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WO2008016676A2 - Certain chemical entities, compositions, and methods - Google Patents

Certain chemical entities, compositions, and methods Download PDF

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Publication number
WO2008016676A2
WO2008016676A2 PCT/US2007/017246 US2007017246W WO2008016676A2 WO 2008016676 A2 WO2008016676 A2 WO 2008016676A2 US 2007017246 W US2007017246 W US 2007017246W WO 2008016676 A2 WO2008016676 A2 WO 2008016676A2
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Prior art keywords
methyl
optionally substituted
chlorophenyl
ethylphenyl
carboxamide
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PCT/US2007/017246
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French (fr)
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WO2008016676A3 (en
Inventor
Xiangping Qian
Jeffrey T. Finer
Pu-Ping Lu
Chihyuan Chuang (Grace)
Bradley P. Morgan
David J. Morgans, Jr.
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Cytokinetics Inc
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Cytokinetics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Myosin is present in all muscle and non-muscle cells. Of the ten distinct classes of myosin in human cells, myosin-ll is thought to be the form responsible for contraction of skeletal, cardiac, and smooth muscle. Myosin -Il is also the isoform present in non- muscle myosins, also known as cytoplasmic myosins. The non-muscle myosins are ubiquitously present in eukaryotic cells, where the smooth muscle myosins are generally present in smooth muscle cells.
  • Myosin-ll is significantly different in amino acid composition and in overall structure from myosins in the other nine distinct classes.
  • Myosin-ll consists of two globular head domains, called Subfragment-1 or S1 , linked together by a long alpha- helical coiled-coiled tail.
  • S1 contains the ATPase and actin-binding properties of the molecule. S1 has been shown to be sufficient to move actin filaments in vitro, and is therefore likely to be the motor domain of the molecule.
  • myosin-ll isoforms from various tissues differ in a number of biological properties, they share the same basic molecular structure as a dimer of two heavy chains (approximately 200 kDa) which are noncovalently associated with two pairs of light chains (approximately 20 and 17 kDa).
  • the two globular amino-terminal heads are tethered together by the carboxy-terminal alpha-helical coiled-coil that forms a tail.
  • the tails are believed to be involved in the assembly of myosin molecules into filaments, whereas the heads are thought to have an actin-activated Mg 2+ -ATPase activity.
  • Each myosin head can be divided by three protease-sensitive regions into peptides of approximately 25, 50, and 20 kDa. The more amino-terminal 25 kDa - 50 kDa junction is close to the ATP binding region, whereas the actin-binding domain is near the 50 kDa - 20 kDa junction.
  • S1 consists of a globular actin binding and nucleotide binding region known as the catalytic domain. This domain is attached at its carboxy-terminus to an alpha-helix that has two light chains of about 20 kDa each wrapped around it. This light-chain binding domain of S1 is known as the lever arm. Upon transitioning from the pre-stroke to the post-stroke state, the lever arm is believed to swing through an angle of about 90 degrees about a fulcrum point in the catalytic domain near the nucleotide-binding site. The "power stroke” is driven by the hydrolysis of ATP.
  • the other end of the myosin molecule is an alpha-helical coiled-coiled tail involved in self assembly of myosin molecules into bipolar thick filaments. These thick filaments interdigitate between thinner actin filaments, and the two filament systems slide past one another during contraction of the muscle. This filament sliding mechanism is thought to involve conformational changes in the myosin heads causing them to walk along the thin actin filaments at the expense of ATP hydrolysis. While non-muscle myosins act in a similar manner, they are understood to slide at a slower velocity than the smooth muscle myosins.
  • U is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and * - W 1 COW 2 , where the "*" indicates the point of attachement to Z 1 ;
  • W 1 and W 2 are independently selected from CR 11 R 12 , NR 13 , and O; provided at least one of W 1 and W 2 is NR 13 ;
  • W 3 is selected from CR 1 R 2 , NR 14 and O;
  • Z 1 is aryl
  • Z 2 is aryl
  • R 8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • R 1 , R 2 , R 11 , and R 12 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 1 and R 2 may together with any intervening atoms to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
  • R 13 and R 14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; for each occurrence, R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, hydroxy I, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl, optionally substituted
  • R 7 and R 10 are independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alky I, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2, 3, and 4; p is selected from 0, 1 , 2,
  • a pharmaceutical composition comprising at least one chemical entity described herein, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.
  • methods of treatment of one or more diseases associated with smooth muscle myosin or non-muscle myosin comprise administering a therapeutically effective amount of at least one chemical entity provided herein or a pharmaceutical composition comprising at least one chemical entity described herein, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.
  • TBS TBDMS tert-butyldimethylsilyl
  • UV ultraviolet vol volume equivalent in mUg or LVKg or the limiting reagent unless otherwise specified
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • ATPase refers to an enzyme that is capable of hydrolyzing ATP. ATPases include proteins comprising molecular motors such as myosins.
  • 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 6 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.
  • C 0 alkylene indicates a covalent bond and C 1 alkylene is a methylene group.
  • alkyl residue having a specific number of carbons all geometric combinations 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.
  • Alkenyl refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans configuration about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-i-yl, prop-i-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-i-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1 ,3-dien-1-yl, buta-1 ,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyc!obuta-1 ,3-dien-1-yl; and the like.
  • an alkenyl group has from 2 to 20 carbon atoms
  • Alkynyl refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-i-yl, prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.
  • an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms.
  • Cycloalkyl indicates a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms. The ring may be saturated or have one or more carbon-carbon double bonds.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, 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, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like.
  • Alkoxy groups will usually have from 1 to 7 carbon atoms attached through the oxygen bridge. "Lower alkoxy” refers to alkoxy groups having one to four carbons.
  • R 3 and R b are independently chosen from hydrogen and alkyl groups of the indicated number of carbon atoms, provided that R a and R b are not both hydrogen.
  • Acyl refers to the groups H-C(O)-; (alkyl)-C(O)-; (cycloalkyl)-C(O)-; (aryl)-C(O)-;
  • Forml refers to the group -C(O)H.
  • Carmate refers to the group (amino)-C(O)-O-.
  • Substituted carbamate refers to the group (subtituted amino)-C(O)-O-.
  • Carboxy and/or “carboxyl” refer to the group -C(O)OH.
  • a Ci-C 6 alkoxycarbonyl group is an alkoxy group having from 1 to
  • amino is meant the group -NH 2 .
  • “Mono- and di-(alkyl)amino” encompasses secondary and tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen.
  • Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.
  • aminocarbonyl refers to the group -CONR b R c , where R b is chosen from H, optionally substituted Ci-C ⁇ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
  • R c is independently chosen from hydrogen and optionally substituted Ci-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 1 N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from Ci-C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, Ci-C 4 haloalkyl, -OCi-C 4 alkyl, -OCi-C 4 alkylphenyl, -
  • Aryl encompasses:
  • 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 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or more heteroatoms chosen from N,
  • 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 the group -alkyl-aryl.
  • -R a , -OR b optionally substituted amino (including -NR c COR b , -NR 0 CO 2 R 3 , -NR c CONR b R c , -NR b C(NR c )NR b R c , -NR b C(NCN)NR b R c , and -NR 0 SO 2 R 3 ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO 2 R"), aminocarbonyl (such as -CONR b R°), -OCOR b , -OCO 2 R 3 , -OCONR b R c , -OP(O)(OR b )OR°, sulfanyl (
  • R is chosen from H, optionally substituted Ci-Ce alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and c
  • R is independently chosen from hydrogen and optionally substituted C1-C4 alkyl
  • halo includes fluoro, chloro, bromo, and iodo
  • 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:
  • 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; and tricyclic heterocycloalkyl rings containing one or more, for example, from 1 to 5, or in certain embodiments, from 1 to 4, 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 or heterocycloalkyl ring.
  • bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at either 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. In certain embodiments, the total number of S and
  • O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority
  • 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, cycloalkyl, or heterocycloalkyl, as defined herein
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O ' ) substituents, such as pyridinyl N-oxides.
  • heterocycloalkyl is meant a single, non-aromatic 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.
  • the ring may be saturated or have one or more carbon-carbon double bonds.
  • Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolidinyl, 2,4- imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, and 2,5-pipehzinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1).
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains 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; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteratoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
  • modulation refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of 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 compound with the a target or due to the interaction of the compound with one or more other factors that in turn affect the target's activity.
  • the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.
  • sulfanyl includes the groups: -S-(optionally substituted (Ci-C ⁇ jalkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl).
  • sulfanyl includes the group Ci-C 6 alkylsulfanyl.
  • sulfinyl includes the groups: -S(O)-(optionally substituted (Ci- C 6 )alkyl), -S(0)-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 )-(optionally substituted (Ci- C ⁇ jalkyl), -S( ⁇ 2 )-optionally substituted aryl), -S(C> 2 )-optionally substituted heteroaryl), - S(O 2 )-(optionally substituted heterocycloalkyl) ,-S(O 2 )-(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.
  • Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
  • 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.
  • R a is chosen from optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is chosen from hydrogen, optionally substituted C 1 -Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted Ci-C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and 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(O)Ci-C 4 alkyl -C(O)C 1 -C 4 alkylphenyl, -C(O)C 1 -C 4 haloalkyl, -OC(O)C 1 -C 4 alkyl, - SO 2 (Ci-C 4 alkyl), -SO 2 (phenyl), -SO 2 (C 1 -C 4 haloalkyl), -SO 2 NH 2 , -SO 2 NH(C 1 -C 4 alkyl), -SO 2 NH(phenyl), -NHSO 2 (C 1 -C 4 alkyl), -NHSO 2 (phenyl), and -NHSO 2 (C 1 -C 4 haloalkyl).
  • substituted acyl refers to the groups H-C(O)-; (substituted alkyl)-C(O)- ; (substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)-; and (substituted heterocycloalkyl)-C(O)-, wherein the group 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: -R a , -OR b , optionally substituted amino (including -
  • R b is chosen from H, optionally substituted C 1 -Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted Ci-C 4 alkyl; or R b and R°, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and 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 1 -C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroary 1-Ci-C 4 alkyl-, Ci-C 4 haloalkyl, -OC 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -OC 1 -C 4 haloalkyl, halo, -OH, -NH 2 , -C 1 -C 4 alkyl-NH 2 , -N(C 1 -C 4 alkyl)(C r C 4 al
  • 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 b is chosen from H, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted C 1 -C 4 alkyl; or R b and R c , and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and 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 1 -C 4 alkyl, aryl, heteroaryl, aryl-d-C 4 alkyl-, heteroaryl-d-d alkyl-, C 1 -C 4 haloalkyl, -OCi-C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -OC 1 -C 4 haloalkyl, halo, -OH, -NH 2 , -C 1 -C 4 alkyl-NH 2 , -N(C 1 -C 4 8 ⁇ yI)(C 1
  • -C(O)Ci-C 4 alkyl -C(O)Ci-C 4 alkylphenyl, -C(O)Ci-C 4 haloalkyl, -OC(O)Ci-C 4 alkyl, - SO 2 (Ci-C 4 alkyl), -SO 2 (phenyl), -SO 2 (Ci-C 4 haloalkyl), -SO 2 NH 2 , -SO 2 NH(CrC 4 alkyl), -SO 2 NH(phenyl), -NHSO 2 (C 1 -C 4 alkyl), -NHSO 2 (phenyl), and -NHSO 2 (Ci-C 4 haloalkyl).
  • 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 -0(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)-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:
  • -R a , -OR b optionally substituted amino (including -NR c COR b , -NR 0 CO 2 R 3 , -NR°CONR b R c , -NR b C(NR c )NR b R c , -NR b C(NCN)NR b R°, and -NR c SO 2 R a ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO 2 R"), aminocarbonyl (such as -CONR b R°), -OCOR b , -OCO 2 R 3 , -OCONR b R c , -OP(O)(OR b )OR c , sulfanyl (
  • R b is chosen from H, optionally substituted CrC ⁇ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R c is independently chosen from hydrogen and optionally substituted C 1 -C 4 alkyl; or R b and R c , and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from Ci-C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, CrC 4 haloalkyl, -OCi-C 4 alkyl, -OCi-C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -OCi-C 4
  • substituted amino refers to the group -NHR d or -NR d R e wherein R d is chosen from: hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein R e is chosen from: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and
  • -R a , -OR b optionally substituted amino (including -NR c COR b , -NR 0 CO 2 R 8 , -NR c CONR b R c , -NR b C(NR c )NR b R c , -NR b C(NCN)NR b R c , and -NR 0 SO 2 R 3 ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO 2 R b ), aminocarbonyl (such as -CONR b R c ), -OCOR b , -OCO 2 R 8 , -OCONR b R c ,
  • R a is chosen from optionally substituted Ci-C 6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is chosen from H, optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
  • R c is independently chosen from hydrogen and optionally substituted C 1 -C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from Ci-C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, Ci-C 4 haloalkyl, -OCi-C 4 alkyl, -OC 1 -C 4 alkylphenyl, -d-C 4 alkyl-OH, -OCi-C 4 haloalkyl, halo, -OH, -NH 2 , -d-C 4 alkyl-NH 2 , -N(Ci-C 4 alkyl)(Ci-C 4 alkyl), -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl)
  • substituted amino also refers to N-oxides of the groups -NHR d , and NR d R d each as described above.
  • N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m- chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.
  • Compounds of Formula X include, but are not limited to, optical isomers of compounds of Formula X, 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.
  • compounds of Formula X include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds.
  • chemical entities described herein include all tautomeric forms of the compound.
  • Chemical entities described herein include, but are not limited to compounds of Formula X and all pharmaceutically acceptable forms thereof.
  • Pharmaceutically acceptable forms of the chemical entities recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof.
  • the chemical entities 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 hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC-(CH 2 ) ⁇ -COOH where n is 0-4, and like salts.
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Those skilled in the art will recognize various synthetic methodologies that 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 X.
  • chemical entities for example ester or amide derivatives of the compounds of Formula X.
  • prodrugs includes any chemical entities that become compounds of Formula X when administered to a patient, e.g., upon metabolic processing of the prodrug.
  • prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula X.
  • 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-cpvalent 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
  • an active agent is used to indicate a chemical entity which has biological activity.
  • an “active agent” is a compound having pharmaceutical utility.
  • an active agent may be an anti-cancer therapeutic.
  • terapéuticaally effective amount of a chemical entity described herein 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.
  • Treatment 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 described herein can be useful in both human therapy and veterinary applications.
  • the patient is a mammal; in some embodiments the patient is human; and in some embodiments the patient is chosen from cats and dogs.
  • U is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and * - W 1 COW 2 , where the "*" indicates the point of attachement to Z 1 ;
  • W 1 and W 2 are independently selected from CR 11 R 12 , NR 13 , and O; provided at least one of W 1 and W 2 is NR 13 ;
  • W J is selected from NR , 1 14 4 and O;
  • Z 1 is aryl;
  • Z 2 is aryl;
  • R 8 is selected from hydrogen, optionally substituted a Iky I, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • R 1 , R 2 , R 11 , and R 12 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted ami ⁇ osulfonyl; or R 1 and R 2 may together with any intervening atoms to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
  • R 13 and R 14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; for each occurrence, R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, hydroxy I, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl, optionally substituted
  • R 7 and R 10 are independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2, 3, and 4; p is selected from 0, 1 , 2,
  • U is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl.
  • U is *-W 1 COW 2 , where the "*" indicates the point of attachement to Z 1 .
  • W 1 and W 2 are independently selected from CR 11 R 12 , NR 13 , and O; provided at least one of W 1 and W 2 is NR 13 ;
  • W 3 is selected from CR 1 R 2 , NR 14 and O;
  • Z 1 is aryl
  • Z 2 is aryl
  • R 8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • R 1 , R 2 , R 11 , and R 12 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 1 and R 2 may together with any intervening atoms to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
  • R 13 and R 14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; for each occurrence, R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, hydroxy I, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aryl, optionally substituted
  • R 7 and R 10 are independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2, 3, and 4; p is selected from 0, 1 , 2,
  • Z 1 is chosen from phenyl, naphthyl, and indanyl. [075] In some embodiments of compounds of Formula I, Z 1 is phenyl. [076] In some embodiments, Z 2 is chosen from phenyl, naphthyl, and indanyl. [077] In some embodiments of compounds of Formula I, Z 2 is phenyl. [078] In some embodiments of compounds of Formula I, W 1 is CR 11 R 12 . [079] In some embodiments of compounds of Formula I, W 1 is NR 13 . [080] In some embodiments of compounds of Formula I, W 1 is O.
  • W 2 is CR 11 R 12 .
  • W 2 is NR 13 .
  • W 2 is O.
  • W 3 is CR 1 R 2 .
  • W 3 is NR 14 .
  • R 8 is selected from hydrogen and optionally substituted lower alkyl.
  • R 8 is selected from hydrogen and lower alkyl.
  • R 8 is selected from hydrogen and methyl.
  • R 8 is hydrogen.
  • R 11 and R 12 are independently selected from hydrogen and optionally substituted lower alkyl.
  • R 11 and R 12 are independently selected from hydrogen and lower alkyl.
  • R 11 and R 12 are independently selected from hydrogen and methyl.
  • R 11 is hydrogen and R 12 is methyl.
  • R 13 is selected from hydrogen and optionally substituted lower alkyl.
  • R 13 is selected from hydrogen and lower alkyl.
  • R 13 is selected from hydrogen and methyl.
  • R 13 is methyl
  • q is 2.
  • each R 5 and R 6 is independently selected from hydrogen, optionally substituted lower alkyl, and lower alkoxycarbonyl.
  • each R 5 and R 6 is independently selected from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, and methoxycarbonyl.
  • each R 5 and R 6 is hydrogen.
  • m is selected from 1 and
  • R 7 is selected from halo, lower alkyl, and optionally substituted lower alkyl.
  • R 7 is selected from chloro, fluoro, methyl, and trifluoromethyl.
  • R 7 is chloro
  • R 7 is at position 2 or 3 relative to the point of attachment of the phenyl ring.
  • n is selected from 1 and
  • n 1
  • each R 3 and R 4 is independently selected from hydrogen, optionally substituted lower alkyl, and lower alkoxycarbonyl.
  • each R 3 and R 4 is independently selected from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, and methoxycarbonyl.
  • each R 3 and R 4 is hydrogen.
  • p is selected from 1 and
  • p is 1.
  • each R 10 is independently selected from cyano, halo, optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted phenyl.
  • each R 10 is independently selected from cyano, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, hydroxymethyl, trifluoromethyl, methoxycarbonyl, phenoxy, phenyl, trifluoromethoxy, methoxy, N 1 N- dimethyamino, and 1H-imidazolyl.
  • each R 10 is independently selected from cyano, chloro, fluoro, bromo, trifluoromethyl, methyl, ethyl, vinyl, and phenyl.
  • each R 10 is selected from methyl, ethyl, isopropyl, and trifluoromethyl.
  • p is selected from 1 and
  • each R 10 is independently selected from cyano, halo, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted aryl.
  • (R 10 ) P together with Z 1 to which is attached, forms a group selected from 2-naphthyl, 5-indanyl, 4-ethylphenyl, 4- methylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4- phenylphenyl, 4-methyl-2-chlorophenyl, 4-methyl-3-fluorophenyl, 4-ethyl-3-fluorophenyl, and 4-ethyl-2-chlorophenyl.
  • compounds of Formula I 1 p is 1 and R 10 is selected from ethyl and isopropyl.
  • R 14 is selected from hydrogen and optionally substituted lower alkyl.
  • R 14 is selected from hydrogen and lower alkyl.
  • R 14 is hydrogen
  • each R 1 and R 2 is independently selected from hydrogen, lower alkyl, and substituted alkyl.
  • each R 1 and R 2 is independently selected from hydrogen and methyl.
  • R 1 and R 2 are hydrogen.
  • R 1 and R 2 are methyl.
  • R 1 is hydrogen and R 2 is methyl.
  • R 1 and R 2 together with the carbon to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.
  • R 1 and R 2 together with the carbon to which they are attached, form a group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, and 2H-3,4,5,6-tetrahydropyranyl, each of which is optionally substituted.
  • R 1 and R 2 together with the carbon to which they are attached, form a group selected from cyclopentyl, cyclohexyl, piperidinyl, and 2H-3,4,5,6-tetrahydropyranyl, each of which is optionally substituted.
  • R 1 , R 2 , n, R 3 , R 4 , q, m, R 7 , R 8 , p, and R 10 are as described for compounds of Formula I.
  • R 1 , R 2 , n, R 3 , R 4 , q, m, R 7 , R 8 , p, and R 10 are as described for compounds of Formula I.
  • R 14 , n, R 3 , R 4 , q, R 5 , R 6 , m, R 7 , R 8 , p, and R 10 are as described for compounds of Formula I.
  • W 4 is an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
  • W 5 is selected from CR 1 R 2 , NR 14 , and O;
  • Z 1 is aryl
  • Z 2 is aryl
  • R 1 and R 2 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 1 and R 2 may optionally be joined together with the carbon atom bonded thereto, to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; for each occurrence, R 3 , R 4 ,
  • R 8 and R 14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2 and 3; p is selected from 0, 1, 2, and 3; and q is selected from 0, 1, 2 and 3.
  • Z 1 is phenyl
  • Z 2 is phenyl
  • W 4 is
  • W 1a , W 1b , and W 1c are independently selected from -CH and N.
  • At least one of W 1a , W 1b , and W 1c is N.
  • At least two of W 1a , W 1b , and W 1c are N.
  • W 1a , W 1b , and W 1c are N.
  • n is chosen from 1 and 2.
  • n 1
  • each R 3 and R 4 is independently chosen from hydrogen, optionally substituted lower alkyl and lower alkoxycarbonyl.
  • each R 3 and R 4 is independently chosen from hydrogen, methyl, ethyl, isopropyl. hydroxy methyl, and methoxycarbonyl.
  • each R 3 and R 4 is hydrogen.
  • p is chosen from 1 and 2. [0152] In certain embodiments of compounds of Formula II, p is 1.
  • q is chosen from 1 and 2.
  • q is 1. In certain embodiments of compounds of Formula II, q is 0.
  • each R 10 is independently selected from cyano, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, hydroxymethyl, trifluoromethyl, methoxycarbonyl, phenoxy, trifluoromethoxy, methoxy, N.N-dimethyamino, and 1 H-imidazolyl.
  • each R 10 is chosen from methyl, ethyl, isopropyl, and CF 3 .
  • p is 1 and R 10 is ethyl or isopropyl.
  • one R 10 group is in the 4-position of the phenyl group.
  • R 1 and R 2 are independently chosen from hydrogen and lower alkyl.
  • R 1 and R 2 are independently chosen from hydrogen and methyl.
  • R 1 and R 2 are hydrogen.
  • R 1 and R 2 are methyl.
  • R 1 is hydrogen and R 2 is methyl.
  • R 1 and R 2 are joined together to form a group selected from cycloalkyl and heterocycloalkyl.
  • R 1 and R 2 are joined together to form a group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, and 2H-3,4,5,6-tetrahydropyranyl, each of which is optionally substituted.
  • R 1 and R 2 are joined together to form a group selected from optionally substituted cyclopropyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, and optionally substituted 2H-3,4,5,6-tetrahydropyranyl.
  • each R 5 and R 6 is independently chosen from hydrogen, optionally substituted lower alkyl and lower alkoxycarbonyl.
  • each R 5 and R 6 is independently chosen from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, and methoxycarbonyl.
  • each R 5 and R 6 is hydrogen.
  • m is 1 or 2.
  • m is 1 and R 7 is Cl, F, methyl, or CF 3 .
  • m is 1 and R 7 is Cl.
  • m is 2 and each R 7 is Cl.
  • those chloros are positioned at the 2 and 3 positions of the phenyl ring.
  • m is 2 and each R 7 is Cl or F.
  • the compound of Formula X is chosen from Structure Chemical Name
  • R 10 is ethyl
  • W 2 is NR 13
  • R 13 is hydrogen
  • W 1 is O 1
  • R 5 is hydrogen
  • R 6 is hydrogen
  • W 3 is CR 1 R 2
  • R 1 and R 2 form a cyclobutyl group with the carbon atom to which they are bound
  • R 8 is hydrogen
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 7 is chloro
  • a chemical name generated for a structure drawn in a certain software environment may or may not give the same structure when that name is converted into a structure in a different software environment.
  • Step 1 to a solution of a compound of Formula 101 and an excess (such as about 1.2 equivalents) of a compound of Formula 102 in a non-polar solvent such as toluene is added an excess (such as about 1.5 equivalents) of trialkylaluminum (for example, 2M trimethylaluminum in hexanes).
  • a non-polar solvent such as toluene
  • trialkylaluminum for example, 2M trimethylaluminum in hexanes.
  • the reaction mixture is stirred at about rt to 150 0 C for about 1 h to 24 h.
  • the product, a compound of Formula 103 is isolated and optionally purified.
  • Step 2 to a solution of a compound of Formula 103 in a non-polar solvent such as dichloromethane is added a catalytic amount of 4-dimethylaminopyridine and an excess (such as about 1.5 equivalents) of a compound of Formula 104.
  • the reaction mixture is stirred for about 1 h to 24 h.
  • the product, a compound of Formula 105, is isolated and optionally purified.
  • Step 1 to a solution of a base such as diisopropylamine in a polar, aprotic solvent such as tetrahydrofuran at about -78 0 C to rt is added an excess (such as about 1.2 equivalents) of an organometallic reagent such as n-butyllithium (for example, 2M n-butyllithium in hexane).
  • an organometallic reagent such as n-butyllithium (for example, 2M n-butyllithium in hexane).
  • n-butyllithium for example, 2M n-butyllithium in hexane
  • a solution of a compound of Formula 201 in a polar, aprotic solvent such as tetrahydrofuran is then added dropwise at about -78 0 C to rt.
  • the reaction mixture is stirred for about 1 h to 24 h and then an excess (such as about 1.1 equivalent
  • Step 2 to a solution of a compound of Formula 202 in a polar solvent system such as a 1:1 mixture of tetrahydrofuran and methanol is added an aqueous solution of an excess (such as about 1.1 equivalents) of a base such as lithium hydroxide (for example, 2N lithium hydroxide in water).
  • a base such as lithium hydroxide (for example, 2N lithium hydroxide in water).
  • the reaction mixture is stirred at about rt to 150 0 C for about 1 h to 24 h.
  • the product, a compound of Formula 203 is isolated and optionally purified.
  • Step 3 to a solution of a compound of Formula 203 in a polar, aprotic solvent such as dimethylformamide is added an excess (such as about 1.2 equivalents) of a peptide coupling reagent such as N,N,N',N'- tetramethyl-0-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, an excess (such as about 1.2 equivalents) of a compound of Formula 102, and about 0.1 equivalents of a base such as diisopropylethylamine.
  • the reaction mixture is stirred for about 1 h to 24 h.
  • the product, a compound of Formula 204 is isolated and optionally purified.
  • Step 4 to a solution of a compound of Formula 204 in a polar solvent system such as a 1:1 mixture of tetrahydrofuran and methanol is added an excess of a reducing agent such as lithium borohydride. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 205, is isolated and optionally purified.
  • a polar solvent system such as a 1:1 mixture of tetrahydrofuran and methanol
  • a reducing agent such as lithium borohydride
  • Step 1 to a solution of a compound of Formula 301 in a polar, aprotic solvent such as tetrahydrofuran is added an excess (such as about 1.1 equivalents) of a compound of Formula 102 and about 0.5 equivalents of trialkylaluminum (for example, 2M trimethylaluminum in toluene). The reaction mixture is stirred for about 1 day to 7 days. The product, a compound of Formula 205, is isolated and optionally purified.
  • aprotic solvent such as tetrahydrofuran
  • Step 1 to a solution of a compound of Formula 103 in a polar, aprotic solvent such as tetrahydrofuran is added an excess (such as about 1.5 equivalents) of phthalimide (Formula 401) and an excess (such as about 1.5 equivalents) of a phosphine such as triphenylphosphine. An excess (such as about 1.5 equivalents) of a dialkyl azodicarboxylate such as diisopropyl azodicarboxylate is then added dropwise into the reaction mixture. The resulting mixture is stirred from 1 h to 48 h. The product, a compound of Formula 402, is isolated and optionally purified.
  • a aprotic solvent such as tetrahydrofuran
  • Step 2 to a solution of a compound of Formula 402 in a polar, protic solvent such as methanol is added an excess of hydrazine. The reaction mixture is stirred from 1 h to 48 h. The product, a compound of Formula 403, is isolated and optionally purified.
  • a polar, protic solvent such as methanol
  • Step 2 to a solution of a compound of Formula 503 in a polar, aprotic solvent such as tetrahydrofuran is added an excess (such as about 1.5 equivalents) of a compound of Formula 104. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 504, is isolated and optionally purified.
  • aprotic solvent such as tetrahydrofuran
  • Step 1 to a solution of a compound of Formula 601 in a non-polar solvent such as dichloromethane is added an excess (such as about 1.1 equivalents) of a silyl protecting group reagent such as tert- butyldimethylsilyl chloride and an excess (such as about 1.5 equivalents) of a base such as diisopropylethylamine.
  • a silyl protecting group reagent such as tert- butyldimethylsilyl chloride
  • a base such as diisopropylethylamine
  • Formula 605 in a polar, protic solvent such as methanol is added an excess (such as about 3.0 equivalents) of an acid such as hydrogen chloride (for example, 4M hydrogen chloride in dioxane).
  • an acid such as hydrogen chloride (for example, 4M hydrogen chloride in dioxane).
  • the resulting reaction mixture is stirred for about 1 h to 24 h.
  • the product, a compound of Formula 606, is isolated and optionally purified.
  • Formula 606 in a polar, aprotic solvent such as tetrahydrofuran is added about 1 equivalents of a compound of Formula 607 and an excess (such as about 2.5 equivalents) of a base such as diisopropylethylamine.
  • a base such as diisopropylethylamine.
  • the reaction mixture is stirred for about 1 h to 24 h.
  • the product, a compound of Formula 608, is isolated and optionally purified.
  • 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 3.0 equivalents) of an acid such as hydrogen chloride (for example, 4 M hydrogen chloride in dioxane). The resulting reaction mixture is stirred about 1 h to 48 h. The product, a compound of Formula 702, is isolated and optionally purified.
  • a polar, protic solvent such as methanol
  • an excess such as about 3.0 equivalents
  • an acid such as hydrogen chloride (for example, 4 M hydrogen chloride in dioxane).
  • the resulting reaction mixture is stirred about 1 h to 48 h.
  • the product, a compound of Formula 702 is isolated and optionally purified.
  • Step 1 to a solution of a compound of formula 101 in an inert solvent such as DMF are added an excess (such as about 1.4 equivalents) of NaCN and an excess (such as about 1.4 equivalents) of NH 4 CI. The reaction mixture is heated. The product, a compound of formula 103, is isolated and optionally purified.
  • an inert solvent such as DMF
  • Reaction Scheme VIII 1 Step 2 to a mixture of a compound of formula 105 and an excess (such as about 1.4 equivalents) of a compound of formula 106 in an inert solvent such as toluene is added an excess (such as about 1.4 equivalents) AIMe 3 .
  • the reaction mixture is stirred for about 30 min followed by stirring at about rt -150 0 C for about 1 h to 24 h .
  • the product, a compound of formula 107 is isolated and optionally purified.
  • Step 2 to a solution of a compound of formula 201 in an inert solvent such as DMF are added an excess (such as about 1.5 equivalents) of a coupling reagent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N"- tetramethyluroniumhexafluorophosphate (HATU) and an excess (such as about 1.5 equivalents) of a compound of formula 203.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N"- tetramethyluroniumhexafluorophosphate
  • the reaction mixture is stirred for about 1 h to 24 h.
  • the product, a compound of formula 205 is isolated and optionally purified.
  • Step 3 to a solution of an excess (such as 2 equivalents) of a compound of formula 207 in an inert solvent such as THF are added about an equivalent of a phospine reagent such as triphenyl phosphine, about 1 equivalent of an azadicarboxylate reagent such as diethylazadicarboxylate (DIAD), and a compound of formula 208.
  • a phospine reagent such as triphenyl phosphine
  • an azadicarboxylate reagent such as diethylazadicarboxylate (DIAD)
  • DIAD diethylazadicarboxylate
  • Isolation and purification of the compounds 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 are provided herein. However, other equivalent separation or isolation procedures can, of course, also be used.
  • the (R) and (S) isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step may be required to liberate the desired enantiomeric form.
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts and/or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the chemical entities described herein may be useful in a variety of applications involving smooth muscle cells and/or non-muscle cells.
  • the chemical entities may be used to inhibit smooth muscle myosin.
  • the chemical entities may be useful to bind to, and/or inhibit the activity of, smooth muscle myosin.
  • the smooth muscle myosin is human, although the chemical entities may be used to bind to or inhibit the activity of smooth muscle myosin from other organisms, such as other mammals.
  • the chemical entities may be used to inhibit non- muscle myosin.
  • the chemical entities may be useful to bind to, and/or inhibit the activity of, non-muscle myosin.
  • the non-muscle myosin is human, although the chemical entities may be used to bind to or inhibit the activity of non-muscle myosin from other organisms, such as other mammals.
  • the chemical entities described herein may be used to treat disease states associated with smooth muscle and/or non-muscle myosin. Such disease states which can be treated by the chemical entities described herein include, but are not limited to, hypertension, asthma, incontinence, chronic obstructive pulmonary disorder, pre-term labor, and the like. It is appreciated that in some cases the cells may not be in an abnormal state and still require treatment. Thus, in certain embodiments, the chemical entities described herein may be applied to cells or individuals afflicted or subject to impending affliction with any one of these disorders or states.
  • the cchemical entities described herein may be useful for the treatment of diseases or symptoms related to abnormal increased muscle tone or excessive contraction, or spasm of vascular smooth muscle in systemic, coronary, pulmonary circulation, and micro-circulatory smooth muscle as well, such as systemic hypertension, malignant hypertension, hypertension crisis, symptomatic hypertension, pulmonary hypertension, pulmonary infarction, angina pectoris, cardiac infarction, micro-circulation malfunction under shock condition, and infarction occurred in other location or organs of the human or animal body.
  • diseases or symptoms related to abnormal increased muscle tone or excessive contraction, or spasm of vascular smooth muscle in systemic, coronary, pulmonary circulation, and micro-circulatory smooth muscle as well such as systemic hypertension, malignant hypertension, hypertension crisis, symptomatic hypertension, pulmonary hypertension, pulmonary infarction, angina pectoris, cardiac infarction, micro-circulation malfunction under shock condition, and infarction occurred in other location or organs of the human or animal body.
