid (90%). ESMS [M+H]+ = 519.4.
N-((lΛ)-l- {[4-(2-acetyl-l-methyl-lH-ιmidazol-4-yl)phenyl]methyl}-4-amino-4-oxobutyl)-3- chloro-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000218_0001
[00429] Following the procedure described in above with (4i?)-5-[4-(2-acetyl-l- methyl-lH-imidazol-4-yl)phenyl]-4-[({3-chloro-4-[(l- methylethyl)oxy]phenyl}carbonyl)amino]pentanoic acid and purification by Gilsin reverse phase ΗPLC provided the title compound as a white solid. ESMS [M+Η]+ = 511.2.
Scheme I:
Figure imgf000218_0002
(3S)-4-[4-(2-acetyl-l-methyl-lH-imidazol-4-yl)phenyl]-3-[({3-chloiO-4-[(l- methylethyl)oxy]phenyl } carbonyl)amino]butyl dimethyl phosphate:
Figure imgf000218_0003
[00430] To a solution ofN-((15)-l-{[4-(2-acetyl-l-methyl-lH-imidazol-4- yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(l -methylethyl)oxy]benzamide (500 mg, 1 ,04 mmol) in dry CΗ2C12 (10 mL) under Ν2, was added dimethyl chlorophosphate (748 mg, 5.18 mmol) followed by DMAP (660 mg, 5.41 mmol) at rt. After 30 min, TLC (95:5 EtOAc/MeOH) showed -50% conversion, so an additional portion of dimethyl chlorophosphate (748 mg, 5.18 mmol) and DMAP (660 mg, 5.41 mmol) were added. After an additional 30 min, the reaction was quenched with saturated aqueous NH C1 and diluted with CH2C12. The aqueous layer was back-extracted with CH C12 and the combined organics were dried (Na2S0 ), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100%) EtOAc; isocratic on Analogix) to give 475 mg (77%) of the title compound as a pale yellow oil. LC/MS (ES) e 592.4 (M + H)+. Note that the product was contaminated with -leq of the starting dimethyl chlorophosphate/dimethyl hydrogenphosphate reagent and carried on as is.
(3S)-4-[4-(2-acetyl-l-methyl-lH-imidazol-4-yl)phenyl]-3-[({3-chloro-4-[(l- methylethyl)oxy]phenyl } carbonyl)amino]butyl dihydrogen phosphate:
Figure imgf000219_0001
[00431] A yellow solution of (35)-4-[4-(2-acetyl-l -methyl- lH-imidazol-4-yl)phenyl]-
3-[({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]butyl dimethyl phosphate (475 mg, 0.804 mmol) in 30% ΗBr in AcOΗ was placed in a pre-heated (60 ° C) bath for 10 min, then immediately allowed to cool to rt. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO (6 mL), filtered and purified by Gilson reverse phase ΗPLC (MeCN/Η20 with 0.1% TFA). The MeCN of the clean fractions was removed under reduced pressure and the remaining aqueous solution was frozen and lyophilyzed ovemight to give 84 mg (19%) of the title compound as a yellow poλvder. LC/MS (ES) m/e 564.2 (M + H)+.
(3S)-3-[({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4-[4-(8- methylimidazo[l ,2-rt]pyridin-2-yl)phenyl]butyl dihydrogen phosphate:
Figure imgf000219_0002
[00432] Following the procedures described above, except substituting 3-chloro-N-
((lS)-3-hydroxy-l-{[4-(8-methylimidazo[l ,2-fl]pyridin-2-yl)phenyl]methyl}propyl)-4-[(l- methylethyl)oxy]benzamide for N-(( 1 S)- 1 - { [4-(2-acetyl- 1 -methyl- 1 H-imidazol-4- yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(l-methylethyl)oxy]benzamide and potassium te/t-butoxide for DMAP, the title compound was prepared as a white powder (35%) yield). LC/MS (ES) m e 563 (M + Η)+.
Scheme J:
Figure imgf000220_0001
3-Cyano-N-[(lS)-l-({4-[8-(3,5-dimethyl-4-isoxazolyl)imidazo[l,2-α]pyridin-2- yl]phenyl}methyl)-3-hydiOxypiOpyl]-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000220_0002
[00433] To a solution ofN-((lS)-l-{[4-(8-bromoimidazo[l,2-α]pyridin-2- yl)phenyl]methyl}-3-hydroxypiOpyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide (200 mg, 0.366 mmol) in dry DMF (2 mL) were added 3,5-dimethyl-isoxazole-4-boronic acid (63 mg, 0.439 mmol), tetrakistriphenylphosphine palladium(O) (21 mg, 0.01 S mmol) and 2.0M aqueous K C03 (0.46 mL) successively at rt. The reaction mixture was purged with argon and heated to 100 °C, stilted for 22 h, cooled to rt, filtered and purified directly by reverse phase HPLC (MeCΝ/H2O with 0.1% TFA). The clean fractions were adjusted to pH -8 with saturated aqueous NaHC03 and extracted with 3% MeOH/EtOAc (3 X 30 mL). The extracts were dried (Na2SO ), filtered and concentrated under reduced pressure to give 45 mg (22%) of the title compound as an off-white solid. LC/MS (ES) m e 564.2 (M + H)+.
Scheme K: 1 LIH DS THF -78 °C 2 THF β, "a
Figure imgf000221_0001
Figure imgf000221_0002
1 P CljPiPh,), dioxane, 100C
Figure imgf000221_0003
Figure imgf000221_0004
Figure imgf000221_0005
3-chloro-Λr-((lS)-l-{[3-chloro-4-(8-methylimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}-3- hydiOxypiOpyl)-4-[(l-methylethyl)oxy]benzamide:
Figure imgf000221_0006
[00434] Following the procedures described in the literature (J. Org. Chem. 2003, 68,
4215; J. Org. Chem. 2002, 67, 1738; J. I/?;. Chem. Soc. 1972, - , 6203), as well as the procedures above, the title compound was prepared as a wliite solid. LC/MS (ES) m/e 526 (M + H)+.
The following compounds were prepared using the procedures described above:
Structure Name (M + H)+
Figure imgf000221_0007
N-(( 1 R)- 1 -{ [4-(2-Acetyl- 1 -methyl- 1 H-imidazol-4-yl)ρhenyl]methyl } -4-amino-4-oxobutyl)-3- cyano-4-[(l-methylethyl)oxy]benzamide 502.4
Figure imgf000222_0001
N-[( 1 R)-4-Amino- 1 -( {4-[2-( 1 -hydroxy- 1 -methylethyl)- 1 -methyl- 1 H-imidazol-4- yl]phenyl)methyl)-4-oxobutyl]-3-cyano-4-[(l-methyleth)l)oxy]benzamide 518.4
Figure imgf000222_0002
N-[( 1 S)-2-(D-Alanyl amino)- 1 -( (4-[ 1 -(2-aminoethyl)-2-( 1 , 1 -dimethylethyl)- 1 H-imidazol-4- yl]phenyl}methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide 583.6
Figure imgf000222_0003
N-((lS)-2-{4-[l-(2-Aminoethyl)-2-(l,l-dimethylethyl)-lH-imidazol-4-yl]phenyl}-l-{[(2- methylalanyl)amino]methyl}ethyl)-3-chloro-4-[(l-methylethyl)oxy]benzamide 597.6
Figure imgf000222_0004
N-[(lS)-2-(D-Alanylamino)-l-({4-[l-(2-aminoethyl)-2-(l,l-dimethylethyl)-lH-imidazol-4- yl]phenyl}methyl)ethyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide 574.4
Figure imgf000223_0001
N-(( 1 S)-2- (4-[ 1 -(2- Aminoethyl)-2-( 1 , 1 -dimethylethyl)- 1 H-imidazol-4-yl]phenyl } - 1 - {[(hydroxyacetyl)amino]methyl}ethyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide 561.4
Figure imgf000223_0002
N-((l S)-2- {4-[ 1 -(2-Aminoethyl)-2-(l , 1 -dimethylethyl)- 1 H-imidazol-4-yl]phenyl } - 1 - {[(2- methylalanyl)amino]methyl}ethyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide 58S.2
Figure imgf000223_0003
N-((l S)-2- {4-[ 1 -(2-Aminoethyl)-2-( 1 , 1 -dimethylethyl)- 1 H-imidazol-4-yl]phenyl } - 1 - { [(N,N- dimethylglycyl)amino]methyl}ethyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide 588.4
Figure imgf000224_0001
3-Cyano-N-[( 1 S)-2- {4-[8-(l -hydroxyethyl)imιdazo[ 1 ,2-α]pyndιn-2-} l]phenyl} - 1 -( {[(2R)-2- hydroxypiOpanoyl]amino) methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 569.4
Figure imgf000224_0002
Ν-((l S)-2-[(Aminocarbonyl)amino]-l-{[4-(8-bromoιnudazo[l,2-a]pyndιn-2- yl)phenyl]methyl}ethyl)-3-chloro-4-[(l-methylethyl)o\y]benzamide 584.2
Figure imgf000224_0003
N-{(lS)-2-[4-(S-Bromoimidazo[l,2-a]pyndin-2-yl)phenyl]-l-[(2-oxotetrahydro-l(2H)- pyιimidinyl)methyl]ethyl}-3-chloro-4-[(l-methylethyl)oxy]benzamιde 625.1
Figure imgf000224_0004
N-{(lS)-2-[4-(8-Bromoimιdazo[l,2-a]p\tidin-2-yl)phenyl]-l-[(2-oxohexahydro-lH-l,3- diazepιn-l-yl)methyl]ethyl}-3-chloro-4-[(l-methylethyl)oxy]benzamide 639.2
Figure imgf000225_0001
N-((l S)-2-[(Aminocarbonothioyl)amino]-l-{[4-(S-bromoimidazo[l,2-a]pyridιn-2- yl)phenyl]methyl}ethyl)-3-chloro-4-[(l-methylethyl)oxy]benzamide 601.2
Figure imgf000225_0002
2-(4-{(2S)-2-[({3-Cyano-4-[(l-methylethyl)oxy]phenyl] carbonyl)amino]-3-[(l,2,3- thiadiazol-4-ylcarbonyl)amino]propyl}phenyl)imidazo[l,2-a]pyridine-8-carboxamide
Figure imgf000225_0003
N-((lS)-2-[(Aminosulfonyl)amino]-l-{[4-(8-methylimidazo[l,2-a]p>tidin-2- yl)phenyl]methyl}ethyl)-3-cyano-4-[(l -methylethyl)oxy]benzamide 547.2
Figure imgf000225_0004
(3S)-3-[({3-Chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4-[2-(l,l- dimethyl ethyl)- 1 -methyl- lH-imidazol-4-yl]phenyl}butanoic acid 512,4
Figure imgf000226_0001
N-[(lS)-2-[(Aminosulfonyl)amino]-l-({4-[2-(l ,l-dimethylethyl)-l-methyl-lH-imidazol-4- yl]phenyl}methyl)ethyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide 553.2
Figure imgf000226_0002
N-((lS)-l-{[4-(lH-Benzimidazol-2-yl)phenyl]methyl}-3-hydroxypropyl)-3-chloro-4-[(L methylethyl)oxy]benzamide 477.8
Figure imgf000226_0003
3-Chloro-N-[(lS)-3-hydroxy-l-({4-[5-(trifluoromethyl)-lH-benzimidazol-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide 546.2
Figure imgf000226_0004
3-Chloro-N-((lS)-l-{[4-(5,6-dimethyl-lH-benzimidazol-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[(l-methylethyl)oxy]benzamide 506.2
Figure imgf000227_0001
3-Chloro-JV-[(1 )-3-hydroxy-l-({4-[5-(methyloxy)-lH-benzimidazol-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide 508.2
Figure imgf000227_0002
3-Ch]oro-N-((15)-l-{[4-(5-chloro-lH-benzimidazol-2-yl)phenyl]methyl}-3-hydroxypropyl)- 4-[(l -methylethyl)oxy]benzamide 512.0
Figure imgf000227_0003
3-Chloro-N-((15)-3-hydroxy-l-{[4-(4-methyl-lH-benzimidazol-2-yl)phenyl]methyl}propyl)- 4-[(l-methylethyl)oxy]benzamide 492.2
Figure imgf000227_0004
3-Chloro-N-((lS)-l-{[4-(6-chloro-lH-imidazo[4,5-ύ]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[(l-methylethyl)oxy]benzamide 513.2
Figure imgf000228_0001
Ethyl 2-(4-{(2S)-2-[({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl] phenyl)- lH-benzimidazole-5-carboxylate 550.2
Figure imgf000228_0002
2-(4- {(2S)-2-[({3-ChloiO-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl} phenyl)- lH-benzimidazole-5-carboxylic acid
Figure imgf000228_0003
N-((15)-3-Amino-l-([4-(lH-benzimidazol-2-yl)phenyl]methyl}propyl)-3-chloro-4-[(l- methylethyl)oxy]benzamide 477.0
Figure imgf000228_0004
3-Cyano-N-((lS)-l-{[4-(8-cyanoimidazo[l,2-fl]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[( 1 -methylethyl)oxy]benz amide 494.4
Figure imgf000228_0005
N-((lS)-l-{[4-(8-Chloroimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}-3-hydroxyproρyl)-3- cyano-4-[(l-methylethyl)oxy]benzamide 504.2
Figure imgf000229_0001
3-Cyano-N-[(15)-3-hydiOxy-l-({4-[8-(trifluoromethyl)imidazo[l,2-α]p τidin-2- yl]phenyl}methyl)piOpyl]-4-[(l -methylethyl)oxy]benzamide 537.2