  • spasm of gastro-intestine smooth muscle including sphincters, such as gastric spasm, pylorospasm, and spasms of biliary tract, pancreatic tract, urinary tract, caused by inflammation, stimulation of stones or parasites; spasm of other visceral organs such as uterus, Fallopian tube, and so on; spasm of trachea-bronchial tree smooth muscle, diaphragm muscle, such as various asthma, breathlessness, dyspnea, diaphragmatic convulsion, and so on; spasm of alimentary canal smooth muscle, including stomach, intestine and colons, biliary and pancreatic duct etc.; and spasm of urinary tract smooth muscle.
  • sphincters such as gastric spasm, pylorospasm, and spasms of biliary tract, pancreatic tract, urinary tract, caused by inflammation, stimulation of stones or parasites
  • spasm of other visceral organs
  • the chemical entities described herein can be used for control, management and manipulation of, labor during pregnancy.
  • the method is particularly useful for inhibition of spontaneous preterm labor which would, if untreated, result in premature delivery or abortion and for inhibition of surgically induced labor during transuterine fetal surgery.
  • the method is also useful for inducing the labor in overterm pregnancies where the labor does not occur on term and when it is necessary to induce labor in order to assure the normal delivery.
  • airway wall remodeling is a condition associated with diseases or conditions characterized by airway wall thickening and air obstruction, which may, for example occur in the small airways of patients with certain respiratory disease conditions, such as, chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Such disease states which can be treated by the chemical entities, compositions and methods provided herein also include, but are not limited to glaucoma and other ocular indications. More specifically, chemical entities described herein may be useful for the treatment of diseases or symptoms related to glaucoma, including increased intraocular pressure, reduced flow of intraocular aqueous humor, and optical nerve damage. Other diseases or symptoms that can be treated with the chemical entities, compositions, and methods described herein including intraocular hypertenstion.
  • ATP hydrolysis is employed by myosin to produce force.
  • An increase in ATP hydrolysis would correspond to an increase in the force or velocity of muscle contraction.
  • myosin ATPase activity is stimulated more than 100-fold.
  • Assays for such activity may employ smooth muscle myosin from a human source, although myosin from other organisms can also be used. Systems that model the regulatory role of calcium in myosin binding may also be used.
  • the in vitro rate of ATP hydrolysis correlates to smooth muscle myosin potentiating activity, which can be determined by monitoring the production of either ADP or phosphate, for example as described in U.S. Patent No. 6,410,254.
  • ADP production can also be monitored by coupling the ADP production to NADH oxidation (using, for example, the enzymes pyruvate kinase and lactate dehydrogenase) and monitoring the NADH level, by example, either by absorbance or fluorescence (Greengard, P., Nature 178 (Part 4534): 632-634 (1956); MoI Pharmacon970 Jan;6(1):31-40).
  • Phosphate production can be monitored using purine nucleoside phosphorylase to couple phosphate production to the cleavage of a purine analog, which results in either a change in absorbance (Proc Natl Acad Sci U S A 1992 Jun 1 ;89(11):4884-7) or fluorescence (Biochem J 1990 Mar 1 ;266(2):611-4). While a single measurement is employed, multiple measurements of the same sample at different times in order may be used to determine the absolute rate of the protein activity; such measurements have higher specificity particularly in the presence of test compounds that have similar absorbance or fluorescence properties with those of the enzymatic readout.
  • Test compounds may be assayed in a highly parallel fashion using multiwell plates by placing the compounds either individually in wells or testing them in mixtures. Assay components including the target protein complex, coupling enzymes and substrates, and ATP may then be added to the wells and the absorbance or fluorescence of each well of the plate can be measured with a plate reader.
  • One method uses a 384 well plate format and a 25 ⁇ l_ reaction volume. A pyruvate kinase/lactate dehydrogenase coupled enzyme system (Huang TG and hackney DD. (1994) J Biol Chem 269(23):16493-16501) is used to measure the rate of ATP hydrolysis in each well.
  • the assay components are added in buffers and reagents. Since the methods outlined herein allow kinetic measurements, incubation periods may be optimized to give adequate detection signals over the background. The assay is performed in real time to give the kinetics of ATP hydrolysis to increase the signal-to-noise ratio of the assay. [0218] Selectivity for smooth muscle myosin may be determined by substituting other myosins in one or more of the above-described assays and comparing the results obtained against those obtained using the cardiac equivalents.
  • Chemical entities identified by the methods described herein as smooth muscle myosin modulators may be further tested in an efficacy screen, such as a screen using strips of permeabilized smooth muscle from, e.g., chicken gizzard.
  • Calcium-sensitive smooth muscle strips are prepared by dissecting chicken gizzard tissue, followed by treatment with 1% Triton X-100 to make the strips permeable to exogenous compounds (Barsotti, RJ, et al., Am J Physiol. 1987 May;252(5 Pt 1):C543- 54). These strips can be stored in 50% glycerol for several weeks at -20 0 C 1 allowing multiple experiments to be performed with each batch of muscle strips.
  • the chemically skinned gizzard fibers are relaxed when bathed in low calcium solutions (pCa 8), but develop isometric tension when the free calcium of the bathing solution is increased to pCa 5. These fibers can be repeatedly contracted and relaxed by switching between high and low calcium bathing solutions.
  • Compounds are first tested for their ability to prevent contraction of gizzard strips, by preincubating relaxed fibers with a compound, followed by transfer to high calcium solution containing the compound. Next, compounds are tested for their ability to cause relaxation of contracting fibers by adding the compound to fibers already incubating in high calcium solution. Washout experiments are performed to ensure that the inhibitory effects are reversible, so that the compounds do not cause denaturation or other irreparable damage to the smooth muscle myosin.
  • the chemical entities are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment of the disease states previously described.
  • a daily dose is from about 0.05 to about 100 mg/kg of body weight, such as from about 0.10 to about 10 mg/kg of body weight or from about 0.15 to about 1 mg/kg of body weight.
  • the dosage range is from about 3.5 to about 7000 mg per day, such as from about 7 to about 700 mg per day or from about 10 to about 100 mg per day.
  • the amount of active chemical entity administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician; for example, a dose range for oral administration may be from about 70 to about 700 mg per day, whereas for intravenous administration the dose range may be from about 700 to about 7000 mg per day.
  • the active agents may be selected for longer or shorter plasma half-lives, respectively.
  • Administration of the chemical entities described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, sublingually, intramucosally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, and intraocularly (including intraocular injection). Oral, topical, parenteral, and intraocular administration are customary in treating many of the indications recited herein.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, and the like.
  • the chemical entities can also be administered in sustained- or control led-release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, drops and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compositions may be provided in unit dosage forms suitable for single administration of a precise dose.
  • the chemical entities may be administered either alone or in combination with a conventional pharmaceutical carrier or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarr ⁇ ellose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
  • a conventional pharmaceutical carrier or the like e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarr ⁇ ellose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical composition may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate.
  • the pharmaceutical composition may contain from about 0.005% to about 95%, for example, from about 0.5% to about 50%, by weight of at least one chemical entity described herein.
  • Actual methods of preparing such dosage forms are known or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • Pharmaceutical compositions are also referred to as pharmaceutical formulations.
  • the chemical entities may be co-administered with, and the pharmaceutical compositions can include, other medicinal agents, pharmaceutical agents, adjuvants, and the like.
  • the compositions are in the form of a pill or tablet and contain, along with the active ingredient, one or more of a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives and the like.
  • a powder, marume, solution or suspension e.g., in propylene carbonate, vegetable oils or triglycerides
  • Liquid pharmaceutical compositions may, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and one or more optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like) to form a solution or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like
  • injectables may be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject.
  • percentages of active ingredient ranging from about 0.01% to about 10% in solution may be used, and may be higher if the composition is a solid which will be subsequently diluted to the above percentages.
  • the composition has from about 0.2% to about 2% of the active agent in solution.
  • compositions comprising at least one chemical entity may be administered intraocularly (including intraocular, periocular, and retrobulbar injection and perfusion). When admi ⁇ sitered intraocularly the sterile composition is typically aqueous. An appropriate buffer system may be added to prevent pH drift under storage conditions. When administered during intraocular surgical procedures, such as retrobulbar or periocular injection and intraocular perfusion or injection, the use of balanced salt irrigating solutions may be necessary. When used in a multidose form, preservatives may be required to prevent microbial contamination during use. [0229] Compositions comprising at least one chemical entity may also be administered topically as eye drops, eye wash, creams, ointments, gels, and sprays.
  • the active ingredients When administered as eye drops or eye wash, the active ingredients are typically dissolved or suspended in suitable carrier, typically a sterile aqueous solvent.
  • suitable carrier typically a sterile aqueous solvent.
  • An appropriate buffer system may be added to prevent pH drift under storage conditions.
  • preservatives When used in a multidose form, preservatives may be required to prevent microbial contamination during use.
  • compositions comprising at least one chemical entity may also be administered to the respiratory tract as an aerosol or in a solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the composition typically have diameters of less than 50 microns, for example, less than 10 microns.
  • smooth muscle myosin is bound to a support and at least one chemical entity is added to the assay.
  • the chemical entity may be bound to the support and the smooth muscle myosin 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 purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.), and the like. See, e.g., U.S. Patent No. 6,495,337.

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Abstract

Chemical entities that modulate smooth muscle myosin and/or non-muscle myosin, pharmaceutical compositions and methods of treatment of diseases and conditions associated with smooth muscle myosin and/or non-muscle myosin are described.

Description

CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS
[001] This application claims the benefit of U.S. Provisional Patent Application No. 60/835,251 , filed August 2, 2006, and U.S. Provisional Patent Application No. 60/835,249, filed August 2, 2006, each of which is incorporated herein by reference for all purposes.
[002] Provided are certain chemical entities that modulate smooth muscle myosin and/or non-muscle myosin, pharmaceutical compositions and methods of treatment of diseases and conditions associated with smooth muscle myosin and/or non-muscle myosin.
[003] Myosin is present in all muscle and non-muscle cells. Of the ten distinct classes of myosin in human cells, myosin-ll is thought to be the form responsible for contraction of skeletal, cardiac, and smooth muscle. Myosin -Il is also the isoform present in non- muscle myosins, also known as cytoplasmic myosins. The non-muscle myosins are ubiquitously present in eukaryotic cells, where the smooth muscle myosins are generally present in smooth muscle cells.
[004] Myosin-ll is significantly different in amino acid composition and in overall structure from myosins in the other nine distinct classes. Myosin-ll consists of two globular head domains, called Subfragment-1 or S1 , linked together by a long alpha- helical coiled-coiled tail. Proteolysis of myosin generates either S1 or heavy meromyosin (HMM, a two-headed form with a truncated tail), depending on the proteolysis conditions. S1 contains the ATPase and actin-binding properties of the molecule. S1 has been shown to be sufficient to move actin filaments in vitro, and is therefore likely to be the motor domain of the molecule.
[005] Although myosin-ll isoforms from various tissues differ in a number of biological properties, they share the same basic molecular structure as a dimer of two heavy chains (approximately 200 kDa) which are noncovalently associated with two pairs of light chains (approximately 20 and 17 kDa). The two globular amino-terminal heads are tethered together by the carboxy-terminal alpha-helical coiled-coil that forms a tail. The tails are believed to be involved in the assembly of myosin molecules into filaments, whereas the heads are thought to have an actin-activated Mg2+-ATPase activity. Each myosin head can be divided by three protease-sensitive regions into peptides of approximately 25, 50, and 20 kDa. The more amino-terminal 25 kDa - 50 kDa junction is close to the ATP binding region, whereas the actin-binding domain is near the 50 kDa - 20 kDa junction.
[006] S1 consists of a globular actin binding and nucleotide binding region known as the catalytic domain. This domain is attached at its carboxy-terminus to an alpha-helix that has two light chains of about 20 kDa each wrapped around it. This light-chain binding domain of S1 is known as the lever arm. Upon transitioning from the pre-stroke to the post-stroke state, the lever arm is believed to swing through an angle of about 90 degrees about a fulcrum point in the catalytic domain near the nucleotide-binding site. The "power stroke" is driven by the hydrolysis of ATP.
[007] The other end of the myosin molecule is an alpha-helical coiled-coiled tail involved in self assembly of myosin molecules into bipolar thick filaments. These thick filaments interdigitate between thinner actin filaments, and the two filament systems slide past one another during contraction of the muscle. This filament sliding mechanism is thought to involve conformational changes in the myosin heads causing them to walk along the thin actin filaments at the expense of ATP hydrolysis. While non-muscle myosins act in a similar manner, they are understood to slide at a slower velocity than the smooth muscle myosins.
[008] The complete cDNA of the human smooth muscle myosin has been described. The sequence of human smooth muscle myosin is 52% identical to human cardiac myosin in the catalytic S1 region. See, for example, PCT publication No. WO 03/14323. [009] Provided is at least one chemical entity chosen from compounds of Formula X:
Figure imgf000003_0001
Formula X and pharmaceutically acceptable salts thereof, wherein
U is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and *- W1COW2, where the "*" indicates the point of attachement to Z1;
W1 and W2 are independently selected from CR11R12, NR13, and O; provided at least one of W1 and W2 is NR13;
W3 is selected from CR1R2, NR14 and O;
Z1 is aryl;
Z2 is aryl;
R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
R1, R2, R11, and R12 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and R2 may together with any intervening atoms to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
R13 and R14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; for each occurrence, R3, R4, R5, and R6 are independently selected from hydrogen, hydroxy I, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and one occurrence of R5 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; or R14 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and R1 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
R7 and R10 are independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alky I, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2, 3, and 4; p is selected from 0, 1 , 2, and 3; and q is selected from 0, 1 , 2, 3, and 4.
[010] Also provided is a pharmaceutical composition comprising at least one chemical entity described herein, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients. [011] Also provided are methods of treatment of one or more diseases associated with smooth muscle myosin or non-muscle myosin. The methods of treatment comprise administering a therapeutically effective amount of at least one chemical entity provided herein or a pharmaceutical composition comprising at least one chemical entity described herein, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.
[012] Other aspects and embodiments will be apparent to those skilled in the art from the following detailed description.
[013] 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.
[014] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.
[015] The following abbreviations and terms have the indicated meanings throughout:
PIPES 1 ,4-piperazinediethanesulfonic acid
ATP adenosine 5'-triphosphate
DTT DL-dithiothreitol
BSA bovine serum albumin
NADH nicotinamide adenine dinucleotide
PEP phosphoenolpyruvic acid
EGTA ethylene glycol-bis(2-aminoethylether)-N, N1N1, N'-tetraacetic acid
Ac acetyl
APCI atmospheric pressure chemical ionization atm atomosphere
Boc tert-butoxycarbonyl c- cyclo
CBZ carbobenzyloxy = benzyloxycarbonyl
CDI carbonyldiimidazole
DCM dichloromethane = methylene chloride = CH2CI2
DIAD diisopropyl azodicarboxylate DIEA DIPEA = N.N-diisopropylethylamine
DMAP = 4-(dimethylamino)pyridine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
(DPPF)PdCI2 = [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
Et ethyl
EtOAc ethyl acetate
EtOH ethanol g gram
GC gas chromatograghy h or hr = hour
HATU O-(7-azabenzotriazol-1-yl)-/V,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate
HBTU O-(benzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluronium hexafluorophosphate
HOBT 1 -hyd roxybenzotriazole
HPLC high pressure liquid chromatography i- iso kg or Kg = kilogram
L or i liter
LC/MS LCMS = liquid chromatography-mass spectrometry
LDA lithium diisopropylamide
LRMS low resolution mass spectrometry m/z = mass-to-charge ratio
Me methyl
NMP N-Methyl-2-pyrrolidone
NMR nuclear magnetic resonance
MPLC medium pressure liquid chromatography min = minute mL milliliter
MW microwave n- = normal
Ph phenyl
(Ph3P)4Pd = tetrakis(triphenylphosphine)palladium(0)
(Ph3P)2PdCI2 = dichlorobis(triphenylphosphine)palladium(ll)
RP-HPLC = reverse phase-high pressure liquid chromatography rt or RT room temperature s- = sec- = secondary t- tert- = tertiary
TBAF tetrabutylammonium fluoride
TBS TBDMS = tert-butyldimethylsilyl
TES triethylsilyl or triethylsilane
TMS trimethylsilyl or trimethylsilane
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
UV ultraviolet vol = volume equivalent in mUg or LVKg or the limiting reagent unless otherwise specified
[016] 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.
[017] 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. [018] The term "ATPase," as used herein, refers to an enzyme that is capable of hydrolyzing ATP. ATPases include proteins comprising molecular motors such as myosins.
[019] "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-C6 alkyl 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, C0 alkylene indicates a covalent bond and C1 alkylene is a methylene group. When an alkyl residue having a specific number of carbons is named, all geometric combinations 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. [020] "Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans configuration about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-i-yl, prop-i-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-i-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1 ,3-dien-1-yl, buta-1 ,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyc!obuta-1 ,3-dien-1-yl; and the like. In certain embodiments, an alkenyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms.
[021] "Alkynyl" refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-i-yl, prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like. In certain embodiments, an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms.
[022] "Cycloalkyl" indicates a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms. The ring may be saturated or have one or more carbon-carbon double bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, as well as bridged and caged saturated ring groups such as norbornane.
[023] 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, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like.
Alkoxy groups will usually have from 1 to 7 carbon atoms attached through the oxygen bridge. "Lower alkoxy" refers to alkoxy groups having one to four carbons.
[024] "Mono- and di-alkylcarboxamide" encompasses a group of the formula -
(C=O)NR3Rb where R3 and Rb are independently chosen from hydrogen and alkyl groups of the indicated number of carbon atoms, provided that Ra and Rb are not both hydrogen.
[025] "Acyl" refers to the groups H-C(O)-; (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)-.
[026] "Formyl" refers to the group -C(O)H.
[027] "Carbamate" refers to the group (amino)-C(O)-O-. "Substituted carbamate" refers to the group (subtituted amino)-C(O)-O-.
[028] "Carboxy" and/or "carboxyl" refer to the group -C(O)OH. [029] By "alkoxycarbonyl" is meant a 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 Ci-C6 alkoxycarbonyl group is an alkoxy group having from 1 to
6 carbon atoms attached through its oxygen to a carbonyl linker.
[030] By "amino" is meant the group -NH2.
[031] "Mono- and di-(alkyl)amino" encompasses secondary and tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen.
Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.
[032] The term "aminocarbonyl" refers to the group -CONRbRc, where Rb is chosen from H, optionally substituted Ci-Cβ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
Rc is independently chosen from hydrogen and optionally substituted Ci-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 O1 N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from Ci-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, Ci-C4 haloalkyl, -OCi-C4 alkyl, -OCi-C4 alkylphenyl, -
Ci-C4 alkyl-OH, -OCi-C4 haloalkyl, halo, -OH, -NH2, -Ct-C4 alkyl-NH2,
-N(Ci-C4 alkyl)(Ci-C4 alkyl), -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)(Ci-C4 alkylphenyl),
-NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4 alkyl,
-CON(Ci-C4 alkyl)(Ci-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(Ci-C4 alkyl),
-NHC(OXphenyl), -N(C1-C4 alkyl)C(O)(CrC4 alkyl), -N(Cn-C4 alkyl)C(O)(phenyl).
-C(O)Ci-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)Ci-C4 haloalkyl, -OC(O)Ci-C4 alkyl, -
SO2(Ci-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(Ci-C4 alkyl).
-SO2NH(phenyl), -NHSO2(Ci-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl). [033] "Aryl" encompasses:
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.
[034] For example, aryl includes 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or more heteroatoms chosen from N,
O1 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.
[035] The term "aryloxy" refers to the group -O-aryl.
[036] The term "aralkyl" refers to the group -alkyl-aryl.
[037] "Carbamimidoyl" refers to the group -C(=NH)-NH2-
[038] "Substituted carbamimidoyl" refers to the group -C(=NRe)-NR R9 where Re, is chosen from: hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally f g substituted heterocycloalkyl; and R and R are independently chosen from: hydrogen optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, provided β f g that at least one of R , R , and R is not hydrogen and wherein 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:
-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NR0CO2R3, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NR0SO2R3), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2R"), aminocarbonyl (such as -CONRbR°), -OCORb, -OCO2R3, -OCONRbRc, -OP(O)(ORb)OR°, sulfanyl (such as SRb), sulfinyl (such as -SOR3), and sulfonyl (such as -SO2R3 and -SO2N RbR°), where R is chosen from optionally substituted C1-C5 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; b
R is chosen from H, optionally substituted Ci-Ce alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and c
R is independently chosen from hydrogen and optionally substituted C1-C4 alkyl; or
R and R°, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from Ci-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl, -Od-C4 alkyl, -OCi-C4 alkylphenyl, -Ci-C4 alkyl-OH, -OCi-C4 haloalkyl, halo, -OH, -NH2, -Ci-C4 alkyl-NH2t -N(Ci-C4 alkyl)(d-C4 alkyl), -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)(Ci-C4 alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4 alkyl, -CON(C1-C4 alkyl)(Ci-C4 alkyl), -CONH(Ci-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(Ci-C4 alkyl)C(O)(Ci-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 phenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, - SO2(Ci-C4 alkyl), -SO2(pheπyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(Ci-C4 alkyl),
-SO2 NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl).
[039] The term "halo" includes fluoro, chloro, bromo, and iodo, and the term "halogen" includes fluorine, chlorine, bromine, and iodine.
[040] "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.
[041] "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; 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; and tricyclic heterocycloalkyl rings containing one or more, for example, from 1 to 5, or in certain embodiments, from 1 to 4, 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.
[042] For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl 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 either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1 , those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and
O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority
1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5- pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, indolinyl, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8- tetrahydroisoquinolinyl. 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, cycloalkyl, or heterocycloalkyl, as defined herein
[043] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O') substituents, such as pyridinyl N-oxides.
[044] By "heterocycloalkyl" is meant a single, non-aromatic 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. The ring may be saturated or have one or more carbon-carbon double bonds. Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolidinyl, 2,4- imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, and 2,5-pipehzinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1). Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo (=0) or oxide (-O ) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1- dioxo-1 -thiomorpholinyl.
[045] "Heterocycloalkyl" also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains 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; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteratoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
[046] As used herein, "modulation" refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of 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 compound with the a target or due to the interaction of the compound with one or more other factors that in turn affect the target's activity. For example, the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.
[047] The term "sulfanyl" includes the groups: -S-(optionally substituted (Ci-Cβjalkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl). Hence, sulfanyl includes the group Ci-C6 alkylsulfanyl. [048] The term "sulfinyl" includes the groups: -S(O)-(optionally substituted (Ci- C6)alkyl), -S(0)-optionally substituted aryl), -S(O)-optionally substituted heteroaryl), -S(O)-(optionally substituted heterocycloalkyl); and -S(O)-(optionally substituted amino). [049] The term "sulfonyl" includes the groups: -S(O2)-(optionally substituted (Ci- Cβjalkyl), -S(θ2)-optionally substituted aryl), -S(C>2)-optionally substituted heteroaryl), - S(O2)-(optionally substituted heterocycloalkyl) ,-S(O2)-(optionally substituted alkoxy), -S(O2)-optionally substituted aryloxy), -S(O2)-optionally substituted heteroaryloxy), -S(O2)-(optionally substituted heterocyclyloxy); and -S(O2)-(optionally substituted amino).
[050] 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 intermediates. 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 (cyctoalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. [051] 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:
-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NR0CO2R8,
-NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as
-CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2R3, -OCONRbRc,
-OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Ra and -SO2NRbRc), where Ra is chosen from optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rb is chosen from hydrogen, optionally substituted C1-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
Rc is independently chosen from hydrogen and optionally substituted Ci-C4 alkyl; or
Rb and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from
Ci-C4 alkyl, aryl, heteroaryl, aryl-d-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-C4 haloalkyl,
-OC1-C4 alkyl, -OCi-C4 alkylphenyl, -C1-C4 alkyl-OH, -OCi-C4 haloalkyl, halo, -OH, -NH2,
-C1-C4 alkyl-NH2, -N(Ci-C4 alkyl)(Ci-C4 alkyl), -NH(C1-C4 alkyl),
-N(Ci-C4 alkyl)(Ci-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4 alkyl,
-CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl),
-NHC(O)(phenyl), -N(C1-C4 8^yI)C(O)(C1-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl),
-C(O)Ci-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, - SO2(Ci-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl). [052] The term "substituted acyl" refers to the groups H-C(O)-; (substituted alkyl)-C(O)- ; (substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)-; and (substituted heterocycloalkyl)-C(O)-, wherein the group 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, optionally substituted amino (including -NRcCORb, -NR0CO2R3, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NR0SO2R3), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbR°), -OCORb, -OCO2R3, -OCONRbRc, -OP(O)(ORb)OR°, sulfanyl (such as SRb), sulfinyl (such as -SOR3), and sulfonyl (such as -SO2R3 and -SO2N RbRc), where Ra is chosen from optionally substituted C1-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rb is chosen from H, optionally substituted C1-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
Rc is independently chosen from hydrogen and optionally substituted Ci-C4 alkyl; or Rb and R°, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and 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-Ci-C4 alkyl-, heteroary 1-Ci-C4 alkyl-, Ci-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 alkyl)(CrC4 alkyl), -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)(Ci-C4 alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(d-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(OXphenyl), -N(C1-C4 alkyl)C(O)(Ci -C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)C1-C4 haloalkyl, -OC(O)C1-C4 alkyl, - SO2(C1-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl). [053] 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, optionally substituted amino (including -NRcCORb, -NRcCO2Ra, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2R3, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2R3 and -SO2NRbRc), where Ra is chosen from optionally substituted C1-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rb is chosen from H, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
Rc is independently chosen from hydrogen and optionally substituted C1-C4 alkyl; or Rb and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and 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-d-C4 alkyl-, heteroaryl-d-d alkyl-, C1-C4 haloalkyl, -OCi-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NH2, -N(C1-C4 8^yI)(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)(Ci-C4 alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4 alkyl, -CON(Ci-C4 alkyl)(Ci-C4 alkyl), -CONH(Ci-C4 alkyl), -CONH2, -NHC(O)(Ci-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(Ci-C4 alkyl), -N(Ci-C4 alkyl)C(O)(phenyl). -C(O)Ci-C4 alkyl, -C(O)Ci-C4 alkylphenyl, -C(O)Ci-C4 haloalkyl, -OC(O)Ci-C4 alkyl, - SO2(Ci-C4 alkyl), -SO2(phenyl), -SO2(Ci-C4 haloalkyl), -SO2NH2, -SO2NH(CrC4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(Ci-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 -0(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.
[054] 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, optionally substituted amino (including -NRcCORb, -NR0CO2R3, -NR°CONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbR°, and -NRcSO2Ra), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2R"), aminocarbonyl (such as -CONRbR°), -OCORb, -OCO2R3, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Ra and -SO2NRbRc), where Ra is chosen from optionally substituted Ci-Cε alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rb is chosen from H, optionally substituted CrCβ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and Rc is independently chosen from hydrogen and optionally substituted C1-C4 alkyl; or Rb and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from Ci-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, CrC4 haloalkyl, -OCi-C4 alkyl, -OCi-C4 alkylphenyl, -Ci-C4 alkyl-OH, -OCi-C4 haloalkyl, halo, -OH, -NH2, -Ci-C4 alkyl-NH2, -N(Ci-C4 alkyl)(Ci-C4 alkyl), -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)(Ci-C4 alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCrC4 alkyl, -CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(CrC4 alkyl), -CONH2, -NHC(O)(CrC4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(CrC4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)C1-C4 alkyl, -C(O)C1-C4 alkylphenyl, -C(O)CrC4 haloalkyl, -OC(O)CrC4 alkyl, - SO2(CrC4 alkyl), -SO2(phenyl), -SO2(CrC4 haloalkyl), -SO2NH2, -SO2NH(C1-C4 alkyl), -SO2NH(phenyl), -NHSO2(CrC4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl). [055] The term "substituted amino" refers to the group -NHRd or -NRdRe wherein Rd is chosen from: hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein Re is chosen from: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, and wherein 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:
-Ra, -ORb, optionally substituted amino (including -NRcCORb, -NR0CO2R8, -NRcCONRbRc, -NRbC(NRc)NRbRc, -NRbC(NCN)NRbRc, and -NR0SO2R3), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -CORb), optionally substituted alkoxycarbonyl (such as -CO2Rb), aminocarbonyl (such as -CONRbRc), -OCORb, -OCO2R8, -OCONRbRc,
-OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Ra and -SO2NRbRc), where Ra is chosen from optionally substituted Ci-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rb is chosen from H, optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
Rc is independently chosen from hydrogen and optionally substituted C1-C4 alkyl; or
Rb and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from Ci-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C4 alkyl-, Ci-C4 haloalkyl, -OCi-C4 alkyl, -OC1-C4 alkylphenyl, -d-C4 alkyl-OH, -OCi-C4 haloalkyl, halo, -OH, -NH2, -d-C4 alkyl-NH2, -N(Ci-C4 alkyl)(Ci-C4 alkyl), -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)(Ci-C4 alkylphenyl), -NH(Ci-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OCi-C4 alkyl, -CON(Ci-C4 alkyl)(Ci-C4 alkyl), -CONH(Ci-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(Ci-C4 alkyl)C(O)(Ci-C4 alkyl), -N(C1-C4 alkyl)C(O)(phenyl), -C(O)Ci-C4 alkyl, -C(O)Ci-C4 alkylphenyl, -C(O)Ci-C4 haloalkyl, -OC(O)Ci-C4 alkyl, - SO2(Ci-C4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2. -SO2NH(Ci-C4 alkyl), -SO2NH(phenyl), -NHSO2(C1-C4 alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4 haloalkyl); and wherein optionally substituted acyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.
[056] The term "substituted amino" also refers to N-oxides of the groups -NHRd, and NRdRd each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m- chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.
[057] Compounds of Formula X include, but are not limited to, optical isomers of compounds of Formula X, 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 X include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds. Where compounds of Formula X exists in various tautomeric forms, chemical entities described herein include all tautomeric forms of the compound. [058] Chemical entities described herein include, but are not limited to compounds of Formula X and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the chemical entities recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the chemical entities 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.
[059] "Pharmaceutically acceptable salts" include, but are not limited to salts with inorganic acids, such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC-(CH2)π-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.
[060] In addition, if the compound of Formula X 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 pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
[061] As noted above, prodrugs also fall within the scope of chemical entities, for example ester or amide derivatives of the compounds of Formula X. The term
"prodrugs" includes any chemical entities that become compounds of Formula X when administered to a patient, e.g., upon metabolic processing of the prodrug. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula X.
[062] 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.
[063] The term "chelate" refers to the chemical entity formed by the coordination of a compound to a metal ion at two (or more) points.
[064] The term "non-cpvalent 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).
[065] The term "active agent" is used to indicate a chemical entity which has biological activity. In certain embodiments, an "active agent" is a compound having pharmaceutical utility. For example an active agent may be an anti-cancer therapeutic.
[066] By "significant" is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p <
0.05.
[067] The term "therapeutically effective amount" of a chemical entity described herein 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.
[068] "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. [069] "Patient" refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein 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.
[070] Provided is at least one chemical entity chosen from compounds of Formula X:
Figure imgf000025_0001
Formula X
and pharmaceutically acceptable salts thereof, wherein
U is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and *- W1COW2, where the "*" indicates the point of attachement to Z1;
W1 and W2 are independently selected from CR11R12, NR13, and O; provided at least one of W1 and W2 is NR13;
WJ is selected from
Figure imgf000025_0002
NR ,1144 and O; Z1 is aryl; Z2 is aryl; R8 is selected from hydrogen, optionally substituted a Iky I, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
R1, R2, R11, and R12 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted amiπosulfonyl; or R1 and R2 may together with any intervening atoms to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
R13 and R14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; for each occurrence, R3, R4, R5, and R6 are independently selected from hydrogen, hydroxy I, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and one occurrence of R5 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; or R14 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and R1 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
R7 and R10 are independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2, 3, and 4; p is selected from 0, 1 , 2, and 3; and q is selected from 0, 1 , 2, 3, and 4.
[071] In some embodiments, U is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl.
[072] In some embodiments, U is *-W1COW2, where the "*" indicates the point of attachement to Z1.
[073] Provided is at least one chemical entity selected from compounds of Formula I
Figure imgf000028_0001
and pharmaceutically acceptable salts thereof, wherein
W1 and W2 are independently selected from CR11R12, NR13, and O; provided at least one of W1 and W2 is NR13;
W3 is selected from CR1R2, NR14 and O;
Z1 is aryl;
Z2 is aryl;
R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
R1, R2, R11, and R12 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and R2 may together with any intervening atoms to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
R13 and R14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; for each occurrence, R3, R4, R5, and R6 are independently selected from hydrogen, hydroxy I, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and one occurrence of R5 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; or R14 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and R1 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
R7 and R10 are independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2, 3, and 4; p is selected from 0, 1 , 2, and 3; and q is selected from 0, 1 , 2, 3, and 4.
[074] In some embodiments, Z1 is chosen from phenyl, naphthyl, and indanyl. [075] In some embodiments of compounds of Formula I, Z1 is phenyl. [076] In some embodiments, Z2 is chosen from phenyl, naphthyl, and indanyl. [077] In some embodiments of compounds of Formula I, Z2 is phenyl. [078] In some embodiments of compounds of Formula I, W1 is CR11R12. [079] In some embodiments of compounds of Formula I, W1 is NR13. [080] In some embodiments of compounds of Formula I, W1 is O. [081] In some embodiments of compounds of Formula I, W2 is CR11R12. [082] In some embodiments of compounds of Formula I, W2 is NR13. [083] In some embodiments of compounds of Formula I, W2 is O. [084] In some embodiments of compounds of Formula I, W3 is CR1R2. [085] In some embodiments of compounds of Formula I, W3 is NR14. [086] In some embodiments of compounds of Formula I, R8 is selected from hydrogen and optionally substituted lower alkyl.
[087] In some embodiments of compounds of Formula I, R8 is selected from hydrogen and lower alkyl.
[088] In some embodiments of compounds of Formula I, R8 is selected from hydrogen and methyl.
[089] In some embodiments of compounds of Formula I, R8 is hydrogen. [090] In some embodiments of compounds of Formula I, R11 and R12 are independently selected from hydrogen and optionally substituted lower alkyl. [091] In some embodiments of compounds of Formula I1 R11 and R12 are independently selected from hydrogen and lower alkyl. [092] In some embodiments of compounds of Formula I1 R11 and R12 are independently selected from hydrogen and methyl.
[093] In some embodiments of compounds of Formula I, R11 is hydrogen and R12 is methyl.
[094] In some embodiments of compounds of Formula I, R13 is selected from hydrogen and optionally substituted lower alkyl. [095] In some embodiments of compounds of Formula I1 R13 is selected from hydrogen and lower alkyl.
[096] In some embodiments of compounds of Formula I, R13 is selected from hydrogen and methyl.
[097] In some embodiments of compounds of Formula I, R13 is methyl.
[098] In some embodiments of compounds of Formula I, q is 2.
[099] In some embodiments of compounds of Formula I1 q is 1.
[0100] In some embodiments of compounds of Formula I, q is 0.
[0101] In some embodiments of compounds of Formula I, each R5 and R6 is independently selected from hydrogen, optionally substituted lower alkyl, and lower alkoxycarbonyl.
[0102] In some embodiments of compounds of Formula I, each R5 and R6 is independently selected from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, and methoxycarbonyl.
[0103] In some embodiments of compounds of Formula I1 each R5 and R6 is hydrogen.
[0104] In some embodiments of compounds of Formula I, m is selected from 1 and
2.
[0105] In some embodiments of compounds of Formula I, R7 is selected from halo, lower alkyl, and optionally substituted lower alkyl.
[0106] In some embodiments of compounds of Formula I, R7 is selected from chloro, fluoro, methyl, and trifluoromethyl.
[0107] In some embodiments of compounds of Formula I1 R7 is chloro.
[0108] In some embodiments of compounds of Formula I, R7 is at position 2 or 3 relative to the point of attachment of the phenyl ring.
[0109] In some embodiments of compounds of Formula I1 n is selected from 1 and
2.
[0110] In some embodiments of compounds of Formula I, n is 1.
[0111] In some embodiments of compounds of Formula I, each R3 and R4 is independently selected from hydrogen, optionally substituted lower alkyl, and lower alkoxycarbonyl. [0112] In some embodiments of compounds of Formula I1 each R3 and R4 is independently selected from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, and methoxycarbonyl.
[0113] In some embodiments of compounds of Formula I1 each R3 and R4 is hydrogen.
[0114] In some embodiments of compounds of Formula I, p is selected from 1 and
2.
[0115] In some embodiments of compounds of Formula I, p is 1.
[0116] In some embodiments of compounds of Formula I, p is 0.
[0117] In some embodiments of compounds of Formula I, each R10 is independently selected from cyano, halo, optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted phenyl.
[0118] In some embodiments of compounds of Formula I, each R10 is independently selected from cyano, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, hydroxymethyl, trifluoromethyl, methoxycarbonyl, phenoxy, phenyl, trifluoromethoxy, methoxy, N1N- dimethyamino, and 1H-imidazolyl.
[0119] In some embodiments of compounds of Formula I, each R10 is independently selected from cyano, chloro, fluoro, bromo, trifluoromethyl, methyl, ethyl, vinyl, and phenyl.
[0120] In some embodiments of compounds of Formula I, each R10 is selected from methyl, ethyl, isopropyl, and trifluoromethyl.
[0121] In some embodiments of compounds of Formula I, p is selected from 1 and
2, and each R10 is independently selected from cyano, halo, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted aryl.
[0122] In some embodiments of compounds of Formula I, (R10)P , together with Z1 to which is attached, forms a group selected from 2-naphthyl, 5-indanyl, 4-ethylphenyl, 4- methylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4- phenylphenyl, 4-methyl-2-chlorophenyl, 4-methyl-3-fluorophenyl, 4-ethyl-3-fluorophenyl, and 4-ethyl-2-chlorophenyl.
[0123] In some embodiments of compounds of Formula I1 p is 1 and R10 is selected from ethyl and isopropyl. [0124] In some embodiments of compounds of Formula I1 R14 is selected from hydrogen and optionally substituted lower alkyl.
[0125] In some embodiments of compounds of Formula I, R14 is selected from hydrogen and lower alkyl.
[0126] In some embodiments of compounds of Formula I, R14 is hydrogen.
[0127] In some embodiments of compounds of Formula I, each R1 and R2 is independently selected from hydrogen, lower alkyl, and substituted alkyl.
[0128] In some embodiments of compounds of Formula I, each R1 and R2 is independently selected from hydrogen and methyl.
[0129] In some embodiments of compounds of Formula I, R1 and R2 are hydrogen.
[0130] In some embodiments of compounds of Formula I, R1 and R2 are methyl.
[0131] In some embodiments of compounds of Formula I, R1 is hydrogen and R2 is methyl.
[0132] In some embodiments of compounds of Formula I, R1 and R2, together with the carbon to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.
[0133] In some embodiments of compounds of Formula I, R1 and R2, together with the carbon to which they are attached, form a group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, and 2H-3,4,5,6-tetrahydropyranyl, each of which is optionally substituted.
[0134] In some embodiments of compounds of Formula I, R1 and R2, together with the carbon to which they are attached, form a group selected from cyclopentyl, cyclohexyl, piperidinyl, and 2H-3,4,5,6-tetrahydropyranyl, each of which is optionally substituted.
[0135] Also provided is at least one chemical entity selected from compounds of
Formula Ia
Figure imgf000034_0001
Formula 1a
and pharmaceutically acceptable salts thereof, wherein R1, R2, n, R3, R4, q, m, R7, R8, p, and R10 are as described for compounds of Formula I.
[0136] Also provided is at least one chemical entity selected from compounds of Formula Ib
Figure imgf000034_0002
Formula 1b
and pharmaceutically acceptable salts thereof, wherein R1, R2, n, R3, R4, q, m, R7, R8, p, and R10 are as described for compounds of Formula I.
[0137] Also provided is at least one chemical entity selected from compounds of Formula Ic
Figure imgf000034_0003
Formula Ic and pharmaceutically acceptable salts thereof, wherein R1, R2, n, R3, R4, q, m, R7, Rβ, p, and R10 are as described for compounds of Formula I.
[0138] Also provided is at least one chemical entity selected from compounds of Formula Id
Figure imgf000035_0001
and pharmaceutically acceptable salts thereof, wherein R14, n, R3, R4, q, R5, R6, m, R7, R8, p, and R10 are as described for compounds of Formula I.
[0139] Provided is at least one chemical entity chosen from compounds of Formula Il
Figure imgf000035_0002
and pharmaceutically acceptable salts thereof, wherein
W4 is an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
W5 is selected from CR1R2, NR14, and O;
Z1 is aryl;
Z2 is aryl;
R1 and R2 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and R2 may optionally be joined together with the carbon atom bonded thereto, to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; for each occurrence, R3 , R4, R5 and R6 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; each R7 and R10 is independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl;
R8 and R14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2 and 3; p is selected from 0, 1, 2, and 3; and q is selected from 0, 1, 2 and 3.
[0140] In certain embodiments of compounds of Formula II, Z1 is phenyl.
[0141] In certain embodiments of compounds of Formula II, Z2 is phenyl.
[0142] In certain embodiments of compounds of Formula II, W4 is
Figure imgf000037_0001
wherein W1a, W1b, and W1c are independently selected from -CH and N.
[0143] In certain embodiments of compounds of Formula II, at least one of W1a, W1b, and W1cis N.
[0144] In certain embodiments of compounds of Formula II, at least two of W1a, W1b, and W1care N.
[0145] In certain embodiments of compounds of Formula II, W1a, W1b, and W1c are N.
[0146] In certain embodiments of compounds of Formula II, n is chosen from 1 and 2.
[0147] In certain embodiments of compounds of Formula II, n is 1.
[0148] In certain embodiments of compounds of Formula II, each R3 and R4 is independently chosen from hydrogen, optionally substituted lower alkyl and lower alkoxycarbonyl.
[0149] In certain embodiments of compounds of Formula II, each R3 and R4 is independently chosen from hydrogen, methyl, ethyl, isopropyl. hydroxy methyl, and methoxycarbonyl.
[0150] In certain embodiments of compounds of Formula II, each R3 and R4 is hydrogen.
[0151] In certain embodiments of compounds of Formula II, p is chosen from 1 and 2. [0152] In certain embodiments of compounds of Formula II, p is 1.
[0153] In certain embodiments of compounds of Formula II, q is chosen from 1 and 2.
[0154] In certain embodiments of compounds of Formula II, q is 1. In certain embodiments of compounds of Formula II, q is 0.
[0155] In certain embodiments of compounds of Formula II, each R10 is independently selected from cyano, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, hydroxymethyl, trifluoromethyl, methoxycarbonyl, phenoxy, trifluoromethoxy, methoxy, N.N-dimethyamino, and 1 H-imidazolyl.
[0156] In certain embodiments of compounds of Formula II, each R10 is chosen from methyl, ethyl, isopropyl, and CF3.
[0157] In certain embodiments of compounds of Formula II, p is 1 and R10 is ethyl or isopropyl.
[0158] In certain embodiments of compounds of Formula II, one R10 group is in the 4-position of the phenyl group.
[0159] In certain embodiments of compounds of Formula II, R1 and R2 are independently chosen from hydrogen and lower alkyl.
[0160] In certain embodiments of compounds of Formula H1 R1 and R2 are independently chosen from hydrogen and methyl.
[0161] In certain embodiments of compounds of Formula II, R1 and R2 are hydrogen.
[0162] In certain embodiments of compounds of Formula II, R1 and R2 are methyl.
[0163] In certain embodiments of compounds of Formula II, R1 is hydrogen and R2 is methyl.
[0164] In certain embodiments of compounds of Formula II, R1 and R2 are joined together to form a group selected from cycloalkyl and heterocycloalkyl.
[0165] In certain embodiments of compounds of Formula II, R1 and R2 are joined together to form a group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, and 2H-3,4,5,6-tetrahydropyranyl, each of which is optionally substituted. [0166] In certain embodiments of compounds of Formula II, R1 and R2 are joined together to form a group selected from optionally substituted cyclopropyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, and optionally substituted 2H-3,4,5,6-tetrahydropyranyl.
[0167] In certain embodiments of compounds of Formula II, each R5 and R6 is independently chosen from hydrogen, optionally substituted lower alkyl and lower alkoxycarbonyl.
[0168] In certain embodiments of compounds of Formula II, each R5 and R6 is independently chosen from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, and methoxycarbonyl.
[0169] In certain embodiments of compounds of Formula II, each R5 and R6 is hydrogen.
[0170] In certain embodiments of compounds of Formula II, m is 1 or 2.
[0171] In certain embodiments of compounds of Formula II, m is 1 and R7 is Cl, F, methyl, or CF3.
[0172] In certain embodiments of compounds of Formula II, m is 1 and R7 is Cl.
[0173] In certain embodiments of compounds of Formula II, m is 2 and each R7 is Cl. In certain embodiments of compounds of Formula II, those chloros are positioned at the 2 and 3 positions of the phenyl ring.
[0174] In certain embodiments of compounds of Formula II, m is 2 and each R7 is Cl or F.
[0175] In certain embodiments, the compound of Formula X is chosen from Structure Chemical Name
N-[(2-chlorophenyl)methyl]-3-{[(4- ethylphenyl)amino]carbonylamino}-2,2- dimethylpropanamide
Figure imgf000039_0001
}(2H-3,4,5,6-
lH∑H-SAS.β-
Figure imgf000040_0001
N-[(2-chlorophenyl)methyl](4-{tN-(3- methoxyphenyl)carbamoyloxy]methyl}(2H-
3,4,5,6-tetrahydropyran-4-yl))carboxamide
Figure imgf000040_0002
2-(acetylamino)-N-[(2-chlorophenyl)methyl]-3- [N-(4-ethylphenyl)carbamoyloxy]propanamide
Figure imgf000040_0003
ethyl 4-{[(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-2H-3,4,5,6- tetra hyd ropy ran-4-
Figure imgf000040_0004
yl)methoxy]carbonylamino}benzoate
N-[(2-chlorophenyl)methyl](4-{[N-(4- methylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6-
Figure imgf000040_0005
tetrahyd ropyran-4-yl))carboxam ide N-[(2-chlorophenyl)methyl][4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(2
H-3,4,5,6-tetrahydropyran-4-yl)]carboxamide
Figure imgf000041_0001
N-[(2-chlorophenyl)methyl](4-{[N-(2- cyanophenyl)carbamoyloxy]methyl}(2H-314,5,6- tetrahydropyran-4-yl))carboxamide
Figure imgf000041_0002
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)-N-methylcarbamoyloxy]methyl}(2H-
Figure imgf000041_0003
3,4,5,6-tetrahydropyran-4-yl))carboxamide
methyl 4-{[(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-2H-3,4,5,6- tetrahydropyran-4- yl)methoxy]carbonylamino}benzoate
N-[(2-chlorophenyl)methyl][4-({N-[4-(2- methyl(1 ,3-thiazol-4- yl))phenyl]carbamoyloxy}methyl)(2H-3,4,5,6-
Figure imgf000041_0004
tetrahydropyran-4-yl)]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(3-fluoro-4- methylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6- tetrahydropyran-4-yl))carboxamide
Figure imgf000041_0005
N-[(2-chlorophenyl)methyl]{4-[(N-indan-5- ylcarbamoyloxy)methyl](2H-3,4,5,6-
Figure imgf000042_0001
tetrahydropyran-4-yl)}carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(6-fluoro-2- methylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6-
Figure imgf000042_0002
tetrahydropyran-4-yl))carboxamide
(4-{[N-(3-chloro-2- methylphenyl)carbamoyIoxy]methyl}(2H-3,4,5,6- tetrahydropyran-4-yl))-N-[(2-
Figure imgf000042_0003
chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl][4-({N-[4-methyl-3-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(2
Figure imgf000042_0004
H-3,4,5,6-tetrahydropyran-4-yl)]carboxamide
l}(2H-
Figure imgf000042_0005
chlorophenyl)methyl]carboxamide
(4-{[N-(3-chloro-4- methylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6- tetrahydropyran-4-yl))-N-[(2-
Figure imgf000042_0006
chlorophenyl)methyl]carboxamide N-[(2-chlorophenyl)methyl][4-({N-[4-
(methylethyl)phenyl]carbamoyloxy}methyl)(2H-
3,4,5,6-tetrahydropyran-4-yl)]carboxamide
Figure imgf000043_0001
}(2H-
l}(2H-
Figure imgf000043_0002
α chlorophenyl)methyl]carboxamide
methyl 3-{N-[(2- chlorophenyl)methyl]carbamoyl}-3-{[(4- ethylphenyl)amino]carbonylamiπo}pyrrolidinecar
Figure imgf000043_0003
boxylate
N-[(2-chlorophenyl)methyl][4-({N-[4-
(hydroxyethyl)phenyl]carbamoyloxy}methyl)(2H-
3,4,5,6-tetrahydropyran-4-yl)]carboxamide
N-[(2-chlorophenyl)methyl]{4-[(N- phenylcarbamoyloxy)methyl](2H-3t4,5,6- tetrahydropyran-4-yl)}carboxamide
Figure imgf000043_0004
4-{[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-
2H-3,4,5,6-tetrahydropyran-4- yl)methoxy]carbonylamino}benzamide
N-[(2-chlorophenyl)methyl][4-({[(4- ethylphenyl)amino]carbonylamino}methyl)(4- piperidyl)]carboxamide
N-[(2-chlorophenyl)methyl][4-({[(4- ethylphenyl)amino]carbonylamino}methyl)-1-(2- hydroxyacetyl)(4-piperidyl)]carboxamide
N-[(2-chlorophenyl)methyl][4-({[(4- ethylphenyl)amino]-N- methylcarbonylamino}methyl)-1-(2-
Figure imgf000044_0001
hydroxyacetyl)(4-piperidyl)]carboxamide
2-(acetylamino)-N-[(2-chlorophenyl)methyl]-3-
[N-(4-ethylphenyl)carbamoyloxy]-2- methylpropanamide
Figure imgf000044_0002
N-[(2-chlorophenyl)methyl]-3-[N-(4- ethylphenyl)carbamoyloxy]-2-
Figure imgf000044_0003
(methoxycarbonylamino)-2-methylpropanamide N-[(2-chlorophenyl)methyl]-3-[N-(4- ethylphenyl)carbamoyloxy]-2-(2- hydroxyacetylamino)-2-methylpropanamide
2-{2-[(tert-butoxy)carbonylamino]acetylamino}- N-[(2-chlorophenyl)methyl]-3-[N-(4- ethylphenyl)carbamoyloxy]-2-
Figure imgf000045_0001
methylpropanamide
2-(2-aminoacetylamino)-N-[(2- chlorophenyl)methyl]-3-[N-(4- ethylphenyl)carbamoyloxy]-2-
Figure imgf000045_0002
methylpropanamide
2-((2S)-2-amino-3-hydroxypropanoylamino)-N- [(2-chlorophenyl)methyl]-3-[N-(4- ethylphenyl)carbamoyloxy]-2- methylpropanamide
{[1-(2-aminoacetyl)-4-({[(2- chlorophenyl)methyl]amino}methyl)(4- piperidyl)]methoxy}-N-(4- ethylphenyl)carboxamide
N-[(1 -(2-aminoacetyl)-4-{N-[(2- chlorophenyl)methyl]carbamoyl}(4- piperidyl))methyl][(4-ethylphenyl)amino]-N-(3-
Figure imgf000045_0003
methoxypropyl)carboxamide N-[(1 -(2-aminoacetyl)-4-{N-[(2- chlorophenyl)methyl]carbamoyl}(4- piperidyl))methyl]-N-(2-aminoethyl)[(4-
Figure imgf000046_0001
ethylphenyl)amino]carboxamide
l)carboxa
Figure imgf000046_0002
3-(1-(2-aminoacetyl)-4-{N-[(2- methylphenyl)methyl]carbamoyl}(4-piperidyl))-N-
(4-ethy!phenyl)propanamide
Figure imgf000046_0003
N-{(1S)-2-[N-(4-ethylphenyl)carbamoyloxy]- isopropylK[(2-
Figure imgf000046_0004
chlorophenyl)methyl]amino}carboxamide
2- ino)acet
Figure imgf000046_0005
)carbamoyloxy]- rbonylamino)aceti
Figure imgf000046_0006
N-{(1S)-2-[N-(4-ethylphenyl)carbamoyloxy]- isopropyiχ[(2-chlorophenyl)methyl]amino}-N- methylcarboxamide
Figure imgf000047_0001
[(2R)-2-({[(2-chlorophenyl)methyl]amino}-N- methylcarbonylamino)propoxy]-N-(4-
Figure imgf000047_0002
ethylphenyl)carboxamide
N-{(1 S)-3-[N-(4-ethylpheπyl)carbamoyloxy]-1 - methylpropyl}{[(2-chlorophenyl)methyl]amino}-
Figure imgf000047_0003
N-methylcarboxamide
{[(2-chlorophenyl)methyl]amino}-N-{4-[N-(4- ethylphenyl)carbamoyloxy]butyl}-N- methylcarboxamide
Figure imgf000047_0004
{[(2-chlorophenyl)methyl]amino}-N-{3-[N-(4- ethylphenyl)carbamoyloxy]propyl}-N-
Figure imgf000047_0005
methylcarboxamide
(tert-butoxy)-N-[2-({[(2- chlorophenyl)methyl]amiπo}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carbonylamino)
Figure imgf000047_0006
ethylj-N-methylcarboxamide {[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}-N-[2-
(methylamino)ethyl]carboxamide
Figure imgf000048_0001
]amino}- ylamino)
Figure imgf000048_0002
Figure imgf000048_0003
onylamino]ethyl}-N-methylacetamide
[2-({[(2-chlorophenyl)methyl]amino}-N- methylcarbonylamino)-isopropoxy]-N-(4-
Figure imgf000048_0004
ethylphenyl)carboxamide
lorophenyl)methyl]amino}-N-methyl-N-{2-
Figure imgf000048_0005
phenyl)carbamoyloxy]ethyl}carboxamide
{[(2-chlorophenyl)methyl]amino}-N-methyl-N-[2-
Figure imgf000048_0006
(N-(2-naphthyl)carbamoyloxy)ethyl]carboxamide 3-(2-chlorophenyl)-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}-N-
Figure imgf000049_0001
methylpropanamide
N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-2- hydroxy-N-methyl-3-[2-
Figure imgf000049_0002
(trifluoromethyl)phenyl]propanamide
N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-N- methyl-3-[2-(trifluoromethyl)phenyl]propanamide
Figure imgf000049_0003
{[(2-chlorophenyl)methyl]methylamino}-N-{2-[N-
(4-ethylphenyl)carbamoyloxy]ethyl}-N-
Figure imgf000049_0004
methylcarboxamide
amoyloxy}ethoxy)-N-
Figure imgf000049_0005
de
N-[(2-chlorophenyl)methyl]-4-{[N-(4- ethylphenyl)carbamoyl]amino}-212-
Figure imgf000049_0006
dimethylbutanamide N-[(2-chlorophenyl)methyl]-2-{[(4- ethylphenyl)amino]carbonylamino}-2-
Figure imgf000050_0001
methylpropanamide
N-[(2-chlorophenyl)methyl]-3-[N-(4- ethylphenyl)carbamoyloxy]-2,2-
Figure imgf000050_0002
dimethylpropanamide
ethyl]carbamoyl}cyclopropyl)met
Figure imgf000050_0003
πyl)amiπo]carboxamide
clopropyl)met
Figure imgf000050_0004
hyl]carbamoyl}cyclobutyl)meth
Figure imgf000050_0005
enyl)carboxamide
N-[(2-chlorophenyl)methyf]({[N-(4- ethylphenyl)carbamoyloxy]methyl}cyclohexyl)car
Figure imgf000050_0006
boxamide tert-butyl 4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidinecarb
Figure imgf000051_0001
oxylate
N-[(2-chloroρhenyI)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-
Figure imgf000051_0002
piperidyl))carboxamide
l}(2H-3,4,5,6-
Figure imgf000051_0003
N-[(2-chlorophenyl)methyl](1-{[N-(4- ethylphenyOcarbamoyloxyjmethyljcyclopent-S-
Figure imgf000051_0004
enyl)carboxamide
N-[(2-chlorophenyl)methyl](1-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-3,4- dihydroxycyclopentyl)carboxamide
Figure imgf000051_0005
methyl 4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidinecarb
Figure imgf000051_0006
oxylate no]carbonylamino}cydohexyl)-
Figure imgf000052_0001
nyl)methyl]carboxamide
(1-acetyl-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-
(methylsulfonyl)(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxyjmethyl}-1-(2- hydroxyacetyl)(4-piperidyl))carboxamide
(tert-butoxy)-N-[2-(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-2- oxoethyl]carboxam ide
(tert-butoxy)-N-[4-(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-4-
Figure imgf000052_0002
oxobutyl]carboxamide (1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyljcarboxamide
(1 -(4-aminobutanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
Figure imgf000053_0001
Figure imgf000053_0002
1- o o α methyl-2-oxoethyl](tert-butoxy)carboxamide
( 1 -((2S)-2-aminopropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
methyl 4-(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-4- oxobutanoate
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(4- hydroxybutanoyl)(4-piperidyl))carboxamide
Figure imgf000053_0003
N-[<2-chlorophenyl)methyl]{3-[N-(4- ethylphenyl)carbamoyloxyjpiperidyl}carboxamid
Figure imgf000054_0001
{3-[N-(4-ethylphenyl)carbamoyloxy]piperidyl}-N-
Figure imgf000054_0002
[(2-methylphenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxyjmethyl}-1-(N- methylcarbamoyl)(4-piperidyl))carboxamide
(tert-butoxy)-N-[2-(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-1- (hydroxymethyl)-2-oxoethyl]carboxamide
(1-(2-amino-3-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]ιηethyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
Figure imgf000054_0003
1-
Figure imgf000054_0004
(1-((2R)-2-aminopropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
(1-(2-amino-3-methylbutanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
tert-butyl 4-[(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)carb onyl]piperidinecarboxylate
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(4- piperidylcarbonyl)(4-piperidyl))carboxamide
tert-butyl 3-[(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)carb onyl]morpholine-4-carboxylate
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(morpholin-
3-ylcarboπyl)(4-piperidyl))carboxamide
Figure imgf000055_0001
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxyjmethyl}-1-benzyl(4- piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](1-ethyl-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))carboxamide
Figure imgf000056_0001
l]carbamoyl}~4-{[N-(4- oyloxy]methyl}piperidyl)acet
Figure imgf000056_0002
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-[3-hydroxy- 2-(hydroxymethyl)-2-methylpropanoyl](4- piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(2- hydroxyethyl)(4-piperidyl))carboxamide
(1-(2-amino-2-methylpropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
Figure imgf000056_0003
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-[2-
(methylamino)acetyl](4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxyjmethyl}-1-methyl(4- piperidyl))carboxamide
Figure imgf000057_0001
l)-1-
Figure imgf000057_0002
(1-((2R)-2-amino-3-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoy!oxy]methyl}(4-piperidyl))- N-[(2-chlorophenyl)methyl]carboxamide
Figure imgf000057_0003
l)-1-
Figure imgf000057_0004
(1-((2S)-2-amino-3-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))- N-[(2-chlorophenyl)methyl]carboxamide
Figure imgf000057_0005
(1 -(2-aminoethyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
(1-(2-amino-3-cyanopropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl][4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4- piperidyl)]carboxamide
(1-[(2-aminoethyl)sulfonyl]-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyljcarboxamide
(1-(2,3-diaminopropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyljcarboxamide
(1 -(2,4-diaminobutanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
Figure imgf000058_0001
xyacetyl)- methyl)(4-
Figure imgf000059_0001
[1-(2-aminoacetyl)-4-({N-[4- (trifluoromethyl)phenyl]carbamoyloxy}methyl)(4- piperidyl)]-N-[(2- chlorophenyl)methyl]carboxamide
[1-((2S)-2-amino-3-hydroxypropanoyl)-4-({N-[4- (trifluoromethyl)phenyl]carbamoyloxy}methyl)(4- piperidyl)]-N-[(2- chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyt](4-{[N-(4- ethy I phe ny l)ca rba moyloxy] methyl}- 1 -(2- methoxyacetyl)(4-piperidyl))carboxamide
tert-butyl 2-[(4-{N-t(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)carb onyl]azetidinecarboxylate
(1-(azetidin-2-ylcarbonyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
Figure imgf000059_0002
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(3- methoxypropanoyl)(4-piperidyl))carboxamide
(1-(2.5-diaminopentanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
Figure imgf000060_0001
oyloxy]piperidyl}-N-[(2-
Figure imgf000060_0002
l]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-
(phenylcarbonyl)(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylpheπyl)carbamoyloxy]methyl}-1-(3- pyridylcarbonyl)(4-piperidyl))carboxamide
(tert-butoxy)-N-[2-(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-
Figure imgf000060_0003
methyl-2-oxoethyl]-N-methylcarboxamide N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-[2- (methylamino)propanoyl](4-
Figure imgf000061_0001
piperidyl))carboxamide
N-[(2-chlorophenyl)methyl]-N'-(4-ethylphenyl)-
Figure imgf000061_0002
2,2-dimethylpentane-i ,5-diamide
methyl (3S)-3-amino-4-(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-4- oxobutanoate
(1-(3-amino-2-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
(1-(4-amino-2-hydroxybutanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
(1-(2,3-dihydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyljcarboxamide
Figure imgf000061_0003
oyloxy]piperidyl}-N-[(2-
Figure imgf000062_0001
l]carboxamide
3-amino-4-(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-4- oxobutanoic acid
N-[(2-chlorophenyl)methyl](1- (cyclopropylcarbonyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](1- (cyclohexylcarbonyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(2- pyridylcarbonyl)(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(imidazol-
2-ylcarbonyl)(4-piperidyl))carboxamide
Figure imgf000062_0002
(tert-butoxy)-N-[2-(3-{N-[(2- chlorophenyl)methyl]carbamoyl}-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-2-
Figure imgf000063_0001
oxoethyl]carboxamide
l)-1-
Figure imgf000063_0002
(1 -(2-aminoacetyl)-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(3-piperidyl))-
N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(2- hydroxyacetyl)(3-piperidyl))carboxamide
(1-((2S)-2-amiπo-3-hydroxypropaπoyl)-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(3-piperidyl))- N-[(2-chlorophenyl)methyl]carboxamide
2-aminoethyl 4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidinecarb
Figure imgf000063_0003
oxylate N-(2-aminoethyl)(4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)carb oxamide
methyl 3-{N-[(2- chlorophenyl)methyl]carbamoyl}-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidinecarb oxylate
(1 -(2-aminoacetyl)-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}pyrrolidin-3- yl)-N-[(2-chlorophenyl)methyl]carboxamide
(1-((2S)-2,5-diaminopentanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyljcarboxamide
Figure imgf000064_0001
(1 -(2-aminoacetyl)-4-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
[1-(2-aminoacetyl)-4-({N-[2-chloro-4- (trifluoromethyl)phenyl]carbamoyloxy}methyl)(4- piperidyl)]-N-[(2-
Figure imgf000064_0002
chlorophenyl)methyl]carboxamide [1-(2-aminoacetyl)-4-({N-[4-methyl-3- (trifluoromethyl)phenyl]carbamoyloxy}methyl)(4- piperidyl)]-N-[(2- chlorophenyl)methyl]carboxamide
(1-(2-aminoacetyl)-4-{[N-(2-chloro-4- methylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-
Figure imgf000065_0001
chlorophenyl)methyl]carboxamide
{ 1 -(2-aminoacetyl)-4-[(N-indan-5- ylcarbamoyloxy)methyl](4-piperidyl)}-N-[(2- chlorophenyl)methyl]carboxamide
( 1 -(2-aminoacetyl)-4-{[N-(4- chlorophenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2- chlorophenyl)methyl]carboxamide
methyl 4-{[(1 -(2-aminoacetyl)-4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4- piperidyl)methoxy]carbonylamino}benzoate
Figure imgf000065_0002
(1-(2-aminoacetyl)-4-{[N-(3-fluoro-4- methylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-
Figure imgf000065_0003
chlorophenyl)methyl]carboxamide N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoy!oxy]methyl}-T-{[4- (phenylcarbonyl)phenyl]carbonyl}(4- piperidyl))carboxamide
(1 -(2-aminoacetyl)-4-{[N-(4- phenylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2- chloropheπyl)methyl]carboxamide
{1-(2-aminoacetyl)-4-[(N-(2- naphthyl)carbamoyloxy)methyl](4-piperidyl)}-N-
[(2-chlorophenyl)methyl]carboxamide
Figure imgf000066_0001
N-[(2-chlorophenyl)methyl]-4-[N-(4-
Figure imgf000066_0002
ethylphenyl)carbamoyloxy]butanamide
2-amino-N-[(2-chlorophenyl)methyl]-4-[N-<4-
Figure imgf000066_0003
ethylphenyl)carbamoyloxy]butanamide
2-(2-aminoacetylamino)-N-[(2- chlorophenyl)methyl]-4-[N-(4- ethylphenyl)carbamoyloxy]butanamide
Figure imgf000066_0004
2-(1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-chlorophenyl)methyljacetamide
Figure imgf000067_0001
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6-
Figure imgf000067_0002
tetrahydropyran-4-yl))carboxamide
methyl 1-(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidine-4- carboxylate
(tert-butoxy)-N-[2-(4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-4-{N-[(2- methylphenyl)methyl]carbamoyl}piperidyl)-2- oxoethyl]carboxamide
(tert-butoxy)-N-[2-(4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-4-[N- benzylcarbamoyl]piperidyl)-2- oxoethyl]carboxamide
(tert-butoxy)-N-[2-(4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-4-{N-[(2- fluorophenyl)methyl]carbamoyl}piperidyl)-2-
Figure imgf000067_0003
oxoethy l]carboxam ide (1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-pipeιϊdyl))-
N-[(2-methylphenyl)methyl]carboxamide
(1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-benzylcarboxamide
(1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-fluorophenyl)methyl]carboxamide
(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{[N- (4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2- methoxyphenyl)methyl]carboxamide
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N- i(4-chlorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(4-{N-[(2,3-dichlorophenyl)methyl]carbamoyl}- 1-{2-[(tert-butoxy)carbonylamino]acetyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000068_0001
ethylpheπyl)carboxamide (1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-methoxyphenyl)methyl]carboxamide
{[1 -(2-aminoacetyl)-4-(N-{[2- (trifluoromethyl)phenyl]methyl}carbamoyl)(4- pi peridyl)] m ethoxy}-N-(4-
Figure imgf000069_0001
ethylphenyl)carboxamide
[( 1 -(2-am inoacetyl)-4-{N-[(4- chlorophenyl)methyl]carbamoyl}(4- pi peridyl)) m ethoxy]-N-(4- ethylphenyl)carboxamide
[(1-(2-amiπoacetyl)-4-{N-[(2.3- dichlorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000069_0002
ethylphenyl)carboxamide
[( 1 -(2-aminoacetyl)-4-{N-[(3-methyl(2- pyridyl))methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
K 1 -(2-aminoacetyl)-4-{N-[(2- bromophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000069_0003
ethylphenyl)carboxamide [(1 -(2-aminoacetyl)-4-{N-[(3- chlorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000070_0001
ethylphenyl)carboxamide
[(4-{N-[(2,3-difluorophenyl)methyl]carbamoyl}-1- {2-[(tert-butoxy)carbonylamino]acetyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(1 -(2-aminoacetyl)-4-{N-[(2,3- difluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000070_0002
ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-chloro-2- fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-fluoro-2- methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-chloro-2- methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000070_0003
ethylphenyl)carboxamide t(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N- [(3-fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N- i(4-fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3- fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[( 1 -(2-aminoacetyl)-4-{N-[(4- fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000071_0001
ethylphenyl)carboxamide
({ 1 -(2-aminoacetyl)-4-[N -(2- pyridylmethyl)carbamoyl](4-piperidyl)}methoxy)-
N-(4-ethylphenyl)carboxamide
[(H2-[(tert-butoxy)carbonylamino]acetyl}-4-[N- (imidazol-2-ylmethyl)carbamoyl](4- piperidyl))methoxy]-N-(4-
Figure imgf000071_0002
ethylphenyl)carboxamide [(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-
[(3-fluoro-2-methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-[4-
(trifluoromethyl)phenyl]carboxamide
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N- i(3-chloro-2-fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-[4- (trifluoromethyl)phenyl]carboxamide
[(4-{N-[(2,3-dichlorophenyl)methyl]carbamoyl}-
1-{2-[(tert-butoxy)carbonylamino]acetyl}(4- piperidyl))methoxy]-N-[4-
(trifluoromethyl)phenyl]carboxamide
({1-(2-aminoacetyl)-4-[N-(imidazol-2- ylmethyl)carbamoyl](4-piperidyl)}methoxy)-N-(4- ethylphenyl)carboxamide
(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{[N-
(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2- cyanophenyl)methyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-fluoro-2- methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-[4-
Figure imgf000072_0001
(trifluoromethyl)phenyl]carboxamide [(1-(2-aminoacetyl)-4-{N-[(3-chloro-2- fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-[4- (trifluoromethyl)phenyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2,3- dichlorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-[4-
Figure imgf000073_0001
(trifluoromethyl)phenyl]carboxamide
Figure imgf000073_0002
(1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-
N-[(2-cyanophenyl)methyl]carboxamide
[1 -(2-aminoacetyl)-4-({N-[4- (trifluoromethyl)phenyl]carbamoyloxy}methyl)(4- piperidyl)]-N-[(2- cyanophenyl)methyl]carboxamide
[( 1 -(2-aminoacetyl)-4-{N-[(3-chloro-2- methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-[4-
Figure imgf000073_0003
(trifluoromethyl)phenyl]carboxamide methyl 2-({[1 -(2-aminoacetyl)-4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)-4- piperidyl]carbonylamino}methyl)benzoate
({1 -(2-aminoacetyl)-4-[N- (naphthylmethyl)carbamoyl](4- piperidyl)}methoxy)-N-(4- ethylphenyl)carboxamide
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N- [(2-chloro-4-fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2-chloro-4- fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000074_0001
ethylphenyl)carboxamide
{[1-(2-aminoacetyl)-4-(N-{[2-fluoro-4- (trifluoromethyl)phenyl]methyl}carbamoyl)(4- piperidyl)]methoxy}-N-(4-
Figure imgf000074_0002
ethylphenyl)carboxamide .