Figure imgf000229_0002
3-Cyano-N-((lS)-3-hydroxy-l-{[4-(8-hydroxyimidazo[l,2-α]pyridin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]berιzamide 485.2
Figure imgf000229_0003
2-(4-{(2S)-2-[({3-Cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl } phenyl)imidazo[ 1 ,2-a]pyridine-7-carboxamide 512.2
Figure imgf000229_0004
Ethyl 2-(4-{(2S)-2-[({3-cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)imidazo[l,2-α]pyridine-7-carboxylate
Figure imgf000229_0005
3-Cyano-N-((15)-3-hydroxy-l-{[4-(8-nitroimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}propyl)- 4-[(l-methylethyl)oxy]benzamide 514.4
Figure imgf000230_0001
Λr-((lS)-l-{[4-(8-Aminoimidazo[l,2-Λ]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3- cyano-4-[(l-methylethyl)oxy]benzamide 484.2
Figure imgf000230_0002
2-(4- {(2S)-2- [( { 3 -Cyano-4-[( 1 -methylethyl)oxy]phenyl } carbonyl)amino]-4- hydroxybutyl}phenyl)imidazo[l,2-α]pyridine-8-carboxamide 512.2
Figure imgf000230_0003
3-Cyano-N-[(lS)-3-hydroxy-l-({4-[8-(hydiOxymethyl)imidazo[l,2-α3pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]beιrzamide 499.4
Figure imgf000230_0004
N-[(15)-l-({4-[8-(Aminomethyl)imidazo[l,2-α]pyridin-2-yl]phenyl}methyl)-3- hydroxypropyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide 498,4
Figure imgf000230_0005
N-((15)-l-{[4-(8-Acetylimidazo[l ,2-α]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3- cyano-4-[(l-methylethyl)oxy]benzamide 511,2
Figure imgf000231_0001
3-Cyano-N-[(15)-3-hydroxy-l-({4-[8-(l-hydroxy-l-methylethyl)imidazo[l ,2-α]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide 527.4
Figure imgf000231_0002
3-Cyano-N-[(l^)-3-hydroxy-l-({4-[S-(l-hydroxyethyl)imidazo[l,2-α]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide 513.4
Figure imgf000231_0003
3-Cyano-N-((lS)-3-hydroxy-l-{[4-(8-methyl-5,6,7,8-tetrahydiOimιdazo[l,2-fl]pyridin-2- yl)phenyl]methyl)propyl)-4-[(l-methylethyl)oxy]benzamide 487,2
Figure imgf000231_0004
3-Cyano-N-[(15)-l-({4-[2-(l,l-dimethylethyl)-l-(2-hydroxyethyl)-lH-imidazol-4- yl]phenyl}methyl)-3-hydroxypropyl]-4-[(l-methylethyl)oxy]benzamide 519.4
Figure imgf000231_0005
N-[(15)-l-({4-[l-[2-(Acetylamino)ethyl]-2-(l ,l-dimethylethyl)-lH-imidazol-4- yl]phenyl}methyl)-3-hydroxypropyl]-3-cyano-4-[(l -methylethyl)oxy]benzamide 560.4
Figure imgf000232_0001
3-Cyano-N-{(15)-3-hydiOxy-l-[(4-{8-[(lΛ)-l-hydroxyethyl]imidazo[l ,2-α]pyridin-2- yl}phenyl)meth}d]propyl}-4-[(l-methylethyl)oxy]benzamide 513.4
Figure imgf000232_0002
3-Cyano-N-{(lS)-3-hydiOxy-l-[(4-{S-[(15)-l-hydroxyethyl]imidazo[l,2-α]p>tidin-2- yl}phenyl)methyl]propyl}-4-[(l-methylethyl)oxy]benzamide 513.4
Figure imgf000232_0003
3-Chloro-N-[(lS)-3-hydroxy-l-({4-[8-(l-hydrox)φropyl)imidazo[l ,2-«]pyridin-2- yl]phenyl}methyl)piOpyl]-4-[(l-methylethyl)oxy]benzamide 536.2
Figure imgf000232_0004
N-((15)-l-{[4-(S-Bromoimidazo[l,2-<7]pyridin-2-yl)phenyl]methyl}-3-hydrox propyl)-3- chloro-4-[(l-methj'lethyl)oxy]benzamide 556.2
Figure imgf000232_0005
3-Chloro-N-(( 1 S)- 1 - { [4-(8-chloroimidazo[ 1 ,2-α]pyridin-2-yl)phenyl]methyl } -3- hydroxypropyl)-4-[( 1 -methylethyl)oxy]benzamide 512.4
Figure imgf000233_0001
3-Chloro-N-[(lS)-3-hydroxy-l-({4-[S-(l-hydroxy-2-methylρiOpyl)imidazo[l ,2-d']pyndιn-2- yl]phenyl } methyl)propyl] -4- [( 1 -methyl ethyl)oxy]benzamide 550.4
Figure imgf000233_0002
N-[(lΛ)-4-Amino-l-({4-[8-(l-hydiOxyethyl)imιdazo[l,2-β]pyridin-2-yl]phenyl}methyl)-4- oxobutyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide 549.2
Figure imgf000233_0003
N-[(lΛ)-4-Amino-l-({4-[S-(l-hydiOxyethyl)imιdazo[l,2-α]pyridin-2-)'l]phenyl}methyl)-4- oxobutyl]-3-cyano-4-[(l-methylethyl)oxy]benzamιde 540.6
Figure imgf000233_0004
3-Chloro-N-((lS)-l-{[4-(3-fluoro-8-methylimidazo[l ,2-fl]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[( 1 -methylethyl)oxy]benzamιde 510.2
Figure imgf000233_0005
3-Cyano-N-((lS)-l-{[4-(3-fluoro-S-methylimidazo[l,2-α]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[(l-methylethyl)oxy]benzamide 501.2
Figure imgf000234_0001
3-Chloro-N-((15)-2-hydroxy-l-{[4-(8-methylimidazo[l,2-α]pyridin-2- yl)phenyl]methyl}ethyl)-4-[(l -methylethyl)oxy]benzamide 478.2
Figure imgf000234_0002
3-ChloiO-4-[(l-methylethyl)oxy]-N-[(lS)-2-[4-(8-methylimidazo[l,2-β]pyridin-2-yl)phenyl]- l-(4-mo holinylmethyl)ethyl]benzamide 547.2 Chiral
Figure imgf000234_0003
3-Chloro-N-((lS)-2-(4-hydroxy-l-piperidinyl)-l-{[4-(8-methylimidazo[l,2-«]pyridin-2- yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide 561.2 chiral
Figure imgf000234_0004
3-Chloro-N-((lS)-2-(3-hydroxy-l-pyrrolidinyl)-l-{[4-(S-methylimidazo[l ,2-α]pyridin-2- yl)phenyl]methyl] ethyl)-4-[(l -methylethyl)oxy]benzamide Chiral
Figure imgf000235_0001
3-Chloro-N-(( 1 S)-2-[(2S)-2-(hydiOxymethyl)- 1 -pytrolidinyl]- 1 - { [4-(8-meth) limidazo[ 1 ,2- α]pyndιn-2-yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamιde 561.2 Chiral
Figure imgf000235_0002
3-Chloro-N-((15)-2-[(2Λ)-2-(hydrox αnethyl)-l-pyτrolιdιnyl]-l-{[4-(8-methyhmιdazo[l ,2- ]pyridm-2-yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamιde
Figure imgf000235_0003
3-Chloro-4-[(l-methylethyl)oxy]-N-((lS)-2-[4-(8-methylιmιdazo[l ,2-α]pyndιn-2-yl)phenyl]- 1 - {[(2,2,2-trifluoroethyl)amιno]methyl}ethyl)benzamιde 559.2 Chiral
Figure imgf000235_0004
3-Chloro-N-((lS)-2-[(2-hydroxyethyl)amιno]-l-{[4-(8-methyhmιdazo[l ,2-α]p>τidin-2- yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide 521.2 Chiral
Figure imgf000236_0001
3-Cyano-N-((lS)-l-{[4-(8-ethyl-5-methylimidazo[l,2-β]ρyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[(l-methylethyl)oxy]benzamide 511.2 \ / Chiral
Figure imgf000236_0002
Methyl (3S)-3-[({3-chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4- [(phenylcarbonyl)amino]phenyl}butanoate 509 Chiral
Figure imgf000236_0003
3-Chloro-N-[(lS)-3-hydroxy-l-({4-[(phenylcarbonyl)amino]phenyl}methyl)propyl]-4-[(l- methylethyl)oxy]benzamide 481
Figure imgf000236_0004
3-Chloro-N-{(15)-l-[(4-{[(4-chlorophenyl)carbonyl]amino}phenyl)methyl]-3- hydroxypropyl)-4-[(l-methylethyl)oxy]benzamide 515 hiral
Figure imgf000237_0001
Phenylmethyl (4-{(25)-2-[({3-chloro-4-[(l -methylethyl)oxy]phenyl] carbonyl)amino]-4- hydroxybutyl } phenyDcarbamate 51 1
Figure imgf000237_0002
3-Chloro-N-((lS)-3-hydroxy-l-{[4-({[2-
(methylamino)phenyl]carbonyl)amino)phenyl]methyl)propyl)-4-[(l- methylethyl)oxy]benzamide 510 hiral
Figure imgf000237_0003
N-(4-{(25)-2-[({3-Chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)-4-pyridinecarboxamide 482 Chiral
Figure imgf000237_0004
3-ChloiO-N-[(lS)-l-({4-[(cyclohexylcarbonyl)amino]phenyl}methyl)-3-hydroxypropyl]-4- [(l-methylethyl)oxy]benzamιde 487 Chiral
Figure imgf000238_0001
3-Chloro-N- [( 1 S)- 1 -( {4- [(3 ,3 -dimethylbutanoyl)amino]phenyl } methyl)-3 -hydroxypropyl] -4- [( 1 -methyl ethyl)oxy]benzamide 475 hiral
Figure imgf000238_0002
3-Chloro-N-[(lS)-3-hydiOxy-l-({4-[(phenylacetyl)amino]phenyl}methyl)propyl]-4-[(l- methylethyl)oxy]benzamide 495 , ' Chiral
Figure imgf000238_0003
3-Chloro-N-{(lS)-3-hydroxy-l-[(4-{[(phenylamino)carbonyl]amino}phenyl)methyl]propyl}- 4-[(l -methylethyl)oxy]benzamide 496 Chiral
Figure imgf000238_0004
3-Cyano-N-((15)-3-hydroxy-l -{[4-(8-methyl-5-oxo-5,6-dihydroimidazo[l ,2-c]pyrimidin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide 500 Chiral
Figure imgf000239_0001
3-Cyano-N-((lS)-3-hydroxy-l-{[4-(l-methyl-3-oxo-2,3-dihydro-lH-imidazo[l,2-«]imidazol- 6-yl)phenyl]methyl}propyl)-4-[(l-methylethyl)ox}' r]benzamide 48S hiral
Figure imgf000239_0002
3-Cyano-N-((lS)-3-hydroxy-l - {[4-(8-oxo-7,8-dihydroimidazo[l,2-α]p tazin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide 486
Figure imgf000239_0003
2,3-Dichloro-N-((lS)-3-hydroxy-l-{[4-(S-methylimidazo[l,2-β]pyridin-2- yl)phenyl]methyl } propyl)-4-[( 1 -methylethyl)oxy]benzamide 526 Chiral
Figure imgf000239_0004
N-((lS)-3-Ηydroxy-l-{[4-(8-methylimidazo[l ,2-α]pyridin-2-yl)phenyl]methyl}propyl)-4-[(l- methylethyl)oxy]-3-nitrobenzamide 503
Figure imgf000240_0001
3-Chloro-N-[(15)-2-[(hydroxyacetyl)amino]-l-({4-[8-(l-hydroxyethyl)imidazo[l ,2-fl]p)τidin- 2-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 565
Figure imgf000240_0002
3-Chloro-N-[(15r)-2-{4-[8-(l-hydroxyethyl)imidazo[l,2-«]pyridin-2-yl]phenyl}-l-({[(2Λ)-2- hydiOxypropanoyl]amino}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 579 hiral
Figure imgf000240_0003
3-Chloro-N-[(l S)-2- {4-[8-(l -hydroxyethyl)imidazo[ 1 ,2-α]pyridin-2-yl]phenyl } -1 -( {[(25)-2- hydroxypropanoyl]amino}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 579
Figure imgf000240_0004
3-Chloro-N-[(lS)-2-[(NN-dimethylglycyl)amino]-l-({4-[8-(l-hydroxyethyl)imidazo[l,2- α]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 592 hiral
Figure imgf000241_0001
N-[(lS)-2-(D-Alanylamino)-l-({4-[8-(l-hydroxyethyl)imidazo[l,2-α]p>tidin-2- yl]phenyl}methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide 57S
Figure imgf000241_0002
3-Chloro-N-[(lS)-3-hydroxy-l-({4-[8-(l -hydiOxyethyl)imidazo[l,2-fl]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide 522
Figure imgf000241_0003
3-ChloiO-N-((lS)-2-{4-[8-(l-hydroxyethyl)imidazo[l,2-α]pyridin-2-yl]phenyl}-l -{[(2- methylalanyl)amino]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide 592 Chiral
Figure imgf000241_0004
(3S)-3-[({3-Chloro-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4-{4- [(phenylcarbonyl)amino]phenyl}butanoic acid 495
Figure imgf000242_0001
3-Chloro-N-{(lS)-3-hydroxy-l-[(4-imidazo[l,2-a]pyridin-6-ylphenyl)methyl]propyl}-4-[(l- methylethyl)oxy]benzamide 477,8 Chiral
Figure imgf000242_0002
3-Chloro-.V-[(lS)-l-({4-[2-(l,l-dimethylethyl)imidazo[l,2-α]p)tidin-6-yl]phenγl}methyl)-3- hydiOxypropyl]-4-[(l-methylethyl)oxy]benzamide 534.2 Chiral
Figure imgf000242_0003
3-Chloro-N-{(lS)-3-hydroxy-l-[(4-imidazo[l ,2-α]pyridin-2-ylphenyl)methyl]propyl}-4-[(l- methylethyl)oxy]benzamide 478.2 Chiral
Figure imgf000242_0004
3-Chloro-N-{(lS)-3-hydroxy-l-[(4-imidazo[l,2-α]pyrimidin-2-ylphenyl)methyl]propyl}-4- [(1 -methylethyl)oxy]benzamιde 479.2 hiral
Figure imgf000243_0001
3-Chloro-N-((lS)-3-hydiOxy-l-{[4-(5-methylimidazo[l,2-σ]p}tidin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]beιιzamide 492.2 Chiral
,Ν.