[(1-(2-aminoacetyl)-4-{N-[(4-chloro-2- fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000074_0003
ethylphenyl)carboxamide [(1 -(2-aminoacetyl)-4-{N-[(2,4- dimethylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[( 1 -(2-aminoacety l)-4-{N-[(4-chloro-2- methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(1 -(2-aminoacetyl)-4-{N-[(2,4- dichlorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2-methyl(3- pyridyl))methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000075_0001
ethylphenyl)carboxamide
ridyl))-
Figure imgf000075_0002
de
[( 1 -(2-am inoacetyl)-4-{N-[(2- ethylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-
Figure imgf000075_0003
ethylphenyl)carboxamide (4-(2-amiπoacetyl)-3-{N-t(2- chlorophenyl)methyl]carbamoyl}piperazinyl)-N-
(4-ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl][2-({[(4- ethylphenyl)amino]carbonylamino}methyl)pyrroli dinyljcarboxamide
(4-(2-aminoacetyl)-2-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperazinyl)-
N-[(2-chlorophenyl)methyljcarboxamide
Figure imgf000076_0001
rrolidinyl)-
Figure imgf000076_0002
ide
N-[(1 -(2-aminoacetyl)-4-{N-[(2- chlorophenyl)methyl]carbamoyl}(4- piperidyl))methyl]-2-(4-ethylphenyl)acetamide
(1 -(2-aminoacetyl)-4-{[N-(4- cyanophenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-
Figure imgf000076_0003
chlorophenyl)methyl]carboxamide (1-(2-aminoacetyl)-4-{[N-(4- methylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2- chlorophenyl)methyl]carboxamide
(1-(2-aminoacetyl)-4-{[N-(4- fluorophenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-
Figure imgf000077_0001
chlorophenyl)methyl]carboxamide
{1 -(2-aminoacetyl)-4-[(N- phenylcarbamoyloxy)methyl](4-piperidyl)}-N-[(2- chloropheπyl)methyl]carboxamide
(4-{tN-(4-acetylphenyl)carbamoyloxy]methyl}-1-
(2-aminoacetyl)(4-piperidyl))-N-[(2- chlorophenyl)methyl]carboxamide
((5S,3R)-3-amino-5-{[N-(4- ethylphenyl)carbamoyloxy]methyl}pyrrolidinyl)-
N-[(2-chlorophenyl)methyl]carboxamide
N-((5S,3R)-1-{N-[(2- chlorophenyl)methyl]carbamoyl}-5-{[N-(4- ethylphenyl)carbamoyloxy]methyl}pyrrolidin-3-
Figure imgf000077_0002
yl)-2-aminoacetamide in-3-
Figure imgf000078_0001
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}-N-
Figure imgf000078_0002
methylcarboxamide
{[(2,3-dichlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}-N-
Figure imgf000078_0003
methylcarboxamide
[2-({[(2-chlorophenyl)methyl]amino}-N-(2- hydroxyethyl)carbonylamino)ethoxy]-N-(4-
Figure imgf000078_0004
ethylphenyl)carboxamide
N-[2-({[(2-chlorophenyl)methyl]amino}-N- methylcarbonylamino)ethyl][(4-
Figure imgf000078_0005
ethylphenyl)amino]carboxamide
oyl}morpholin-2-
Figure imgf000078_0006
l)carboxamide N-(3-aminopropyl){[(2- ch!orophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carboxamide
2-[(tert-butoxy)carbonylamino]-N-t3-({[(2- chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carbonylamino)
Figure imgf000079_0002
propyl]acetamide
]amino}- ylamino)
Figure imgf000079_0003
N-(2-aminoethyl){[(2- chlorophenyl)methyl]amiπo}-N-{2-[N-(4-
Figure imgf000079_0004
ethylphenyl)carbamoyloxy]ethyl}carboxamide
]amino}- ylamino)
Figure imgf000079_0005
[2-(N-(4-aminobutyl){[(2- chlorophenyl)methyl]amino}carbonylamino)etho xy]-N-(4-ethylphenyl)carboxamide
Figure imgf000079_0006
Figure imgf000080_0001
)carbamoyloxy]ethyl}acetamide
Figure imgf000080_0002
{[(2-chlorophenyl)methyl]amiπo}-N-methyl-N-[2-
Figure imgf000080_0003
(N-(6-quinolyl)carbamoyloxy)ethyl]carboxamide
N-(5-aminopentyl){[(2- chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carboxamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-{4- ethylphenyl)carbamoyloxy]ethyl}-N-(4- hydroxybutyl)carboxamide
(tert-butoxy)-N-[2-(4-{N-[(2- bromophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-2-
Figure imgf000080_0004
oxoethyl]-N-methylcarboxamide [(4-{N-[(2-bromophenyl)methyl]carbamoyl}-1-[2-
(methylamino)acetyl](4-piperidyl))methoxy]-N-
(4-ethylphenyl)carboxamide
N-[(2-chloropheπyl)methyl]({[N-(4- ethylphenyl)carbamoyloxy]methyl}cyclopropyl)c arboxamide
4-(acetylamino)-N-[(2-chlorophenyl)methyl]-2-
{[N-(4-ethylphenyl)carbamoyloxy]methyl}-2- methylbutanamide
4-{2-[(tert-butoxy)carbonylamino]acetylamino}- N-[(2-chlorophenyl)methyl]-2-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-2-
Figure imgf000081_0001
methylbutanamide
4-amino-N-[(2-chlorophenyl)methyl]-2-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-2-
Figure imgf000081_0002
methylbutanamide
4-(2-aminoacetylami no)-N-[(2- chlorophenyl)methyl]-2-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-2-
Figure imgf000081_0003
methylbutanamide N-[(2-chlorophenyl)methyl]-4-[N-(4- ethylphenyl)carbamoyloxy]-2,2- dimethylbutanamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]-tert-butyl}-N- methylcarboxamide
Figure imgf000082_0001
(2-chlorophenyl)methyl (2S)-2-({[(4- ethylphenyl)amino]carbonylamino}methyl)pyrroli dinecarboxylate
Figure imgf000082_0002
N-[(2-chlorophenyl)methyl]-3-{5-[4- (methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}propanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 l2l3,4-tetraazol- 2-yl)}-N-ben2ylpropanamide
2l2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 ,2,3,4-tetraa20l- 2-yl)}-N-(2-pyridylmethyl)propanamide
Figure imgf000082_0003
N-[(2-fluorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}propanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1,2,3,4-tetraazol- 2-yl)}-N-[(2-methylphenyl)methyl]propanamide
N-[(3-fluorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}propanamide
N-[2-(2-chlorophenyl)ethyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1 ,2>3,4-tetraazol-2-yl)}propanamide
2.2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 ,2,3,4-tetraazol- 2-yl)}-N-(3-thienylmethyl)propanamide
Figure imgf000083_0001
Figure imgf000083_0002
N-[(2-chlorophenyl)methyl]-3-[5-(4-ethylphenyl)(1,2l3,4- tetraazol-2-yl)]-2,2-dimethylpropanamide
Figure imgf000083_0003
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{5-[4-
{trifluoromethoxy)phenyl](1,2,3,4-tetraazol-2- yl)}propanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-[5-(4- phenoxyphenyl)(1 ,2,3,4-tetraazol-2-yl)]prc>panamide
N-[(2-chloro-4-fluorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}propanamide
N-[(2,4-dichlorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1,2,3,4-tetraazol-2-yl)}propanamide
Figure imgf000084_0001
Figure imgf000084_0002
4-[(2,2-dimethyl-3-{5-t4-(methylethyl)phenyl](1>2l3,4- tetraazol-2-yl)}propanoylamino)methyl]benzoic acid
Figure imgf000084_0003
3-[5-(4-bromophenyl)(1 ,2,3,4-tetraazol-2-yl)]-N-[(2- chlorophenyl)rnethyl]-2,2-dimethyIpropanamide
N-[(2,3-dichlorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1,2,3,4-tetraazol-2-yl)}propanamide
N-[(2-chlorophenyl)methyl]-3-[5-(4-cyanophenyl)(1, 2,3,4- tetraazol-2-yl)]-2,2-dimethylpropanamide
3-{5-[4-(dimethylamino)phenyl](1 ,2,3,4-tetraazol-2-yl)}-N- [(2-chlorophenyl)methyl]-2,2-dimethylpropanamide
methyl 4-[2-(2-{N-[(2-chlorophenyl)methyl]carbamoyl}-2- methylpropyl)-1 ,2,3,4-tetraazol-5-yl]benzoate
N-[(2-chlorophenyl)methyl]-3-{5-[4-
(hydroxymethyl)phenylJ(1,2,3,4-tetraazol-2-yl)}-2,2- dimethylpropanamide
Figure imgf000085_0001
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}propanamide
Figure imgf000085_0002
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{2-[4- (methylethyl)phenyl](1 ,2,3,4-tetraazol-5-yl)}propanamide
Figure imgf000086_0001
N-[(2-chlorophenyl)methyl]-2-methyl-3-{2-[4- (methylethyl)phenyl]( 1,2,3 ,4-tetraazol-5-yl)}propanam ide
Figure imgf000086_0002
N-[(2-chlorophenyl)methyl]-3-{3-[4- (methylethyl)phenyl](1,2,4-oxadiazol-5-yl)}propanamide
Figure imgf000086_0003
methyl 2-(2,2-dimethyl-3-{5-[4-
(methy!ethyl)phenyl](1,2,3,4-tetraazol-2- yl)}propanoylamino)-2-(2-chlorophenyl)acetate
Figure imgf000086_0004
N-[1-(2-chlorophenyl)-2-hydroxyethyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1,2,3,4-tetraazol-2-yl)}propanamide
Figure imgf000086_0005
N-[(2-chlorophenyl)methyl]({[5-(4-ethylphenyl)(1 , 2,3,4-
Figure imgf000086_0006
tetraazol-2-yl)]methyl}cyclopropyl)carboxamide N-[(2-chlorophenyl)methyl]({[5-(4-ethylphenyl)(1 ,2,3,4-
Figure imgf000087_0001
tetraazol-2-yl)]methyl}cyclobutyl)carboxamide
N-[(2-chlorophenyl)methyl](4-{[5-(4-ethylphenyl)(1l2,3,4- tetraazol-2-yl)]methyl}(2H-3,4,5,6-tetrahydropyran-4-
Figure imgf000087_0002
yl))carboxamide
N-[(2-chlorophenyl)methyl](1 -{[5-(4-ethylphenyl)(1 ,2,3,4-
Figure imgf000087_0003
tetraazol-Σ-yOJmethylJcyclopent-S-enyOcarboxamide
N-[(2-chlorophenyl)methyl](1-{[5-<4-ethylphenyl)(1, 2,3,4- tetraazol-2-yl)]methyl}-3,4-
Figure imgf000087_0004
dihydroxycyclopentyl)carboxamide
3-[5-(4-chlorophenyl)(1,2,3,4-tetraazol-2-yl)]-N-[(2- chlorophenyl)methyl]-2,2-dimethylpropanamide
N-[(2-chlorophenyl)methyl]-3-[5-(4- methoxyphenyl)(1 ,2,3,4-tetraazol-2-yl)]-2,2- dimethylpropanamide
3-{5-[4-(tert-butyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}-N-[(2- chlorophenyl)methyl]-2,2-dimethylpropanamide
Figure imgf000087_0005
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-[5-(4- rnethylphenyl)(1 ,2,3,4-tetraazol-2-yl)]propanamide
3-[5-(3-chlorophenyl)(1,2,3,4-tetraazol-2-yl)]-N-[(2- chlorophenyl)methyl]-2,2-dimethylpropanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (trifluoromethyl)phenyl]( 1 ,2,3,4-tetraazol-2- yl)}propanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-[5-(3- methylphenyl)(1,2,3,4-tetraazol-2-yl)]propanamide
Figure imgf000088_0001
Figure imgf000088_0002
(2S)-N-[(2-chlorophenyl)methyl]-2-methyl-3-[5-(4- methylphenyl)(1,2,3,4-tetraazol-2-yl)]propanamide
Figure imgf000088_0003
{[(2-chlorophenyl)methyl]amino}-N-{2-[5-(4- ethylphenyl)(1,2,3,4-tetraazol-2-yl)]ethyl}-N-
Figure imgf000089_0001
methylcarboxamide
[0176] The compounds described herein can be named and numbered (e.g. using NamExpert™ available from Chemlnnovation Software, Inc. or the struct <=> name feature of ChemDraw Ultra version 10.0 from CambridgeSoft Corporation) as described below. For example, the compound:
Figure imgf000089_0002
i.e. the compound according to Formula I where R10 is ethyl, W2 is NR13, R13 is hydrogen, W1 is O1 R5 is hydrogen, R6 is hydrogen, W3 is CR1R2, R1 and R2 form a cyclobutyl group with the carbon atom to which they are bound, R8 is hydrogen, R3 is hydrogen, R4 is hydrogen, and R7 is chloro, can be named [({N-[(2- chlorophenyl)methyl]carbamoyl}cyclobutyl)methoxy]-N-(4-ethylphenyl)carboxamide or (1-(2-chlorobenzylcarbamoyl)cyclobutyl)methyl 4-ethylphenylcarbamate. Also, a chemical name generated for a structure drawn in a certain software environment may or may not give the same structure when that name is converted into a structure in a different software environment.
[0177] Many of the optionally substituted starting compounds and other reactants are commercially available, e.g. from Aldrich Chemical Company (Milwaukee, Wl) or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.
[0178] The chemical entities described herein can be synthesized utilizing techniques well known in the art from commercially available starting materials and reagents. For example, the chemical entities described herein can be prepared as illustrated below with reference to the examples and reaction schemes.
Reaction Scheme I
Figure imgf000090_0001
[0179] Referring to Reaction Scheme I, Step 1 , to a solution of a compound of Formula 101 and an excess (such as about 1.2 equivalents) of a compound of Formula 102 in a non-polar solvent such as toluene is added an excess (such as about 1.5 equivalents) of trialkylaluminum (for example, 2M trimethylaluminum in hexanes). The reaction mixture is stirred at about rt to 150 0C for about 1 h to 24 h. The product, a compound of Formula 103, is isolated and optionally purified. [0180] Referring to Reaction Scheme I, Step 2, to a solution of a compound of Formula 103 in a non-polar solvent such as dichloromethane is added a catalytic amount of 4-dimethylaminopyridine and an excess (such as about 1.5 equivalents) of a compound of Formula 104. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 105, is isolated and optionally purified.
Reaction Scheme Il
Figure imgf000091_0001
[0181] Referring to Reaction Scheme II, Step 1 , to a solution of a base such as diisopropylamine in a polar, aprotic solvent such as tetrahydrofuran at about -78 0C to rt is added an excess (such as about 1.2 equivalents) of an organometallic reagent such as n-butyllithium (for example, 2M n-butyllithium in hexane). The reaction mixture is stirred for about 1 h to 24 h. A solution of a compound of Formula 201 in a polar, aprotic solvent such as tetrahydrofuran is then added dropwise at about -78 0C to rt. The reaction mixture is stirred for about 1 h to 24 h and then an excess (such as about 1.1 equivalents) of methyl chloroformate is added. The product, a compound of Formula of 202, is isolated and optionally purified.
[0182] Referring to Reaction Scheme II, Step 2, to a solution of a compound of Formula 202 in a polar solvent system such as a 1:1 mixture of tetrahydrofuran and methanol is added an aqueous solution of an excess (such as about 1.1 equivalents) of a base such as lithium hydroxide (for example, 2N lithium hydroxide in water). The reaction mixture is stirred at about rt to 150 0C for about 1 h to 24 h. The product, a compound of Formula 203, is isolated and optionally purified. [0183] Referring to Reaction Scheme II, Step 3, to a solution of a compound of Formula 203 in a polar, aprotic solvent such as dimethylformamide is added an excess (such as about 1.2 equivalents) of a peptide coupling reagent such as N,N,N',N'- tetramethyl-0-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, an excess (such as about 1.2 equivalents) of a compound of Formula 102, and about 0.1 equivalents of a base such as diisopropylethylamine. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 204, is isolated and optionally purified. [0184] Referring to Reaction Scheme II, Step 4, to a solution of a compound of Formula 204 in a polar solvent system such as a 1:1 mixture of tetrahydrofuran and methanol is added an excess of a reducing agent such as lithium borohydride. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 205, is isolated and optionally purified.
Reaction Scheme III
Figure imgf000092_0001
[0185] Referring to Reaction Scheme III, Step 1, to a solution of a compound of Formula 301 in a polar, aprotic solvent such as tetrahydrofuran is added an excess (such as about 1.1 equivalents) of a compound of Formula 102 and about 0.5 equivalents of trialkylaluminum (for example, 2M trimethylaluminum in toluene). The reaction mixture is stirred for about 1 day to 7 days. The product, a compound of Formula 205, is isolated and optionally purified.
Reaction Scheme IV
Figure imgf000093_0001
[0186] Referring to Reaction Scheme IV, Step 1 , to a solution of a compound of Formula 103 in a polar, aprotic solvent such as tetrahydrofuran is added an excess (such as about 1.5 equivalents) of phthalimide (Formula 401) and an excess (such as about 1.5 equivalents) of a phosphine such as triphenylphosphine. An excess (such as about 1.5 equivalents) of a dialkyl azodicarboxylate such as diisopropyl azodicarboxylate is then added dropwise into the reaction mixture. The resulting mixture is stirred from 1 h to 48 h. The product, a compound of Formula 402, is isolated and optionally purified.
[0187] Referring to Reaction Scheme IV, Step 2, to a solution of a compound of Formula 402 in a polar, protic solvent such as methanol is added an excess of hydrazine. The reaction mixture is stirred from 1 h to 48 h. The product, a compound of Formula 403, is isolated and optionally purified.
[0188] Referring to Reaction Scheme IV, Step 3, to a solution of a compound of Formula 403 in a non-polar solvent such as dichloromethane is added an excess (such as about 2.0 equivalents of) a base such as diisopropylethylamine and an excess (such as about 1.5 equivalents) of a compound of Formula 104. The reaction mixture is stirred for about 0.1 h to 24 h. The product, a compound of Formula 404, is isolated and optionally purified. Reaction Scheme V
Figure imgf000094_0001
[0189] Referring to Reaction Scheme V1 Step 1 , to a solution of an excess (such as about 1.1 equivalents) of a compound of Formula 501 in a polar, aprotic solvent such as tetrahydrofuran is added a compound of Formula 502. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 503, is isolated and optionally purified.
[0190] Referring to Reaction Scheme V, Step 2, to a solution of a compound of Formula 503 in a polar, aprotic solvent such as tetrahydrofuran is added an excess (such as about 1.5 equivalents) of a compound of Formula 104. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 504, is isolated and optionally purified.
Reaction Scheme Vl
Step 3 .
Figure imgf000094_0002
Figure imgf000094_0003
Figure imgf000095_0001
[0191] Referring to Reaction Scheme Vl, Step 1 , to a solution of a compound of Formula 601 in a non-polar solvent such as dichloromethane is added an excess (such as about 1.1 equivalents) of a silyl protecting group reagent such as tert- butyldimethylsilyl chloride and an excess (such as about 1.5 equivalents) of a base such as diisopropylethylamine. The reaction is stirred for about 1 h to 24 h. The product, a compound of Formula 602, is isolated and optionally purified. [0192] Referring to Reaction Scheme Vl, Step 2, to a solution of an excess (such as about 1.2 equivalents) of a base such as sodium hydride (for example, 60% sodium hydride in mineral oil) in a polar, aprotic solvent such as dimethylformamide is added a compound of Formula 602. The reaction mixture is stirred for about 0.1 h to 24 h and then an excess (such as about 1.2 equivalents) of R14l-X, wherein R14' is optionally substituted alkyl and X is halo, is added. The reaction mixture is then stirred for about an 1 h to 24 h more. The product, a compound of Formula 603, is isolated and optionally purified.
[0193] Referring to Reaction Scheme Vl, Step 3, to a solution of a compound of Formula 603 in a polar, aprotic solvent such as tetrahydrofuran is added an excess (such as about 1.5 equivalents) of fluoride-releasing reagent such as tetrabutylammonium fluoride (for example, 1M tetrabutylammonium fluoride in tetrahydrofuran). The reaction mixture is stirred for about 0.1 h to 24 h. The product, a compound of Formula 604, is isolated and optionally purified. [0194] Referring to Reaction Scheme Vl, Step 4, to a solution of a compound of Formula 604 in a polar, aprotic solvent such as tetrahydrofuran is added a catalytic amount of 4-dimethylaminopyridine and an excess of equivalents (such as about 1.1 equivalents) of a compound of Formula 104. The reaction mixture is stirred for about
0.1 h to 24 h. The product, a compound of Formula 605, was isolated and optionally purified.
[0195] Referring to Reaction Scheme Vl, Step 5, to a solution of a compound of
Formula 605 in a polar, protic solvent such as methanol is added an excess (such as about 3.0 equivalents) of an acid such as hydrogen chloride (for example, 4M hydrogen chloride in dioxane). The resulting reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 606, is isolated and optionally purified.
[0196] Referring to Reaction Scheme Vl, Step 5, to a solution of a compound of
Formula 606 in a polar, aprotic solvent such as tetrahydrofuran is added about 1 equivalents of a compound of Formula 607 and an excess (such as about 2.5 equivalents) of a base such as diisopropylethylamine. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 608, is isolated and optionally purified.
Reaction Scheme VII
Figure imgf000096_0001
[0197] Referring to Reaction Scheme VII, 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 3.0 equivalents) of an acid such as hydrogen chloride (for example, 4 M hydrogen chloride in dioxane). The resulting reaction mixture is stirred about 1 h to 48 h. The product, a compound of Formula 702, is isolated and optionally purified. [0198] Referring to Reaction Scheme VII1 Step 2, to an excess (such as about 1.2 equivalents) of a compound of Formula 703, wherein Z is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, in a polar, aprotic solvent such as dimethylformamide is added an excess (such as about 1.2 equivalents) of N,N,N1 1N'-tetramethyl-O-(7- azabenzotriazol-1-yl)uronium hexafluorophosphate, a compound of Formula 702, and an excess (such as about 2.0 equivalentsJ) of a base such as diisopropylethylamine. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of Formula 704, is isolated and optionally purified.
Reaction Scheme VIII
Figure imgf000097_0001
107
[0199] Referring to Reaction Scheme VIII, Step 1 , to a solution of a compound of formula 101 in an inert solvent such as DMF are added an excess (such as about 1.4 equivalents) of NaCN and an excess (such as about 1.4 equivalents) of NH4CI. The reaction mixture is heated. The product, a compound of formula 103, is isolated and optionally purified. [0200] Referring to Reaction Scheme VIII1 Step 2, to a solution of a compound of formula 103, an excess (such as about 1.5 equivalents) of a compound of formula 104 and an excess (such as about 1.5 equivalents) of a phospine reagent such as triphenyl phosphine (PPh3) in an inert solvent such as THF is added an excess (such as about 1.5 equivalents) of an azadicarboxylate reagent such as diethylazadicarboxylate (DEAD). The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of formula 105, is isolated and optionally purified.
[0201] Referring to Reaction Scheme VIII1 Step 2, to a mixture of a compound of formula 105 and an excess (such as about 1.4 equivalents) of a compound of formula 106 in an inert solvent such as toluene is added an excess (such as about 1.4 equivalents) AIMe3. The reaction mixture is stirred for about 30 min followed by stirring at about rt -150 0C for about 1 h to 24 h . The product, a compound of formula 107, is isolated and optionally purified.
Figure imgf000098_0001
208
[0202] Referring to Reaction Scheme IX, Step 2, to a solution of a compound of formula 201 in an inert solvent such as DMF are added an excess (such as about 1.5 equivalents) of a coupling reagent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N"- tetramethyluroniumhexafluorophosphate (HATU) and an excess (such as about 1.5 equivalents) of a compound of formula 203. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of formula 205, is isolated and optionally purified. 10203] Referring to Reaction Scheme IX, Step 2, to a solution of a compound of formula 205 and a solvent such as methanol is added an excess (such as about 2 equivalents) of a reducing agent such as sodium borohydride. The reaction mixture is stirred for about 1 h to 24 h and quenched with diluted aqueous acid. The product, a compound of formula 207, is isolated and optionally purified.
[0204] Referring to Reaction Scheme IX, Step 3, to a solution of an excess (such as 2 equivalents) of a compound of formula 207 in an inert solvent such as THF are added about an equivalent of a phospine reagent such as triphenyl phosphine, about 1 equivalent of an azadicarboxylate reagent such as diethylazadicarboxylate (DIAD), and a compound of formula 208. The reaction mixture is stirred for about 1 h to 24 h. The product, a compound of formula 107, is isolated and optionally purified. [0205] Isolation and purification of the compounds 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 are provided herein. However, other equivalent separation or isolation procedures can, of course, also be used.
[0206] When desired, the (R) and (S) isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that when the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be required to liberate the desired enantiomeric form. Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts and/or solvents, or by converting one enantiomer to the other by asymmetric transformation. [0207] The chemical entities described herein may be useful in a variety of applications involving smooth muscle cells and/or non-muscle cells. In certain embodiments, the chemical entities may be used to inhibit smooth muscle myosin. The chemical entities may be useful to bind to, and/or inhibit the activity of, smooth muscle myosin. In certain embodiments, the smooth muscle myosin is human, although the chemical entities may be used to bind to or inhibit the activity of smooth muscle myosin from other organisms, such as other mammals.
[0208] In certain embodiments, the chemical entities may be used to inhibit non- muscle myosin. The chemical entities may be useful to bind to, and/or inhibit the activity of, non-muscle myosin. In certain embodiments, the non-muscle myosin is human, although the chemical entities may be used to bind to or inhibit the activity of non-muscle myosin from other organisms, such as other mammals. [0209] The chemical entities described herein may be used to treat disease states associated with smooth muscle and/or non-muscle myosin. Such disease states which can be treated by the chemical entities described herein include, but are not limited to, hypertension, asthma, incontinence, chronic obstructive pulmonary disorder, pre-term labor, and the like. It is appreciated that in some cases the cells may not be in an abnormal state and still require treatment. Thus, in certain embodiments, the chemical entities described herein may be applied to cells or individuals afflicted or subject to impending affliction with any one of these disorders or states.
[0210] More specifically, the cchemical entities described herein may be useful for the treatment of diseases or symptoms related to abnormal increased muscle tone or excessive contraction, or spasm of vascular smooth muscle in systemic, coronary, pulmonary circulation, and micro-circulatory smooth muscle as well, such as systemic hypertension, malignant hypertension, hypertension crisis, symptomatic hypertension, pulmonary hypertension, pulmonary infarction, angina pectoris, cardiac infarction, micro-circulation malfunction under shock condition, and infarction occurred in other location or organs of the human or animal body. Other diseases or symptoms that can be treated with the chemical entities described herein include: spasm of gastro-intestine smooth muscle, including sphincters, such as gastric spasm, pylorospasm, and spasms of biliary tract, pancreatic tract, urinary tract, caused by inflammation, stimulation of stones or parasites; spasm of other visceral organs such as uterus, Fallopian tube, and so on; spasm of trachea-bronchial tree smooth muscle, diaphragm muscle, such as various asthma, breathlessness, dyspnea, diaphragmatic convulsion, and so on; spasm of alimentary canal smooth muscle, including stomach, intestine and colons, biliary and pancreatic duct etc.; and spasm of urinary tract smooth muscle.
[0211] In addition, the chemical entities described herein can be used for control, management and manipulation of, labor during pregnancy. The method is particularly useful for inhibition of spontaneous preterm labor which would, if untreated, result in premature delivery or abortion and for inhibition of surgically induced labor during transuterine fetal surgery. The method is also useful for inducing the labor in overterm pregnancies where the labor does not occur on term and when it is necessary to induce labor in order to assure the normal delivery.
[0212] Further, the chemical entities described herein can be used for the treatment of "airway wall remodeling", which is a condition associated with diseases or conditions characterized by airway wall thickening and air obstruction, which may, for example occur in the small airways of patients with certain respiratory disease conditions, such as, chronic obstructive pulmonary disease (COPD).
[0213] Such disease states which can be treated by the chemical entities, compositions and methods provided herein also include, but are not limited to glaucoma and other ocular indications. More specifically, chemical entities described herein may be useful for the treatment of diseases or symptoms related to glaucoma, including increased intraocular pressure, reduced flow of intraocular aqueous humor, and optical nerve damage. Other diseases or symptoms that can be treated with the chemical entities, compositions, and methods described herein including intraocular hypertenstion.
[0214] ATP hydrolysis is employed by myosin to produce force. An increase in ATP hydrolysis would correspond to an increase in the force or velocity of muscle contraction. In the presence of actin, myosin ATPase activity is stimulated more than 100-fold. Thus, the measurement of ATP hydrolysis not only measures myosin enzymatic activity but also its interaction with the actin filament. Assays for such activity may employ smooth muscle myosin from a human source, although myosin from other organisms can also be used. Systems that model the regulatory role of calcium in myosin binding may also be used.
[0215] The in vitro rate of ATP hydrolysis correlates to smooth muscle myosin potentiating activity, which can be determined by monitoring the production of either ADP or phosphate, for example as described in U.S. Patent No. 6,410,254. ADP production can also be monitored by coupling the ADP production to NADH oxidation (using, for example, the enzymes pyruvate kinase and lactate dehydrogenase) and monitoring the NADH level, by example, either by absorbance or fluorescence (Greengard, P., Nature 178 (Part 4534): 632-634 (1956); MoI Pharmacon970 Jan;6(1):31-40). Phosphate production can be monitored using purine nucleoside phosphorylase to couple phosphate production to the cleavage of a purine analog, which results in either a change in absorbance (Proc Natl Acad Sci U S A 1992 Jun 1 ;89(11):4884-7) or fluorescence (Biochem J 1990 Mar 1 ;266(2):611-4). While a single measurement is employed, multiple measurements of the same sample at different times in order may be used to determine the absolute rate of the protein activity; such measurements have higher specificity particularly in the presence of test compounds that have similar absorbance or fluorescence properties with those of the enzymatic readout.
[0216] Test compounds may be assayed in a highly parallel fashion using multiwell plates by placing the compounds either individually in wells or testing them in mixtures. Assay components including the target protein complex, coupling enzymes and substrates, and ATP may then be added to the wells and the absorbance or fluorescence of each well of the plate can be measured with a plate reader. [0217] One method uses a 384 well plate format and a 25 μl_ reaction volume. A pyruvate kinase/lactate dehydrogenase coupled enzyme system (Huang TG and Hackney DD. (1994) J Biol Chem 269(23):16493-16501) is used to measure the rate of ATP hydrolysis in each well. As will be appreciated by those of skill in the art, the assay components are added in buffers and reagents. Since the methods outlined herein allow kinetic measurements, incubation periods may be optimized to give adequate detection signals over the background. The assay is performed in real time to give the kinetics of ATP hydrolysis to increase the signal-to-noise ratio of the assay. [0218] Selectivity for smooth muscle myosin may be determined by substituting other myosins in one or more of the above-described assays and comparing the results obtained against those obtained using the cardiac equivalents. [0219] Chemical entities identified by the methods described herein as smooth muscle myosin modulators may be further tested in an efficacy screen, such as a screen using strips of permeabilized smooth muscle from, e.g., chicken gizzard. Calcium-sensitive smooth muscle strips are prepared by dissecting chicken gizzard tissue, followed by treatment with 1% Triton X-100 to make the strips permeable to exogenous compounds (Barsotti, RJ, et al., Am J Physiol. 1987 May;252(5 Pt 1):C543- 54). These strips can be stored in 50% glycerol for several weeks at -200C1 allowing multiple experiments to be performed with each batch of muscle strips. Experiments are performed using a solution of 20 mM imidazole pH 7.0, 5.5 mM ATP, 7 mM MgCI2, 55 mM KCI, 1 μM Calmodulin, and 10 mM EGTA. Free calcium will be controlled by addition of various amounts of CaCb, according to the calculations of MAXChelator (Patton, et al. Cell Calcium. 35/5 pp. 427-431 , 2004). An isometric muscle fiber apparatus is used to measure isometric tension, for example using an Aurora Scientific 400A transducer with National Instruments PCI-MIO-16E-4, 16 channels, 12 bit A/D board for data acquisition. The chemically skinned gizzard fibers are relaxed when bathed in low calcium solutions (pCa 8), but develop isometric tension when the free calcium of the bathing solution is increased to pCa 5. These fibers can be repeatedly contracted and relaxed by switching between high and low calcium bathing solutions. [0220] Compounds are first tested for their ability to prevent contraction of gizzard strips, by preincubating relaxed fibers with a compound, followed by transfer to high calcium solution containing the compound. Next, compounds are tested for their ability to cause relaxation of contracting fibers by adding the compound to fibers already incubating in high calcium solution. Washout experiments are performed to ensure that the inhibitory effects are reversible, so that the compounds do not cause denaturation or other irreparable damage to the smooth muscle myosin.
[0221] The chemical entities are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment of the disease states previously described. Generally, a daily dose is from about 0.05 to about 100 mg/kg of body weight, such as from about 0.10 to about 10 mg/kg of body weight or from about 0.15 to about 1 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range is from about 3.5 to about 7000 mg per day, such as from about 7 to about 700 mg per day or from about 10 to about 100 mg per day. The amount of active chemical entity administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician; for example, a dose range for oral administration may be from about 70 to about 700 mg per day, whereas for intravenous administration the dose range may be from about 700 to about 7000 mg per day. The active agents may be selected for longer or shorter plasma half-lives, respectively. [0222] Administration of the chemical entities described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, sublingually, intramucosally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, and intraocularly (including intraocular injection). Oral, topical, parenteral, and intraocular administration are customary in treating many of the indications recited herein.