Figure imgf000243_0002
3-Chloro-N-(( 15)-3-hydroxy- 1 - {[4-(7-methy lιmιdazo[ 1 ,2-α]pyrimιdin-2- yl)phenyl]methyl}propyl)-4-[(l-methylethyl)oxy]benzamide 494.2 Chiral
Figure imgf000243_0003
3-Cyano-Λ^-{(lS)-3-hydroxy-l -[(4-imidazo[2,l-έ][l,3]thιazol-6-ylphenyl)methyl]butyl)-4- [(1 -methyl ethyl)oxy]benzamide 489.0 Chiral
Figure imgf000243_0004
3-Cyano-N-((15)-3-hydroxy-l-{[4-(3-methylimidazo[2,l-6][l,3]thiazol-6- yl)phenyl]methyl}butyl)-4-[(l-methylethyl)oxy]benzamide 503.2 hiral
Figure imgf000244_0001
3-Cyano-N-(( 1 S)- 1 - {[4-(2,3-dihydroimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)phenyl]methyl} -3- hydroxybutyl)-4-[( 1 -methylethyl)oxy]benzamide 491.2 hiral
Figure imgf000244_0002
3-Cyano-N-((lS)-l-{[4-(l,l-dioxido-2,3-dihydroimidazo[2,l-ά][l ,3]thiazol-6- yl)phenyl]methyl}-3-hydroxybutyl)-4-[(l-methylethyl)oxy]benzamide 523.2
^Y
N-[(lS)-l-({4-[l-(3-Aminopropyl)-2-(l,l-dimethylethyl)-lH-imidazol-4-yl]phenyl}methyl)- 3-hydroxypropyl]-3-cyano-4-[(l-methylethyl)oxy]benzamide 532.4
Figure imgf000244_0003
24: l-(5-methyl-l,2,4-oxadiazol-3-yl)ethyl]benzamide 521.4
Figure imgf000245_0001
3-Cyano-N-[(lS)-l-({4-[8-(3,5-dimethyl-4-isoxazolyl)imidazo[l ,2-α]pyridin- yl]phenyl}methyl)-3-hydroxypropyl]-4-[(l-methylethyl)oxy]benzamide 564.2
Figure imgf000245_0002
3-Cyano-Λ^-((lS)-3-hydroxy-l-{[4-(8-phenylimidazo[l,2-<3]pyridin-2- yl)phenyl]methyl}propyl)-4-[(l -methylethyl)oxy]benzamide 545.4
Figure imgf000245_0003
3-Cyano-N-[(15)-3-hydiOxy-l-({4-[8-(lH-ρyrazol-4-yl)imidazo[l,2-fl]pyιidin-2- yl]phenyl)methyl)propyl]-4-[(l-methylethyl)oxy]benzamide 535.4
Figure imgf000245_0004
3-Cyano-N-[(lS)-3-hydroxy-l-({4-[8-(4-isoxazolyl)imidazo[l,2-α]pyridin-2- yl]phenyl}methyl)propyl]-4-[(l-methylethyl)oxy]benzamide 536.2 Chiral
Figure imgf000246_0001
Λr-((1 )-l-{[4-(8-Acetylimidazo[l,2-<2]pyridin-2-yl)phenyl]methyl}-3-hydroxypropyl)-3- chloro-4-[( 1 -methylethyl)oxy]benzamide 520.2
Figure imgf000246_0002
Ethyl (2£)-3-[2-(4-{(2S)-2-[({3-cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydroxybutyl}phenyl)imidazo[ 1 ,2-α]pyridin-S-yl]-2-propenoate 567.6
Figure imgf000246_0003
(2£)-3-[2-(4-{(2S)-2-[((3-Cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-4- hydiOxybutyl}phenyl)imidazo[l ,2-α]pyridin-S-yl]-2-propenoic acid 539.4 hiral
Figure imgf000246_0004
7V-{(lS)-l-[(4-{8-[(l£')-3-Amino-3-oxo-l-propen-l-yl]imidazo[l,2- ]pyridin-2- yl}phenyl)methyl]-3-hydroxypropyl}-3-c)'ano-4-[(l-methylethyl)oxy]benzamide 538.4
Figure imgf000246_0005
N-[(lS)-l-({4-[8-(3-Amino-3-oxopropyl)imidazo[l,2-α]pyτidin-2-yl]phenyl}methyl)-3- hydroxypropyl]-3-cyano-4-[(l -methylethyl)oxy]benzamide Chiral
Figure imgf000247_0001
3-ChloiO-7V-((15)-l-{[4-(3-chloiO-S-methy]imidazo[] ,2-«]pyridin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[(l-methylethyl)oxy]benz amide
Chiral
Figure imgf000247_0002
N-((15)-l-{[4-(3-ChloiO-S-methylιmidazo[l,2-«]p>τidin-2-yl)phenyl]methyl}-3- hydroxypropyl)-3-cyano-4-[(l-methylethyl)oxy]benzamide 517.2
Figure imgf000247_0003
3-Cyano-N-[(lS)-l -({3-fluoro-4-[2-(l -hydroxy-1 -methyl ethyl)- 1 -methyl- lH-imidazol-4- yljphenyl } methyl)- 3 -hydroxypropyl] -4- [( 1 -methyl ethyl)oxy]benzamide 509.2
Figure imgf000247_0004
3-Chloro-N-((lS)-2-hydroxy-l-{[5-(8-methylimidazo[l ,2-Λ]pyridin-2-yl)-2- pyridinyl]methyl)ethyl)-4-[(l-methylethyl)oxy]benzamide 479
Figure imgf000248_0001
3-Chloro-N-((lS)-2-hydroxy-l -{[5-(8-methylimidazo[l,2-β]pyridin-2-yl)-2- thienyl]methyl } ethyl)-4-[( 1 -methylethyl)oxy]benzamide 484 Chiral
Figure imgf000248_0002
3-Chloro-N-[( 1 S)- 1 -( {4-[2-( 1 , 1 -dimethylethyl)- 1 -methyl- lH-imidazol-4-yl]-2- fluorophenyl}methyl)-3-hydroxypropyl]-4-[(l -methyl ethyl)oxy]benzamide 516 Chiral
Figure imgf000248_0003
3-Chloro-N-[( 15)-l -( {4-[2-(l , 1 -dimethylethyl)- 1 -methyl-lH-imidazol-4-yl]-2,6- difluorophenyl methyl)-3-hydiOxypropyl]-4-[(l-methylethyl)oxy]benzamide 534 Υ0-γ-^ Chiral ! cιWγΝ
Figure imgf000248_0004
3-ChloiO-N-[(lS)-l-({2-chloiO-4-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4- yl]phenyl } methyl)-3 -hydroxypropyl] -4-[( 1 -methyl ethyl)oxy]benzamide 532
Figure imgf000249_0001
3-Chloro-N-[(15)-l-({5-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4-yl]-2- P)τidinyl)methyl)-3-hydroxypropyl]-4-[(l-methylethyl)oxy]benzamide 499
Figure imgf000249_0002
3-Chloro-N-((15)-l-{[2-chloro-4-(8-methylimidazo[l,2-α]pyι-idin-2-yl)phenyl]methyl) -3- hydrox)prop)'l)-4-[(l-methylethyl)oxy]benzamide 526 Chiral
Figure imgf000249_0003
3-Chloro-N-((15)-l-{[2-chloro-4-(8-chloroimidazo[l,2-σ]pyndιn-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[( 1 -methylethyl)oxy]benzamide 546
Figure imgf000249_0004
3-Chloro-N-((lS)-l-{[2,5-dιfluoro-4-(S-methylimidazo[l ,2-β]p}τidin-2-yl)phenyl]methyl}-3- hydroxypropyl)-4-[( 1 -methylethyl)oxy]benzamide 528
Figure imgf000250_0001
3-Chloro-N-[(lS)-l-({4-[2-(l,l-dimethylethyl)-l -methyl-lH-imidazol-4-yl]phenyl}methyl)- 3 -(methyl amino)-3 -oxopropyl] -4- [( 1 -methylethyl)oxy]benzamide 525.4
Figure imgf000250_0002
3-Cyano-N-[(lS)-2-{4-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4-yl]phenyl}-l- ({[(phenylamino)carbonyl]amino}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 593.2
Figure imgf000250_0003
3 -Cyano-N-[( 1 S)-2- {4-[2-( 1 , 1 -dimethylethyl)- 1 -methyl- 1 H-imidazol-4-yl]phenyl } - 1 ■ ({[(ethylamino)carbonyl]amino}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 545.2
Figure imgf000250_0004
N-[(lS)-2-(Aminosulfonyl)-l-({4-[2-(l,l-dimethylethyl)-l-methyl-lH-imidazol-4- yl]phenyl}methyl)ethyl]-3-chloro-4-[(l-methylethyl)oxy]benzamide 548.2
Figure imgf000251_0001
3-Cyano-N-(( 1 S)-2- {4-[2-( 1 , 1 -dimethylethyl)- 1 -methyl- 1 H-imidazol-4-yl]phenyl } - 1 - {[(methylsulfonyl)amino]methyl)ethyl)-4-[(l-methylethyl)oxy]benzamide
Figure imgf000251_0002
3-Cyano-N- {( 1 S)-2- {4-[2-( 1 , 1 -dimethylethyl)- 1 -methyl- 1 H-imidazol-4-yl]phenyl } - 1 -[( { [(2- hydroxyethyl)amino]carbonyl } amino)methyl]ethyl } -4-[( 1 -methylethyl)oxy]benzamide 561.2
Figure imgf000251_0003
N-[(S)- 1 -[4-(2-tert-Butyl- 1 -methyl- 1 H-imidazol-4-yl)-benzyl]-2-(2-methoxy-ethanoylamino)- ethyl]-3-cyano-4-isopropoxy-benzamide 546.2
(4R)-4-[({3-Cyano-4-[(l-methylethyl)oxy]phenyl}carbonyl)amino]-5-{4-[2-(l,l- dimethylethyl)- 1 -methyl- 1 H-imidazol-4-yl]phenyl }pentanoic acid 517.4
Figure imgf000252_0001
3-Cyano-N-{(lS)-2-{4-[2-(l ,l-dimethylethyl)-l-methyl-lH-imidazol-4-yl]phenyl}-l-[(2-oxo- l -imidazolidinyl)methyl]ethyl}-4-[(l-methylethyl)oxy]benzamide 543.4 CNrsl
Figure imgf000252_0002
N-((lS)-2-Amino-l-{[4-(8-methylimidazo[l,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-cyano- 4-[(l -methylethyl)oxy]benzamide 468.2
Figure imgf000252_0003
N-((lS)-2-(Acetylamino)-l -{[4-(8-methylιmidazo[l,2-a]pyι-idin-2-yl)phenyl]methyl}ethyl)-3- cyano-4-[(l-methylethyl)oxy]benzamide 510.4
Figure imgf000252_0004
3-Chloro-N-((l S)-2-{[(2R)-2-hydroxypropanoyl]amino}-l-{[4-(8-methylimidazo[l,2- a]p)τidin-2-yl)phenyl]methyl}ethyl)-4-[(l-methylethyl)oxy]benzamide 549.2
Figure imgf000253_0001
3-ChloiO-N-[(lS)-2-[(N,N-dimethylglycyl)amino]-l-({4-[2-(l-hydroxy-l-methylethyl)-l- methyl-lH-imidazol-4-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 570.4
Figure imgf000253_0002
3-Cyano-N-[(l S)-2-[(N,N-dimethylglycyl)amino]-l-({4-[2-(l-hydroxy-l-methylethyl)-l- methyl- lH-imidazol-4-yl]phenyl}methyl)ethyl]-4-[(l-methylethyl)oxy]benzamide 561.4
Example 67
Figure imgf000253_0003
(50% yield, two steps)
[00435] To a 0° C solution of compound 1 (10.7 g, 61.37 mmol), (R)- 1,1,1 - trifluoropropanol (3.5 g, 30.68 mmol) in dimethylfomiamide (200 mL) was added sodium hydride( 3.7g, 92.05 mmol) portion wise over 5 minutes. After 10 min, the ice bath was removed and the reaction mixture was stirred while warming to room temperature. The reaction mixture was heated to 80° C and stirred overnight. The reaction was monitored by LC/MS. After the reaction was done it was cooled to room temperature. The reaction mixture was quenched with HCI (0.5N, 200 mL) and extracted with ethyl acetate (3 x 250 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo giving crude compound 2 (8.2 g) which was used directly in the next step without further purification.
[00436] To a 0 °C crude solution of compound 2 ( 4.1g , 15.34 mmol ), triethylamine(6.4mL, 46.02mmol) in dicholoromethane (200ml) was added pentafluorophenyl trifluoroacetate(6.35mL , 36.82 mmol) via syringe over 3 mins . After 5 mins the ice bath was removed and the reaction mixture was stined while warming to room temperature for another 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was purified by flash chromatography( silica gel, hexanes/ethyl acetate = 1 :0 , 50:1) to give compound 3 (3.5 g, 50% yield).
Example 68
Figure imgf000254_0001
[00437] Methyl 4-hydroxy-3-iodobenzoate 2: Methyl 4-hydroxybenzoate (35.5g, 0.233 mol) was dissohed in 200 mL of acetic acid, and the stirred mixture was warmed to 65°C. A solution of ICl (37.8 g, 0,233 mol) in 50 mL of AcOH was added dropwise over 40 min. The mixture was stirred at 65°C for 5 h and then stirred an additional 16 h at room temperature. The precipitated product was isolated via filtration, washed with water and dried under vacuum to give 27,5 g (99% pure by LCMS and HNMR)) of desired product. The mother liquors were evaporated and resulting residue was washed with water and dried under vacuum to give another 31 g (95% pure by LCMS and NMR) of desired product. The combined yield of methyl 4-hydroxy-3-iodobenzoate was 58.5 g (90.3% yield). LCMS m z = . [00438] Methyl 3-cyano-4-hydroxybenzoate 3: 28 g (0.1 mol) of methyl 4-hydroxy-3- iodobenzoate 2 dissolved in 100 mL of DMF was treated with 9,92 g (0.11 mol) of CuCN and 0.49 g (0.1 1 mol) of NaCN. The system was flushed with nitrogen after which the mixture warmed to 105 C and stirred to IS h. The mixture was allowed to cool to room temperature, and any precipitates were removed via filtration and washed with EtOAc. The combined organics were diluted with 200 mL of water and then extracted with EtOAc (2x200 mL). The combined layers were dried over sodium sulfate, filtered and evaporated to dryness. After drying under vacuum, the resulting 18 g (100% yield) of 3 was characterized by LCMS and HNMR.
[00439] Methyl 3-cyano-4-isopropoxybenzoate 4: Methyl 3-cyano-4-hydroxybenzoate
3 (18 g, 0.1 mol) was dissolved in 100 mL of DMF and treated with 14.2 mL (0.15 mol) of 2- bromopropane and 41 ,9 g (0.3 mol) of anhydrous potassium carbonate. The system was flushed with nitrogen, and the mixture was heated to 90°C and stirred ovemight. After cooling to room temperature, the mixture was diluted with 200 mL of water and extracted with CH2C1 (2x200 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness to give 20.5 g (99% yield) of 4 as an oil that was characterized by LCMS and HNMR.
[00440] Perfluorophenyl 3-cyano-4-isopropoxybenzoate 6: 20.5 g (0.093 mol) of methyl 3-cyano-4-isopropoxybenzoate 4 was dissolved in 200 mL of a 6:4 mixture of methanol and water. To this was added 5.61 g (0.14 mol) of NaOH, and the mixture was stilted for 2 hours at room temperature. The solution was then filtered through a silica gel plug and the solvents removed under vacuum. The resulting solid was re-dissolved in 200 mL of CH2CI2 and treated with 19.3 mL (0.1 1 mol) of perfluorophenyl 2,2,2-trifluoroacetate 5 and 19.5 mL (0.14 mol) of triethylamine. After stimng overnight, the solution was filtered and any solids rinsed with CH2C12 The combined organic mixtures were run tlirough a short silica gel column and then evaporated to dryness to give 29 g (83.5% yield) of 6 which was characterized by LCMS and HNMR.
Example 69
Figure imgf000256_0001
[00441] To a solution of compound 1 (200 mg, 1.077 mmol) and 2-iodopropane,
(322uL, 3.23 mmol) in DMF (10 mL) was added DIEA (750uL, 4.31 mmol). The reaction mixture was heated to 80°C and stirred overnight. The reaction was monitored by LC/MS. After the reaction was done it was cooled to room temperature. The reaction mixture was quenched with HCI (0.5N, 30 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over sodium sulfate and concentrated and dried under high vacuum. The resulting residue was purified by reverse phase chromatography (using a mixture of acetonitrile and water) to give compound 2 (50 mg, 20%).
Figure imgf000256_0002
[00442] To a solution of compound 2 (50mg, 0.22 mmol), in MEOH (1.0 mL) was added NaOH in water (1 ,0M, 330uL, 0.330mmol). The reaction mixture was stined at ambient temperature for 2 hours. The reaction was monitored by LC/MS. The reaction mixture was quenched with HCI (0.5N, 5 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was dried over sodium sulfate, and concentrated to give 2 (45 mg). LRMS (M-H+) ,?,/ 212.0
Example 70
Figure imgf000257_0001
[00443] To a solution of compound 1 (200 mg, 1.077 mmol) and 2-iodopropane, (322 uL, 3.23 mmol) in DMF (10-mL) was added DIEA (750 uL, 4,31 mmol). The reaction mixture was heated to 80° C and stirred overnight. The reaction was monitored by LC/MS, After the reaction was done it was cooled to room temperature. The reaction mixture was quenched with HCI (0.5 N, 30 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over sodium sulfate and concentrated and dried under high vacuum. The resulting residue was purified by reverse phase chromatography using a mixture of acetonitrile and water to give compound 2 (50 mg, 20%).
Figure imgf000257_0002
2 3
To a solution of compound 2 (50 mg, 0.22 mmol), in MEOH (1.0 mL) was added NaOH in water (1.0 M, 330 uL, 0.330 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction was monitored by LC/MS. The reaction mixture was quenched with HCI (0.5 N, 5 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was dried over sodium sulfate, and concentrated to give 2 (45 mg). LRMS (M-H+) m/z 212.0
Example 71
Figure imgf000257_0003
compound 1
[00444] 4-bromo-2-chlorophenol (5,04 g, 24.3 mmol) was dissolved in DMF (30 mL) and K CO (10.10 g, 72.9 mmol) was added, followed by 2-chloroethyl-p-toluenesulfonate (4.86 mL, 26.7 mmol). The resulting mixture was heated to 60°C for 3 hours and then cooled to room temperature. The reaction was diluted with EtOAc (350 mL) and washed with water (5 x 150 mL). The organic phase was dried (Na2S0 ) and concentrated to a viscous oil which solidified to a white solid while under high vacuum. Compound 1 (6,46 g, 24.1 mmol, quantitative yield) was characterized using ]H NMR and used in the following step without further purification.
Figure imgf000258_0001
compound 1 compound 2
[00445] Compound 1 (6.46 g, 24.1 mmol) was dissolved in DMF (30 mL) and sodium hydride (1.94 g of 60% dispersion in mineral oil, 48.6 mmol) was added. The resulting mixture was stilted at room temperamre for 16 hours. The reaction was diluted with water (100 mL) and EtOAc (350 mL). The layers were separated, and the organic layer was washed with water (4 x 150 mL). The organic phase was dried (Na2S04) and concentrated to a white solid, Compound 2 (5.56 g, 24.0 mmol, quantitative yield) was dried under high vacuum and characterized using Η NMR. It was used in the following step without further purification.
Figure imgf000258_0002
compound 2 compound 3
[00446] Compound 2 (5.56 g, 24.0 mmol) was combined with chloroiodomethane (5.59 mL, 76.8 mmol) and dissolved in 1 ,2-dichloroethane (35 mL) under an atmosphere of nitrogen, The solution was cooled to 0°C with an ice bath and diethyl zinc (38,4 mL, 1 ,0 M in hexanes, 38.4 mmol) was added over 10 minutes. The resulting mixture was stirred for 30 minutes and allowed to warm to room temperature. It was cooled to 0°C with an ice bath, and saturated aqueous NH C1 (150 mL) was added, followed by concentrated aqueous NH OH (25 mL) and EtOAc (200 mL). The layers were separated and the aqueous phase was e trated with additional EtOAc (2 x 100 mL). The organic phases were combined, dried (Na2SO4) and concentrated to a crude oil which was purified using silica gel (100 % hexanes), Compound 3 (1.76 g, 7.2 mmol, 30 % yield) was a colorless oil which was characterized using H NMR,
Figure imgf000259_0001
compound 3 compound 4
[00447] In a high-pressure reactor, compound 3 (1.76 g, 7,2 mmol) was dissolved in
EtOH (40 L). Triethylamine (5.0 mL 35.8 mmol) was added, followed by [1 ,1 - bis(diphenylphosphino)fenocene]dichloiOpalladium (II) (188 mg, 0.36 mmol). The reaction vessel was pressurized with carbon monoxide (100 psi), evacuated and repressurized with carbon monoxide (100 psi). The vessel was evacuated and then pressurized again with carbon monoxide (350 psi), The reaction was heated to 90°C and stined for 16 h. It was cooled to room temperature, depressurized and filtered through celite. The solvents were evaporated, and the remaining residue was partitioned between dichloromethane (150 mL) and 1 M aqueous KHS0 (75 mL). The layers were separated and the organic phase was washed with additional 1 M aqueous KHSO (1 x 75 mL). The organic phase was dried (Na2S0 ) and concentrated to an oil which was purified using silica gel (EtOAc/Hexanes), providing compound 4 (648 mg, 2,70 mmol, 38% yield) as a white solid, characterized using 'H NMR.