[0223] Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, and the like. The chemical entities can also be administered in sustained- or control led-release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, drops and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. The compositions may be provided in unit dosage forms suitable for single administration of a precise dose.
[0224] The chemical entities may be administered either alone or in combination with a conventional pharmaceutical carrier or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarrπellose, glucose, gelatin, sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate. Generally, depending on the intended mode of administration, the pharmaceutical composition may contain from about 0.005% to about 95%, for example, from about 0.5% to about 50%, by weight of at least one chemical entity described herein. Actual methods of preparing such dosage forms are known or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. Pharmaceutical compositions are also referred to as pharmaceutical formulations.
[0225] In addition, the chemical entities may be co-administered with, and the pharmaceutical compositions can include, other medicinal agents, pharmaceutical agents, adjuvants, and the like.
[0226] In certain embodiments, the compositions are in the form of a pill or tablet and contain, along with the active ingredient, one or more of a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives and the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) may be encapsulated in a gelatin capsule.
[0227] Liquid pharmaceutical compositions may, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and one or more optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like) to form a solution or suspension. Injectables may be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject. However, percentages of active ingredient ranging from about 0.01% to about 10% in solution may be used, and may be higher if the composition is a solid which will be subsequently diluted to the above percentages. In certain embodiments, the composition has from about 0.2% to about 2% of the active agent in solution.
[0228] Compositions comprising at least one chemical entity may be administered intraocularly (including intraocular, periocular, and retrobulbar injection and perfusion). When admiπsitered intraocularly the sterile composition is typically aqueous. An appropriate buffer system may be added to prevent pH drift under storage conditions. When administered during intraocular surgical procedures, such as retrobulbar or periocular injection and intraocular perfusion or injection, the use of balanced salt irrigating solutions may be necessary. When used in a multidose form, preservatives may be required to prevent microbial contamination during use. [0229] Compositions comprising at least one chemical entity may also be administered topically as eye drops, eye wash, creams, ointments, gels, and sprays. When administered as eye drops or eye wash, the active ingredients are typically dissolved or suspended in suitable carrier, typically a sterile aqueous solvent. An appropriate buffer system may be added to prevent pH drift under storage conditions. When used in a multidose form, preservatives may be required to prevent microbial contamination during use.
[0230] Compositions comprising at least one chemical entity may also be administered to the respiratory tract as an aerosol or in a solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. The particles of the composition typically have diameters of less than 50 microns, for example, less than 10 microns.
[0231] Generally, to employ the chemical entities described herein in methods of screening for smooth muscle myosin binding, smooth muscle myosin is bound to a support and at least one chemical entity is added to the assay. Alternatively, the chemical entity may be bound to the support and the smooth muscle myosin 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 purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.), and the like. See, e.g., U.S. Patent No. 6,495,337.
EXAMPLES
[0232] The following examples serve to more fully describe the manner of using the invention. These examples are presented for illustrative purposes and should not serve to limit the true scope of the invention.
Example I
Preparation of 3-(2-chlorobenzylamino)-2,2-dimethyl-3-oxopropyl 4- ethylphenylcarbamate
Figure imgf000107_0001
3-{2-chlorobenzylamino)-2,2-dimethyl-3-oxopropyl 4-ethylphenylcarbamate
Figure imgf000107_0002
[0233] To a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (1 g, 7.31 mmol) and 2-chlorobenzylamine (1 mL, 8.75 mmol, 1.2 equiv.) in toluene (7 ml_) was added trimethylaluminum (2 M in hexane, 5.4 mL, 10.8 mmol, 1.5 equiv.). The reaction mixture was stirred at 80 0C for 2 h. The reaction mixture was quenched with saturated NaHCO3. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO.! and concentrated to give Λ/-(2-chlorobenzyl)-3-hydroxy-2,2- dimethylpropanamide (1.5 g, 85%), which was used without further purification. LRMS (M+H+) m/z 242.1.
Figure imgf000108_0001
[0234] To a solution of Λ/-(2-chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (30 mg, 0.12 mmol,) in CH2CI2 were added DMAP and 4-ethylphenylisocyanate (21 μl_, 0.15 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated. The resulting residue was to purify on RP-HPLC to give 3-(2- chlorobenzylamino)-2,2-dimethyl-3-oxopropyl 4-ethylphenylcarbamate (10 mg, 17%). LRMS (M+H+) m/z 389.1.
Example Il
Preparation of (1 -(2-aminoacetyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4- yl)methyl 4-ethylphenylcarbamate
Figure imgf000108_0002
(1-(2-aminoacetyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4- yl)methyl 4-ethylphenylcarbamate
Figure imgf000108_0003
[0235] To a chilled solution of diisopropylamine (3.5 mL, 24.7 mmoJ) in THF (20 ml_) at -78 0C was added n-BuLi (2M in hexane, 14.8 mL, 1.2 equiv.). The reaction mixture was stirred for 1 h. A solution of 1-te/f-butyl 4-methyl piperidine-1 ,4-dicarboxylate (5 g, 20.6 mmol, 1 equiv.) in THF (15 mL) was added dropwise at -78 0C. The reaction mixture was stirred for 1 h. Methyl chloroformate (1.7 mL, 22.6 mmol, 1.1 equiv.) was added to the above mixture. The reaction mixture was warmed to rt slowly while stirring. After 3h, the reaction mixture was quenched with saturated NH4CI and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to give 1-te/f- butyl 4,4-dimethyl piperidine-1 ,4,4-tricarboxylate (6.2 g, quant.), which was used without further purification. LRMS (M+H+-Boc) m/z 202.1.
Figure imgf000109_0001
[0236] To a solution of 1-te/t-butyl 4,4-dimethyl piperidine-1 ,4,4-tricarboxylate (6.2 g, 20.5 mmol) in THF (11 mL) and CH3OH (11 mL) was added aqueous LiOH (2 N, 11 mL, 22 mmol, 1.1 equiv.). The reaction mixture was stirred at 80 0C for 1 h. The reaction mixture was neutralized with HCI (1N) and was concentrated to dryness. The residue was dissolved in ethyl acetate and dried over Na2SO4 and concentrated to give 1-(te/f- butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4-carboxylic acid (4.7 g, 80%), which was used without further purification. LRMS (M+H+-Boc) m/z 188.0.
Figure imgf000109_0002
[0237] To a solution of 1-(te/Y-butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4- carboxylic acid (3.7 g, 13.2 mmol) in DMF (30 mL) were added HATU (6.0 g, 15.8 mmol, 1.2 equiv.), 2-chlorobenzylamine (1.9 mL, 15.8 mmol, 1.2 equiv.) and DIEA (228 μl_, 1.31 mmol, 0.1 equiv.). The reaction mixture was stirred for 3 h and purified on RP- HPLC using a mixture of acetonitrile and H2O to give 1-te/f-butyl 4-methyl 4-(2- chlorobenzylcarbamoylJpiperidine-M-dicarboxylate (2.8 g, 52%). LRMS (M+H+-Boc) m/z 311.0.
Figure imgf000110_0001
[0238] To a solution of 1-fe/f-butyl 4-methyl 4-(2-chlorobenzylcarbamoyl)piperidine- 1 ,4-dicarboxylate (2.8 g, 6.8 mmol) in THF (20 mL) and CH3OH (10 mL) was added lithium borohydride (1.4 g, 68 mmol, 10 equiv.). The reaction mixture was stirred for 3 h and neutralized with HCI (1N). The residue was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4 and concentrated to purify on RP-HPLC using a mixture of acetonitrile and H2O to give terf-butyl 4-(2-chlorobenzylcarbamoyl)-4- (hydroxymethyl)piperidine-i-carboxylate (2.2 g, 84%). LRMS (M-'BU+H+) m/z 327.0.
Figure imgf000110_0002
[0239] To a solution of tert-butyl 4-(2-chlorobenzylcarbamoyl)-4- (hydroxymethyl)piperidine-i-carboxylate (1.8 g, 4.8 mmol) in THF were added DMAP (118 mg, 0.9 mmol, 0.1 equiv.) and 4-ethylphenylisocyanate (1.1 mL, 7.3 mmol, 1.5 equiv.) at r. t. The reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness. To a solution of the above product in CH3OH was added 4M HCI in dioxane (3.6 mL, 3 equiv.), which was stirred overnight. The white solid was filtered and dried to give (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4- ethylphenylcarbamate hydrochloride (1.7 g, 81 %). LRMS (M-Boc+H+) m/z 430.1.
Figure imgf000111_0001
[0240] To a solution of Boc-Gly-OH (54 mg, 0.31 mmol, 1.2 equiv.) in DMF (1 mL) were added HATU (120 mg, 0.31 mmol, 1.2 equiv.), followed by addition of (4-(2- chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate hydrochloride (120 mg, 0.26 mmol, 1 equiv.) and DIEA (89 μl_, 0.51 mmol, 2 equiv.) at rt The reaction mixture was stirred for 3 h and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (1-(2-(terf-butoxycarbonyl)aminoacetyl)-4-(2- chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (127 mg, 84%). LRMS (M-Boc+H*) m/z 487.1.
Figure imgf000111_0002
[0241] To a solution of (1-(2-(terf-butoxycarbonyl)aminoacetyl)-4-(2- chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (87 mg, 0.15 mmol) in CH3OH (1 mL) was added HCI (4M in dioxane, 100 μL, 0.4 mmol, 2.6 equiv.), which was stirred for 2 h. The reaction mixture was concentrated to dryness by co- evaporating with toluene to give (1-(2-aminoacetyl)-4-(2- chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (81 mg, quant.). LRMS (M+H+) m/z 487.1.
Example III
Preparation of (S)-(I -(2-amino-3-hydroxypropanoyl)-4-(2- chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate
Figure imgf000112_0001
(S)-(I -(2-amino-3-hydroxypropaπoyl)-4- (2- chlorobenzylcarbamoyl)piperidin-4- yl)methyl 4- (trjfluoromethyl)phenylcarbamate
Figure imgf000112_0002
[0242] To a solution of terf-butyl 4-(2-chlorobenzylcarbamoyl)-4- (hydroxymethyl)piperidine-i-carboxylate (500 mg, 1.3 mmol,) in THF were added DMAP (32 mg, 0.26 mmol, 0.2 equiv.) and 4-trifloromethylphenylisocyanate (0.28 ml_, 1.97 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness. To a solution of the above crude mixture in CH3OH (3 ml_) was added HCI (4 M in dioxane, 1 ml_, 4 mmol, 3 equiv.). The reaction mixture was stirred overnight. The white solid was filtered and dried to give (4-(2- chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (615 mg, 93%). LRMS (M-Boc+H+) m/z 470.1.
Figure imgf000113_0001
[0243] To a solution of Boc-Ser-OH (162 mg, 0.79 mmol, 2 equiv.) in DMF (2 mL) were added HATU (300 mg, 0.79 mmol, 2 equiv.), followed by addition of (4-(2- chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (200 mg, 0.39 mmol, 1 equiv.) and DIEA (140 μl_, 0.79 mmol, 2 equiv.). The reaction mixture was stirred overnight and purified on RP-HPLC using a mixture of acetonitrile and H2O to give ( S)-(I -(2-(te/ϊ-butoxycarbonyl)amino-3-hydroxypropanoyl)-4-(2- chlorobenzylcarbamoyOpiperidin^-ylJmethyM-OrifluoromethyOphenylcarbamate t^δ mg, 56%). LRMS (M+H+-Boc) m/z 557.1.
Figure imgf000113_0002
[0244] To a solution of (S)-(I -(2-(tert-butoxycarbonyl)amino-3-hydroxypropanoyl)-4- (2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (145 mg, 0.22 mmol) in CH3OH (1 mL) was added 4M HCI in dioxane (200 μL, 0.8 mmol, 3.6 equiv.), which was stirred for 2 h. The reaction mixture was concentrated to dryness by co-evaporating with toluene to give (S)-(I -(2-amino-3-hydroxypropanoyl)-4-(2- chlorobenzylcarbarnoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (130 mg, quant.). LRMS (M+H+) m/z 557.1. Example IV
Preparation of 4-(2-chlorobenzylamino)-3,3-dimethyl-4-oxobutyl 4- ethylphenylcarbamate
Figure imgf000114_0001
4-(2-chlorobenzylamino)-3,3-<limethyt-4-oxobutyl 4-ethylphenylcarbamate
Figure imgf000114_0002
[0245] To a solution of 3,3-dimethyl-dihydrofuran-2(3H)-one (2.04 g, 17. 9 mmol) in THF (15 ml_) were added 2-chlorobenzylamine (2.4 ml_, 19.9 mmol, 1.1 equiv.) and AIMe3 (2M in toluene, 4.5 ml_, 9 mmol, 0.5 equiv.). The reaction mixture was stirred for 3 days. The reaction mixture was saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4, and concentrated to give Λ/-(2-chlorobenzyl)-4-hydroxy-2,2-dimethylbutanamide as a white solid (3.8 g, 83%), which was used without further purification. LRMS (M+H+) m/z 256.0.
Figure imgf000114_0003
[0246] To a solution of Λ/-(2-chlorobenzyl)-4-hydroxy-2,2-dimethylbutanamide (400 mg, 1.6 mmol) in THF (25 ml_) were added 4-ethylphenylisocyanate (276 μl_, 1.92 mmol, 1.2 equiv.) and DMAP (293 mg, 2.4 mmol, 1.5 equiv.). The reaction mixture was stirred overnight. The reaction mixture was concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O, and further purified by flash column chromatography using a mixture of hexanes and EtOAc to give 4-(2- chlorobenzylamino)-3,3-dimethyl-4-oxobutyl 4-ethylphenylcarbamate (160 mg, 25%). LRMS (M+H+) /n/z 403.1.
Example V
Preparation of Λ/-(2-chlorobenzyl)-3-(3-(4-ethylphenyl)ureido)-2,2- dimethylpropanamide
Figure imgf000115_0001
/V-(2-chlorobenzyl)-3-(3-(4-ethylphenyl)ureido)-2,2-climethylpropanamicle
Figure imgf000115_0002
[0247] To a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (1.0 g, 7.57 mmol) and 2-chlorobenzylamiπe (1.09 mL, 9.08 mmol, 1.2 equiv.) in toluene (10 mL) was added trimethylalumium (2M in hexanes, 5.6 mL, 11.4 mmol, 1.5 equiv.). The reaction mixture was stirred at 80 0C for 2 hours. The reaction mixture was concentrated. The resulting residue was dissolved in EtOAc (100 mL). The organic layer was washed with saturated NaHCO3, dried over Na2SO4, and concentrated. The resulting residue was purified on silica gel column using a mixture of hexanes and ethyl acetate to give Λ/-(2- chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (1.55 g, 84%). LRMS (M+H+) m/z 242.1.
Figure imgf000116_0001
[0248] To a solution of Λ/-(2-chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (0.50 g, 2.07 mmol) in THF (5 ml_) were added phthalimide (0.457 g, 3.10 mmol, 1.5 equiv.) and PPh3 (0.813 g, 3.10 mmol, 1.5 equiv.). DIAD (600 μl_, 3.10 mmol, 1.5 equiv.) was added dropwise into the reaction mixture. The resulting mixture was stirred overnight. LCVMS indicated that starting material was consumed. The reaction mixture was concentrated. The resulting residue was purified on silica gel column a mixture of hexanes and ethyl acetate to give Λ/-(2-chlorobenzyl)-3-(1,3-dioxoisoindolin-2-yl)-2,2- dimethylpropanamide (0.50 g, 65%). LRMS (M+H+) m/z 371.1.
Figure imgf000116_0002
[0249] To a solution of Λ/-(2-chlorobenzyl)-3-(1 ,3-dioxoisoindolin-2-yl)-2,2- dimethylpropanamide (0.50 g, 1.35 mmol) in methanol (5 mL) was added hydrazine (423 μL, 13.5 mmol, 10 equiv.). The reaction mixture was stirred overnight. The crude mixture was concentrated. The resulting residue was dried in vacuum to give 3-amino- Λ/-(2-chlorobeπzyl)-2,2-dimethylpropanamide, which was used without further purification. LRMS (M+H+) m/z 241.1.
Figure imgf000116_0003
[0250] To a solution of 3-amino-Λ/-(2-chlorobenzyl)-2,2-dimethylpropanamide (0.45 mmol) in DCM (5 mL) was added DIEA (157 μL, 0.90 mmol, 2 equiv.) and 4-ethylphenyl isocyanate (97.0 μL, 0.675 mmol, 1.5 equiv.). The reaction mixture was stirred for 30 min. The mixture was concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give Λ/-(2-chlorobenzyl)-3-(3-(4-ethylphenyl)ureido)-2,2- dimethylpropanamide (29.6 mg, 17% for two steps). LRMS (M+H+) m/z 388.1.
Example Vl
Preparation of (S)-(I -(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4- ethylphenylcarbamate
Figure imgf000117_0001
(S)-(I -(2 -chlorobenzylcarbamoyl)pyrrolidin-2-yl)m ethyl 4-ethylphenylcarbamate
Figure imgf000117_0002
[0251] To a solution of (S)-pyrrolidin-2-ylmethanol (110 mg, 1.1 mmol) in THF (2.0 mL) was added 2-chlorobenzyl-isocyanate (167 mg, 1.0 mmol). The reaction mixture was stirred for 1 h and concentrated under reduced pressure to give (S)-Λ/-(2- chlorobenzyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide as an oil (277 mg), which was used without further purification. LRMS (M+H+) m/z 269.0.
Figure imgf000117_0003
[0252] To a solution of (S)-Λ/-(2-chlorobenzyl)-2-(hydroxymethyl)pyrrolidine-1- carboxamide (268 mg, 1.0 mmol) in THF (2.0 mL) was added 4-ethyl-phenyl-isocyanate (220 mg, 1.5 mmol). The reaction mixture was stirred for 1 h. LC/MS indicated the reaction was complete. The reaction was concentrated and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-(I -(2- chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (42 mg, 10% for two steps). LRMS (M+H+) m/z 416.0.
Example VII
Preparation of (S)-2-(3-(2-chlorobenzyl)-1-methylureido)propyl 4- ethylphenylcarbamate
Figure imgf000118_0001
(S)-2-(3-(2-chlorobenzyl)-1-methylureido)propyl 4-ethylphenylcarbamate
Figure imgf000118_0002
[0253] To a solution of (S)-te/f-butyl 1 -hydroxypropan-2-ylcarbamate (3.06 g, 17.46 mmol) in DCM (30 mL) were added TBDMSCI (2.90 g, 19.2 mmol, 1.1 equiv.) and DIEA (4.3 mL, 26.2 mmol, 1.5 equiv.). The reaction was stirred for 1 h. LC/MS indicated the reaction was complete. The reaction mixture was then poured into H2O and diluted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 and brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give (S)-terf-butyl 1-(te/Y-butyldimethylsilyloxy)propaπ-2-ylcarbamate, which was used for the next step without further purification. LRMS (M-Boc+H+) m/z 190.1.
Figure imgf000118_0003
[0254] To a solution of NaH (60% dispersed in mineral oil, 60 mg, 1.49 mmol, 1.15 equiv.) in DMF (2.0 ml_) was added (S)-fθrf-butyl 1-(tert-butyldimethylsilyloxy)propan-2- ylcarbamate (360 mg, 1.3 mmol). The reaction mixture was stirred for 30 min followed by addition of methyl iodide (93 μL, 1.49 mmol, 1.15 equiv.) and stirred for 1 h. LC/MS indicated the reaction was complete. The reaction mixture was quenched with saturated NH4CI and diluted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give (S)-terf-butyl 1-(te/f-butyldimethylsilyloxy)propan-2-yl(methyl)carbamate as an oil, which was used in the next step without further purification. LRMS (M-Boc+H+) m/z 204.1.
Figure imgf000119_0001
[0255] To a solution of (S)-tert-butyl 1-(terf-butyldimethylsilyloxy)propan-2- yl(methyl)carbamate (301 mg, 1.0 mmol) in THF was added TBAF (1M in THF, 1.5 ml_, 1.5 mmol, 1.5 equiv.) and the mixture was stirred for 1 h followed by quenched with saturated NaHCO3 and diluted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO.!, and filtered. The filtrate was concentrated under reduced pressure to give a crude oil, which was re-dissolved in THF (2.0 ml_). To this THF solution were added DMAP and 4-ethylphenyl isocyanate. The reaction mixture was stirred for 30 min. LC/MS indicated the completion of the reaction and the mixture was filtered and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-2-(methyl(terf-butoxycarbonyl)amino)propyl 4-ethylphenylcarbamate (118 mg. 30% from 1). LRMS (M-Boc+H+) m/z 237.1.
Figure imgf000119_0002
[0256] To a solution of (S)-2-(methyl(fert-butoxycarbonyl)amino)propyl A- ethylphenylcarbamate (105 mg, 0.27 mmol) in MeOH was added HCI (4M in dioxane, 0.2 ml_, 0.81 mmol, 3 equiv.) and the mixture was stirred for 2 h. LC/MS indicated the reaction was complete and the mixture was concentrated under reduced pressure to give a crude oil, which was re-dissolved in THF. To this THF solution was added 4- ethylphenyl isocyanate (30 μl_, 0.26 mmol) followed by DIEA (0.11 mL, 0.66 mmol, 2.5 equiv.). The reaction mixture was stirred for 2 h. LC/MS indicated the completion of the reaction. The mixture was filtered and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-2-(3-(2-chlorobenzyl)-1-methylureido)propyl 4-ethylphenylcarbamate (88.6 mg, 81% for two steps). LRMS (M+H+) m/z 404.1.
Example VIII
Preparation of (1 -(2-amiπoacetyl)-4-(3-fluoro-2-methylbenzylcarbamoyl)piperidin-
4-yl)methyl 4-ethylphenylcarbamate
Figure imgf000120_0001
(i-^-aminoacetylJ^-p-fluoro-Σ-methylbenzylcarbamoyOpiperidin^-yOmethyl
4-ethy I pheny lcarbam ate
Figure imgf000120_0002
[0257] To a solution of 1-(te/ϊ-butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4- carboxylic acid (6 g, 21 mmol) and DIEA (7.3 mL, 42 mmol, 2.0 equiv.) in THF (60 mL) was added methyl chloroformate (1.94 mL, 25 mmol, 1.2 equiv.) at 0 0C. The mixture was stirred at 0 0C until the reaction was complete. NaBH4 (3.16 g, 84 mmol, 4.0 equiv.) was added at 0 0C. MeOH (10 mL) was then added. The mixture was stirred at 0 °C for 90 min. The reaction mixture was then quenched by saturated NaHCO3 and concentrated to dryness. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3, water and brine, dried over Na2SO-J, and concentrated. The resulting residue was purified by column chromatography to give 1-te/Y-butyl 4-methyl 4- (hydroxymethyl)piperidine-1 ,4-dicarboxylate (2.6 g, 46%). LRMS (M-Boc+H+) m/z 174.1.
Figure imgf000121_0001
[0258] To a solution of 1-tert-butyl 4-methyl 4-(hydroxymethyl)piperidine-1 ,4- dicarboxylate (470 mg, 1.72 mmol, 1.0 equiv.) in MeOH (1 mL) was added HCI (4 M in dioxane, 1 mL). The mixture was stirred at rt for about 1 h and concentrated to dryness to give methyl 4-(hydroxymethyl)piperidine-4-carboxylate, which was used without further purification. LRMS (M+H+) m/z 174.0. oc
Figure imgf000121_0002
[0259] To a solution of Boc-Gly-OH (331 mg, 1.89 mmol, 1.1 equiv.) in DMF (1 mL) was added HBTU (718 mg, 1.89mmol, 1.1 equiv.), followed by addition of methyl 4- (hydroxymethyl)piperidine-4-carboxylate (1.72 mmol, 1 equiv.) and DIEA (749 μL, 4.30 mmol, 2.5 equiv.) at rt. The reaction mixture was stirred for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed by saturated NaHCO3 , water and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by column chromatography to give methyl 1-(2-(fert- butoxycarbonylamino)acetyl)-4-(hydroxymethyl)piperidine-4-carboxylate (560 mg, 98%, two steps). LRMS (M-Boc+H+) m/z 231.1.
Figure imgf000122_0001
[0260] To a solution of methyl 1-(2-(terf-butoxycarbonylamino)acetyl)-4- (hydroxymethyl)piperidine-4-carboxylate (2.5 g, 7.56 mmol, 1.0 equiv.) in THF (10 mL) and CH3OH (10 mL) was added aqueous LiOH (2N, 7.56 mL, 15.13 mmol, 2.0 equiv.). The reaction mixture was stirred at 60 0C for 1 h. The reaction mixture was neutralized with HCI (1 N) and was concentrated to dryness to give J\-(2-(tert- butoxycarbonylamino)acetyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid (3.0 g), which was used without further purification. LRMS (M-Boc+H+) m/z 261.0.
Figure imgf000122_0002
[0261] To a solution of crude 1-(2-(terf-butoxycarbonylamino)acetyl)-4- (hydroxymethyl)piperidine-4-carboxylic acid (120 mg, -0.379 mmol, 1.0 equiv) in DMF (30 mL) were added HBTU (144 mg, 0.379 mmol, 1.0 equiv.), 2-methyl, 3- fluorobenzylamine (53 mg, 0.379 mmol, 1.0 equiv.) and DIEA (132 μL, 0.758 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at rt. The mixture was partitioned between EtOAc and H2O. The organic layer was washed by 1 N HCI, Saturated NaHCO3.water and brine, dried over Na2SO4, and concentrated to dryness to give tert- butyl 2-(4-(3-fluoro-2-methylbenzylcarbamoyl)-4-(hydroxymethyl)piperidin-1-yl)-2- oxoethylcarbamate (185 mg), which was used without further purification. LRMS (M+H+) m/z 439.1.
Figure imgf000123_0001
[0262] To a solution of crude terf-butyl 2-(4-(3-fluoro-2-methylbenzylcarbamoyl)-4- (hydroxymethyl)piperidin-1-yl)-2-oxoethylcarbamate (185 mg, -0.422 mmol, 1.0 equiv.) in THF(2 mL) were added DMAP (10 mg, 0.085 mmol, 0.2 equiv.) and 4- ethylphenylisocyanate (61 μl_, 0.422 mmol, 1.0 equiv.). The reaction mixture was stirred overnight, and then concentrated. The resulting residue was purified on RP- HPLC using a mixture of acetonitrile and H2O to give (1-(2-(fe/f- butoxycarbonylaminoJacetyO^^S-fluoro^-methylbenzylcarbamoyOpiperidin^-ylJmethyl 4-ethylphenylcarbamate (12 mg, 5% for three steps). LRMS (M-Boc+H*) m/z 485.2.
Figure imgf000123_0002
[0263] To a solution of give (1-(2-(terf-butoxycarbonylamino)acetyl)-4-(3-fluoro-2- methylbenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (12 mg, 0.021 mmol, 1.0 equiv.) in CH2CI2 (1 mL) was added 4N HCI (1 mL). The mixture was stirred at rt for about 1 h and concentrated to dryness. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (1-(2-aminoacetyl)-4-(3-fluoro- 2-methylbenzylcarbamoyl)piperidin~4-yl)methyl 4-ethylphenylcarbamate (8 mg, 79%). LRMS (M+H+) m/z 485.1. Example IX
Preparation of 2-(3-(2-chlorobenzyl)-1-methylureido)ethyl naphthalen-2- ylcarbamate
Figure imgf000124_0001
2-(3-(2-chlorobenzvl)-1-methvlureido)ethvl naphthalen-2-vlcarbamate
Figure imgf000124_0002
[0264] To a solution of 2-(methy!amino)ethanol (600 mg, 7.99 mmol) in THF (5.0 ml_) was added 2-chlorobenzylisocyanate (0.75 mL, 6.66 mmol). The reaction was stirred at rt for 30 min. The mixture was concentrated, re-dissolved in MeOH, filtered, and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2- chlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (950 mg, 49%). LRMS (M+H+) m/z 243.0.
Figure imgf000124_0003
[0265] To a solution of 3-(2-chlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (120 mg, 0.50 mmol) in THF (1.0 mL) were added DMAP (3.0 mg, 0.02) and 2- isocyanatonaphthalene (100 mg, 0.60 mmol). The reaction mixture was stirred for 30 min. LC/MS indicated the completion of the reaction. The mixture was filtered and the filtrate was purified by RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-(2- chlorobenzyl)-1-methylureido)ethyl naphthalen-2-ylcarbamate (165 mg, 80%). LRMS (M-Boc+H+) m/z 412.1. Example X
Preparation of 2-(3-(2,3-dichlorobenzyl)-1-methylureido)ethyl 4- ethylphenylcarbamate
Figure imgf000125_0001
2-(3-(2,3-dichlorobenzyl)-1-methylureido)ethyl 4-ethylphenylcarbamate
Figure imgf000125_0002
[0266] To a solution of triphosgene (89 mg, 0.3 mmol) in THF were added a solution of 2,3-dichlorobenzylamine (100 mg, 0.59 mmol) in THF dropwise and then DIEA (209 μl_, 1.2 mmol). The reaction mixture was stirred at rt for 10 min, and 2- (methylamino)ethanol (90 mg, 1.2 mmol) was added. The reaction mixture was stirred at rt for 15 min and purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (70 mg, 44%). LRMS (M+H+) m/z 277.1.
Figure imgf000125_0003
[0267] To a solution of 3-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-1-methylurea (70 mg, 0.27 mmol) in DMF were added DMAP and 4-ethylphenylisocyanate (80 mg, 0.54mmol). The reaction mixture was stirred overnight. The reaction mixture was concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-(2,3-dichlorobenzyl)-1-methylureido)ethyl A- ethylphenylcarbamate (7 mg, 6.5 %). LRMS (M+H+) m/z 424.1. Example Xl
Preparation of 2-(3-(2-chlorobenzyl)-1-(2-hydroxyethyl)ureido)ethyl 4- ethylphenylcarbamate
Figure imgf000126_0001
2-(3-(2-chlorobenzyl)-1-(2-hydroxyethyl)ureido)ethyl 4-ethylphenylcarbamate
Figure imgf000126_0002
[0268] To a solution of 2,2'-azanediyldiethanol (1.58 g, 15 mmol) in DMF (5 ml_) was added 2-chlorobenzylisocyanate (1.26 g, 7.5 mmol). The reaction mixture was stirred at rt for 30min. The mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1 ,1-bis(2-hydroxyethyl)urea (1.3 g, 65%) . LRMS (M+H+) m/z 272.1.
Figure imgf000126_0003
[0269] To a solution of 3-(2-chlorobenzyl)-1,1-bis(2-hydroxyethyl)urea (2.3 g, 8.46 mmol,) in THF were added DMAP and 4-ethylphenylisocyanate (1.24 g, 8.46 mmol). The reaction mixture was stirred for 1 h and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-(2- chlorobenzyl)-1-(2-hydroxyethyl)ureido)ethyl 4-ethylphenylcarbamate (1.7 g, 48%). LRMS (M+H+) m/z 420.1. Example XII
Preparation of ((2S,4/?)-4-(2-aminoacetamido)-1-(2- chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamatθ
Figure imgf000127_0001
((2S,4R)-4-(2-aminoacetamldo)-1-(2-chloroben2ylcarbamoyl)py^olidin-2-yl)methyl
4-ethylphenylcarbamate
Figure imgf000127_0002
[0270] To a solution of (2S,4R)-ferf-butyl 4-(((9H-fluoren-9- yl)methoxy)carbonylamino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (403 mg, 0.92 mmol) and DMAP( 134 mg, 1.1 mmol) in THF (10 ml_) was added 4-ethylphenyl isocyanate (162 mg, 11 mmol). The reaction mixture was stirred at rt overnight and concentrated to give (2S,4fi)-terf-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2- ((4-ethylphenylcarbamoyloxy)methyl)pyrrolidine-1-carboxylate, which was used without further purification. LRMS (M+H+) m/z 585.1.
Figure imgf000127_0003
[0271] To a solution of crude (2S,4R)-terf-butyl 4-(((9H-fluoren-9- yl)methoxy)carbonylamino)-2-((4-ethylphenylcarbamoyloxy)methyl)pyrrolidine-1- carboxylate in MeOH was added HCI ( 4 N in dioxane). The reaction was stirred at rt for 1h and concentrated. The residue was dissolved in THF (10 ml_). To this solution were added DIEA (469 μL, 2.7 mmol) and 2-chlorobenzylisocyanate. The mixture was stirred at rt for 1h and concentrated. The residue was dissolved in 10 ml of 20% piperidine in DCM. The reaction mixture was stirred at rt for 15 min, concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give ((2S,4F?)-4-amino-1-(2- chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (210 mg, 53% for 4 steps). LRMS (M+H+) m/z 431.1.
Figure imgf000128_0001
[0272] To a solution of ((2S,4R)-4-amino-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2- yl)methy! 4-ethylphenylcarbamate (60 mg, 0.14 mmol) in DMF were added Boc-Gly-OH (37 mg, 0.21 mmol) and HBTU (80 mg, 0.21 mmol). The reaction mixture was stirred at rt overnight and purified on RP-HPLC using a mixture of acetonitrile and H2O. The fraction containing the product was combined and concentrated. The residue was dissolved in MeOH and 4N HCI in dioxane. The reaction mixture was stirred at rt for 1 h and concentrated to give ((2S,4R)-4-(2-aminoacetamido)-1-(2- chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (37 mg, 51%). LRMS (M+H+) m/z 488.1.
Example VIII
Additional Synthesized Compounds
[0273] Using procedures similar to those described herein, the compounds in the following table were synthesized and tested.