Figure imgf000259_0002
compound 4 compound 5
[00448] To a solution of compound 4 (648 mg. 2.70 mmol) in dichloromethane (3 mL) and EtOH (15 mL) was added 1 M aqueous KOH (7 mL, 7 mmol). The resulting cloudy mixture was heated to 60°C for 1 h. The dichloromethane and EtOH were evaporated under reduced pressure, and the remaining aqueous solution was acidified using concentrated HCI. The resulting precipitate was filtered. The filtered, white solid was pure compound 5 (506 mg, 2,39 mmol, 88% yield), characterized using LC/MS (LRMS (M-H) 211.1 m/z).
Example 72
Figure imgf000260_0001
[00449] To a solution of the amine (580 mg, 1.7 mmol) and triethylamine (449 μl, 3.4 mmol, 2 eq.) in THF (8.5 ml, 0.2 M), was added chloroethyl chloroformate (278 μl, 2.6 mmol, 1.5 eq). The mixmre was stirred for 30 min. at room temperature. Then, it was diluted in ethyl acetate, washed with 1 N HCI and brine. The organic layer λvas dried, filtered, and concentrated in vacuo to yield a crude material as a yellow oil (900 mg). To a solution of the cmde material in DMF (10 ml), NaH (272 mg, 6.S mmol, 4 eq) was added and stined at room temperature for 16 hrs. The mixture was diluted in ethyl acetate (100 ml) and washed with brine (5 x 50 ml). The organic layer was dried, filtered, and concentrated in vacuo to yield a crude material as an oil. Purification by column chromatography (1 :1 Ethyl acetate:Hexanes) gave S00 mg (24 %) of the desired product, m/z (+1) = 398.0.
Example 73
Figure imgf000260_0002
[00450] (R)-4-chloro-N-(l-(4-(4-iodophenyl)-l -methyl- lH-imidazol-2- yl)ethyl)butanamide. To a 100 mL round bottom flask was added (R)-benzyl l-(4-(4- iodophenyl)-l -methyl- lH-ιmidazol-2-yl)ethylcarbamate (1.50 g, 3,27 mmol, 1 ,0 equiv), CH3CN (20 mL), and TMSl (900 μL, 6.3 mmol, 1.9 equiv). The reaction mixture was capped and stin-ed for 2 hours. Methanol (40 mL) was then added to the flask and the mixture was concentrated, dissolved in EtOAc (100 mL), and washed with water. The organic layer was dried over Na2SO , filtered, and concentrated. The residue was dissolved in DCM and purified by silica gel chromatography (35-60% CH3CN/CH2C12, then 20% MeOH/ CH2C12) to afford 950 mg (90%)of the desired primary amine as an oil (M+H (m/z) = 328), To this amine was added CH2C1 (20 mL) and pyridine (260 μL, 1.1 equiv), followed by 4- chlorobutyryl chloride (344 μL, 1 ,05 equiv) in a dropwise fashion. The reaction was stined for 15 min, followed by the addition of EtOAc (50 mL) and water (10 mL). The organic layer was separated, dried over Na2SO , filtered, and concentrated. The residue was dissolved in DCM and purified by silica gel chromatography (5-35% CH3CN/CH2C12) to afford 747 mg (60%)of (R)-4-chloro-N-(l -(4-(4-iodophenyl)- 1 -methyl- 1 H-imidazol-2-yl)ethyl)butanamide as an off-white solid (M+H (m/z) = 432),
Example 74
Figure imgf000261_0001
[00451] (R)-l -(1 -(4-(4-iodophenyl)- 1 -methyl- 1 H-imidazol-2-yl)ethyl)pyτrolidin-2-one.
To a 20-dram vial was added (R)-4-chloro-N-(l-(4-(4-iodophenyl)-l-methyl-lH-imidazol-2- yl)ethyl)butanamide and THF (10 mL). The vial was then cooled to 0 °C under a nitrogen atmosphere and potassium /-butoxide (214 mg, 1 ,91 mmol) was added. The reaction was stined for 1.5 h. To the reaction mixture was added EtOAc (50 mL) and water (10 mL). The organic layer was separated, dried over Na2SO , filtered, and concentrated. The residue was then dissolved in DCM and purified by silica gel chromatography (5-50% CH3CN/CH2C12) to afford 593 mg (86%)of (R)-l-(l-(4-(4-iodophenyl)-l -methyl- lH-imidazol-2- yl)ethyl)p)trolidin-2-one as a white solid (M+H (m z) = 396).
Example 75
Figure imgf000262_0001
[00452] To a solution of 1 (10 g, 45.7 mmol) in DMF (150 mL) were added HBTU (26 g, 6S.5 mmol), dimethylhydroxylamine HCI salt (5.35 g, 54,8 mmol) and DIEA (9.6 mL, 55.0 mmol) at 0°C. After stimng for 2h, the mixture was allowed to warm up to room temperature. Stilting continued for 2 days. The reaction mixture was partitioned between EtOAc (500 mL) and H2O (200 mL). The organic layer was washed with NaOH (2N, 200 mL). HCI (2N, 200 mL), H20, bnne, dried over Na2SO4, and concentrated to give 2 (9.6 g), which was used without further purification. LRMS (M+H+) m/z 262.0. [00453] To a solution of 2 (9.6 g, -36.8 mmol) in Et20 (100 mL) was added MeMgBr
(3 M in Et2θ, 27 ml) at 0°C. The resulting mixture was stilted for 4 h while it was allowed to warm up to room temperature. The reaction mixture was quenched with saturated NH4C1 (100 mL), The organic layer was washed with H20, brine, dried over Na2SO , and concentrated to give 3 (7 g, 71 % from 1), which was characterized by NMR.
[00454] To a solution of 3 (6.5 g, 30 mmol) in DCM (200 mL) and MeOH ( 100 mL) was added tetrabutylammonium tribromide (14.5 g, 30 mmol). The reaction mixture was stilted for 14 h. The mixture was concentrated, and dried under high vacuum to give 5 (characterized by NMR), which was used in the next step without further purification. [00455] To a solution of 4 (5 g, -16.9 mmol) in DCM (50 mL) was added hexamethylenetetramine (2.6 g, 18.5 mmol). The reaction mixture was stined for 2 h. The mixture was diluted with DCM (500 mL). The precipitate was collected, washed with DCM (500 mL x 2), and dried under high vacuum. To the resulting residue was added EtOH ( 60 mL) and concentrated HCI (30 mL). The reaction mixture was stirred for 2 h. The mixture was concentrated, dried to give 5, which was used without further purification. LRMS (M+H4) m/z 231.9.
[00456] To a solution of cmde 5 (-16.9 mmol) in dioxane (50 mL) were added NaOAc
(6.93 g, 84.5 mmol), HOAc (4.8 mL, 84.5 mmol), and 5.1. (5.93 g, 84.5 mmol). After 1 h, the reaction mixture was warmed up to 80 °C and stiπ-ed for 3 h, The reaction mixture was partitioned between EtOAc (500 mL) and saturated NaHCO3 (200 mL). The aqueous layer was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine, dried over Na2S0 , and concentrated. The resulting residue was purified on silica gel (hexane/EtOAc, 1 :0, 1 :2, 1 : 1, 0:1) to give 6 (1.2 g, 23% from 4). LRMS (M+H+) m/z 312.9.
Example 76
Figure imgf000263_0001
[00457] To a solution of ethyl thiooxamate (10.0 g, 75 mmol) in dichloromethane (400 mL) was slowly added trimethyloxonium tetrafluoroborate (13.1 g, 89 mmol) at 0 °C. After 10 min the ice bath was removed, and the reaction mixture was stirred overnight. The solvent was removed to give 1S.0 g of product 2 as white solid, which was used without further purification.
Figure imgf000263_0002
[00458] A mixture of 2-amino-4'-bromoacetophene hydrochloride (10.0 g, 40 mmol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65 ° C until TLC showed no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO3 solution and extracted with ethyl acetate. The organic solution was dried over Na2SO and concentrated. Purification with flash column cliromatography (EtOAc:Hexs 1:1) gave product 3 (9.11 g, 79 %) as a white solid.
Figure imgf000264_0001
[00459] In a round-bottom flask, product 3 (2.00 g, 6.8 mmol) was dissolved in DMF
(20 mL), followed by the addition of Iodomethane (5.1 mL, 10.1 mmol), and K2CO3 (1.4 g, 10,1 mmol). The mixture was allowed to stir at 60°C for 3 hours until complete by TLC, The solution was quenched with brine, extracted three times with EtOAc, dried over sodium sulfate and concentrated. Purification via column chromatography using EtAc:Hex 1 :1 , gave 1.381 g (66 % yield) of product 4.
(2-bromoethoxy)-tert-butyldimeth lsilane K2COj. DMF, 55 overnight
Figure imgf000264_0002
Figure imgf000264_0003
[00460] To a solution of compound 3 (3.174 g. 10.8 mmol) in DMF (15 mL) was added K2C03 (4.478 g, 32.4 mmol) and (2-bromoethoxy)-/er/-butyldimethylsilane (2.780 mL, 13.0 mmol). The resulting mixture was stined at 55 °C overnight. The solution was concentrated, diluted with water and extracted with EtOAc (3 x 50 mL). The organic layers were combined and dried over Na2S04. The solvent was removed to give a viscous oil (4.805 g, 10.6 mmol, 98.4%), which was used in the subsequent step without further purification.
Figure imgf000264_0004
[00461] To a solution of compound 4 (2.174 g, 4.8 mmol) in anhydrous THF (25 mL) was added dropwise methylmagnesium bromide (4.8 mL, 3 M in diethyl ether, 14.4 mmol) under nitrogen at 0 °C. The reaction was stirred at 0 °C for 15 minutes. The reaction was carefully quenched with saturated ammonium chloride solution (5 mL) and water (30 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2SO and concentrated to a crude oil. Purification with flash column chromatography (15 % EtOAc/Hexanes) gave the desired product 5 (1.371 g, 65%) as a white amorphous solid.
Figure imgf000265_0001
[00462] To a solution of compound 5 (1.371 g, 3.1 mmol) in THF (5 mL) was added
35 mL of HCI (4 M in 1,4-dioxane). The resulting solution was stilted at room temperature overnight. The solvents were removed to give the product 6 (1.0 g, 99%) as white solid.
Figure imgf000265_0002
[00463] A mixture of compound 6 (0.5 g, 1.54 mmol) and 1 mL of TFA in toluene (60 mL) was refluxed ovemight. The solid 6 did not dissolve until around the boiling point of toluene. The solvent was removed. The residue was diluted with EtOAc, washed with NaHC03 aqueous solution, dried over Na2SO , and concentrated. Purification with flash column chi-omatography (EtOAc:Hexanes 1 :1) gave the product 7 (0,348 g, 74%) as a white solid.
Example 77
Figure imgf000265_0003
[00464] (R)-methyl l-(4-(4-iodophenyl)-l -methyl- lH-imidazol-2- vDethvKmethyDcarbamate, To a 250 mL round bottom flask was added (R)-l-(4-(4- iodophenyl)-l -methyl- lH-imidazol-2-yl)-N-methylethanamine (3.1 g, 9.1 mmol), methyl chloroformate (0.84 mL, 10.9 mmol), Na2CO3 (1.15 g, 10.9 mmol), and THF (100 mL). The reaction was stin-ed for 2 hours, followed by the addition of EtOAc (50 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give 1.50 g (41 %) of (Λ)-methyl 1 -(4-(4-iodophenyl)- 1 -methyl- 1 H-imidazol-2-yl)ethyl(methyl)carbamate as an off-white solid (M+H (m/z) = 400).
Example 78
Figure imgf000266_0001
Ref: J. Med. Chem. 2001 , 44, 2990-3000
[00465] To a stirring solution of/ iodoacetophenone 1 (30.0 g, 122 mmol) in dioxane
(200 mL) over an ice-bath was added bromine (6.56 mL, 128 mmol) dropwise. The reaction mixture was stirred at room temperature and monitored by LC/MS. After completion (about 1 hour), the solvent was evaporated by rotovap, and the residue was dried under vacuum to give solid 2 (40g, 100%).
[00466] (Based on J. Med. Chem. 2001, 44, 2990-3000) To a solution of Cbz-D-Ala-
OH 3 (5.0 g, 22.4 mmol) in NMP (100 mL) was added cesium carbonate (3,72 g, 11.4 mmol). After stirring at RT for 1 h, 2 (7.60 g, 22.4 mmol) was added. The reaction mixture was stined at room temperature and monitored by LC/MS to form 4. The reaction solution was diluted with xylene (100 mL) and ammonium acetate (9.25g, 120 mmol) and then stirred at 120°C for 4 hours. Up to 50eq of additional ammonium acetate may be needed depending on the reaction progress. The key is to see solid in the flask at all times. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL). The EtOAc solution was washed with saturated sodium bicarbonate solution (200 mL) twice, and dried by sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure, The residue was dissolved in DCM (100 mL) and stined for 1 h to give a precipitate, and the solid 5 (4.0g) was filtered off and dried under λ'acuum. The mother solution was concentrated by rotovap, the residue was purified on Bio-tage to give 5 (Hexane: EtOAc = 1 : 1 to EtOAc 100%). The two products were combined and dried under vacuum to give 5 (5.8 g. 58%).
Example 79
Figure imgf000267_0001
[00467] (R)-Benzyl l-(4-(4-iodophenyl)-l -methyl- lH-imidazol-2- yl)ethyl(methyl)carbamate 2: A stined mixture of (/?)-benzyl l-(4-(4-iodophenyl)-lH- imidazol-2-yl)ethylcarbamate 1 (5 g, 11 mmol) in 55 mL of DMF was cooled to 0°C and treated with NaH (1.33 g, 60% dispersion in oil, 33 mmol) in small portions to avoid foaming. λVhen bubbling from the last portion ceased, Mel (2.1 mL, 34 mmol) was added all at once and the mixture stirred an additional 30 min. The solvents were removed under vacuum and the residue dissolved in 200 mL of EtOAc. The solution was washed with saturated NH4C1 (4x100 mL) and saturated NaCl (4x100 mL), and then filtered and evaporated to dryness. The crude residue was purified via flash column chromatography over silica gel (60:40, EtOAc/hexanes) to give 5.13 g (97% yield) of 2 which was characterized by LCMS.
Example 80 BocHN 0
Figure imgf000268_0001
0 1 2 3 .. DU TBDPSCI NaBH< NHBoc NHBoc PPh, / 12 NHBoc EIOH OH DIEA ^^^-^^OTBDPS imidazole "^"'^-"'^OTBDPS CH CI2 Et20-MeCN 4 5 6
[00468] Acetyl chloride (54,6 mL, 0.75 mol) was added drop-wise into ethanol (316 mL) at 0-5 C. When the addition was completed, the ice bath was removed and the solution was allowed to stir while warming to room temperature for another 30 mins. D-aspartic acid 1 (25 g, 0.188 mol) was then added. The reaction mixmre was refluxed for 2 hours. The reaction solution was then concentrated in vacuo and placed under high vacuum (0.4 mm Hg) overnight. Compound 2 was obtained as a white solid (42g, 99%) and used directly in the next step.
[00469] (BOC)2O (44.7 g, 0.21 mol) was added portion-wise over 10 mins to a 0 C solution of compound 1 (42 g, 0.19 mol), trimethyl amine (51 ,9 ml, 0.37 mol), dioxane (140 mL) and water (56 mL), After another 10 min, the ice bath was removed and the reaction mixmre was sti ed while warming to room temperamre for another 2 hours. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with 0.5 N HCI (200 mL x 3). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo giving compound 3 (52 g, yield 97%) which was used directly in the next step. [00470] NaBH (54.4 g, 1.44 mol) was added portion-wise over 30 mins to a 0 C solution of compound 3 (52 g, 86.4 mmol) and ethanol (600 mL). The reaction mixture was extremely exothennic and great care was exercised during the addition of reducing agent. After the addition was complete, the reaction mixture was heated to reflux for 1 hour. The solution was cooled to ambient temperature and the reaction mixture solidified. The solid was broken-up to a slurry, which was then poured into brine (250 mL). The resulting mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was vigorously stilted with ether (200 mL x 5). The ether layers were successively decanted from the residue. The combined ether extracts were dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo giving compound 4 as white solid (25.2g, yield 68%). [Note: Yield was S9% when performed on a 25 g (compound 3) scale.] [00471] r-Butyldiphenylchlorosilane (31.9 mL, 0.123 mol) was added to a solution of compound 4 (25.2 g, 0.123 mol), diisopropylethylamine (42.8 mL, 0.245 mol), and CH2C12 (500 mL). The reaction solution was stin-ed at ambient temperature for 24 hrs. The reaction solution was then washed with 0.5 N HCI (150 mL x 3) and brine (150 mL). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 4: 1 hexanes:EtOAc) to give compound 5 (42g, yield 77%). [Note: Yield was S5% when performed on 15 g (compound 4) scale.]
[00472] Iodine (24 g, 94.7 mmol) was added portion-wise over 15 mins to a 0 C solution of compound 5 (28 g, 63.1mmol), Ph3P (24.8 g, 94,7 mmol), imidazole (6.4g, 94.7 mmol), diethyl ether (450 mL) and acetonitrile (150mL). The ice bath was removed and the reaction solution was allowed to wann to ambient temperature over 30 mins. The reaction was judged complete by TLC analysis (4:1 hexanes:EtOAc). The reaction was quenched with water (400 mL). The layers were separated and the aqueous layer was extracted by diethyl ether (100 mL). The combined organic layers were washed with saturated aqueous Na2S03 (100 x 2) and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 4:1 hexanes:EtOAc) to give compound 6 (32 g, 92%).
Example 81
Figure imgf000270_0001
3 , 4
Figure imgf000270_0002
6
PP 3/Iv'imιdazole/DCM
Figure imgf000270_0003
1 h v° NHCbz Negishi Coupling
Figure imgf000270_0004
10
[00473] Under ice-bath, to a solution of D-Aspartic acid 1 (59g, 0.376 mol) in methanol (200 mL) was bubbled HCI gas for 10 minutes. After the reacting solution was stirred at RT ovemight, the solvent was' evaporated. The resulting residue was dried under
Vacuum to have product 2 as HCI salt (0.376 mol).
[00474] To a stirred solution of 2 (0.376mol), DIEA (196 mL, 1.13 mol) and THF (200 mL), benzyl chloroformate (59.0 L, 0.414 mol) was dropped in. After the reaction solution was stilted at room temperature for 1 hr, the solution was concentrated on rot-vap. Then the residue was dissolved in NaHCO3 solution (300 mL) and extracted with DCM (100 mL X 3).
The combined DCM solution was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuum to have the product 3 (0.376 mol).
[00475] To a solution of 3 (0.376 mol), THF (200 mL) and Water (100 mL) was added
Lithium hydroxide (31.6g, 0.752 mol) and stined for 2 hours. The reaction mixture was filtered through a silic gel plug (the pH of the filtrate was about 7) and concentrated. The residue was dried under Vacuum to give 4 (0.376 mol).
[00476] After a solution of 4 (0.376 mol) and acetic anhydrate (200 mL) was stirred for
1 hour, the reaction mixture was concentrated. The residue was dried under Vacuum to give 5
(0.376 mol).
[00477] Under ice-bath, to a solution of 5 (0,376 mol) and THF (1000 mL) was added Sodium borohydride (14.2g, 0.376 mol) during 30 minutes and stirred for 3 hrs. Then HCI solution (4N) was dropped into the reaction solution until the pH was about 2, The solution was concentrated to about a quarter left, diluted with water (300 mL) and extracted by ethyl ether (200 mL X 3). The combined ether solution was dned over sodium sulfate, filtered, and the filtrate was concentrated in vacuum. The resulting residue was dissolved in benzene (300 mL) and TsOH (500 mg) was added. Then the reaction mixture was stirred at reflux 3 hrs. The solution was concentrated to about 100 ml and ether (200 mL) was added to form precipitate. The white solid 6 (57.5g, 65% from 1) was filtered out, washed with some ether and dried under Vacuum.
[00478] To a solution of 6 (30.0g, 0.128 mol) and methanol (200 mL) was added triethylamine (142 mL, 1.02 mol) and stilted overnight. The reaction mixmre was concentrated. The residue was dried under Vacuum to give 7 (LC-MS showed about 20%mol 6 was left) which was directly used in the next step.
[00479] Under ice-bath, to a solution of compound 7 (0.128 mol), Ph3P (50.4 g, 0.192 mol), imidazole (13. I g, 0.192 mol) and DCM (300 mL) was stirred for 10 min. Iodine (48.7 g, 0.192 mol) was added portion-wise over 15 minutes. The ice bath was removed and the reaction solution was stirred at room temperature over 1 hour. The solid was filtered out. The filtrate was washed with saturated aqueous Na2SO3 (200 mL x 2) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue w as purified by flash silica gel column chi-omatography (hexanes: EtOAc 4:lto 1 :1) to give compound 8 (27.5 g, 59.2% from 6) as a white solid. [00480] To a mixture of zinc powder (Strem, 10.1 g, 0, 154 mol) and DMF ( 15 mL) was purged under Nitrogen for 10 minutes and added 1 ,2 dibromoethane (0.758 mL, 8.80 mmol). The mixture was heated with a heat gun for ~2 minutes, cooled down for 5 minutes and heated with a heat gun again, then cooled to room temperature. TMSC1 (281 μL, 2.20 mmol) was added to the mixture. After the mixture was stirred for 30 minutes, 8 (9.98 g, 26.5 mmol) was added. After 1 hour, LCMS showed complete consumption of 8. To above reaction solution was added aryl iodide 9 (7.50 g, 22,0 mmol), Pd2(dba) (50.4 mg, 0.55 mmol) and tri-o-tolylphosphine (670 mg, 2.20 mmol). The reaction mixture was maintained at 50 C for 1 hour (monitered on LC-MS analysis). The reaction mixture was directly loaded to a silica gel plug and washed with hexanes:EtOAc (3:1 to 1 : 1 ) to give compound 10 (5.0 g, 49%). Example 82
Figure imgf000272_0001
[00481] To an oven dried round-bottom flask, zinc powder (1753 mg, 27 mmol) was added followed by DMF (15 mL). The flask was capped and purged with nitrogen for 10 min. To the solution Avas added 1,2 dibromoethane (0.139 mL, 1.6 mmol). The mixture was then heated using a heat gun for about 30 seconds until gas began to evolve indicating the activation of the zinc. The mixture was allowed to cool while stirring for 1 min before it was heated again using a heat gun until gas evolved. The mixture was then allowed to cool to room temperature, followed by the addition of TMSCl (0.042 mL, 0.33 mmol) and stirring for 30 min. Reagent A was then dissolved in DMF, bubbled with nitrogen, added to the zinc solution, and allowed to stir for 1 hour at room temperature. Bromide 4 (1.381 g, 4.5 mmol) was dissolved in DMF, bubbled with nitrogen and then injected into the solution, followed by the addition of Pd2(dba3) (102 mg, 0.11, mmol) and Tri-o-tolylphospine (136 mg, 0.44 mmol). The solution mixture was bubbled with nitrogen and held under nitrogen while stirring for one hour at room temperamre. After 1 hour, the stilting solution was heated to 40°C for 2 hours until complete by TLC and LC/MS, The solution was quenched using brine and extracted five times using EtOAc. The combined organic layers were dried over sodium sulfate and concentrated. The crude product 5 was purified via column chromatography using EtOAc: Hex 1 :1 to obtain 2.0 g (70 % yield) of pure product 5.
Example 83
Figure imgf000272_0002
compound 6 compound 7
[00482] To a solution of compound 6 (940 mg, 1.78 mmol) in THF (5 mL) was added 4 M HCI in 1,4-dioxane (20 mL, 80 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solvents were evaporated, and the remaining compound 7 (726 mg, 1.78 mmol, quantitative yield) was thoroughly dried under high vacuum. Compound 7 was characterized using LCMS (LRMS (MH) 373 m/z) and used in the following step without further purification.
Figure imgf000273_0001
compound ? compound s compound 9
To a solution of compound 7 (662 mg, 1.62 mmol) in DMF (5 mL) was added DIEA (930 μL, 5.34 mmol) and compound 8 (678 mg, 1.78 mmol). The resulting solution was stined at room temperamre for 1 hour, The DMF was evaporated and the cmde residue was directly purified using preparative HPLC to provide compound 9 (435 mg, 0.77 mmol, 48% yield), which was characterized by ]H NMR and LC/MS (LRMS (MH) 569 /z.)
Figure imgf000273_0002
compound 9 compound 10
[00483] Compound 9 (100 mg, 0.176 mmol) was combined with HATU (134 mg,
0.352 mmol), HOAT (48 mg, 0.352 mmol) and NH C1 (50 mg, 0.944 mmol). The solids were dissolved in N-methylpyrrolidinone (5 mL) and DIEA was added (93 μL, 0.528 mmol). The resulting mixture was stined at room temperature for 2 hours and then directly purified with preparative HPLC to provide compound 10 (16 mg, 0.028 mmol, 16% yield) as a glassy solid which was characterized by Η NMR and LC/MS (LRMS (MH) 568 m/z.)
172
Figure imgf000274_0001
compound 9
[00484] Compound 9 (91 mg, 0,160 mmol) was combined with HBTU (121 mg, 0.320 mmol) and HOBt (43 mg, 0.320 mmol). The solids were dissolved in DMF (3 mL), and dimethylamine (400 μL, 0,800 mmol, 2 M in THF) and DIEA (93 μL, 0.528 mmol) were added. The resulting solution was stirred at room temperature for 2 hours, The crude product was directly purified using preparative HPLC to provide compound 11 (25 mg, 0.042 mmol, 26% yield) as a glassy solid which was characterized by ]H NMR and LC MS (LRMS (MH) 596 m/z.) Example 84
BocHN X BocHN OH 1 ) isobutyl chloroformate, DIEA, THF Nf^ trifluoroacetic anhydride 2) NH3(g), r.t. 16 h pyridine, 1.4-dioxane Br Br
Figure imgf000274_0002
[00485] To a 0 DC solution of 1 (40,2 g, 1 17 mmol) in THF (250 mL) and DIEA (11.4 mL, 175 mmol) was added isobutyl chloroformate (21.2 mL, 163 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction was purged with gaseous ammonia for 1 hour and then stirred at room temperature for 16 hours. It was diluted with water (200 mL), ethyl acetate (200 mL) and filtered. The white, filtered solid was the desired product. Additional product was obtained by transferring the biphasic filtrate to a separator/ funnel and separating the layers. The aqueous phase was extracted with additional ethyl acetate (3 x 150 mL). The organic phases were combined, dried (Na2SO4) and concentrated to a white solid, which was recrystallized from ethyl acetate to afford the desired product. The pure product 2 (20.6 g, 60 mmol) was characterized by Η-NMR and LC/MS (LRMS (MU) m/z: 34 A).
[00486] Amide 2 (18,1 g, 53 mmol) was suspended in 1,4-dioxane (200 mL) and pyridine (10.7 mL, 132 mmol). Trifluoroacetic anhydride (22.0 L, 158 mmol) was added, and the white, suspended solid immediately dissolved. The homogeneous solution was stined at room temperature for 30 minutes. The solvents were removed under reduced pressure, and the remaining residue was dissolved in ethyl acetate (200 mL) and washed with 1 M aqueous HSO4 (2 x 100 mL) and saturated aqueous NaHCO3 (2 x 100 mL). The organic phase was dried over Na2SO and concentrated in vacuo. The remaining, desired product 3 (14.9 g, 46 mmol) was determined to be sufficiently pure for the next transfonnation (LC/MS (LRMS (MH) m/z 198.0)).
[00487] Nitrile 3 (14,9 g, 46 mmol) was dissolved in 1 ,4-dioxane (100 mL) and tributyl
(l-ethoxyvinyl)tin (23.3 mL, 69 mmol) was added, followed by Pd(PPh3)2Cl2 (1.6 g, 5 mol %). The resulting mixture was heated to 90 DC and stined for 4 hours. It was cooled to room temperature and the solvent was removed under reduced pressure. The remaining residue was directly purified using silica gel, prepared in a sluny using 95% hex ane/tri ethyl amine. Elution was stepwise, beginning with 95% hexane/triethylamine and changing to 50% ethyl acetate/hexane/5% triethylamine. The desired product 4 eluted with the latter mobile phase and was a viscous yellow oil, characterized by LC/MS (LRMS (MH) m/z: 317.1), The product was used immediately in the next transformation.
[00488] To a solution of vinyl ether 4 (14.5 g, 46 mmol) in THF (60 mL) and water (20 mL) was added N-bromosuccinimide (12.3 g, 69 mmol), The resulting mixture was stined at 50 DC for 30 minutes. It was cooled to room temperature and diluted with 2 M aqueous Na2CO3. The mixture was extracted with ethyl acetate (2 x 150 mL), the organic extracts were combined, dried over Na S0 and concentrated to an amorphous solid which was purified using silica gel (dichloromethane/ethyl acetate). The desired product 5 (10.6 g, 29 mmol) was a yellow solid, characterized by Η-NMR and LC/MS (LRMS (MH) m/z: 239,9).
Example 85 BocHN
Figure imgf000276_0001
Figure imgf000276_0002
BocHN Raney Ni, 60 psi H2 HOAc, MeOH
Figure imgf000276_0003
[00489] A solution of ketone 5 (10.6 g, 29 mmol) in 1,4-dioxane (50 mL) was dripped into a solution of methylamine (72 mL, 144 mmol, 2 M in THF) over 45 minutes at 0 DC. The resulting cloudy solution was stirred for an additional 15 minutes at room temperature. The THF and methylamine were evaporated under reduced pressure, and care was taken not to evaporate 1 ,4-dioxane. To the resulting mixmre at room temperature was added triethylamine (12 mL, 87 mmol), followed by trimethylacetyl chloride (15 mL, 144 mmol). The resulting suspension was stined at toom temperature for 30 minutes. It was diluted with water (125 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, dried over Na2SO4 and concentrated in vacuo. The crude product 6 was characterized by LC/MS (LRMS (MH) m/z: 402.1) and carried forward without further purification.
[00490] Amide 6 (11.6 g. 29 mmol) was combined with ammonium acetate (55 g, 723 mmol) and formamide (150 mL). The resulting mixture was heated to 100 DC and stined for 3 hours. It was cooled to room temperature, diluted with ethyl acetate (500 mL) and washed with water (3 x 200 mL). The organic phase was dried over Na2SO and concentrated under reduced pressure. The remaining crude residue was purified using silica gel (diethyl ether/hexane) to provide pure 7 (6.1 g, 16 mmol) as a foamy yellow solid, characterized by Η-NMR and LC/MS (LRMS (MH) m/z 383,2).
[00491] Imidazole 7 (1.316 g, 3,4 mmol) was combined with hydroxylamine hydrochloride (478 mg, 6,9 mmol) and dissolved in a solution of sodium methoxide in methanol (14 mL, 6.9 mmol, 0.5 M). The resulting solution was stined at 50 DC for 4 hours. It was concentrated under reduced pressure and directly purified using silica gel (5 % methanol/dichloromethane) to provide the desired amidoxime 8 (913 mg, 2.2 mmol) as a white solid, characterized by LC/MS (LRMS (MH) m/z: 416.1).
[00492] To a solution of amidoxime 8 (652 mg, 1.6 mmol) in methanol (10 mL) was added Raney nickel (50 mg) and acetic acid (250 μL). The mixture was stirred at room temperature under 60 psi H for 3 hours and then filtered through a bed of celite, Concentration under reduced pressure provided pure amidine 9 as a white solid (638 mg, 1.6 mmol), characterized using LC/MS (LRMS (MH) m/z: 400,2),
[00493] Chloroacetaldehyde (360 mL, 5.7 mmol) was added to a solution of amidine 9
(283 mg, 0.71 mmol) in DMF (4 mL) and K2C03 (1 5 mg, 1 ,4 mmol). The mixture was heated to 50 DC and stined for 4 hours. The reaction was filtered and directly purified by reverse-phase HPLC using a mobile phase gradient consisting of acetonitrile and water. The pure product 10 (25 mg, 0.06 mmol)* was a glassy solid characterized by Η-NMR and LC/MS (LRMS (MH) m/z: 424.1). N =\ BocHN BocHN ^ O
Figure imgf000277_0001
Figure imgf000277_0002
[00494] To a solution of amidoxime 8 (148 mg, 0.35 mmol) in trimethylorthoacetate (5 mL) was added glacial acetic acid (100 μL), The resulting solution was stilted at 65 DC for 16 hours. The solvents were evaporated and the residue was directly purified tlirough silica gel (5% methanol/dichloromethane) to provide the desired product 9 as a glassy solid, characterized by LC/MS (LRMS (MH) m/z: 440.1. Example 86
Figure imgf000278_0001
[00495] To a solution of 1 (200 mg, 0.5 mmol) in THF (3 mL) were added Bu3P (150 uL, 0.6 mmol) and 2-nitrophenylselenocyanate (136 mg, 0.6 mmol) at room temperamre. The reaction mixture was stin-ed for 14 h. The mixture was partitioned between EtOAc (200 mL) and H 0 (50 mL). The organic layer was washed with brine, dried over Na2S0 , and concentrated. The resulting residue was used without further purification. LRMS (M+H+) w/ 5S7.1.