IC50
Arithmetic
Mean Ion m/z MW ChemicalNamβ
N-[(2-chlorophenyl)methyl]-3-{[(4- 8.821 M+H* 388.1 387.9 ethylphenyl)amino]carbonylamiπo}-2,2-dimethylpropanamide IC50
Arithmetic
Mean Ion m/z MW ChemicalName
(4-{[N-(4-acetylphenyl)carbamoyloxy]methyl}(2H-3,4.5,6- 4.273 M+H* 445.1 444.91 tetrahydropyraπ-4-yl))-N-[(2-chlorophenyl)methyl]carboxamide
(4-{[N-(2-chlorophenyl)carbamoyloxy]methyl}(2H-3.4,516- 17.331 M+H* 437.0 437.32 tetrahydropyran-4-yl»-N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(3- methoxyphenyl)carbamoyloxy]methyl}(2H-3,4,5,6- 19.039 M+H* 433.1 432.9 tetrahydropyran-4-yl))carboxamide
2-(acetylamino)-N-[(2-chlorophenyl)methyl]-3-[N-(4- 13.723 M+H* 418.1 417.89 ethylphenyl)carbamoyloxy]propanamide ethyl 4-{[(4^N-[(2-chlorophenyl)methyl]carbamoyl}-2H-3,4,5,6- 6.388 M+H* 475.1 474.93 tetrahydropyran-4-yl)methoxy]carbonylamino}benzoate
N-[(2-chlorophenyl)methyl](4-{[N-(4- methylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6- 0.697 M+H* 417.0 416.9 tetrahydropyran-4-yl))carboxamide
N-[(2-ch!orophenyl)methyl][4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(2H-3,4,516- 1.135 M+H* 471.1 470.87 tetrahydropyran-4-yl)jcarboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(2- cyanophenylJcarbamoyloxylmethylK∑H-S^.S.Θ-tetrahydropyran- 17.023 M+H* 428.1 427.88 4-yl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)-N- methylcarbamoyloxy]methyl}(2H-3,4,5,6-tetrahydropyran-4- 7.628 M+H* 445.2 444.95 yl))carboxamide methyl 4-{[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-2H-314>516- 3.555 M+H* 461.1 460.91 tetrahydropyran-4-yl)methoxy]carbonylamino}benzoate
N-[(2-chlorophenyl)methyl][4-({N-[4-(2-methyl(1,3-thiazol-4- yl))phenyl]carbamoyloxy}methyl)(2H-3,4,5,6-tetrahydropyran-4- 3.915 M+H* 500.0 500.01 yl)]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(3-fluoro-4- methylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6- 2.215 M+H* 435.1 434.89 tetrahydropyran-4-yl))carboxamide
N-[(2-chlorophenyl)methyl]{4-[(N-indan-5- ylcarbamoyloxy)methyl](2H-3,4,5,6-tetrahydropyran-4- 0.361 M+H* 443.1 442.94 yl)}carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(6-fluoro-2- methylphenyl)carbamoyloxy]methyl}(2H-3.4,5.6- 14.25 M+H* 435.1 434.89 tetrahydropyran-4-yl))carboxamide
(4-{[N-(3-chloro-2-methylphenyl)carbamoyloxy]methyl}(2H-
3,4,5,6-tetrahydropyran-4-yl))-N-[(2- 16.159 M+H* 451.0 451.34 chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl][4-({N-[4-methyl-3-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(2H-3,4,5,6- 12.137 M+H* 485.0 484.9 tetrahydropyran-4-yl)]carboxamide
(4-{[N-(3,4-difnethylphenyl)carbamoyloxy]methyl}(2H-3,4l5,6- 2.335 M+H* 431.1 430.92 tetrahydropyran-4-yl))-N-[(2-chlorophenyl)methyl]carboxamide
(4-{[N-(3-chloro-4-methylphenyl)carbamoyloxy]methyl}(2H-
3,4,5,6-tetrahydropyran-4-yl))-N-[(2- 1.961 M+H* 451.0 451.34 chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl][4-({N-[4-
(methylethyl)phenyl]carbamoyloxy}methyl)(2H-3,4,5,6- 0.498 M+H* 445.1 444.95 tetrahydropyran-4-yl)]carboxamide IC50
Arithmetic
Mean Ion m/z MW ChemicalName
(4-{[N-(3,5<lichlorophenyl)carbamoyloxy]methyl}(2H-3A5,6- 18.341 M+H* 471.0 471.76 tetrahydropyran-4-yl))-N-[(2-chloropheny!)methyl]carboxamide
(4-{[N-(2,4-dimethylphenyl)carbamoyloxyimethyl}(2H-3,4,5,6- 1.262 M+H* 431.1 430.92 tetrahydropyran-4-yl))-N-[(2-chlorophenyl)methyl]carboxamide methyl 3-{N-[(2-chlorophenyl)methyl]carbamoyl}-3-{[(4- 18.559 M+H* 459.1 459.92 ethylphenyl)amino]carbonylamino}pyrrolidinecarboxylate
N-[(2-chlorophenyl)methyl][4-({N-[4-
(hydroxyethyl)phenylJcarbamoyloxy}methyl)(2H-3.4,5,6- 5.229 M+H* 447.1 446.92 tetrahydropyran-4-yl)]carboxamide
N-[(2-chlorophenyl)methyl]{4-[(N- phenylcarbamoyloxy)methyl](2H-3l415,6-tetrahydropyran-4- 15.244 M+H* 403.1 402.87 yl)}carboxamide
4-{[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-2H-3p415,6- 16.101 M+H* 446.1 445.9 tetrahydropyran-4-yl)methoxy]carbonylamino}benzamide
N-[(2-chlorophenyl)methyl][4-({[(4- ethylphenyl)amino]carbonylamino}methyl)(4- 18.192 M+H* 429.1 428.95 piperidyl)]carboxamide
N-[(2-chloropheπyl)methyl][4-({[(4- ethylphenyl)amino]carbonylamino}methyl)-1-(2- 1.879 M+H* 487.1 486.99 hydroxyacetyl)(4-piperidyl)]carboxamide
N-[(2-chlorophenyl)methyl][4-({[(4-ethylphenyl)amino]-N- methylcarbonylamino}rnethyl)-1-(2-hydroxyacetyl)(4- 18.738 M+H* 501.1 501.02 piperidyl)]carboxamide
2-(acetylamino)-N-[(2-chlorophenyl)methyl]-3-[N-(4- 3.138 M+H* 432.0 431.91 ethylphenyl)carbamoyloxy]-2-methylpropanamide
N-[(2-chlorophenyl)methyl]-3-[N-(4-ethytphenyl)carbamoyloxy]- 4.088 M+H* 448.1 447.91 2-(methoxycarbonylamino)-2-methylpropanamide
N-[(2-chlorophenyl)methylj-3-[N-(4-ethylphenyl)carbamoyloxy]- 9.184 M+H* 448.0 447.91 2-(2-hydroxyacetylamino)-2-methylpropanamide
2-{2-[(tert-butoxy)carbonylamino]acetylamino}-N-[(2- chlorophenyl)methyl]-3-[N-(4-ethylphenyl)carbamoyloxy]-2- 19.38 M+H* 547.1 547.04 methylpropanamide
2-(2-aminoacetylamino)-N-[(2-chlorophenyl)methyl]-3-[N-(4- 3.988 M+H* 447.1 446.93 ethylphenyl)carbamoyloxy]-2-methylpropanamide
2-((2S)-2-amino-3-hydroxypropanoylamino)-N-[(2- chlorophenyl)methylj-3-[N-(4-ethylphenyl)carbamoyloxy]-2- 11.172 M+H* 477.1 476.95 methylpropanamide
{[1 -(2-aminoacetylH-({[(2- chlorophenyl)methyl]amino}methyl)(4-piperidyl)]methoxy}-N-(4- 13.086 M+H* 473.3 473.01 ethylphenyl)carboxamide
N-[(1-(2-aminoacetyl)-4-{N-[(2- chlorophenyl)methyl]carbamoyl}(4-piperidyl))methyl][(4- 12.353 M+H* 558.1 558.11 ethylphenyl)amino]-N-(3-methoxypropyl)carboxamide
N-[(1-(2-aminoacetyl)-4-{N-[(2- chlorophenyl)methyl]carbamoyl}(4-piperidyl))methyl]-N-(2- 16.385 529.07 aminoethyl)[(4-ethylpheπyl)amiπo]carboxamide
(tert-butoxy)-N-(2-{N-[( 1 -{2-[(tert-butoxy)carbonylamino]acetyl}-
4-{N-[(2-chlorophenyl)methyl]carbamoyl}(4-piperidyl))methyl][(4- 19.481 M+H* 729.3 729.31 ethylphenyl)amino]carbonylamino}ethyl)carboxamide ICSO Arithmetic Mean Ion m/z MW ChemicalName
3-( 1 -(2-aminoacetyl)-4-{N-[(2- methylphenyl)methyl]carbamoyl}(4-piperidyl))-N-(4-
15.319 464.6 ethylphenyl)propanamide
N-{(1S)-2-[N-(4-ethy!phenyl)carbamoyloxy]-isopropylK[(2-
1.632 M+H* 390.1 389.88 chlorophenyl)methyl]amino}carboxamidβ tert-butyl 2-(N-{(1 S)-2-[N-(4-ethylphenyl)carbamoyloxy]-
M- isopropylK((2-
18.521 'Bu+H* 448.1 504.02 ch!orophenyl)methyl]amino}carbonylamino)acetate M- H2CHH 2-(N-{(1S)-2-[N-(4-ethylphenyl)carbamoyloxy]-isopropyl}{[(2- 1.67 430.1 447.91 chlorophenyl)methyl]amino}carbonylamino)acetic acid
N-{(1S)-2-[N-(4-ethylpheπyl)carbamoyloxy]-isopropyl}{[(2-
0.148 M+H* 404.1 403.9 chlorophenyl)methyl]amino}-N-methylcarboxamide
[(2R)-2-({[(2-chlorophenyl)methyl]amino}-N-
6.814 M+H* 404.1 403.9 methylcarbonylamino)propoxy]-N-(4-ethylphenyl)carboxamide
N-{( 1 S)-3-[N-(4-ethylphenyl)carbamoyloxy]-1 -methylpropyl}{[(2-
0.198 M+H* 418.1 417.93 chloropheπyl)methyl]amino}-N-methylcarboxamide
{[(2-chlorophenyl)methyl]amino}-N-{4-[N-(4-
6.071 M+H* 418.0 417.93 ethylphenyl)carbamoyloxy]butyl}-N-methylcarboxamide
{[(2-chlorophenyl)methyl]amino}-N-{3-[N-(4-
1.669 M+H* 404.1 403.9 ethylphenyl)carbamoyloxy]propyl}-N-methylcarboxamide
(tert-butoxy)-N-[2-({[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carbonylamino)ethyl]-N-
18.247 M+H* 533.1 533.06 methylcarboxamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}-N-[2-
16.325 M+H+ 433.1 432.94 (methylamino)ethyl]carboxamide
2-amino-N-[2-({[(2-chlorophenyl)methyl]amiπo}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carbonylamino)ethyl]-N-
5.856 M+H* 490.1 489.99 methylacetamide
2-amino-N-{2-[{[(2-chlorophenyl)methyl]amino}-N-(2-{N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}ethyl)carbonylamino]ethyl}
15.008 M+H* 530.1 529.94 -N-methylacetamide
(2-({[(2-chlorophenyl)methyl]amino}-N-methylcarbonylamino)-
8.52 M+H* 404.3 403.9 isopropoxy]-N-(4-ethylphenyl)carboxamide
{[(2-chlorophenyl)methyl]amino}-N-methyl-N-{2-[N-(4-
0.248 M+H* 438.1 437.92 phenylphenyl)carbamoyloxy]ethyl}carboxamide
{[(2-chloraphenyl)methyl]amino}-N-methyl-N-[2-(N-(2-
0.03 M+H* 412.1 411.88 naphthyl)carbamoyloxy)ethyl]carboxamide
3-(2-chlorophenyl)-N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-
0.875 M+H* 389.1 388.89 N-methylpropanamide
N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-2-hydroxy-N-methyl-
17.505 M+H* 439.1 438.44 3-[2-(trifluoromethyl)pheπyl]propanamide
N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-N-methyl-3-[2-
1.21 M+H* 423.1 422.44 (trifluoromethyl)phenyljpropanamide
{[(2-chloropheπyl)methyl]methylamiπo}-N-{2-[N-(4-
2.075 M+H* 404.1 403.9 ethylphenyl)carbamoyloxy]ethyl}-N-methylcarboxamide
(2-{N-[(2-chlorophenyl)methyl]carbamoyloxy}ethoxy)-N-(4-
3.69 M+H* 377.2 376.83 ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl]-4-{[N-(4-
4.732 M+H* 402.2 401.93 ethylphenyl)carbamoyl]amino}-2,2-dimethylbutaπamide ICSO
Arithmetic
Mean Ion m/z MW ChemicalName
N-[(2-chlorophenyl)methyl]-2-{[(4- 13.629 M+H* 374.1 373.88 ethylpheny^aminojcarbonylamino^-methylpropanamide
N-[(2-chlorophenyl)methyl]-3-[N-(4-ethyIphenyl)carbamoyloxy]- 2.515 M+H* 389.1 388.89 2,2-dimethylpropanamide
N-[({N-[(2- chlorophenyl)methyl]carbamoyl}cyclopropyl)methyl][(4- 5.232 M+H* 385.1 385.89 ethytphenyl)amino]carboxamide
N-[({N-[(2-chlorophenyl)methyl]carbamoyl}cyclopropyl)nriethyl]- 18.156 M+H* 385.1 384.9 2-(4-ethylphenyl)acetamide
[({N-[(2-chlorophenyl)methyl]carbamoyl}cyclobutyl)methoxy]-N- 1.879 M+H* 401.2 400.9 (4-ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl]({[N-(4- 0.238 M+H* 429.3 428.95 ethylphenylJcarbamoyloxyjmethylfcyclohexyOcarboxamide tert-butyl 4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- 3.211 M+H* 430.2 530.06 ethylphenyl)carbamoyloxy]methyl}piperidinecarboxylate
N-[(2-ch1orophenyl)methyl](4-{[N-(4- 1.663 M+H* 430.2 429.94 ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))carboxamide
(4-{[N-<4-chlorophenyl)carbamoyloxy]methyl}(2H-3,4,5,6- 2.784 M+H* 437.0 437.32 tetrahydropyran-4-yl))-N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chloropheny!)methyl](1-{[N-(4- 1.362 M+H* 413.1 412.91 ethylphenyl)carbamoyloxyjmethyl}cydopent-3-enyl)carboxamide
N-[(2-chloropheny l)methyl]( 1 -{[N-(4- ethylphenyl)carbamoyloxy]methyl}-3,4- 5.511 M+H* 447.1 446.92 dihydroxycyclopentyOcarboxamide methyl 4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- 0.53 M+H* 488.1 487.98 ethylphenyljcarbamoyloxylmethyljpiperidinecarboxylate
(( 1 S,2S)-2-{[(4-ethylphenyl)amino]carbonylamino}cyclohexyl)-N- 16.807 M+H* 414.1 413.94 [(2-chlorophenyl)methyl]carboxamide
(1-acetyl-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- 0.418 M+H* 472.1 471.97 piperidyl))-N-[(2-chloropheπyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4H[(N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(methylsulfonyl)(4- 0.496 M+H* 508.1 508.03 piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(2-hydroxyacetyl)(4- 0.173 M+H* 488.1 487.98 piperidyl))carboxamide
(tert-butoxy)-N-[2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-
{[N-(4-ethylphenyl)carbamoyloxy]methyl}piperidyl)-2- 0.919 M+H* 487.1 587.11 oxoethyljcarboxamide
(tert-butoxy)-N-[4-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-
{[N-(4-ethylphenyl)carbamoyloxy]methyl}piperidyl)-4- 0.481 M+H* 616.2 615.16 oxobutyl]carboxamide
(1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- 0.175 M+H* 487.1 486.99 chlorophenyl)methyl]carboxamide
(1-(4-aminobutanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- 0.246 M+H* 515.2 515.04 chlorophenyl)methyl]carboxamide
N-[(1S)-2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}pipeιϊdyl)-1-methyl-2- 1.511 M+H* 501.1 601.13 oxoethyl](tert-butoxy)carboxamide IC50
Arithmetic Mean Ion m/z MW ChemicalName
(1-((2S)-2-aminopropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.724 M+H+ 501.1 501.02 chlorophenyl)methyl]carboxamide methyl 4-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4-
0.426 M+l-T 545.1 544.04 ethylphenyl)carbamoyloxy]methyl}piperidyl)-4-oxobutanoate
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(4-hydroxybutanoyl)(4-
0.492 M+H* 516.2 516.03 piperidyl))carboxamide
N-[(2-chlorophenyl)methyl]{3-[N-(4-
2.261 M+H* 416.1 415.91 ethylphenyljcarbamoyloxyjpiperidyljcarboxamide
{3-[N-(4-ethylphenyl)carbamoyloxy]piperidyl}-N-[(2-
5.544 M+H* 396.2 395.49 methylphenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(N-methylcarbamoyl)(4-
0.302 M+H* 487.1 486.99 piperidyl))carboxamide
M- (tert-butoxy)-N-[2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-
Boc+H {[N-(4-ethylphenyl)carbamoyloxy]methyl}piperidyl)-1- 0.661 + 517.2 617.13 (hydroxymethyl)-2-oxoethyl]carboxamide
(1-(2-amino-3-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.143 M+H* 517.1 517.02 chlorophenyl)methyl]carboxamide
M- N-[(1R)-2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4-
Boc+H ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-methyl-2-
11.978 501.2 601.13 oxoethyl](tert-butoxy)carboxamide
(1-((2R)-2-aminopropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.255 M+H* 501.2 501.02 chlorophenyl)methyl]carboxamide
( 1 -(2-amino-3-methylbutanoyl)-4-{[N-(4- ethylpheπyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.54 M+H* 529.2 529.07 chlorophenyl)methyl]carboxamide
M- tert-butyl 4-[(4-(N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4-
Boc+H ethylphenyljcarbamoyloxylmethylJpiperidyOcarbonylJpiperidinec
3.549 541.1 641.2 arboxylate
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]nnethyl}-1-(4-piperidylcarbonyl)(4-
0.808 M+H* 541.2 541.08 piperidyl))carboxamide tert-butyl 3-[(4-{N-[(2-chloropheπyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyljcarbamoyloxylmethylJpiperidyOcarbonyllmorpholine-
1.679 M+H* 643.3 643.17 4-carboxylate
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(morpholin-3-ylcarbonyl)(4-
0.515 M+H* 543.2 543.05 piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-benzyt(4-
14.41 M+H* 520.2 520.06 piperidyl))carboxamide
N-[(2-chlorophenyl)methyl]( 1 -ethyl-4-{[N-(4-
6.276 M+H* 458.1 457.99 ethylphenyl)carbamoyloxyjmethyl}(4-piperidyl))carboxamide methyl 2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4-
1.52 M+H* 503.4 502 ethylphenyl)carbamoyloxy]methyl}piperidyl)acetate IC50 Arithmetic Mean Ion m/z MW ChemicalName
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxyjmethyl}-1-[3-hydroxy-2-
0.275 M+H* 546.2 546.05 (hydroxymethyl)-2-methylpropanoyl](4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(2-hydroxyethyl)(4-
4.036 M+H+ 474.1 473.99 piperidyl))carboxamide
(1-(2-amino-2-methylpropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.67 M+H+ 515.2 515.04 ch loropheny l)methyl]carboxam ide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-[2-(methylamino)acetyl](4-
0.213 M+H+ 501.2 501.02 piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-<4- ethylphenyl)carbamoyloxy]methyl}-1-methyl(4-
4.928 M+H+ 444.1 443.97 piperidyl))carboxamide M- N-[(1R)-2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- Boc+H ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-(hydroxymethyl)- 3.502 517.1 617.13 2-oxoethyl](tert-butoxy)carboxamide
(1-((2R)-2-amino-3-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.164 M+H+ 517.2 517.02 ch lorophenyl)methy l]carboxam ide M- N-[(1S)-2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{tN-(4- Boc+H ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-(hydroxymethyl)- 0.416 517.1 617.13 2-oxoethyl](tert-butoxy)carboxamide
(1-((2S)-2-amino-3-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.125 M+H+ 518.2 517.02 chlorophenyl)methyl]carboxamide
(1-(2-aminoethyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-
1.162 M+H+ 474.1 473.01 piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
(1-(2-amino-3-cyanopropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.797 M+H+ 526.1 526.03 chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl][4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-
5.936 M+H+ 470.1 469.88 piperidyl)]carboxamide
(1-[(2-aminoethyl)sulfonyl]-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.274 M+H+ 537.1 537.07 chlorophenyl)methyl]carboxamide
( 1 -(2, 3-diaminopropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
1.023 M+H+ 516.1 516.03 chlorophenyl)methyl]carboxamide
(1-(2,4-diamiπobutanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.585 M+H+ 530.2 530.06 chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl][1-(2-hydraxyacetyl)-4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-
0.456 M+H+ 528.1 527.92 piperidyl)]carboxamide
[1 -(2-aminoacetyl)-4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]-N-[(2-
0.285 M+H+ 527.1 526.94 chlorophenyl)methyl]carboxamide IC50
Arithmetic Mean Ion m/z MW ChemicalName
[1-((2S)-2-amino-3-hydroxypropanoyl)-4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]-N-[(2-
0.138 M+H* 557.1 556.96 chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(2-methoxyacetyl)(4- 0.486 M+H* 502.2 502 piperidyl))carboxamide tert-butyl 2-[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenytycarbamoyloxylmethytypiperidyOcarbonyllazetidineca 4.829 M+H* 513.2 613.14 rboxylate
<1-(azetidin-2-ylcarbonyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- 0.221 M+H* 513.2 513.03 chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(3-methoxypropanoyl)(4- 0.606 M+H* 517.2 516.03 piρeridyl))carboxamide
(1-(2,5-diaminopentanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
1.495 M+H* 544.1 544.09 chlorophenyl)methyl]carboxamide
{(3R)-3-[N-(4-ethylphenyl)carbamoyloxy]piperidyl}-N-[(2- 1.564 M+H+ 416.1 415.91 chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(phenylcarbonyl)(4-
0.412 M+H* 535.2 534.05 piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-(3-pyridylcarbonyl)(4-
0.695 M+H* 536.2 535.03 piperidyl))carboxamide M- (tert-butoxy)-N-[2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4- Boc+H {[N-(4-ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-methyl-2- 6.184 515.2 615.16 oxoethyl]-N-methylcarboxamide
N-[(2-chlorophenyl)methyl](4-{tN-(4- ethylphenyl)carbamoyloxy]methyl}-1-[2-
1.784 M+H* 516.1 515.04 (methylamino)propanoyl](4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl]-N'-(4-ethylphenyl)-2,2-
18.544 M+H* 387.1 386.91 dimethylpentane-1 ,5-diamide methyl (3S)-3-amino-4-(4-{N-[(2-
M- chlorophenyl)methyl]carbamoyl}-4-{[N-(4-
1.119 Me+H* 545.2 559.05 ethylphenyl)carbamoyloxy]methyl}piperidyl)-4-oxobutanoate
(1-(3-amino-2-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.12 M+H* 517.2 517.02 chlorophenyl)methyl]carboxamide
(1-(4-amino-2-hydroxybutanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.187 M+H* 532.2 531.04 chlorophenyl)methyl]carboxamide
(1-(2,3-dihydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.123 M+H* 518.2 518 chlorophenyl) methyl]carboxamide
{(3S)-3-[N-(4-ethylphenyl)carbamoyloxy]piperidyl}-N-[(2-
10.197 M+H* 416.1 415.91 chlorophenyl)methyl]carboxamide
3-amino-4-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4-
1.526 M+H* 545.1 545.03 ethylphenyl)carbamoyloxy]methyl}piperidyl)-4-oxobutanoic acid IC50
Arithmetic
Mean Ion m/z MW ChemicalName
N-[(2-chlorophenyl)methyl]( 1 -(cyclopropylcarbonyl)-4-{[N-{4-
0.641 M+H+ 499.3 498.01 ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](1-(cyclohexylcarboπyl)-4-{[N-(4-
2.766 M+H+ 540.2 540.09 ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxyjmethyl}-1-(2-pyridylcarbonyl)(4-
0.757 M+H+ 535.1 535.03 piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1 -(im idazol-2-ylcarbonyl)(4-
0.394 M+H* 524.1 524.01 piperidyl))carboxamide
M- (tert-butoxy)-N-[2-(3-{N-[(2-chlorophenyl)methyl]carbamoyl}-3-
Boc+H {[N-(4-ethylphenyl)carbamoyloxy]methyl}piperidyl)-2- 1.431 + 487.2 587.11 oxoethyl]carboxamide
M- N-[(1S)-2-(3-{N-[(2-chlorophenyl)methyl]carbamoyl}-3-{[N-(4-
Boc+H ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-(hydroxymethyl)- 9.088 + 517.3 617.13 2-oxoethyl](tert-butoxy)carboxamide
( 1 -<2-aminoacetyl)-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(3-piperidyl))-N-[(2-
0.474 M+H+ 487.1 486.99 chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-{2-hydroxyacetyl)(3-
0.399 M+H* 488.1 487.98 piperidyl))carboxamide
(1-((2S)-2-amino-3-hydroxypropanoyl)-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(3-piperidyl))-N-[(2-
1.483 M+H+ 517.3 517.02 chlorophenyl)methyl]carboxamide
2-aminoethyl 4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4-
0.336 M+H* 517.1 517.02 ethylphenyl)carbamoyloxy]methyl}piperidinecarboxylate
N-(2-aminoethyl)(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-
0.159 M+H* 516.2 516.03 {[N-(4-ethylphenyl)carbamoyloxy]methyl}piperidyl)carboxamide methyl 3-{N-[(2-chlorophenyl)methyl]carbamoyiy-3-{[N-(4-
0.474 M+H* 488.1 487.98 ethylphenyl)carbamoyloxy]methyl}piperidinecarboxylate
(1 -(2-aminoacetyl)-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}pyrrolidin-3-yl)-N-[(2-
0.526 M+H* 472.1 472.96 chlorophenyl)methyl]carboxamide
(1-(2-aminoacetyl)-4-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}(4-piperidyl))-N-[(2-
2.44 M+H* 501.2 501.02 chloropheπyl)methyl]carboxamide
[1-(2-aminoacetyl)-4-({N-[2-chloro-4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]-N-[(2-
0.44 M+H* 561.1 561.38 chlorophenyl)methyl]carboxamide
[1-(2-aminoacetyl)-4-({N-[4-methyl-3-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]-N-[(2-
1.966 M+H* 541.1 540.96 chlorophenyl)methyl]carboxamide
(1-(2-aminoacetyl)-4-{[N-(2-chloro-4- methylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.281 M+H* 507.1 507.41 chlorophenyl)methyl]carboxamide
{1-(2-aminoacetyl)-4-[(N-indan-5-ylcarbamoyloxy)methyl](4- 0.126 M+H+ 499.2 499 piperidyl)}-N-[(2-chlorophenyl)methyl]carboxamide
( 1 -(2-aminoacetyl)-4-{[N-(4- chlorophenyl)carbamoyloxy]methyl}(4-piperidyl))-N-t(2-
0.569 M+H* 493.1 493.38 chlorophenyl)methyl]carboxamide IC50
Arithmetic Mean Ion m/z MW ChemicalName methyl 4-{[( 1 -(2-aminoacetyl)-4-{N-[(2- chlorophenyl)methyl]carbamoyl}-4-
1.81 M+H* 517.2 516.97 piperidyl)methoxy]carbonylamino}benzoate
(1-(2-aminoacetyl)-4-{[N-(3-fluoro-4- methylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- 0.742 M+H* 491.1 490.95 chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-1-{[4- 4.948 M+H* 638.1 638.15 (phenylcarbony^phenylJcarbonyl^-piperidyOJcarboxamide
(1-(2-aminoacetyl)-4-{[N-(4- phenylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.277 M+H4 535.1 535.03 chlorophenyl)methyl]carboxamide
{1-(2-aminoacetyl)-4-[(N-(2-naphthyl)carbamoyloxy)methyl](4- 0.083 M+H4 509.2 509 piperidyl)}-N-[(2-chlorophenyl)methyl]carboxamtde
N-((2-chlorophenyl)methyl]-4-[N-(4- 3.429 M+H4 375.1 374.86 ethylphenyl)carbamoyloxy]butanamide
2-amino-N-[(2-chloropheπyl)methyl]-4-[N-(4- 6.808 M+H' 390.1 389.88 ethylphenyl)carbamoyloxy]butanamide
2-(2-aminoacetylamino)-N-[(2-chloropheπyl)methyl]-4-[N-(4- 4.37 M+H' 447.0 446.93 ethylphenyl)carbamoyloxy]butanamide
2-(1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
3.744 M+H* 501.1 501.02 chlorophenyl)methyl]acetamide
N-[(2-chlorophenyl)methyl](4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6-tetrahydropyraπ-
0.197 M+H 431.2 430.92 4-yl))carboxamide methyl 1-(2-aminoacetyl)-4-{tN-(4-
17.962 M+H* 378.1 377.43 ethylphenyl)carbamoyloxy]methyl}piperidine-4-carboxylate
(tert-butoxy)-N-t2-(4-{[N-(4-ethylphenyl)carbamoyloxylmethyl}-4-
{N-[(2-methylphenyl)methyl]carbamoyl}piperidyl)-2-
0.975 M+H* 567.2 566.69 oxoethyljcarboxamide M- Boc+H (tert-butoxy)-N-[2-(4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-4-
+ 11.102 453.2 552.66 [N-benzylcarbamoyl]piperidyl)-2-oxoethyl]carboxamide
(tert-butoxy)-N-[2-(4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-4-
{N-[(2-fluorophenyl)methyl]carbamoyl}piperidyl)-2-
3.769 M+H* 471.2 570.65 oxoethyl]carboxamide
(1 -(2-amiπoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.167 M+H* 467.2 466.57 methylphenyl)methyl]carboxamide
(1 -(2-aminoacetylH-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
8.111 M+H* 453.1 452.55 benzylcarboxamide
( 1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.307 M+H* 471.1 470.54 fluorophenyl)methyl]carboxamide M- (1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{[N-(4-
Boc+H ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
+ 11.307 483.2 582.69 methoxyphenyl)methyl]carboxamide IC50
Arithmetic
Mean Ion m/z MW ChemicalName
M- K 1 -{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(4-
Boc+H chlorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy)-N-(4-
14.457 * 487.1 587.11 ethyl phenyl)carboxam ide
M- [(4H[N-[(2l3-clichlorophenyl)methyl]carbamoyl}-1-{2-[(tert-
Boc+H butoxy)carbonylamino]acetyl}(4-piperidyl))methoxy]-N-(4- 0.313 * 521.1 621.55 ethylphenyl)carboxamide
( 1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
2.164 M+H* 483.2 482.57 methoxyphenyl)methyl]carboxamide
{[1-(2-aminoacetyl)-4-(N-{[2-
(trifluoromethyl)phenyl]methyl}carbamoyl)(4-piperidyl)]methoxy}-
0.086 M+H* 521.2 520.54 N-(4-ethylphenyl)carboxamide
[(i^-aminoacetylJ^^N-^-chlorophenylJmethyllcarbamoy^- 1.28 M+H+ 487.1 486.99 piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
[( 1 -(2-aminoacetyl)-4-{N-[(2,3- dichlorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
0.088 M+H* 521.0 521.44 ethylphenyl)carboxamide
[( 1 -(2-aminoacetyl)-4-{N-[(3-methyl(2- pyridyl))methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
2.98 M+H* 468.2 467.56 ethylphenyl)carboxamide
[( 1 -{2-aminoacetyl)-4-{N-[(2-bromopheny l)methyl]carbamoyl}(4-
0.146 M+H* 531.1 531.44 piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
[( 1 -(2-aminoacetyl)-4-{N-[(3-chlorophenyl)methyl]carbamoyl}(4-
0.729 M+H* 487.1 486.99 piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
[(4-{N-[(2,3-difluorophenyl)methyl]carbamoyl}-1-{2-[(tert- butoxy)carbonylamino]acetyl}(4-piperidyl))methoxy]-N-(4-
1.593 M+H* 589.2 588.64 ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2,3- difluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
0.164 M+H* 489.1 488.53 ethylpheπyl)carbσxamide
I(1-(2-aminoacetyl)-4-{N-[(3-chloro-2- fluoropheπyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
0.099 M+H* 505.2 504.98 ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-fluoro-2- methylphenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
0.081 M+H* 485.2 484.56 ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-chloro-2- methylphenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
0.083 M+H* 501.1 501.02 ethylphenyl)carboxamide M- [( 1 -{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(3-
+ Boc+H fluorophenyl)methyl]carbamoyiχ4-piperidyl))methoxy]-N-(4- 8.238 471.1 570.65 ethylphenyl)carboxamide
M- [( 1 -{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(4- Boc+H
+ fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4- 10.12 471.1 570.65 ethylphenyl)carboxamide
[(1-(2-amiπoacetyl)-4-{N-[(3-fluorophenyl)methyl]carbamoyl}(4-
1.03 M+H* 471.1 470.54 piperidyl))methoxy]-N-(4-ethylρhenyl)carboxamide t(1-(2-aminoacetyl)-4-{N-[(4-fluorophenyl)methyl]carbamoyl}(4-
1.098 M+H* 471.1 470.54 piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
({1-(2-aminoacetyl)-4-lN-(2-pyridylmethyl)carbamoyl](4-
7.22 M+H* 454.1 453.53 piperidyl)}methoxy)-N-(4-ethylphenyl)carboxamide IC50
Arithmetic Mean Ion m/z MW ChemicalName
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-[N-(imidazol-2- ylmethyl)carbamoyl](4-piperidyl))methoxy]-N-(4-
1.769 M+H* 543.2 542.63 ethylphenyl)carboxamide
M- [(H2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(3-fIuoro-2-
Boc+H methylphenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-[4- 3.176 525.2 624.62 (trifluoromethyl)phenyl]carboxamide
M- [( 1424(tert-butoxy)carbonylamino]acetyl}-4-{N-[(3-chlorc>-2- Boc+H fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-[4- 6.558 545.1 645.04 (trifluoromethyl)phenyl]carboxamide
M- [(4-{N-[(2,3-dichlorophenyl)methyl]carbamoyl}-1-{2-[(tert- Boc+H butoxy)carbonylamino]acetyl}(4-piperidyl))methoxy]-N-[4-
3.718 560.1 661.5 (trifluoromethyl)phenyl]carboxamide
({1-(2-aminoacetyl)-4-[N-(imidazol-2-ylmethyl)carbamoyl](4- 18.473 M+H* 443.0 442.51 piperidyl)}methoxy)-N-(4-ethylphenyl)carboxamide
M- (1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{[N-(4-
Boc+H ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-((2-
7.688 478.2 577.67 cyanophenyl)methyl]carboxamide
[(1-(2-aminoacetylH-{N-[(3-fluoro-2- methylphenyl)metnyl]carbamoyl}(4-piperidyl))methoxy]-N-[4- 0.412 M+H+ 525.1 524.51 (trifluoromethyl)phenyl]carboxamide
[( 1 -(2-aminoacetyl)-4-{N-[(3-chloro-2- fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-[4- 0.37 M+H+ 545.0 544.93 (trifluoromethyl)phenyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2,3- dichlorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-[4- 0.284 M+H* 561.0 561.38 (trifluoromethyl)phenyl]carboxamide
[( 1 -{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(3-chloro-2- methylphenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-[4- 5.645 M+H+ 541.0 641.08 (trifluoromethyl)phenyl]carboxamide
(1-(2-aminoacetyl)-4-[[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- 0.904 M+H+ 478.2 477.56 cyanophenyl)methyl]carboxamide