[00496] To a solution of 2 (-0.5 mmol) in DCM (5 mL) were added aqueous KH2PO4
(2 M, 1 ml) and MCPBA (77%, 135 mg, 0.6 mmol). The resulting mixture was stirred for 6 h. The reaction mixture was quenched with saturated Na2S2O3 (10 mL). The organic layer was washed with saturated NaHCO , H20, brine, dried over Na2SO4, and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3 (150 mg, 65% from 1). LRMS (M+H+) m/z 3S4.2.
[00497] To a solution of 3 (150 mg, 0.39 mmol) in DCM (S mL) was added TFA (1 mL). The reaction mixmre was stin-ed for 4h. The mixture was concentrated, and dried under high vacuum. To the resulting residue (90 mg, 0.32 mmol) in THF (4 mL) were added DIEA (165 uL, 0.95 mmol) and 4 (140 mg, 0.38 mmol). The resulting mixture was stined for 14 h. The reaction mixture was concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H20 to give 5 (120 mg, 65%). LRMS (M+H4) m/z 471.2. [00498] To a solution of 5 (90 mg, 0.19 mmol) in THF/H20 (2mL/2mL) were added
OsO4 (4.8 mg, 0.019 mmol), NMO (1 17 mg, 0.95 mmol) and pyridine (1.5 uL, 0.019 mmol). The resulting mixture was stirred for 6 h. NaHS0 (300 mg) was added. The reaction mixture was concentrated. The resulting solid was washed with EtOAc (100 mL x 3). The filtrate was concentrated. The resulting residue was purified on preparative TLC plate (silica gel, 5: 1 EtOAc/MeOH) to give diasteroisomers 6a (23 mg, 24%) and 6b (2 mg, 2%). LRMS (M+H*) m/z 505.2.
Example 87
Figure imgf000279_0001
[00499] To a solution of amine 1 (150 mg, 0.309 mmol), DCM (2 mL) and DIEA
(53,8 uL, 0.309 mmol) was added acetyl chloride (53.8 uL, 0.309 mmol). The resulting solution was stined at room temperature for 10 minutes. The solvent was evaporated, and the remaining residue was purified on reverse phase Prep-HPLC (AcetonitrileAVater) to provide 2 (43,7 mg, 26.8%). MS (MW+1): 527.2
Example 88
Figure imgf000279_0002
[00500] To a solution of amine 1 (150 mg, 0.309 mmol), DCM (2 mL) and DIEA
(53.8 uL, 0.309 mmol) was added trimethylsilyl isocyanate (35.6 uL, 0,309 mmol). The resulting solution was stined at room temperature overnight. The solvent was evaporated, and the remaining residue was purified on reverse phase Prep-HPLC (Acetonitrile Water) to provide 3 (30.3 mg, 18,6%). MS (MW+1): 528.2
Example 89
Figure imgf000280_0001
[00501]
To a solution of amine 1 (150 mg, 0.309 mmol), DCM (2 mL) and DIEA (53.8 uL, 0.309 mmol) was added methanesulfonyl chloride (24 uL, 0.309 mmol). The resulting solution was stirred at room temperature for 30 minutes. The solvent was evaporated, and the remaining residue was purified on Prep-HPLC (Acetonitrile/Water) to provide 4 (18.4 mg, 10.6%). MS (MW+1): 563.1
Example 90
Figure imgf000280_0002
[00502] To a solution of amine 1 (150 mg, 0.309 mmol), DCM (2 mL) and DIEA
(53. S uL, 0.309 mmol) was added methyl chloroformate (24 uL, 0.309 mmol). The resulting solution was stirred at room temperature for 30 minutes. The solvent was evaporated, and the remaining residue was purified on reverse phase Prep-HPLC (Acetonitrile Water) to provide 5 (CK182S648) (25.7 mg, 15.3%). MS (MW+1): 543.1
Example 91
Figure imgf000281_0001
(S)-3 -chloro-N-(4-hydroxy- 1 -(4-(2-( 1 -(methoxyimino)ethyl)- 1 -methyl- 1 H-imidazol-4- yl)phenyl)butan-2-yl)-4-isopropoxybenzamide 2 :
[00503] 80 mg (0.031 mmol) of (S)-N-(l -(4-(2-acetyl-l -methyl- lH-imidazol-4- yl)phenyl)-4-hydroxybutan-2-yl)-3-chloiO-4-isopropoxybenzamide in 2 mL of pyridine was treated with 27.6 mg (0.033 mmol) of hydroxylamine methyl ether hydrochloride. The reaction was stined overnight after which the solvents were evaporated and the residue purified via reverse phase HPLC (acetonitrile/water). 11.2 mg (70% yield) of 2 was obtained and characterized by LCMS and HNMR.
Example 92
Figure imgf000281_0002
(S)-3-chloro-N-(4-hydroxy-l -(4-(2-(l-(hydroxyimino)ethyl)-l -methyl- l H-imidazol-4- yl)phenyl)butan-2-yl)-4-isopropoxybenzamide 3:
[00504] 100 mg (0.21 mmol) of (S)-N-(l -(4-(2-acetyl-l -methyl- lH-imidazol-4- yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide in 2 mL of pyridine was treated with 71.8 mg (1 ,0 m ol) of hydroxylamine hydrochloride. The reaction was stirred overnight after which the solvents were evaporated and the residue punfied via reverse phase HPLC (acetonitrile/water). 69.7 mg (67% yield) of 3 was obtained and characterized by LCMS and HNMR.
Example 93
Figure imgf000282_0001
(S)-3-chloiO-N-(4-hydiOxy-l-(4-(l-methyl-2-(2-methyl-l ,3-dioxolan-2-yl)-lH-imidazol-4- yl)phenyl)butan-2-yl)-4-isopiOpoxybenzamide 4:
[00505] 150 mg (0.31 mmol) of (S)-N-(l -(4-(2-acetyl-l -methyl- lH-imidazol-4- yl)phenyl)-4-hydroxybutan-2-yl)-3-chloro-4-isopropoxybenzamide in 2 mL of benzene was treated with 34.6 uL (0.62 mmol) of ethane- 1 ,2-diol and 59 mg (0,31 mmol) of p- toluenesulfonic acid monohydrate. The reaction was stirred at 70°C for 2 h after which the solvents were evaporated and the residue purified via reverse phase HPLC (acetonitrile/water). 25.5 mg (16% yield) of 4 was obtained and characterized by LCMS and HNMR.
Example 94
BocHN , ,OTBDPS BocHN. „OTBDPS
Figure imgf000282_0002
1 2
[00506] To a solution of 1 (1.5 g, 2.29 mmol), in ethanol (5,0 mL) was added NaOH in water (1.0 M, 3.7 mL, 2.80 mmol). The reaction mixture was stilted at ambient temperature for 2 hours. After the reaction was done it was concentrated to give 2 (1.49 g) which was used directly in the next step without further purification, BocHN ^/ ^OTBDPS BocHN ^^--^^.OTBDPS
Figure imgf000283_0001
[00507] To a solution of 2 (1.49 g, 2.29 mmol), HBTU (1.3 g, 3.44 mmol),
HOBt (530 mg, 3.44 imnol), and N, O-dimethylhydroxyl amine HCI salt (340 mg, 3.44 mmol) in DMF (20 mL) was added DIEA (785 uL, 4.58 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The resulting residue was purified using silica gel (Hexanes/ EtOAc = 1 :3) to give pure compound 3 (1.20 g, 78%) as an off-white, foamy solid.
Figure imgf000283_0002
3 4
[00508] To a 0° C solution of 3 (1.20g, 1.79 mmol) in anhydrous THF (20 mL) was added Methylmagnesium bromide (3 M in Et2O, 2.38 mL), The reaction mixture was stined at 0° C for 1 hour. The reaction mixture was quenched with saturated NH4C1 (5 mL) and water (20 mL). EtOAc (50 mL) was added, and the layers were separated. The aqueous phase was extracted with additional EtOAc (50 mL x 2). The organic phases were combined, dried (Na2S04) and concentrated to a crude oil which was purified using silica gel (50 % EtOAc/Hexanes). The desired compound 4 (0.82 g, 73%) was a viscous oil which became a white foamy solid while drying under high vacuum.
Figure imgf000284_0001
4 5
[00509] To a solution of 4 (0.82 g, 1.31 mmol) in Methanol (10 mL) was added
HCI (4 M in 1 ,4-dioxane, 20 mL). The reaction was stirred at room temperature overnight, The mixture was concentrated, and dried under high vacuum to give 5, which was used in the following step without further purification.
Figure imgf000284_0002
[00510] To a solution of 5 (350 mg, 1 ,09 mmol) in DMF (5 mL) was added DIEA (280 uL, 1.63 mmol) and ester H (472 mg, 1.09 mmol). The resulting solution was stirred at room temperature for 1 hour. The cmde solution was filtered and then purified by reverse phase chi-omatography (using a mixture of acetonitrile and water) to provide CKl 904250 as a foamy white solid (400mg, 68%). LRMS (M+H+)m/z 538.1. BocHN . /^\ .OH _, m, ^ ^-^ BocHN.
Figure imgf000284_0003
Ester D Acid E
[00511] Ester D (10,2 g, 24.5 mmol) was dissolved in EtOH (150 mL) and water (50 mL). Postassium hydroxide (4,1 g, 73.5 mmol) was added, and the reaction was stirred at room temperature ovemight. The reaction mixture was cooled to 0 C and neutralized with concentrated HCI. Great care was taken to not allow thepHto become < 7 during the neutralization. The solvents were evaporated in vauco, and the residue was dried under high vacuum. Acid E (9.5 g, 24.5 mmol) was used in the next step without further purification. BocHN , ,OH
HBTU, HOBt, DIEA - , D _MF » N,0-dimethyLhydroxylaniine HCI
Figure imgf000285_0002
Figure imgf000285_0001
Acid E Amide E
[00512] Acid E (9.5 g, 24.5 mmol) was combined with HBTU (18.5 g, 4S.7 mmol), HOBt (6.6 g, 48,7 imnol), and N,0-dimethylhydroxylamine HCI (4.8 g, 4S.7 mmol). To the solids were added DMF (150 mL) and DIEA (12.7 L, 73.1 imnol). The resulting mixture was stined at room temperature for 4 hours. Most of the DMF was evaporated, and the remaining residue was diluted with ethyl acetate (300 mL) and water (300 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (1 x 200 mL). The organic phases were combined, washed with saturated aqueous sodium bicarbonate (2 x 250 mL), and dried over Na2SO . Concentration under reduced pressure provided crude amide E which was purified using silica gel (3 % MeOH/DCM) to give pure amide E (6.73 g, 17.4 mmol) as an off-white, foamy solid.
BocHN -
Figure imgf000285_0003
Figure imgf000285_0004
Amide E . K..e ,tone „ F
[00513] A solution of amide E (6.73 g, 17.4 mmol) in anhydrous THF (250 mL) was cooled to 0 C with an ice bath. Methylmagnesium bromide (3 M in diethyl ether, 52.2 mL,
1 6.6 mmol) was added, and the reaction was stined at 0 C for 15 minutes. The reaction was carefully quenched with saturated ammonium chloride solution (20 mL) and water (100 mL).
EtOAc (200 mL) was added, and the layers were separated. The aqueous phase was extracted with additional EtOAc (2 x 200 mL). The organic phases were combined, dried
(Na2S0 ) and concentrated to a crude oil which was purified using silica gel (50 %
EtOAc/Hexanes). The desired ketone F (4.45 g, 11.5 mmol) was a viscous oil which became a white foamy solid while drying under high vacuum.
Figure imgf000286_0001
Ketone F .Amine G
[00514] Ketone F (4.45 g, 1 1.5 mmol) was dissolved in THF (25 mL) and 4 M HCI in
1,4-dioxane was added (75 mL). The reaction was sti ed at room temperature for 1.5 hours. The solvents were evaporated in vacuo, and the residue was thoroughly dried under high vacuum to provide amine G. Amine G was used in the following step without further purification.
Figure imgf000286_0002
[00515] To a solution of amine G (3.30 g, 11.5 mmol) in DMF (50 mL) was added
DIEA (8.0 mL, 46.0 mmol) and ester H (5.25 g, 13.S mmol), The resulting solution was stined at room temperature for 1 hour. Most of the DMF was evaporated, and the remaining residue was diluted with EtOAc (250 mL) and water (200 mL), The layers were separated, and the organic phase was λvashed with additional water (2 x 150 mL) and brine (2 x 150 mL). The organic phase was dried (Na2S04) and concentrated. The remaining crude, viscous oil was purified using silica gel (100% EtOAc) to provide CKl 317644 as a foamy white solid (2.98 g, 6.2 mmol).
Example 95
Figure imgf000286_0003
2
[00516] To a solution of ethyl thiooxamate (10.0 g, 75 mmol) in dichloromethane (400 mL) was slowly added trimethyloxonfum tetrafluoroborate (13.1 g, 89 mmol) at 0 °C. After 10 min the ice bath was removed, and the reaction mixture was stirred overnight. The solvent was removed to give 18.0 g of product 2 as white solid, which was used without further purification. ACETIC ACID SODIUM ACETATE
Figure imgf000287_0001
Figure imgf000287_0002
[00517] A mixture of 2-amino-4'-bromoacetophene hydrochloride (10.0 g, 40 imnol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stined at 65 ° C until TLC showed no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO solution and extracted with ethyl acetate. The organic solution was dried over Na2SO4 and concentrated. Purification with flash column chiOmatography (EtOAc:Hexs 1 :1) gave product 3 (9,11 g, 79 %) as a white solid.
Figure imgf000287_0003
[00518] To a solution of compound 3 (3.174 g, 10. S mmol) in DMF ( 15 mL) was added K2CO3 (4.478 g, 32.4 mmol) and (2-bromoethoxy)-/β/ -butyldimethylsilane (2.780 mL, 13.0 mmol). The resulting mixture was stined at 55 °C overnight. The solution was concentrated, diluted with water and extracted with EtOAc (3 x 50 mL), The organic layers were combined and dried over Na2SO4. The solvent was removed to give a viscous oil (4.S05 g, 10.6 mmol, 98.4%), which was used in the subsequent step without further purification.
MeMgBr, THF, 0°C
Figure imgf000287_0005
Figure imgf000287_0004
4 5
[00519] To a solution of compound 4 (2.174 g, 4.S mmol) in anhydrous THF (25 mL) was added dropwise methylmagnesium bromide (4.S mL, 3 M in diethyl ether, 14.4 mmol) under nitrogen at 0 °C. The reaction was stirred at 0 °C for 15 minutes. The reaction was carefully quenched with saturated ammonium chloride solution (5 mL) and water (30 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na?SO4 and concentrated to a cmde oil. Purification with flash column chromatography (1 % EtOAc/Hexanes) gave the desired product 5 (1,371 g, 65%) as a white amorphous solid
Figure imgf000288_0001
[00520] To a solution of compound 5 (1.371 g, 3.1 mmol) in THF (5 mL) was added
35 mL of HCI (4 M in 1 ,4-dioxane). The resulting solution was stined at room temperature overnight. The solvents were removed to give the product 6 (1.0 g, 99%>) as white solid.
Figure imgf000288_0002
6
[00521] A mixture of compound 6 (0.5 g, 1.54 mmol) and 1 mL of TFA in toluene (60 mL) was refluxed overnight. The solid 6 did not dissolve until around the boiling point of toluene. The solvent was removed. The residue was diluted with EtOAc, washed with NaHC03 aqueous solution, dried over Na2SO , and concentrated. Purification with flash column chromatography (EtOAc:Hexanes 1 :1) gave the product 7 (0.348 g, 74%) as a white solid.