[1 -(2-aminoacetyl)-4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]-N-[(2- 3.238 M+H* 518.1 517.5 cyanophenyl)methyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-chloro-2- methylphenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-[4- 0.179 M+H* 541.1 540.96 (trifluoromethyl)phenyl]carboxamide methyl 2-({[1-(2-aminoacetyl)-4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)-4-
2.288 M+H* 551.2 550.53 piperidyl]carbonylamino}methyl)benzoate
({1-(2-aminoacetyl)-4-[N-(naphthylmethyl)carbamoyl](4- 0.439 M+H* 503.2 502.6 piperidyl)}methoxy)-N-(4-ethylphenyl)carboxamide
[( 1 -{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(2-chloro-4- fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
1.081 M+H* 606.2 605.1 ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2-chloro-4- fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-IM-(4- 0.158 M+H* 505.2 504.98 ethylphenyl)carboxamide IC50 Arithmetic Mean Ion m/z MW ChemicalName
{[1-(2-amiπoacetyl)-4-(N-{[2-fluoro-4-
(trifluoromethyl)phenyl]methyl}carbamoyl)(4-piperidyl)]methoxy}-
11.841 M+H+ 539.1 538.53 N-(4-ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(4-chloro-2- fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
0.262 M+H* 505.1 504.98 ethylphenyl)carboxamide
[(1-(2-amiπoacetyl)-4-(N-[(2,4- dimethylphenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
0.576 M+H+ 481.2 480.6 ethylphenyl)carboxamide
[( 1 -(2-aminoacetyl)-4-{N-[(4-ch loro-2- methylphenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
0.145 M+H+ 501.1 501.02 ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2,4- dichlorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
0.197 M+H+ 521.1 521.44 ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2-methyl(3- pyridyl))methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4-
9.436 M+H+ 468.1 467.56 ethylphenyl)carboxamide
( 1 -(2-aminoacetyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-{[2-
0.949 M+H* 483.2 482.57 (hydroxymethyl)phenyl]methyl}carboxamide
[( 1 -(2-aminoacetyl)-4-{N-[(2-ethylphenyl) methyl]carbamoyl}(4-
0.951 M+H+ 481.2 480.6 piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
(4-(2-aminoacetyl)-3-{N-[(2- chlorophenyt)methyl]carbamoyl}piperazinyl)-N-(4-
15.191 M+H+ 458.3 457.95 ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl][2-({[(4- ethylphenyl)amino]carboπylamino}methyl)pyrrolidiπyl]carboxami
2.622 M+H* 415.1 414.93 de
(4-(2-aminoacetyl)-2-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperazinyl)-N-[(2-
2.38 M+H+ 488.1 487.98 chlorophenyOmethyljcarboxamide
((2S)-2-{[N-(4-ethylphenyl)carbamoyloxy]methyl}pyrrolidinyl)-N-
0.185 M+H* 416.0 415.91 [(2-chlorophenyl)methyl]carboxamide
N-[( 1 -(2-amiπoacetyl)-4-{N-[(2- chlorophenyl)methyl]carbamoyl}(4-piperidyl))methyl]-2-(4-
14.906 M+H+ 485.1 485.02 ethylphenyl)acetamide
(1 -(2-aminoacetyl)-4-{[N-(4- cyanophenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
7.784 M+H+ 484.1 483.95 chlorophenyl)methyl]carboxamide (1 -(2-aminoacetyl)-4-{[N-(4- methylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
0.191 M+H* 473.1 472.96 chlorophenyl)methyl]carboxamide ( 1 -(2-aminoacetyl)-4-{[N-(4- fluorophenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2-
14.615 M+H* 477.1 476.93 chloropheny^methyljcarboxamide {1-(2-aminoacetyl)-4-[(N-phenylcarbamoyloxy)methyl](4-
9.212 M+H* 459.1 458.94 piperidyl)}-N-[(2-chlorophenyl)methyl]carboxamide (4-{[N-(4-acetylphenyl)carbamoyloxy]methyl}-1-(2- aminoacetyl)(4-piperidyl))-N-[(2-
1.186 M+H* 501.1 500.97 chlorophenyl)methyl]carboxamide IC50
Arithmetic
Mean Ion m/z MW ChemicalName
((5S,3R)-3-amino-5-{[N-(4- ethylphenyl)carbamoyloxy]methyl}pyrrolidinyl)-N-[(2- 1.443 M+H* 431.1 430.93 chlorophenyl)methyl]carboxamide
N-((5S,3R)-1-{N-[(2-chlorophenyl)methyl]carbannoyl}-5-{[N-{4- ethylphenyl)carbamoyloxy]methyl}pyrrolidin-3-yl)-2- 0.234 M+H+ 488.1 487.98 aminoacetamide
N-((5S,3R)-HN-[(2-chlorophenyl)methyl]carbamoyl}-5-{[N-(4- 1.857 M+H* 473.1 472.96 ethylphenylJcarbamoyloxyJmethy^pyrrolidin-S-yOacetamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- 0.084 M+H* 390.1 389.88 ethylphenyOcarbamoyloxylethyQ-N-methylcarboxamide
{[(2,3-dichlorophenyl)methyl]amino}-N-{2-[N-(4- 0.059 M+H* 424.1 424.32 ethylphenyOcaitjamoyloxyJethyl^N-methylcarboxamide
[2-({[(2-chlorophenyl)methyl]amino}-N-(2- hydroxyethyl)carbonylamino)ethoxy]-N-(4- 0.21 M+H* 420.2 419.9 ethylphenyl)carboxamide
N-[2-({[(2-chlorophenyl)methyl]amino}-N- 6.754 M+H* 389.1 388.89 methylcarbonylamino)ethyl][(4-ethylphenyl)amiπo]carboxamide
[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}moφholin-2- 11.668 M+H* 432.2 431.91 yl)methoxy]-N-(4-ethylphenyl)carboxamide
N-(3-aminopropyl){[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- 2.543 M+H* 433.2 432.94 ethylphenyl)carbamoyloxy]ethyl}carboxamide
2-[(tert-butoxy)carbonylamino]-N-[3-({[(2- chlorophenyl)methyl]amiπo}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carbonylamino)propyl]acetamid 4.087 M+H* 590.3 590.11 e
2-amino-N-[3-({[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyljcarbamoyloxylethy^carbonylaminojpropyllacetamid 0.188 M+H* 490.2 489.99 e
N-(2-aminoethyl){[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- 2.83 M+H* 419.2 418.92 ethylphenyl)carbamoyloxy]ethyl}carboxamide
2-amino-N-[2-({[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- 0.896 M+H* 476.2 475.97 ethylphenyOcarbamoyloxylethylicarbonylaminoJethyllacetamide
[2-(N-(4-aminobutyl){[(2- chlorophenyl)methyl]amino}carbonylamino)ethoxy]-N-(4- 0.346 M+H* 447.2 446.97 ethylphenyl)carboxamide
2-amino-N-[4-({[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4-
0.223 M+H* 504.1 504.02 ethylphenyljcarbamoyloxylethyljcarbonylaminojbutyllacetamide 17.394 M+H* 251.1 250.29 N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}acetamide
{[(2-chlorophenyl)methyl]amino}-N-methyl-N-[2-(N-(6- 1.413 M+H* 413.2 412.87 quinolyl)carbamoyloxy)ethyl]carboxamide
N-(5-aminopentyl){[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- 0.487 M+H* 461.1 461 ethylphenyljcarbamoyloxylethyOcarboxamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- 0.355 M+H* 448.2 447.95 ethylphenyl)carbamoyloxy]ethyl}-N-(4-hydroxybutyl)carboxamide
(tert-butoxy)-N-[2-(4-{N-[(2-bromophenyl)methyl]carbannoyl}-4- {[N-(4-ethylphenyl)carbamoyloxy]methyl}piperidyl)-2-oxoethyl]-
2.865 M+H* 646.3 645.58 N-methylcarboxamide
[(4-{N-[(2-bromophenyl)methyl]carbamoyl}-1-[2- (methylamino)acetyl](4-piperidyl))methoxy]-N-(4-
0.168 M+H* 545.2 545.47 ethylphenyl)carboxamide IC50 Arithmetic Mean Ion m/z MW ChemicalName
N-[(2-chlorophenyl)methyl]({[N-(4-
3.052 M+H+ 387.2 386.87 ethylphenyl)carbamoyloxy]methyl}cyclopropyl)carboxamide 4-(acetylamino)-N-[(2-chlorophenyl)methyl]-2-{[N-(4-
0.742 M+H+ 460.1 459.97 ethylphenyl)carbamoyloxy]methyl}-2-methylbutanamide
4-{2-[(tert-butoxy)carbonylamino]acetylamino}-N-[(2- chlorophenyl)methyl]-2-{[N-(4-
1.297 M+H+ 575.2 575.1 ethylphenyljcarbamoyloxylmethyl^-methylbutanamide
4-amino-N-[(2-chlorophenyl)methyl]-2-{[N-(4-
1.738 M+H+ 418.1 417.93 ethylphenyl)carbamoyloxy]methyl}-2-methylbutanamide
4-(2-aminoacetylamino)-N-[(2-chlorophenyl)methyl]-2-{[N-(4-
0.283 M+H* 475.1 474.98 ethylphenyl)carbamoyloxy]methyl}-2-methylbutanamide
N-t(2-chlorophenyl)methyl]-4-[N-(4-ethylphenyl)carbamoy)oxyJ-
0.235 M+H* 403.1 402.91 2,2-dimethylbutanamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4-
0.621 M+H* 418.2 417.93 ethylphenyOcarbamoyloxyBert-butyl^N-methylcarboxamide
(2-chlorophenyl)methyl (2S)-2-({[(4-
3.526 M+H* 416.3 415.91 ethylphenyl)amino]carbonylamino}methyl)pyrrolidinecarboxylate
Example IX
Preparation of Λ/-(2-chlorobenzyl)-3-(5-(4-isopropylphenyl)-2H-tetrazol-2-yl)-2,2- dimethylpropanamide
Figure imgf000142_0001
Λ/-(2-chlorobenzyl)-3-(5-(4-isopropylphenyl)-2H-tetrazol-2-yl)-2,2- dimethylpropanamide
Figure imgf000142_0002
[0274] To a solution of 4-isopropylbenzonitrile (4.2 g, 28.9 mmol) in DMF (50 mL) were added NaCN (2.6 g, 40.5 mmol, 1.4 equiv.) and NH4CI (2.2 g, 40.5 mmol, 1.4 equiv.). The reaction mixture was heated with stirring overnight. TLC indicated the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 5-(4-isopropylphenyl)-2H-tetrazole as a crude solid, which was used for the next step without further purification. LRMS (M+H+) m/z 189.1.
Figure imgf000143_0001
[0275] To a solution of crude 5-(4-isopropylphenyl)-2H-tetrazole (1.0 g, ~5.3 mmol), methyl 3-hydroxy-2,2-dimethylpropanoate (830 mg, 8.0 mmol), and PPh3 (2.1 g, 8.0 mmol) in THF (5 ml_) was added DEAD (1.35 mL, 8.0 mmol) dropwise. The reaction mixture was stirred for 2 h. LC/MS indicated the reaction was complete. The reaction mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and H2O to give methyl 3-(5-(4-isopropylphenyl)-2H-tetrazol-2-yl)-2,2-dimethylpropanoate (480 mg, 32% for two steps). LRMS (M+H+) m/z 303.2.
Figure imgf000143_0002
AIMe3, Toluene
Figure imgf000143_0003
Figure imgf000143_0004
[0276] To a mixture of methyl 3-(5-(4-isopropylphenyl)-2H-tetrazol-2-yl)-2,2- dimethylpropanoate (210 mg, 0.69 mmol) and 2-chlorobenzylamine (137 mg, 0.97 mmol) in toluene (1 mL) was added AIMe3 (2 M solution in toluene, 0.5 mL, 1.0 mmol, ) dropwise. The reaction mixture was stirred for 30 min followed by stirring at 1000C for 1 h. The reaction was cooled, quenched with saturated NaHCO3, and diluted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude oil. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give Λ/-(2- chlorobenzyl)-3-(5-(4-isopropylphenyl)-2H-tetrazol-2-yl)-2,2-dimethylpropanamide (217 mg, 76%). LRMS (M+H+) m/z 412.2. Example X
Preparation of /V-(2-chlorobenzyl)-1 -((5-(4-ethylphenyl)-2H-tetrazol-2- yl)methyl)cyclopropanecarboxamide
Figure imgf000144_0001
(2-chlorobenzyl)-1-((5-(4-ethylphenyl)-2W-tetraz 2-yl)methyl)cyc1opropanecarboxamide
Figure imgf000144_0002
[0277] To a solution of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (500 mg, 3.5 mmol) in DMF (5 ml_) were added HATU (1.98 g, 5.2 mmol, 1.5 equiv.) and 2- chlorobenzylamine (622 μl_, 5.2 mmol, 1.5 equiv.). The reaction mixture was stirred for 2 h. The reaction mixture was purified twice on RP-HPLC using a mixture of acetonitrile and H2O to give methyl 1-(2-chlorobenzylcarbamoyl)cyclopropanecarboxylate (330 mg, 34%). LRMS (M+H+) m/z 268.0.
Figure imgf000144_0003
[0278] To a solution of methyl 1-(2-chlorobenzylcarbamoyl)cyclopropanecarboxylate (330 mg, 1.2 mmol) in THF (5mL) and CH3OH (5 mL) was added sodium borohydride (93 mg, 2.4 mmol, 2 equiv.). The reaction mixture was stirred for 3 h and quenched with diluted AcOH. The reaction mixture was concentrated and dissolved in EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4, and concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give Λ/-(2-chlorobenzyl)-1- (hydroxymethyl)cyclopropanecarboxamide (164 mg, 55%). LRMS (M+H*) m/z 240 .0.
Figure imgf000145_0001
[0279] To a solution of Λ/-(2-chlorobenzyl)-1 -
(hydroxymethyOcyclopropanecarboxamide (164 mg, 0.69 mmol, 2 equiv.) in THF (2 mL) were added triphenyl phosphine (180 mg, 0.69 mmol, 1 equiv.), DIAD (140 μl_, 0.69 mmol, 1 equiv.) and 5-(4-ethylphenyl)-2H-tetrazole (120 mg, 0.69 mmol). The reaction mixture was stirred for 3 h and concentrated. The resulting residue was purified on RP- HPLC using a mixture of acetonitrile and H2O to give Λ/-(2-chlorobenzyl)-1-((5-(4- ethylphenyO^H-tetrazol^-yOmethyOcyclopropanecarboxamide (95 mg, 74%). LRMS (M+H+) m/z 396.1.
Example Xl
Additional Synthesized Compounds
[0280] Using procedures similar to those described herein, the compounds in the following table were synthesized and tested.
IC50 Object_M
Median Ion m/z W ChemicalName
N-[(2-chlorophenyl)methyl]-3-{5-[4-
(methylethyl)phenyl](1.2,3.4-tetraazol-2-
17.72 M+H* 384.1 383.87 yl)}propanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1,2,3,4-
41.00 M+H+ 378.2 377.48 tetraazol-2-yl)}-N-benzylpropanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1.2,3,4-
48.08 M+H+ 379.3 378.47 tetraazol-2-yl)}-N-(2-pyridylmethyl)propanamide
N-[(2-fluorophenyl)methyl]-2,2-dimethyl-3-{5-[4-
(methylethyl)phenyl](1 ,2,3,4-tetraazol-2-
10.37 M+H+ 396.2 395.47 yl)}propanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1,2,3,4- tetraazol-2-yl)}-N-[(2-
6.79 M+H* 392.3 391.51 methylphenyl)methyl]propanamide
N-[(3-fluorophenyl)methyl]-2,2-dimethyl-3-{5-[4-
(methylethyl)phenyl](1 ,2,3,4-tetraazol-2-
44.20 M+H* 396.2 395.47 yl)}prσpanamide
N-[2-(2-chlorophenyl)ethyl]-2,2-dimethyl-3-{5-[4-
(methylethyl)phenyl](1 ,2,3,4-tetraazol-2-
52.73 M+H+ 426.2 425.95 yl)}propanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1, 2,3,4- 33.81 M+H* 384.2 383.51 tetraazol-2-yl)}-N-(3-thienylmethyl)propanamide IC50 ObjectJM
Median Ion m/z W ChemicalNamβ
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1,2,3,4-
75.92 M+H+ 369.3 368.43 tetraazol-2-yl)}-N-(1,3-oxazol-2-ylmethyl)propanamide
N-[(2-chlorophenyl)methyl]-3-[5-(4- ethylphenyl)(1,2,3,4-tetraazol-2-yl)]-2,2- 1.99 M+H* 398.2 397.9 dimethylpropanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (trifluoromethoxyjphenylKI ^.S^-tetraazol-Σ- 7.44 M+H* 454.1 453.85 yl)}propanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-[5-(4-
15.58 M+H+ 462.2 461.94 phenoxyphenyl)(1,2,3,4-tetraazol-2-yl)]propanamide
N-[(2-chloro-4-fluorophenyl)methyl]-2,2-dimethyl-3-{5- [4-(methylethyl)phenyl]( 1 ,2,3,4-tetraazol-2- 5.97 M+H* 430.1 429.92 yl)}propanamide
N-[(2,4-dichlorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1 ,2,3t4-tetraazol-2- 22.81 M+H+ 446.2 446.37 yl)}propanamide
N-[(6-chloro-2-fluorophenyl)methyl]-2,2-dimethyl-3-{5- [4-(methylethyl)phenyl](1,2,3,4-tetraazol-2- 59.08 M+H* 430.2 429.92 yl)}propanamide
4-[(2,2-dimethyl-3-{5-[4-(rnethylethyl)phenyl](1l2>3l4-
89.13 M+H* 422.2 421.49 tetraazol-2-yl)}propanoylamino)methyl]benzoic acid
3-[5-(4-bromophenyl)(1 ,2,3,4-tetraazol-2-yl)]-N-[(2- 3.92 M+H* 448.1 448.74 chlorophenyl)methyl]-2,2-dimethylpropanamide
N-[(2,3-dichlorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1 ,2,3,4-tetraazol-2- 3.42 M+H* 446.2 446.37 yl)}propaπamide
N-[(2-chlorophenyl)methyl]-3-[5-(4- cyanophenyl)(1,2l3,4-tetraazol-2-yl)]-2,2- 58.92 M+H* 395.1 394.86 dimethylpropanamide
3-{5-[4-(dimethylamino)phenyl](1 ,2,3,4-tetraazol-2-yl)}-
3.63 M+H* 413.2 412.92 N-[(2-chlorophenyl)methylJ-2,2-dimethylpropanamide methyl 4-[2-(2-{N-[(2-chlorophenyl)rnethyl]carbamoyl}-
5.73 M+H* 428.1 427.88 2-methylpropyl)-1,2.3,4-tetraazol-5-yl]benzoate
N-[(2-chlorophenyl)methyl]-3-{5-[4- (hydroxymethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}-2,2- 64.49 M+H* 400.1 399.87 dimethylpropanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1.2,3,4-tetraazol-2- 2.63 M+H* 412.1 411.93 yl)}propanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{2-t4- (methylethyl)phenyl](1 ,2,3,4-tetraazol-5- 35.77 M+H* 412.1 411.93 yl)}propanamide
N-[(2-chlorophenyl)methyl]-2-methyl-3-{2-[4- (methylethyl)phenyl](1 ,2,3,4-tetraazol-5- 50.73 M+H* 398.1 397.9 yl)}propanamide
N-[(2-chlorophenyl)methyl]-3-{3-[4- (methylethyl)phenyl](1 ,2,4-oxadiazol-5- 53.34 M+H* 384.1 383.87 yl)}propanamide methyl 2-(2,2-dimethyl-3-{5-[4- (methylethyl)phenyl](1,2,3,4-tetraazol-2-
15.25 M+H* 470.1 469.96 yl)}propanoylamino)-2-(2-chlorophenyl)acetate
5.36 M+H* 442.1 441.95 N-[1-(2-chloropheπyl)-2-hydroxyethyl]-2,2-dimethyl-3- IC50 Object M Median Ion m/z W ChemicalName
{5-[4-(methylethyl)phenyl](1 ,2,3,4-tetraazot-2- yl)}propanamide
N-[(2-chlorophenyl)methyl]({[5-(4-ethylphenyl)(1,2t3,4-
0.48 M+H+ 396.1 395.89 tetraazol-2-yl)]methyl}cyclopropyl)carboxamide
N-[(2-chlorophenyl)methyl]({[5-(4-ethylpheπyl)(1,2.3,4-
1.57 M+H* 410.1 409.91 tetraazol-2-yl)]methyl}cyclobutyl)carboxamide
N-[(2-chlorophenyl)methyl](4-{[5-(4- ethylphenyl)(1 ,2,3,4-tetraazol-2-yl)]methyl}(2H-3,4,5,6-
10.90 M+H+ 440.1 439.94 tetrahydropyran-4-yl))carboxamide
N-[(2-chlorophenyl)methyl](1-{[5-(4- ethylphenyl)(1 ,2,3,4-tetraazol-2-yl)]methyl}cyclopent-3-
1.10 M+H+ 422.1 421.92 enyl)carboxamide
N-[(2-chlorophenyl)methyl](1-{[5-(4- ethylphenyl)(1 ,2,3,4-tetraazol-2-y!)]methyl}-3,4-
2.64 M+H+ 456.1 455.94 dihydroxycyclopentyl)carboxamide
3-[5-(4-chlorophenyl)(1,2,3,4-tetraazol-2-yl)]-N-[(2-
14.32 M+H* 404.0 404.29 chlorophenyl)methylj-2,2-dimethylpropanamide
N-[(2-chlorophenyl)methyl]-3-[5-(4- methoxyphenyl)(1,2,3,4-tetraazol-2-yl)]-2,2-
5.06 M+H+ 400.1 399.87 dimethylpropanamide
3-(5-[4-(tert-butyl)phenyl](1,2,3,4-tetraazol-2-yl)}-N-[(2-
36.18 M+H* 426.2 425.95 chlorophenyl)methyl]-2,2Hdimethylpropanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-[5-(4-
7.34 M+H* 384.1 383.87 methylphenyl)(1,2t3,4-tetraazol-2-yl)]propanamide
3-[5-(3-chlorophenyl)(1,2,3,4-tetraazol-2-yl)]-N-[(2-
34.04 M+H* 404.1 404.29 chlorophenyl)methyl]-2,2-dimethylpropanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{5-[4-
(trifluoromethyl)phenyl](1,2,3,4-tetraazol-2-
14.98 M+H* 438.1 437.85 yl)}propanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-[5-(3-
43.53 M+H* 384.2 383.87 methylphenyl)(1,2,3,4-tetraazol-2-yl)]propanamide
N-[(2-chlorophenyl)methyl]-3-[5-(4- imidazolylphenyl)(1,2,3,4-tetraazol-2-yl)]-2,2-
8.70 M+H* 436.1 435.91 dimethylpropanamide
(2S)-N-[(2-chlorophenyl)methyl]-2-methyl-3-[5-(4-
26.96 M+H* 370.1 369.85 methylphenyl)(1 ,2,3,4-tetraazol-2-yl)]propanamide
{[(2-chlorophenyl)methy!]amino}-N-{2-t5-(4- ethylphenyl)(1 ,2.3.4-tetraazol-2-yl)]ethyl}-N-
14.92 M+H* 399.0 398.89 methylcarboxamide
Example XII
[0281] Screening assays were performed using a pyruvate kinase and lactate dehydrogenase-coupled ATPase assay containing the following reagents: Potassium PIPES (50 mM), MgCI2 (3 mM), KCI (100 mM), ATP (0.15 mM), DTT (1 mM), BSA (0.1 mg/ml), NADH (0.5 mM), PEP (1.5 mM), pyruvate kinase (4 U/ml), lactate dehydrogenase (8 U/ml), and antifoam (50 ppm) (concentrations expressed are final assay concentrations). The pH was adjusted to 6.80 at 22 0C by addition of potassium hydroxide. Lead optimization assays were performed with a more sensitive pyruvate kinase / horseradish peroxidase / pyruvate oxidase-coupled ATPase assay containing the following reagents: Potassium PIPES (12 mM), MgCI2 (2 mM), KCI (100 mM), ATP (0.15 mM), BSA (0.05 mg/ml), potassium phosphate (2 mM), amplex red (0.1 mM), PEP (0.1 mM), pyruvate kinase (4 U/ml), horseradish peroxidase (0.5 U/ml), pyruvate oxidase (0.5 U/ml), and antifoam (50 ppm) (concentrations expressed are final assay concentrations). The pH was adjusted to 7.00 at 22°C by addition of potassium hydroxide.
[0282] The protein components specific to this assay are chicken gizzard smooth muscle myosin subfragment-1 that has been chemically crosslinked to either cardiac or skeletal actin using an excess of 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride and N-hydroxysuccinimide. The exact concentration of the crosslinked smooth muscle myosin in the assay is determined empirically, by titration to achieve a desired rate of ATP hydrolysis. The concentration varies between protein preparations due to variations in the fraction of active molecules in each preparation. [0283] Compound dose response assays are performed by first preparing a dilution series of test compound, each with an assay mixture containing potassium PIPES, MgCI2, KCI, ATP, BSA, potassium phosphate, amplex red, PEP, crosslinked smooth muscle actomyosin (subfragment-1), antifoam, and water. The assay is started by adding an equal volume of solution containing potassium Pipes, MgCI2, KCI, BSA1 potassium phosphate, pyruvate kinase, horseradish peroxidase, pyruvate oxidase, antifoam, and water. ATP hydrolysis is monitored by measuring the fluorescence of amplex red (excitation at 480 nm, emission at 615 nm). The resulting dose response curve is fit by the 4 parameter equation y = Bottom + ((Top-Bottom)/(1+((IC5o/X)ΛHill))). The IC50 is defined as the concentration at which ATPase activity is midway between the top and bottom of the dose response curve.
[0284] Certain chemical entities described herein have an IC50 less than 10 μM; for example, less than 1 μM.
[0285] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

What is claimed is:
1. At least one chemical entity selected from compounds of Formula X
Figure imgf000150_0001
Formula X
and pharmaceutically acceptable salts thereof, wherein
U is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and *- W1COW2, where the "*" indicates the point of attachement to Z1;
W1 and W2 are independently selected from CR11R12, NR13, and O; provided at least one of W1 and W2 is NR13;
W3 is selected from CR1R2, NR14 and O;
Z1 is aryl;
Z2 is aryl;
R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
R1, R2, R11, and R12 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and R2 may together with any intervening atoms to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
R13 and R14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; for each occurrence, R3, R4, R5, and R6 are independently selected from hydrogen, hydroxy I, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and one occurrence of R5 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; or R14 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and R1 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
R7 and R10 are independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl; m is selected from O1 1, 2 and 3; n is selected from 0, 1 , 2, 3, and 4; p is selected from 0, 1 , 2, and 3; and q is selected from 0, 1 , 2, 3, and 4.
2. At least one chemical entity of claim 1 wherein the compound of Formula X is selected from compounds of Formula I
Figure imgf000152_0001
Formula I wherein
W1 and W2 are independently selected from CR11R12, NR13, and O; provided at least one of W1 and W2 is NR13;
W is selected from CR1 1RD2', NR ,114* and O;
Z1 is aryl;
Z2 is aryl;
R8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
R1, R2, R11, and R12 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and R2 may together with any intervening atoms to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
R13 and R14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; for each occurrence, R3, R4, R5, and R6 are independently selected from hydrogen, hydroxy I, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and one occurrence of R5 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; or R14 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and R1 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; or if W1 is NR13, then R13 and one occurrence of R5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; R7 and R10 are independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2, 3, and 4; p is selected from 0, 1 , 2, and 3; and q is selected from 0, 1, 2, 3, and 4.
3. At least one chemical entity of claim 2 wherein W1 is NR13.
4. At least one chemical entity of claim 3 wherein R13 is selected from hydrogen and optionally substituted lower alkyl.
5. At least one chemical entity of claim 4 wherein R13 is selected from hydrogen and lower alkyl.
6. At least one chemical entity of claim 5 wherein R13 is hydrogen.
7. At least one chemical entity of claim 3 wherein W1 is CR11R12.
8. At least one chemical entity of claim 8 wherein R11 and R12 are each independently selected from hydrogen and optionally substituted lower alkyl.
9. At least one chemical entity of claim 9 wherein R11 and R12 are each independently selected from hydrogen and lower alkyl.
10. At least one chemical entity of claim 9 wherein R11 and R12 are both hydrogen.
11. At least one chemical entity of claim 2 wherein W1 is O.
12. At least one chemical entity of any one of claims 2 to 6 wherein W2 is CR11R12.
13. At least one chemical entity of claim 12 wherein R11 and R12 are each independently selected from hydrogen and optionally substituted lower alkyl.
14. At least one chemical entity of claim 13 wherein R11 and R12 are each independently selected from hydrogen and lower alkyl.
15. At least one chemical entity of claim 14 wherein R11 and R12 are both hydrogen.
16. At least one chemical entity of any one of claims 2 to 11 wherein W2 is NR13.
17. At least one chemical entity of claim 16 wherein R13 is selected from hydrogen and optionally substituted lower alkyl.
18. At least one chemical entity of claim 17 wherein R13 is selected from hydrogen and lower alkyl.
19. At least one chemical entity of claim 18 wherein R13 is hydrogen.
20. At least one chemical entity of any one of claims 2 to 6 wherein W2 is O.
21. At least one chemical entity of any one of claims 2 to 20 wherein W3 is CR1R2.
22. At least one chemical entity of claim 21 wherein R1 and R2 are independently selected from hydrogen and optionally substituted alkyl.
23. At least one chemical entity of claim 22 wherein R1 and R2 are independently selected from hydrogen and optionally substituted lower alkyl.
24. At least one chemical entity of claim 23 wherein R1 and R2 are independently selected from hydrogen and lower alkyl.
25. At least one chemical entity of claim 24 wherein R1 and R2 are independently selected from hydrogen and methyl.
26. At least one chemical entity of any one of claims 2 to 21 wherein R1 and R2, together with the carbon to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.
27. At least one chemical entity of claim 26 wherein R1 and R2, together with the carbon to which they are attached, form a group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, and tetrahydropyranyl, any of which is optionally substituted.
28. At least one chemical entity of claim 27 wherein R1 and R2, together with the carbon to which they are attached, form a group selected from piperidine and tetrahydropyran, either of which is optionally substituted with 2-aminoacetyl or 2- (tert-butoxycarbonylamino)acetyl.
29. At least one chemical entity of claim 28 wherein R1 and R2, together with the carbon to which they are attached, form a group selected from tetrahydropyran, 1-(2-(tert-butoxycarbonylamino)acetyl)piperidin-4-yl, and 1-(2- aminoacetyl)piperidin-4-yl.
30. At least one chemical entity of any one of claims 2 to 20 wherein W3 is NR14.
31. At least one chemical entity of claim 30 wherein R14 is selected from hydrogen and optionally substituted lower alkyl.
32. At least one chemical entity of claim 31 wherein R14 is selected from hydrogen, lower alkyl, and lower alkyl substituted with one or two groups selected from hydroxy, optionally substituted amino, and optionally substituted alkoxy.
33. At least one chemical entity of claim 32 wherein R14 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, wherein methyl, ethyl, propyl, and isopropyl are optionally substituted with one or two groups selected from hydroxy, optionally substituted amino, and optionally substituted alkoxy.
34. At least one chemical entity of claim 33 wherein R14 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, wherein methyl, ethyl, propyl, and isopropyl are optionally substituted with one or two hydroxy groups.
35. At least one chemical entity of claim 34 wherein R14 is selected from methyl, ethyl, hydroxymethyl, 2-hydroxyethyl, and isopropyl.
36. At least one chemical entity of claim 35 wherein R14 is selected from methyl and ethyl.
37. At least one chemical entity of any one of claims 2 to 36 wherein R8 is selected from hydrogen and optionally substituted lower alkyl.
38. At least one chemical entity of claim 37 wherein R8 is selected from hydrogen and lower alkyl.
39. At least one chemical entity of claim 38 wherein R8 is selected from hydrogen and methyl.
40. At least one chemical entity of claim 39 wherein in R8 is hydrogen.
41. At least one chemical entity of any one of claims 2 to 40 wherein q is 2.
42. At least one chemical entity of any one of claims 2 to 40 wherein q is 1.
43. At least one chemical entity of claim 42 wherein R5 is selected from hydrogen and optionally substituted lower alkyl.
44. At least one chemical entity of claim 43 wherein R5 is selected from hydrogen, lower alkyl, and lower alkyl substituted with one, two, or three groups selected from optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, hydroxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, and azido.
45. At least one chemical entity of claim 44 wherein R5 is selected from hydrogen, lower alkyl, and lower alkyl substituted with one, two, or three groups selected from 4-(lower alkyl)piperazin-1-yl, oxopiperazin-1-yl, morpholino, benzyloxy, benzyloxycarbonyl, methoxycarbonyl, hydroxy, amino, dimethylamino, methoxy(methyl)carbamoyl, acetamido, acetyl, and azido.
46. At least one chemical entity of claim 45 wherein R5 is selected from hydrogen, methyl, ethyl, isopropyl, isobutyl, n-propyl, n-butyl, n-pentyl, isopentyl, and 4- methylpentyl, wherein each of methyl, ethyl, isopropyl, isobutyl, n-propyl, n-butyl, n-pentyl, isopentyl, and 4-methylpentyl is optionally substituted with one, two, or three groups selected from 4-methylpiperazin-1-yl, 3-oxopiperazin-1-yl, morpholino, benzyloxy, benzyloxycarbonyl, methoxycarbonyl, hydroxy, amino, dimethylamino, methoxy(methyl)carbamoyl, acetamido, acetyl, and azido.