Figure imgf000288_0003
[00522] To a suspension of zinc powder (255 mg, 3.9 mmol) in dry degassed DMF (15 mL) was added 1,2 dibromoethane (.020 mL, 0.23 mmol) under nitrogen. The mixture was heated using a heat gun for about 30 seconds until gas starts to evolve from the solution, indicating the activation of the zinc. The mixture was then allowed to cool to room temperature followed by the addition of TMSCl (6 uL, 0.05 mmol), and allowed to stir at room temperature for 30 min. A solution of iodo compound A in degassed DMF was added to the zinc solution, and the reaction mixture was stilted for 1 hour at room temperature. Then a solution of compound 7 (200 mg, 0.65 mmol) in degassed DMF was added via a syringe, followed by the addition of Pd2(dba ) (14.9 mg, 0,016 imnol) and tri-o-tolylphospine (19.8 mg, 0.065 mmol). The reaction mixture was stilted for one hour at room temperature, then at 40 ° C for 2 hours. The reaction was complete as shown on TLC. The solution was quenched with brine and extracted with EtOAc (5 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification with flash column chromatography (EtOAc:Hex 1 :1) gave the product 8 (373 mg, 88 %) as a colorless oil.
Boc
HN 3DPS H,N.
Figure imgf000289_0001
8
[00523] To a solution of compound 8 (373 mg, 0.57 mmol) in MeOH (10 mL) was added 2 mL of HCI (4.0 M in Dioxane). The solution was allowed to stir at room temperature for 2 hours. The solvent was removed to give the c de product 9 (180 mg, 99%), which was used without further purification.
Figure imgf000289_0002
9 10
[00524] A mixture of compound 9 (180 mg, 0.57 mmol) and ester reagent B (260 mg,
0.68 mmol) in DMF (10 mL) containing triethylamine (0,24 mL, 1.71 mmol) was stirred at room temperature ovemight. The reaction solution was diluted with brine and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification with HPLC (CIS column) gave the product 10 (141 mg, 50%) as a white solid.
Figure imgf000290_0001
4
[00525] To a suspension of NaH (0.39 g, 9.3 mmol) in DMF (15 mL) was added a solution of 3 (1 ,9 g, 6.5 mmol) in DMF (10 mL) at 0 °C under nitrogen. The reaction was stined for 1.5 hour, and then (2-bromoethoxy)- er/-butyldimethylsilane (2.09 mL, 9.7 mmol) was added. The reaction mixture was stined overnight, diluted with EtOAc, quenched with aqueous ammonium chloride solution, and extracted with EtOAc (3 x 50 mL). The organic layers were combined and dried over Na2SO . Purification with biotage (EtOAc) gave the product 4 (1.2 g, 41 >) as light yellow solid.
Figure imgf000290_0002
[00526] To a suspension of zinc powder (1.2 g, 18.4 mmol) in dry degassed DMF (15 mL) was added 1 ,2 dibromoethane (0.13 mL, 1.5 mmol) under nitrogen, The mixture was heated using a heat gun for about 30 seconds until gas starts to evolve from the solution, indicating the activation of the zinc. The mixture was then allowed to cool to room temperature followed by the addition of TMSCl (100 uL), and allowed to stir at room temperature for 30 min. A solution of iodo compound A (1.71 g, 3,1 mmol) in degassed DMF was added to the zinc solution, and the reaction mixture was stined for 1 hour at room temperature. Then a solution of compound 4 (1.0 g, 2.2 mmol) in degassed DMF was added via a syringer, followed by the addition of Pd2(dba3) (0.14 g, 0.015 mmol) and Tri-o- tolylphospine (0.18 g, 0.06 nunol). The reaction mixture was stirred for one hour at room temperature, then at 60 ° C overnight. The solution λvas quenched with brine and extracted EtOAc (5 x 50 mL), The combined organic layers were dried over sodium sulfate and concentrated. Purification with flash column chiOmatography (EtOAc:Hex 1 :1) gave the product 5 (346 mg, 20%) as colorless oil.
Figure imgf000291_0001
[00527] To a solution was compound 7 (346 mg) in MeOH (10 mL) was added 2 mL of HCI (4.0 M in Dioxane). The solution was allowed to stir at room temperamre for 2 hour. The solvent was removed to give the cmde product 7, which was used for the next step without further purification.
Figure imgf000291_0002
[00528] A mixture of compound 7, ester reagent B (200 mg, 0.52 mmol) in DMF (10 mL) containing triethylamine (0.15 mL, 1 ,08 mmol) was stirred at room temperature over night. The reaction solution was diluted with brine, extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification with HPLC (CI 8 column) gave the product 8 (0.2 g, 87%) as white solid, and the lactone product 9 (15.4 mg, 7.3%) as white solid. LC-MS (CI) m/z 489.1 (MH+)
Example 96
.90 o.
Figure imgf000292_0001
2
[00529] To a solution of ethyl thiooxamate (10.0 g, 75 mmol) in dichloromethane (400 mL) was slowly added trimethyloxonium tetrafluoroborate (13.1 g, 89 mmol) at 0 °C. After 10 min the ice bath was removed, and the reaction mixture was stined overnight. The solvent was removed to give 1S.0 g of product 2 as white solid, which was used without further purification. ACETIC ACID SODIUM ACETATE
Figure imgf000292_0002
Figure imgf000292_0003
[00530] A mixture of 2-amono-4'-bromoacetophene hydrochloride (10.0 g, 40 mmol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, SO mmol) in dioxane (70 mL) was stined at 65 ° C until TLC show no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO3 solution, and extracted with ethyl acetate. The organic solution was dried over Na?SO4 and concentrated. Purification with flash column chromatography (EtOAc:Hexs 1 :1) gave product 3 (9.11 g, 79 %) as white solid.
Figure imgf000292_0004
[00531] To a solution of compound 3 (5.307 g, 18 mmol) in DMF (15 mL) was added
K2C03 (3.73 g, 27 mmol) and iodoethane (3.5 mL, 43.2 mmol). The resulting mixture was stirred at 60 °C for three hours. The mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2SO4( and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 4 (3.2 g, 55 %) as white solid,
Figure imgf000293_0001
[00532] To a suspension of zinc powder (3.90 g, 59.6 mmol) in dry degassed DMF (10 mL) was added 1 ,2 dibromoethane (308 uL, 3.5S mmol) under nitrogen. The mixture was heated using a heat gun for about 30 seconds until gas starts to evolve from the solution, indicating the activation of the zinc. The mixture was then allowed to cool to room temperature followed by the addition of TMSCl (92 uL, 0.735 mmol), and allowed to stir at room temperature for 30 min, A solution of iodo compound A (6.6 g, 1 1.9 mmol) in degassed DMF was added to the zinc solution, and the reaction mixture was stined for 1 hour at room temperature. Then a solution of compound 4 (3.2 g, 9.93 mmol) in degassed DMF was added via a syringe, followed by the addition of Pd2(dba3) (223 mg, 0.244 mmol) and Tri-o- tolylphospine (302 mg, 0.992 mmol). The reaction mixture was stined for one hour at room temperature, then at 60 ° C for 2 hours. The reaction was complete as shown on TLC. The solution was quenched with brine and extracted EtOAc (3 x 80 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification with flash column chromatography (EtOAc:Hex 1 :1) gave the product 5 (5.43 mg, 82 %) as colorless oil.
Figure imgf000293_0002
[00533] To a solution of compound 5 (5.43 g, 8.1 mmol) in THF (50 mL) λvas added dropwise a solution of MeMgBr bromide in ether (9.0 mL, 27 mmol) at 0 ° C under nitrogen. The reaction was complete in 10 min via TLC. The solution was quenched by aqueous ammonium chloride solution while in ice, extracted with EtOAc (3 x 60 mL). The combined organic layers were dried over sodium sulfate and concentrated, Purification with column chromatography (Hexanes/EtOAc 1 :1) gave the product 6 (4.86 g, 91 %) as colorless oil.
Figure imgf000294_0001
[00534] A mixture of compound 6 (4.86 g, 7.4 mmol), and 18 mL of HCI (4M in
Dioxane) in MeOH (10.0 mL) was stined at room temperature for 1 hour, followed by- heating at 60 ° C for 30 min, The reaction was complete via TLC and LC/MS, The solvent was removed to give the product 7, which was directly used for the next step.
Figure imgf000294_0002
[00535] A mixture of acid B (677 mg, 2.51 mmol), HBTU (3.6 g, 9.49 mmol), HOBT
(1.45 g, 9,46 mmol) and DIEA (2.20 mL, 12.6 mmol) in DMF (40 mL) was stin at room temperature for 1 min followed by the addition of 7 (1.0 g, 3.14 imnol). The reaction was complete in one hour via TLC and LC/MS. The solution was partitioned in EtOAc and brine, and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated down. Purification with HPLC gave product 8 (390 mg) as white solid.
Figure imgf000294_0003
[00536] To a solution of compound 3 (2.66 g, 7.27 mmol) in DMF (15 mL) was added
K2CO3 (2.00 g, 15 mmol) and ethyl bromoacetate (1.61 mL, 14.5 mmol). The resulting mixture was stined at 60 °C for three hours. The mixture was diluted with water and extracted with EtOAc (3 x 50 mL), The organic layers were combined, dried over Na SO > and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 4 (3.02 g, 91 %).
Figure imgf000295_0001
[00537] To a solution of compound 4 (3.02 g, 6.7 mmol) in MeOH (20 mL) was added
HCI (4.0 M) in Dioxane (7.0 mL) and stined at 60 °C for one hours. The mixture was concentrated and no purification was done. The resulting oil was dissolved in DMF (15 mL), added K2C03 (2.0 g, 14.7 mmol) was added, and stined at 60 °C for ovemight. The mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2S04) and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 5 (1.80 g, S8 %).
Figure imgf000295_0002
[00538] To a solution of compound 3 (5.000 g, 17 mmol) in DMF (15 mL) was added
K2C03 (3.51 g, 26 mmol) and Boc-2-amino ethyl bromide (4,56 g, 20.35 mmol). The resulting mixture was stined at 60 °C for three hours. The mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2SO4, and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 4 (4.08 g, 55 %) as white solid.
Figure imgf000295_0003
Example 97
Figure imgf000296_0001
[00539] To a solution of 1 (10.7 g, 34.6 mmol) in MeOH / H2O (60 mL / 20 mL ) was added NaOH (2N, 20.8 ml, 41.6 mmol). After the mixture was stirred at 50 °C for 2 h, the solution then was concentrated and under high vacuum to yield 10.3 g of light yellow solid (LRMS (M-H+) m/z 278.9), which was used for the next step without further purification. To a solution of the cmde mixture in DMF (50 mL) were successively added N,O- dimethylhydroxylamine hydrochloride (4.0 g, 40.7 mmol), HBTU (4.0 g, 40.7 mmol), HOBT (6.2 g, 40.7 mmol) and DIEA (6,0 ml, 40.7 mmol). The mixture was stirred at rt overnight. The solution then was partitioned between EtOAc and H2O. The organic layer was washed with NaOH (1 N), brine, dried over Na S04, filtered and concentrated. The residue was purified by flash column chromatography using a mixture of hexanes and EtOAc to give 2 (8 g, 72%). LRMS (M+H+) m/z 324.0.
Figure imgf000296_0002
[00540] To a solution of 2 (3.7 g, 11.4 mmol) in THF (40 mL) was added dropwise
MeMgBr in Et20 (3M, 11.4 ml, 34.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The solution was quenched by saturated NH4C1 at 0 °C and diluted between EtOAc and H 0. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 3 (3.0 g, 94%) without further purification. LRMS (M+H+) m/z 279.0.
Figure imgf000297_0001
3 4
[00541] To a solution of 3 (3.0 g, 10.S mmol) in THF / MeOH (10 mL / 10 mL) was slowly added NaBH4 (407 mg, 10.8 mmol). The mixture was stirred for 10 min, quenched by saturated NH4C1 and partitioned between EtOAc and H20. The organic layer was washed with Sat NaHCO3, brine, dried over Na2SO , filtered and concentrated to give 4 (3.0 g, 99 %), which was used without further purification. LRMS (M+H*) m/z 281.0.
Figure imgf000297_0002
[00542] To a solution of 4 (3.0 g, 10.7 mmol) in DMF (20 mL) was added TBDMSCI
(1.6 g, 10.7 mmol), imidazole (726 mg, 10.7 mmol ) and DMAP (271 mg, 21.3 mmol ). The mixture was stined at rt overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Sat NaHCO3, H2O, brine, dried over Na2SO , filtered and concentrated. The residue was purified by column chromatography using a mixture of hexanes and EtOAc to give 5 ( 3.5 g, 83%). LRMS (M+H+) m/z 395 A .
Negishi
Figure imgf000297_0003
Figure imgf000297_0004
[00543] To a suspension of Zn (4.S g, 74.4 mmol) in DMF (20 mL) was added
BrCH2CH2Br (320 μL, 3,7 mmol). The mixture was heated by heat gun for 4 min, After the solution was cooled down, trimethylchlorosilane (95 μL, 0.74 mmol) was added, After 30 min, BOC-β-iodo-Ala-OMe (5.2 g, 16.0 mmol) was added, and reaction mixture was stirred at rt for lh. To this mixture then were added Pd (dba)3 (243 mg, 0.27 mmol), (O-Tol)3P (269 mg, 0.88 mmol) and 5 (3.5 g, 8.9 mmol). The mixture was heated at 50 °C for 2h. cooled down and filtered through celite. The solution was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography using a mixture of hexanes and EtOAc to give 6 (3.3 g, 72%). LRMS (M+H*) m/z 518.2 .
BOCHN BOCHN , OH
Figure imgf000298_0001
Figure imgf000298_0002
[00544] To a solution of 6 ( 3.3 g, 6.4 mmol) in THF ( 20 ml) was slowly added LAH
(1 M, 6.4 L, 6.4 mmol) at 0 °C, The mixture was stined at 0 °C in 20 min, quenched by H2O (240 μL), NaOH (3N, 240 μL), H20 (720 μL), filtered. The organic layer was dried over Na S0 , filtered and concentrated. The residue was purified by column chromatography using a mixture of hexanes and EtOAc to give 7 (1.57 g, 50%). LRMS (M+H+) m/z 490.2.
Figure imgf000298_0003
[00545] To a solution of 7 (1 ,57g, 3.2 mmol) in THF (20 mL) were added PPh3 (1.0 g,
3.9 mmol), DIAD (746 μL, 3.9 mmol) and phthalimide (567 mg, 3.9 mmol). After the solution was stined at rt for 4 hours, which was monitored by LCMS, the reaction was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO , filtered and concentrated. The residue was purified by column chromatography using a mixture of hexanes and EtOAc to give 8 (2.0 g, 99%). LRMS (M+H*) m/z 619.2. NH2NH2, MeOH
Figure imgf000299_0002
Figure imgf000299_0001
[00546] To a solution of 7 (2g, 3.2mmol) in MeOH (15 ml) was added NH2NH2
(1.01ml, 32.3 mmol). After the reaction was stirred at room temperature for about 4 h, the solution was precipitated, filtered, washed with CH C12, MeOH. The organic layer was concentrated to give 8 (2.5 g), which was used without further purification. LRMS (M+H*) m/z 489.2.
Figure imgf000299_0003
[00547] To a solution of 8 (1.5g, 3.1 mmol) in CH2C12 / CH3CN (15 ml /l 5 ml ) were added DIEA (588 μL, 3.4 mmol) and chloroacetyl chloride (269 μL, 3.4 mmol). After the reaction was stirred at rt for 10 min, azetidine (2 ml, 30.7 mmol ) and DIEA (2.7 ml, 15.3 mmol) were added. The reaction mixture was stilted overnight, The solution was concentrated and diluted between EtOAc and H2O, The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography using a mixture of hexanes and EtOAc to give 9 (900 mg, 51%) LRMS (M+H*) /r 586.3.
Figure imgf000300_0001
[00548] To a solution of 9 (900 mg, 1.53 mmol) in MeOH (1 mL) were added HCI in dioxane (4 N, 2 ml) and HCI in H O (2 N, 1ml). The solution was stined at rt overnight, concentrated to give white solid and directed for the next coupling step, To a DMF (10ml) solution of the cmde compound were added 9.1 (665 mg, 1 ,53 mmol) and DIEA (800 ul, 4,59 mmol ), The mixture was stined at rt for 1 h and partitioned between EtOAc and H O. The organic layer was washed with brine, dried over Na2SO , filtered and concentrated. The residue was purified by reverse-phase HPLC to give 10 (600 mg, 63 %). LRJVIS (M+H*) m/z 622.2.
Figure imgf000300_0002
[00549] To a solution of 10 (160 mg, 0.24 mmol) in DCM (10 mL) was added MnO2
(416 mg, 4.8 mmol). The suspension was stirred for 14 h. The reaction mixture was filtered, and the filtrate was concentrated and purified on reverse-phase HPLC using a mixture of acetonitrile and H20 to give 11 (90 mg, 60%), LRMS (M+H*) m/z 620.1.
Example 98
[00550] The following compounds were prepared using the procedures described above: Name MS (m z)
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Example 99
Inhibition of CeUular Viability in Tumor Cell Lines Treated with Mitotic Kinesin
Inhibitors
[00551] Materials and Solutions: • Cells: SKOV3, Ovarian Cancer (human). • Media: Phenol Red Free RPMI + 5% Fetal Bovine Serum + 2mM L-glutamine. • Colorimetric Agent for Determining Cell Viability: Promega MTS tetrazolium compound. • Control Compound for max cell kill: Topotecan, lμM,
Procedure: Day 1 - Cell Plating:
[00552] Adherent SKOV3 cells are washed with 1 OmLs of PBS followed by the addition of 2mLs of 0,25% trypsin and incubation for 5 minutes at 37°C. The cells are rinsed from the flask using 8 mL of media (phenol red-free RPMI+ 5%FBS) and transferred to fresh flask. Cell concentration is determined using a Coulter counter and the appropriate volume of cells to achieve 1000 cells/lOOμL is calculated. 100 μL of media cell suspension (adjusted to 1000 cells/100 μL) is added to all wells of 96-well plates, followed by incubation for 18 to 24 hours at 37°C, 100% humidity, and 5% CO2, allowing the cells to adhere to the plates.
Procedure: Day 2 - Compound Addition:
[00553] To one column of the wells of an autoclaved assay block are added an initial
2.5 μL of test compoυnd(s) at 400X the highest desired concentration. 1.25 μL of 400X (400μM) Topotecan is added to other wells (ODs fi-om these λvells are used to subtract out for background absorbance of dead cells and vehicle). 500 μL of media without DMSO are added to the wells containing test compound, and 250 μL to the Topotecan wells. 250 μL of media + 0.5% DMSO is added to all remaining wells, into which the test compound(s) are serially diluted. By row, compound-containing media is replica plated (in duplicate) from the assay block to the conesponding cell plates. The cell plates are incubated for 72hours at 37°C, 100% humidity, and 5% C02.
Procedure: Day 4 - MTS Addition and OD Reading:
[00554] The plates are removed fi-om the incubator and 40 μl MTS / PMS is added to each well. Plates are then incubated for 120 minutes at 37°C, 100% humidity, 5%CO2, followed by reading the ODs at 490nm after a 5 second shaking cycle in a ninety-six well spectrophotometer.
Data Analysis
[00555] The normalized % of control (absorbance- background) is calculated and an
XLfit is used to generate a dose-response curve from which the concentration of compound required to inhibit viability by 50% is determined. The compounds of the present invention
507 show activity when tested by this method.
Example 100
Application of a Mitotic Kinesin Inhibitor
[00556] Human tumor cells Skov-3 (ovarian) were plated in 96-well plates at densities of 4,000 cells per well, allowed to adhere for 24 hours, and treated with various concentrations of the test compounds for 24 hours, Cells were fixed in 4% formaldehyde and stained with antitubulin antibodies (subsequently recognized using fluorescently-labeled secondary antibody) and Hoechst dye (which stains DNA).
[00557] Visual inspection revealed that the compounds caused cell cycle anest.
Example 101
Inhibition of Cellular Proliferation in Tumor Cell Lines Treated with Mitotic Kinesin
Inhibitors.
[00558] Cells were plated in 96-well plates at densities fi-om 1000-2500 cells/well of a
96-well plate and allowed to adhere/grow for 24 hours. They were then treated with various concentrations of dmg for 4S hours. The time at which compounds are added is considered To. A tetrazolium-based assay using the reagent 3-(4,5-dimethylthiazol-2-yl)-5-(3- carbox)methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) (I,S> Patent No. 5,185,450) (see Promega product catalog #G3580, CellTiter 96® AQUeo_s One Solution Cell Proliferation Assay) was used to determine the number of viable cells at To and the number of cells remaining after 48 hours compound exposure. The number of cells remaining after 48 hours was compared to the number of viable cells at the time of dmg addition, allowing for calculation of growth inhibition,
[00559] The growth over 48 hours of cells in control wells that had been treated with vehicle only (0.25% DMSO) is considered 100% growth and the growth of cells in wells with compounds is compared to this. Mitotic kinesin inhibitors inhibited cell proliferation in human ovarian tumor cell lines (SKOV-3).
[00560] A Gi5o λvas calculated by plotting the concentration of compound in μM vs the percentage of cell growth of cell growth in treated wells. The Giso calculated for the compounds is the estimated concentration at which growth is inhibited by 50% compared to control, i.e., the concentration at which: 100 x [(Treated4S - T0) / (Controls - T0)] = 50. [00561] All concentrations of compounds are tested in duplicate and controls are averaged over 12 wells. A very similar 96-well plate layout and Gi50 calculation scheme is used by the National Cancer Institute (see Monks, et al, J. Natl. Cancer Inst. 83:757-766 (1991)). However, the method by which the National Cancer Institute quantitates cell number does not use MTS, but instead employs alternative methods.
Example 102 Calculation of ICso:
Measurement of a composition's IC50 uses an ATPase assay. The following solutions are used: Solution 1 consists of 3 mM phosphoenolpyruvate potassium salt (Sigma P-7127), 2 mM ATP (Sigma A-3377), 1 mM IDTT (Sigma D-9779), 5 μM paclitaxel (Sigma T-7402), 10 ppm antifoam 289 (Sigma A-8436), 25 mM Pipes/KOH pH 6.S (Sigma P6757), 2 mM MgC12 (VWR JT400301), and 1 mM EGTA (Sigma E3889). Solution 2 consists of 1 mM NADH (Sigma NS129), 0.2 mg/ml BSA (Sigma A7906), pyruvate kinase 7U/ml, L-lactate dehydrogenase 10 U/ml (Sigma P0294), 100 nM motor domain of a mitotic kinesin, 50 μg/ml micrombules, 1 mM DTT (Sigma D9779), 5 μM paclitaxel (Sigma T-7402), 10 ppm antifoam 289 (Sigma A-8436), 25 mM Pipes/KOH pH 6.8 (Sigma P6757), 2 mM MgC12 (VWR JT4003-01), and 1 mM EGTA (Sigma E3889). Serial dilutions (8-12 two-fold dilutions) of the composition are made in a 96-well microtiter plate (Coming Costar 3695) using Solution 1. Following serial dilution each well has 50 μl of Solution 1. The reaction is started by adding 50 μl of solution 2 to each well. This may be done with a multichannel pipettor either manually or with automated liquid handling devices. The microtiter plate is then transfened to a microplate absorbance reader and multiple absorbance readings at 340 nm are taken for each well in a kinetic mode. The observed rate of change, which is proportional to the ATPase rate, is then plotted as a function of the compound concentration. For a standard IC50 determination the data acquired is fit by the following four parameter equation using a nonlinear fitting program (e.g., Grafit 4): Range ^ , y = + Background
Figure imgf000310_0001
where y is the observed rate and x the compound concentration.
[00562] Other chemical entities of this class were found to inhibit cell proliferation, although GI5o values varied. GI50 values for the chemical entities tested ranged from 200 nM to greater than the highest concentration tested. By this we mean that although most of the chemical entities that inhibited mitotic kinesin activity biochemically did inhibit cell proliferation, for some, at the highest concentration tested (generally about 20 μM), cell growth was inhibited less than 50%. Many of the chemical entities have GI50 values less than 10 μM, and several have GI50 values less than 1 μM. Anti-proliferative compounds that have been successfully applied in the clinic to treatment of cancer (cancer chemotherapeutics) have GI5o's that vary greatly. For example, in A549 cells, paclitaxel GI50 is 4 nM, doxorubicin is 63 nM, 5-fluorouracil is 1 μM, and hydroxyurea is 500 μM (data provided by National Cancer Institute, Developmental Therapeutic Program, http://dtp.nci.nih.gov/). Therefore, compounds that inhibit cellular proliferation at virtually any concentration may be useful.
What is claimed is:

Claims

At least one chemical entity chosen from compounds of Formula I
Figure imgf000312_0001
Fonnula I
and phannaceutically acceptable salts, solvates, chelates, non-covalent complexes,'prodrugs, and mixtures thereof, wherein
Ri is optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; X is -CO or-SO2-;
R2 is hydrogen or optionally substituted lower alkyl; W is — CR4-, -CH2CR4-, or N; R3 is -CO-R7, hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, cyano, optionally substituted sulfonyl, or optionally substituted aryl; R is hydrogen or optionally substituted alkyl; R5 is hydrogen, hydroxyl, optionally substituted amino, optionally substituted heterocyclyl; or optionally substituted lower alkyl; R6 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; provided that if W is N, then R5 is not hydroxyl or optionally substituted amino, and R6 is not optionally substituted alkoxy, optionally substituted aralkoxy, optionally substituted heteroaralkoxy, or optionally substituted amino.
2. At least one chemical entity of claim 1 wherein Ri is optionally substituted aryl.
3. At least one chemical entity of claim 2, wherein Ri is optionally substituted phenyl.
4. At least one chemical entity of claim 3, wherein Ri is phenyl substituted with one, two or three groups independently selected from optionally substituted heterocyclyl, optionally substituted alkyl, sulfonyl, halo, optionally substituted amino, optionally substituted sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy; acyl, hydroxyl, nitro, cyano, optionally substituted aryl, and optionally substituted heteroaryl-.
5. At least one chemical entity of claim 4, wherein Ri is 3-halo-4-isopropoxy-phenyl or 3 -cyano-4-isopropoxy-phenyl .
6. At least one chemical entity of any one of claims 1 to 4 wherein X is -CO-.
7. At least one chemical entity of claim 1 wherein the compound of Formula I is chosen from compounds of Formula II
Figure imgf000313_0001
(Formula II) wherein Rn is optionally substituted heterocyclyl, optionally substituted lower alkyl, nitro, cyano, hydrogen, sulfonyl, or halo; R1 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 R13 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-.
8. At last one chemical entity of any one of claims 1 to 7 wherein W is — CR4-.
9. At least one chemical entity of any one of claims 1 to 8 wherein R is hydrogen.
10. At least one chemical entity of any one of claims 1 to 9 wherein R5 is hydrogen, hydroxyl, or optionally substituted lower alkyl.
11. At least one chemical entity of claim 10 wherein R5 is hydrogen.
12. At least one chemical entity of claim 7 wherein the compound of Formula II is chosen from compounds of Formula III
Figure imgf000314_0001
(Formula III).
13. At least one chemical entity of any one of claims 1 to 12 wherein R3 is -CO-R7; hydrogen; optionally substituted lower alkyl; cyano; optionally substituted sulfonyl; optionally substituted aryl; or optionally substituted heterocyclyl.
14. At least one chemical entity of claim 13 wherein is optionally substituted lower alkyl.
15. At least one chemical entity of claim 14 wherein R3 is lower alkyl that is optionally substituted with a hydroxyl or a phosphate ester thereof, lower alkyl that is optionally substituted with a lower alkoxy, lower alkyl that is optionally substituted with an optionally substituted amino group, or lower alkyl that is optionally substituted with CO-R7 where R is hydroxyl or optionally substituted amino.
16. At least one chemical entity of claim 15 wherein R3 is lower alkyl that is optionally substituted with a hydroxyl or a phosphate ester thereof or lower alkyl that is optionally substituted with an optionally substituted amino group.
17. At least one chemical entity of claim 12 wherein the compound of Formula III is chosen from compounds of Formula FV
Figure imgf000315_0001
(Foπnula IV).
18. At least one chemical entity of any one of claims 1 to 17 wherein R6 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted alkyl.
19. At least one chemical entity of claim 18 wherein R6 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, ethyl enedioxy, sulfonyl, aminocarbonyl, carboxy, alkoxycarbonyl, nitro, heteroaralkoxy, aralkoxy, and optionally substituted heterocyclyl.
20. At least one chemical entity of claim 12 wherein the compound of Formula III is chosen from compounds of Fomiula V
Figure imgf000316_0001
(Formula V) wherein Rι4 is optionally substituted heteroaryl; and R15 is chosen fi-om hydrogen, halo, hydroxyl, and lower alkyl.
21. At least one chemical entity of claim 20, wherein Rι4 is chosen from 7,8-dihydro-imidazo[ 1 ,2-c][ 1 ,3]oxazin-2-yl, 3a,7a-dihydro-lH-benzoimidazol-2-yl, imidazo[2, 1 -b]oxazol-6-yl, oxazol-4-yl, 5,6,7,8-tetrahydro-imidazo[l,2-a]pyridin-2-yl, lH-[l,2,4]triazol-3-yl, 2,3-dihydro-imidazol-4-yl, lH-imidazol-2-yl, imidazo[l ,2-a]pyridin-2-yl, thiazol-2-yl, thiazol-4-yl, pyrazol-3-yl, and lH-imidazol-4-yl, each of which is optionally substituted with one, two, or three groups chosen from optionally substituted lower alkyl, halo, acyl, sulfonyl, cyano, nitro, optionally substituted amino, and optionally substituted heteroaryl.
22. At least one chemical entity of claim 21 , wherein Rι4 is chosen from lH-imidazol-2-yl, imidazo[l,2-a]pyridin-2-yl; and lH-imidazol-4-yl, each of which is optionally substituted with one or two groups chosen from optionally substituted lower alkyl, halo, and acyl.
23. At least one chemical entity of any one of claims 20 to 22 wherein R15 is hydrogen.
24. At least one chemical entity of claim 12 wherein the compound of Formula II is chosen from compounds of Formula VI
Figure imgf000317_0001
(Formula VI)
25. At least one chemical entity of claim 12 wherein the compound of Formula II is chosen from compounds of Foπnula VII
Figure imgf000318_0001
(Formula VII)
wherein
R9 is chosen fi-om optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted arylalkoxy, optionally substituted amino and optionally substituted lower alkyl.
26. At least one chemical entity of claim 25 wherein R9 is lower alkyl substituted with hydroxyl or optionally substituted amino.
27. At least one chemical entity of claim 26 wherein R9 is lower alkyl substituted with hydroxyl, amino, N-methylamino, or N,N-dimethylamino.
28. At least one chemical entity of any one of claims 7 to 27 wherein Ri 1 is hydrogen, cyano, nitro, or halo.
29. At least one chemical entity of claim 28 wherein Rn is chloro or cyano.
30. At least one chemical entity of any one of claims 7 to 29 wherein Rj2 is optionally substituted lower alkoxy, optionally substituted lower alkyl, or optionally substituted amino-
31. At least one chemical entity of claim 30 wherein Rj2 is lower alkoxy or 2,2,2- trifluoro- 1 -methyl-ethoxy.
32. At least one chemical entity of claim 31 wherein Rj2 is propoxy or 2,2,2-trifluoro-l- methyl-ethoxy.
33. At least one chemical entity of any one of claims 7 to 32 wherein R1 is hydrogen.
34. At least one chemical entity of any one of claims 1 to 33 wherein R2 is hydrogen.
35. At least one chemical entity of claim chosen from the compounds described in Table 1, 2, 3, 4, 5, or 6 and pharmaceutically acceptable salts, solvates, chelates, non-covalent omplexes, prodmgs, and mixtures thereof.
36. At least one chemical entity of claim 35 that is a phosphate ester of chosen from the compounds described in Table 1, 2, 3, 4, 5, or 6.
37. A composition comprising a pharmaceutical excipient and at least one chemical entity of any one of claims 1 to 36.
38. A composition according to claim 37, wherein said composition further comprises a chemotherapeutic agent other than a compound of Formula I.
39. A composition according to claim 38, wherein said composition further comprises a taxane, a vinca alkaloid, or a topoisomerase I inhibitor.
40. A method of modulating CENP-E kinesin activity which comprises contacting said kinesin with an effective amount of at least one chemical entity of any one of claims 1 to 36.
41. A method of inhibiting CENP-E which comprises contacting said kinesin with an effective amount of at least one chemical entity of any one of claims 1 to 36.
42. A method for the treatment of a cellular proliferative disease comprising administering to a subject in need thereof at least one chemical entity of any one of claims 1 to 36.
43. A method for the treatment of a cellular proliferative disease comprising administering to a subject in need thereof a composition according to any one of claims 37 to 39.
44. A method according to claim 42 or 43 wherein said disease is selected from the group consisting of cancer, hypeφlasias, restenosis, cardiac hypertrophy, immune disorders, and inflammation.
45. The use, in the manufacture of a medicament for treating cellular proliferative disease, of at least one chemical entity of any one of claims 1 to 36.
46. The use of at least one chemical entity as defined in claim 45 for the manufacture of a medicament for treating a disorder associated with CENP-E kinesin activity.
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