47. At least one chemical entity of claim 46 wherein R5 is selected from hydrogen, ethyl, 2-(benzyloxy)-2-oxoethyl, benzyloxymethyl, isobutyl, isopropyl, methyl, 2- hydroxyethyl, 2-methoxy-2-oxoethyl, 3-(benzyloxy)-3-oxopropyl, 3-hydroxypropyl, 3-methoxy-3-oxopropyl, 4-aminobutyl, 4-azidobutyl, 4-hydroxybutyl, 4-methoxy-4- oxobutyl, hydroxymethyl, 2-hydroxy-2-methylpropyl, 4-hydroxy-4-methylpentyl, 3- aminopropyl, (4-methylpiperazin-1 -yl)methyl, 2-(3-oxopiperazin-1-yl)ethyl, moφholinoethyl, moφholinomethyl, (3-oxopiperazin-1-yl)methyl, (4- methylpiperazin-1-yl)ethyl, (dimethylamino)methyl, (R)-2-hydroxypropyl, (S)-2- hydroxypropyl, 2-(methoxy(methyl)amino)-2-oxoethyl, 3-(methoxy(methyl)amino)- 3-oxopropyl, 3-hydroxy-3-methylbutyl, 3-hydroxybutyi, 4-acetamidobutyl, 4- hydroxypentyl, and 4-oxopentyl.
48. At least one chemical entity of claim 42 wherein Rβ is selected from hydrogen and optionally substituted lower alkyl.
49. At least one chemical entity of claim 48 wherein R6 is selected from hydrogen and lower alkyl.
50. At least one chemical entity of claim 49 wherein R6 is hydrogen.
51. At least one chemical entity of claim 2 wherein W2 is NH, W1 is O, and W3 is CR1R2.
52. At least one chemical entity of claim 2 wherein W2 is NH, W1 is CH2, and W3 is NR14.
53. At least one chemical entity of claim 2 wherein W2 is NH, W1 is O, and W3 is NR14.
54. At least one chemical entity of any one of claims 2 to 53 wherein m is 0.
55. At least one chemical entity of any one of claims 2 to 53 wherein m is selected from 1 and 2, and each R7 is selected from halo and optionally substituted alkyl.
56. At least one chemical entity of claim 55 wherein each R7 is selected from halo and optionally substituted lower alkyl.
57. At least one chemical entity of claim 56 wherein each R7 is selected from halo and lower alkyl.
58. At least one chemical entity of claim 57 wherein each R7 is selected from chloro, fluoro, and methyl.
59. At least one chemical entity of claim 55 wherein -(R7)m. together with the Z2 ring to which it is attached, forms a group selected from 2-chlorophenyl, 2- methylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-3-fluorophenyl, 2,3- dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, and 3- chloro-2-fluorophenyl.
60. At least one chemical entity of any one of claims 2 to 59 wherein n is selected from 1 and 2.
61. At least one chemical entity of claim 60 wherein n is 1.
62. At least one chemical entity of any one of claims 2 to 61 wherein each R3 and R4 is independently selected from hydrogen and optionally substituted lower alkyl.
63. At least one chemical entity of claim 62 wherein each R3 and R4 is independently selected from hydrogen, methyl, ethyl, isopropyl, and hydroxy methyl.
64. At least one chemical entity of claim 63 wherein each R3 and R4 is hydrogen.
65. At least one chemical entity of any one of claims 2 to 64 wherein p is selected from 0, 1, and 2, and R10 is selected from cyano, halo, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted aryl.
66. At least one chemical entity of claim 65 wherein p is 0.
67. At least one chemical entity of claim 65 wherein p is selected from 1 and 2, and each R10 is independently selected from cyano, halo, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted aryl.
68. At least one chemical entity of claim 67 wherein each R10 is independently selected from cyano, halo, optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted phenyl.
69. At least one chemical entity of claim 68 wherein each R10 is independently selected from cyano, chloro, fluoro, bromo, trifluoromethyl, methyl, ethyl, vinyl, and phenyl.
70. At least one chemical entity of claim 65 wherein (R10)p , together with Z1 to which is attached, forms a group selected from 2-naphthyl, 5-indanyl, 4-ethylphenyl, 4- methylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4- phenylphenyl, 4-methyl-2-chlorophenyl, 4-methyl-3-fluorophenyl, 4-ethyl-3- fluorophenyl, and 4-ethyl-2-chlorophenyl.
71. At least one chemical entity of claim 2 wherein the compound of Formula I is selected from
{[(2-chlorophenyl)methyl]amino}-N-methyl-N-[2-(N-(2- naphthyl)carbamoyloxy)ethyl]carboxamide
{[(2,3-dichlorophenyl)methyl]amino}-N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-
N-methylcarboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-fluoro-2-methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-chloro-2-methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide {1-(2-aminoacetyl)-4-[(N-(2-naphthyl)carbamoyloxy)methyl](4-piperidyl)}-N-[(2- chlorophenyl)methyl]carboxamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-N- methylcarboxamide
{[1-(2-aminoacetyl)-4-(N-{[2-(trifluoromethyl)phenyl]methyl}carbamoyl)(4- piperidyl)]methoxy}-N-(4-ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2,3-dichlorophenyl)methyl]carbamoyl}(4- piperidy l))methoxy]-N-(4-ethylp henyl)ca rboxam ide
[(1-(2-aminoacetyl)-4-{N-[(3-chloro-2-fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
(1-(3-amino-2-hydroxypropanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
(1-(2,3-dihydroxypropanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
(1-((2S)-2-amino-3-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- chlorophenyl)methyl]carboxamide
{1-(2-aminoacetyl)-4-[(N-indan-5-ylcarbamoyloxy)methyl](4-piperidyl)}-N-[(2- chlorophenyl)methyl]carboxamide
[1-((2S)-2-amino-3-hydroxypropanoyl)-4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]-N-[(2- chlorophenyl)methyl]carboxamide
(1-(2-amino-3-hydroxypropanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(4-chloro-2-methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2-bromophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
N-{(1S)-2-[N-(4-ethylphenyl)carbamoyloxy]-isopropyl}{[(2- chlorophenyl)methyl]amino}-N-methylcarboxamide
[(1-(2-aminoacetyl)-4-{N-[(2-chloro-4-fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
N-(2-aminoethyl)(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)carboxamide
(1-((2R)-2-amino-3-hydroxypropanoyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyI}(4-piperidyl))-N-[(2- chlorophenyl)methyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2)3-difluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
(1-(2-aminoacetyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-methylphenyl)methyl]carboxamide
[(4-{N-[(2-bromophenyl)methyl]carbamoyl}-1-[2-(methylamino)acetyl3(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(2- hydroxyacetyl)(4-piperidyl))carboxamide
(1-(2-aminoacetyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-chloro-2-methylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-[4-(trifluoromethyl)phenyl]carboxamide
((2S)-2-{[N-(4-ethylphenyl)carbamoyloxy]methyl}pyrrolidinyl)-N-[(2- chlorophenyl)methyl]carboxamide
(1-(4-amino-2-hydroxybutanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
2-amino-N-[3-({[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carbonylamino)propyl]acetamide
(1-(2-aminoacetyl)-4-{[N-(4-methylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(2H-
3,4,5,6-tetrahydropyran-4-yl))carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2,4-dichlorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
N-{(1 S)-3-[N-(4-ethylphenyl)carbamoyloxy]-1 -methylpropyl}{[(2- chlorophenyl)methyl]amino}-N-methylcarboxamide
[2-({[(2-chlorophenyl)methyl]amino}-N-(2-hydroxyethyl)carbonylamino)ethoxy]-
N-(4-ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-[2-
(methylamino)acetyl](4-piperidyl))carboxamide
(1-(azetidin-2-ylcarbonyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
2-amino-N-[4-({[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyOcarbamoyloxylethyllcarbonylaminoJbutylJacetamide
N-((5S,3R)-1-{N-[(2-chlorophenyl)methyl]carbamoyl}-5-{[N-(4- ethylphenyl)carbamoyloxy]methyl}pyrrolidin-3-yl)-2-aminoacetamide
N-[(2-chlorophenyl)methyl]-4-[N-(4-ethylphenyl)carbamoyloxy]-2,2- dimethylbutanamide
N-[(2-chlorophenyl)methyl]({[N-(4- ethylpheny!)carbamoyloxy]methyl}cyclohexyl)carboxamide
(1-(4-aminobutanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
{[(2-chlorophenyl)methyllamino}-N-methyl-N-{2-[N-(4- pheπylphenyl)carbamoyloxy]ethyl}carboxamide
(1-((2R)-2-aminopropaπoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(4-chloro-2-fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
(1-[(2-amJnoethyl)sulfonyl]-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-[3- hydroxy-2-(hydroxymethyl)-2-methylpropanoyl](4-piperidyl))carboxamide
(1-(2-aminoacetyl)-4-{[N-(4-phenylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
(1-(2-aminoacetyl)-4-{[N-(2-chloro-4-methylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide 4-(2-aminoacetylamino)-N-[(2-chlorophenyl)methyl]-2-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-2-methylbutanamide
[(1-(2-aminoacetyl)-4-{N-[(2,3-dichlorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-[4-(trifluoromethyl)phenyl]carboxamide
[1-(2-aminoacetyl)-4-({N-[4-(trifluoromethyI)phenyl]carbamoyloxy}methyl)(4- piperidyl)]-N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(N- methylcarbamoyl)(4-piperidyl))carboxamide
( 1 -(2-am inoacetyl)-4-{[N-(4-ethylpheny l)ca rbam oy loxy]methyl}(4-piperidyl))-N-
[(2-fluorophenyl)methyl]carboxamide
[(4-{N-[(2,3-dichlorophenyl)methyl]carbamoyl}-1-{2-[(tert- butoxy)carbonylamino]acetyl}(4-piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
2-aminoethyl 4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidinecarboxylate
[2-(N-(4-aminobutyl){[(2-chlorophenyl)methyl]amino}carbonylamino)ethoxy]-N-
(4-ethylphenyl)carboxamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-N-
(4-hydroxybutyl)carboxamide
N-[(2-chlorophenyl)methyl]{4-[(N-indan-5-ylcarbamoyloxy)methylJ(2H-3,4,5,6- tetrahydropyran-4-yl)}carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-chloro-2-fluorophenyl)methyl]carbannoyl}(4- piperidyl))methoxy]-N-[4-(trifluoromethyl)phenyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-
(imidazol-2-ylcarbonyl)(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](3-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(2- hydroxyacetyl)(3-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-
(phenylcarbonyl)(4-piperidyl))carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-fluoro-2-methylphenyl)nnethyl]carbamoyl}(4- piperidyl))methoxy]-N-[4-(trifluoromethyl)phenyl]carboxamide N-[(1S)-2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyOcarbamoyloxylmethy^piperidyO-i-ChydroxymethyO-Z-oxoethylJ^ert- butoxy)carboxamide
(1-acetyl-4-{[N-(4-€thylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- chlorophenyl)methyl]carboxamide methyl 4-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-4-oxobutanoate
({1-(2-aminoacetyl)-4-[N-(naphthylmethyl)carbamoyl](4-piperidyl)}methoxy)-N-
(4-ethylphenyl)carboxamide
[1-(2-aminoacetyl)-4-({N-[2-chloro-4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]-N-[(2- chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl][1-(2-hydroxyacetyl)-4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]carboxamide
(1-(2-aminoacetyl)-3-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(3-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide methyl 3-{N-[(2-chlorophenyl)methyl]carbamoyl}-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidinecarboxylate
(tert-butoxy)-N-[4-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-4-oxobutyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(2- methoxyacetyl)(4-piperidyl))carboxamide
N-(5-aminopentyl){[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(4- hydroxybutanoyl)(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-
(methylsulfonyl)(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl][4-({N-[4-
(methylethyl)phenyl]carbamoyloxy}methyl)(2H-3,4,5,6-tetrahydropyran-4- yl)]carboxamide N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-
(morpholin-3-ylcarbonyl)(4-piperidyl))carboxamide
(1-(2-aminoacetyl)-3-{[N-(4-ethylphenyl)carbamoyloxy]methyl}pyrrolidin-3-yl)-N-
[(2-chlorophenyl)methyl]carboxamide methyl 4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidinecarboxylate
(1-(2-amino-3-methylbutanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
(1-(2-aminoacetyl)-4-{[N-(4-chloropheπyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2l4-dimethylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
(1-(2,4-diaminobutanoyl)-4-{[N-(4-ethylphenyl)carbannoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(3- methoxypropanoyl)(4-piperidyl))carboxamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4-ethylphenyl)carbamoyloxy]-tert- butyl}-N-methylcarboxamide
N-[(2-chlorophenyl)methyl](1-(cyclopropylcarbonyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))carboxamide
(tert-butoxy)-N-[2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-(hydroxymethyl)-2- oxoethyl]carboxamide
(1-(2-amino-2-methylpropanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(3- pyridylcarbonyl)(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-methylphenyl)carbamoyloxy]methyl}(2H-
3,4,5,6-tetrahydropyran-4-yl))carboxamide
(1-((2S)-2-aminopropanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide KI-^-aminoacetyO^^N-KS-chlorophenyOmethyQcarbamoyl}^- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
4-(acetylamino)-N-[(2-chlorophenyl)methyl]-2-{[N-(4- ethylphenyl)carbamoyloxy]methyl}-2-methylbutanamide
(1-(2-aminoacetyl)-4-{[N-(3-fluoro-4-methylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(2- pyridylcarbonyl)(4-piperidyl))carboxamide
(1-(2-amino-3-cyanopropanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(4- piperidylcarbonyl)(4-piperidyl))carboxamide
3-(2-chlorophenyl)-N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-N- methylpropanamide
2-amino-N-[2-({[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyOcarbamoyloxylethy^carbonylaminoJethyllacetamide
(1-(2-amrnoacetyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-cyanophenyl)methyl]carboxamide
(tert-butoxy)-N-[2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]hnethyl}piperidyl)-2-oxoethyl]carboxamide
(1-(2-aminoacetyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
{[2-(hydroxymethyl)phenyl]methyl}carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2-ethylphenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
(tert-butoxy)-N-[2-(4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-4-{N-[(2- methylphenyljmethyllcarbamoy^piperidylj^-oxoethyllcarboxamide
(1-(2,3-diaminopropanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(2-chloro-4- fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[(1-(2-aminoacetyl)-4-{N-[(4-fluorophenyl)methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide methyl (3S)-3-amino-4-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-4-oxobutanoate
N-[(2-chlorophenyl)methyl][4-({N-[4-
(trifluoromethyOphenylJcarbamoyloxy^ethyOCZH-S^.S.β-tetrahydropyran^- yl)]carboxamide
(1-(2-aminoethyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- chlorophenyl)methyl]carboxamide
(4-{[N-(4-acetylphenyl)carbamoyloxy]methyl}-1-(2-aminoacetyl)(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-N-methyl-3-[2-
(trifluoromethyl)phenyl]propanamide
(4-{[N-(214-dimethylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6-tetrahydropyran-4- yl))-N-[(2-chlorophenyl)methy!]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(4-chlorophenyl)methyl]carbamoyl}(4- piperidyl))methoxyJ-N-(4-ethylphenyl)carboxamide
4-{2-[(tert-butoxy)carbonylamino]acetylamino}-N-[(2-chlorophenyl)methyl]-2-{[N-
(4-ethylphenyl)carbamoyloxy]methyl}-2-methylbutanamide
(1-((2S)-2,5-diaminopentanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](H[N-(4- ethylphenyl)carbamoyloxy]methyl}cyclopent-3-enyl)carboxamide
{[(2-chlorophenyl)methyl]amino}-N-methyl-N-[2-(N-(6- quinolyl)carbamoyloxy)ethyl]carboxamide
(tert-butoxy)-N-[2-(3-{N-[(2-chlorophenyl)methyl]carbamoyl}-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-2-oxoethyl]carboxamide
((5S,3R)-3-amino-5-{[N-(4-ethylphenyl)carbamoyloxy]methyl}pyrrolidinyl)-N-[(2- chlorophenyl)methyl]carboxamide (1-((2S)-2-amino-3-hydroxypropanoyl)-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(3-piperidyl))-N-[(2- chlorophenyl)methyl]carboxamide
(1-(2,5-diaminopentanoyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))-N-[(2-chlorophenyl)methyl]carboxamide
N-[(1S)-2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-methyl-2-oxoethyl](tert- butoxy)carboxamide methyl 2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)acetate
3-amino-4-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyOcarbamoyloxylmethy^piperidylJ^-oxobutanoic acid
{(3R)-3-[N-(4-ethylphenyl)carbamoyloxy]piperidyl}-N-[(2- chlorophenyl)methyl]carboxamide
N-[2-(N-benzothiazol-6-ylcarbamoyloxy)ethyl]{[(2-chlorophenyl)methyl]amino}-N- methylcarboxamide
[(4-{N-[(2,3-difluorophenyl)methyl]carbamoyl}-1-{2-[(tert- butoxy)carbonylamino]acetyl}(4-piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
N-{(1 S)-2-[N-(4-ethylphenyl)carbamoyloxy]-isopropylK[(2- chlorophenyl)methyl]amiπo}carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))carboxamide
{[(2-chlorophenyl)methyl]amino}-N-{3-[N-(4-ethylphenyl)carbamoyloxy]propyl}-N- methylcarboxamide
2-(N-{(1S)-2-[N-(4-ethylphenyl)carbamoyloxy]-isopropylK[(2- chlorophenyl)methyl]amino}carbonylamino)acetic acid tert-butyl 3-[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)carbonyl]moφholine-4-carboxylate
4-amino-N-[(2-chlorophenyl)methyl]-2-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-
2-methylbutanamide [(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-[N-(imidazol-2- ylmethyl)carbamoyl](4-piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-[2- (methylamino)propanoyl](4-piperidyl))carboxamide methyl 4-{[(1-(2-aminoacetyl)-4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4- piperidyl)methoxy]carbonylamino}benzoate
N-((5S,3R)-1-{N-[(2-chlorophenyl)methyl]carbamoyl}-5-{[N-(4- ethylphenyl)carbamoyIoxy]methyl}pyrrolidin-3-yl)acetamide
[({N-[(2-chlorophenyl)methyl]carbamoyl}cyclobutyl)methoxy]-N-(4- ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl][4-({[(4-ethylphenyl)amino]carbonylamino}methyl)-1-
(2-hydroxyacetyl)(4-piperidyl)]carboxamide
(4-{[N-(3-chloro-4-methylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6- tetrahydropyran-4-yl))-N-[(2-chlorophenyl)methyl]carboxamide
[1-(2-aminoacetyl)-4-({N-[4-methyl-3-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]-N-[(2- chlorophenyl)methyl]carboxamide
{[(2-chlorophenyl)methyl]methylamino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}-N-methylcarboxaπnide
(1-(2-aminoacetyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-methoxyphenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(3-fluoro-4- methylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6-tetrahydropyran-4- yl))carboxamide
N-[(2-chlorophenyl)methyl]{3-[N-(4- ethylphenyl)carbamoyloxy]piperidyl}carboxamide methyl 2-({[1 -(2-aminoacetyl)-4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)-4- piperidyl]carbonylamino}methyl)benzoate
(4-{[N-(3,4-dimethylphenyl)carbamoyloxy]methyl}(2H-3,4.5,6-tetrahydropyran-4- yl))-N-[(2-chlorophenyl)methyl]carboxamide (4-(2-aminoacetyl)-2-{[N-(4-ethylphenyl)carbamoyloxy]methyl}piperazinyl)-N-[(2- chlorophenyl)methyl]carboxamide
(1-(2-aminoacetyl)-4-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl]-3-[N-(4-ethylphenyl)carbamoyloxy]-2,2- dimethylpropanamide
N-(3-aminopropyl){[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carboxamide
N-[(2-chlorophenyl)methyl][2-({[(4- ethylphenyl)amino]carbonylamino}methyl)pyrrolidinyl]carboxamide
N-[(2-chlorophenyl)methyl](1-(cyclohexylcarbonyl)-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))carboxamide
(4-{[N-(4-chlorophenyl)carbamoyloxy]methyl}(2H-3,4,5,6-tetrahydropyran-4-yl))-
N-[(2-chlorophenyl)methyl]carboxamide
N-(2-aminoethyl){[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carboxamide
(tert-butoxy)-N-[2-(4-{N-[(2-bromophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-2-oxoethyl]-N-methylcarboxamide
[(1-(2-aminoacetyl)-4-{N-[(3-methyl(2-pyridyl))methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl]({[N-(4- ethylphenyl)carbamoyloxy]methyl}cyclopropyl)carboxamide
2-(acetylamino)-N-[(2-chlorophenyl)methyl]-3-[N-(4-ethylphenyl)carbamoyloxy]-
2-methylpropanamide
[( 1 -{2-[(tert-butoxy)carbonyiamino]acetyl}-4-{N-[(3-fluoro-2- methylphenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-[4-
(trifluoromethyl)phenyl]carboxamide tert-butyl 4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidinecarboxylate
[1-(2-aminoacetyl)-4-({N-[4-(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4- piperidyl)]-N-[(2-cyanophenyl)methyl]carboxamide N-[(2-chlorophenyl)methyl]-4-[N-(4-ethylphenyl)carbamoyloxy]butanamide
N-[(1R)-2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-(hydroxymethyl)-2-oxoethyl](tert- butoxy)carboxamide
(2-chlorophenyl)methyl (2S)-2-({[(4- ethylphenyl)amino]carbonylamino}methyl)pyrrolidinecarboxylate tert-butyl 4-[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenylJcarbamoyloxylmethy^piperidyOcarbonyllpiperidinecarboxylate methyl 4-{[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-2H-3,4)5,6- tetrahydropyran-4-yl)methoxy]carbonylamino}benzoate
[(4-{N-[(2,3-dichlorophenyl)methyl]carbamoyl}-1-{2-[(tert- butoxy)carbonylamino]acetyl}(4-piperidyl))methoxy]-N-[4-
(trifluoromethyl)phenyl]carboxamide
2-(1-(2-aminoacetyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]acetamide
(tert-butoxy)-N-[2-(4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-4-{N-[(2- fluorophenyl)methyl]carbamoyl}piperidyl)-2-oxoethyl]carboxamide
N-[(2-chlorophenyl)methyl][4-({N-[4-(2-methyl(1 ,3-thiazol-4- yl))phenyl]carbamoyloxy}methyl)(2H-3,4,5,6-tetrahydropyran-4-yl)]carboxamide
2-(2-aminoacetylamino)-N-[(2-chlorophenyl)methyl]-3-[N-(4- ethylphenyl)carbamoyloxy]-2-methylpropanamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-(2- hydroxyethyl)(4-piperidyl))carboxamide
2-[(tert-butoxy)carbonylamino]-N-[3-({[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyOcarbamoyloxylethy^carbonylaminoJpropyπacetamide
N-[(2-chlorophenyl)methyl]-3-[N-(4-ethylphenyl)carbamoyloxy]-2-
(methoxycarbonylamino)-2-methylpropanamide
(4-{[N-(4-acetylphenyl)carbamoyloxy]methyl}(2H-3,415,6-tetrahydropyran-4-yl))-
N-[(2-chlorophenyl)methyl]carboxamide
2-(2-aminoacetylamino)-N-[(2-chlorophenyl)methyl]-4-[N-(4- ethylphenyl)carbamoyloxy]butanamide N-[(2-chlorophenyl)methyl]-4-{[N-(4-ethylphenyl)carbamoyl]amino}-2,2- dimethylbutanamide tert-butyl 2-[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)carbonyl]azetidinecarboxylate
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1- methyl(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1-{[4-
(phenylcarbonyl)phenyl]carbonyl}(4-piperidyl))carboxamide
N-[(2-chlorophenyl)methyl][4-({N-[4-
(hydroxyethyl)phenyl]carbamoyloxy}methyl)(2H-314,5,6-tetrahydropyran-4- yl)]carboxamide
N-[({N-[(2-chlorophenyl)methyl]carbamoyl}cyclopropyl)methyl][(4- ethylphenyl)amino]carboxamide
N-[(2-chlorophenyl)methyl](1-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-3,4- dihydroxycyclopentyl)carboxamide
{3-[N-(4-ethylphenyl)carbamoyloxy]piperidyl}-N-[(2- methylphenyl)methyl]carboxamide
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(3-chloro-2- methylphenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-[4-
(trifluoromethyl)phenyl]carboxamide
2-amino-N-[2-({[(2-chlorophenyl)methyl]amino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carbonylannino)ethyl]-N-methylacetamide
N-[(2-chlorophenyl)methyl][4-({N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(4-piperidyl)]carboxamide
{[(2-chlorophenyl)methyl]amino}-N-{4-[N-(4-ethylphenyl)carbamoyloxy]butyl}-N- methylcarboxamide
(tert-butoxy)-N-[2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-methyl-2-oxoethyl]-N- methylcarboxamide
N-[(2-chlorophenyl)methyl](1-ethyl-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4- piperidyl))carboxamide ethyl 4-{[(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-2H-3I4l5,6-tetrahydropyran-
4-yl)methoxy]carbonylamino}benzoate
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}^-{N-[(3-chlorc>-2- fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-[4-
(trifluoromethyl)phenyl]carboxamide
N-[2-({[(2-chlorophenyl)methyl]amino}-N-methylcarbonylamino)ethyl][(4- ethylphenyl)amino]carboxamide
2-amino-N-[(2-chlorophenyl)methyl]-4-[N-(4- ethylphenyl)carbamoyloxy]butanamide
[(2R)-2-({[(2-chlorophenyl)methyl]amino}-N-methylcarbonylamino)propoxy]-N-(4- ethylphenyl)carboxamide
({1-(2-aminoacetyl)-4-[N-(2-pyridylmethyl)carbamoyl](4-piperidyl)}methoxy)-N-
(4-ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)-N- methylcarbamoyloxy]methyl}(2H-3>4,5,6-tetrahydropyran-4-yl))carboxamide
(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- cyanophenyl)methyl]carboxamide
(1-(2-aminoacetyl)-4-{[N-(4-cyaπophenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
(1-(2-aminoacetyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N- benzylcarboxamide
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(3- fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
[2-({[(2-chlorophenyl)methyl]amino}-N-methylcarbonylamino)-isopropoxy]-N-(4- ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl]-3-{[(4-ethylphenyl)amino]carbonylamino}-2,2- dimethylpropanamide
N-[(1S)-2-(3-{N-[(2-chlorophenyl)methyl]carbamoyl}-3-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-(hydroxymethyl)-2-oxoethyl](tert- butoxy)carboxamide
N-[(2-chlorophenyl)methyl]-3-[N-(4-ethylphenyl)carbamoyloxy]-2-(2- hydroxyacetylamino)-2-methylpropanamide
{1-(2-aminoacetyl)-4-[(N-phenylcarbamoyloxy)methyl](4-piperidyl)}-N-[(2- chlorophenyl)methyl]carboxamide
[(1-(2-aminoacetyl)-4-{N-[(2-methyl(3-pyridyl))methyl]carbamoyl}(4- piperidyl))methoxy]-N-(4-ethylphenyl)carboxamide
[( 1 -{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(4- fluorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
{(3S)-3-[N-(4-ethylphenyl)carbamoyloxy]piperidyI}-N-[(2- chloropheny l)methyl]ca rboxam ide
(tert-butoxy)-N-[2-(4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-4-[N- benzylcarbamoyl]piperidyl)-2-oxoethyl]carboxamide
2-((2S)-2-amino-3-hydroxypropanoylamino)-N-[(2-chlorophenyl)methyl]-3-[N-(4- ethylphenyl)carbamoyloxy]-2-methylpropanamide
(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}(4-piperidyl))-N-[(2- methoxyphenyl)methyl]carboxamide
[(4-{N-I(2-chlorophenyl)methyl]carbamoyl}morpholin-2-yl)methoxy]-N-(4- ethylphenyl)carboxamide
{[1-(2-aminoacetyl)-4-(N-{[2-fluoro-4-
(trifIuoromethyl)phenyl]methyl}carbamoyl)(4-piperidyl)]methoxy}-N-(4- ethylphenyl)ca rboxam ide
N-[(1R)-2-(4-{N-[(2-chlorophenyl)methyl]carbamoyl}-4-{[N-(4- ethylphenyl)carbamoyloxy]methyl}piperidyl)-1-methyl-2-oxoethyl](tert- butoxy)carboxamide
N-[(2-chlorophenyl)methyl][4-({N-[4-methyl-3-
(trifluoromethyl)phenyl]carbamoyloxy}methyl)(2H-3,4,5,6-tetrahydropyran-4- yl)]carboxamide
N-[(1-(2-aminoacetyl)-4-{N-[(2-chlorophenyl)methyl]carbamoyl}(4- piperidyl))methyl][(4-ethylphenyl)amino]-N-(3-methoxypropyl)carboxamide
{[1-(2-aminoacetyl)-4-({[(2-chlorophenyl)methyl]amino}methyl)(4- piperidyl)]methoxy}-N-(4-ethylphenyl)carboxamide
N-^Z-chlorophenylJmethyll-Σ^^-ethylphenyOaminoJcarbonylamino^- methylpropanamide
2-(acetylamino)-N-[(2-chlorophenyl)methyl]-3-[N-(4- ethylphenyl)carbamoyloxy]propanamide
N-[(2-chlorophenyl)methyl](4-{[N-(6-fluoro-2- methylphenyl)carbamoyloxy]methyl}(2H-3,4,5,6-tetrahydropyran-4- yl))carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}-1- benzyl(4-piperidyl))carboxamide
[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(4- chlorophenyl)methyl]carbamoyl}(4-piperidyl))methoxy]-N-(4- ethylphenyl)carboxamide
(1-(2-aminoacetyl)-4-{[N-(4-fluorophenyl)carbamoyloxy]methyl}(4-piperidyl))-N-
[(2-chlorophenyl)methyl]carboxamide
N-[(1-(2-aminoacetyl)-4-{N-[(2-chlorophenyl)methyl]carbamoyl}(4- piperidyl))methyl]-2-(4-ethylphenyl)acetamide
2-amino-N-{2-[{[(2-chlorophenyl)methyl]amino}-N-(2-{N-[4-
(trifluoromethyl)phenyl]carbamoyloxy}ethyl)carbonylamino]ethyl}-N- methylacetamide
(4-(2-aminoacetyl)-3-{N-[(2-chlorophenyl)methyl]carbamoyl}piperazinyl)-N-(4- ethylphenyl)carboxamide
N-[(2-chlorophenyl)methyl]{4-[(N-phenylcarbamoyloxy)methyl](2H-3,415,6- tetrahydropyran-4-yl)}carboxamide
3-(1-(2-aminoacetyl)-4-{N-[(2-methylphenyl)methyl]carbamoyl}(4-piperidyl))-N-
(4-ethylphenyl)propanamide
4-{[(4-{N-[(2-chlorophenyl)methyl]carbannoyl}-2H-3,4,5,6-tetrahydropyran-4- yl)methoxy]carbonylamino}benzamide
(4-{[N-(3-chloro-2-methylphenyl)carbamoyloxylmethyl}(2H-3,4,5,6- tetrahydropyran-4-yl))-N-[(2-chlorophenyl)methyl]carboxamide
{[(Z-chlorophenyOmethyllaminol-N^-tN^-ethylphenyOcarbamoyloxylethyl^N-
[2-(methylamino)ethyl]carboxamide
N-[(1-(2-aminoacetyl)-4-{N-[(2-chlorophenyl)methyl]carbamoy!}(4- piperidyI))methyl]-N-(2-aminoethyl)[(4-ethylphenyl)amino]carboxamide
((1S,2S)-2-{[(4-ethylphenyl)amino]carbonylamino}cyclohexyl)-N-[(2- chlorophenyl)methyl]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(2-cyanophenyl)carbamoyloxy]methyl}(2H-
3,4,5,6-tetrahydropyran-4-yl))carboxamide
(4-{[N-(2-chlorophenyl)carbamoyloxy]methyl}(2H-314,5,6-tetrahydropyran-4-yl))-
N-[(2-chlorophenyl)methyl]carboxamide
N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}acetamide
N-{2-[N-(4-ethylphenyl)carbamoyloxy]ethyl}-2-hydroxy-N-methyl-3-[2-
(trifluoromethyl)phenyl]propanamide methyl 1-(2-aminoacetyl)-4-{[N-(4-ethylphenyl)carbamoyloxy]methyl}piperidine-
4-carboxylate
N-[({N-[(2-chlorophenyl)methyl]carbamoyl}cyclopropyl)methyl]-2-(4- ethylphenyl)acetamide
N-[(2-chlorophenyl)methyl][4-({[(4-ethylphenyl)amino]carbonylamino}methyl)(4- piperidyl)]carboxamide
(tert-butoxy)-N-[2-({[(2-chlorophenyl)methylJamino}-N-{2-[N-(4- ethylphenyl)carbamoyloxy]ethyl}carbonylamino)ethyl]-N-methylcarboxamide
(4-{[N-(3,5-dichlorophenyl)carbamoyloxy]methyl}(2H-3,4,5,6-tetrahydropyran-4- yl))-N-[(2-chlorophenyl)methyl]carboxamide
({1-(2-aminoacetyl)-4-[N-(imidazol-2-ylmethyl)carbamoyl](4-piperidyl)}methoxy)-
N-(4-ethylphenyl)carboxamide tert-butyl 2-(N-{(1S)-2-[N-(4-ethylphenyl)carbamoyloxy]-isopropylK[(2- chlorophenyl)methyl]amino}carbonylamino)acetate
N-[(2-chlorophenyl)methyl]-N'-(4-ethylphenyl)-2,2-dimethylpentane-1 ,5-diamide methyl 3-{N-[(2-chlorophenyl)methyl]carbamoyl}-3-{[(4- ethylphenyl)amino]carbonylamino}pyrrolidinecarboxylate N-[(2-chlorophenyl)methyl][4-({[(4-ethylphenyl)amino]-N- methylcarbonylamino}methyl)-1-(2-hydroxyacetyl)(4-piperidyl)]carboxamide
N-[(2-chlorophenyl)methyl](4-{[N-(3-methoxyphenyl)carbamoyloxy]methyl}(2H-
3,4,5,6-tetrahydropyran-4-yl))carboxamide
2-{2-[(tert-butoxy)carbonylamino]acetylamino}-N-[(2-chlorophenyl)methyl]-3-[N-
(4-ethylphenyl)carbamoyloxy]-2-methylpropanamide and
(tert-butoxy)-N-(2-{N-[(1-{2-[(tert-butoxy)carbonylamino]acetyl}-4-{N-[(2- chlorophenyl)methyl]carbamoyl}(4-piperidyl))methyl][(4- ethylphenyl)amino]carbonylamino}ethyl)carboxamide
72. At least one chemical entity of claim 1 wherein the compound of Formula X is chosen from compounds of Formula Il
Figure imgf000179_0001
Formula Il wherein
W4 is an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl ring;
W5 is selected from CR1R2, NR14, and O;
Z1 is aryl;
Z2 is aryl;
R1 and R2 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R1 and R2 may optionally be joined together with the carbon atom bonded thereto, to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; for each occurrence, R3 , R4, R5 and R6 are independently selected from hydrogen, hydroxy, carboxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; each R7 and R10 is independently selected from hydrogen, cyano, halo, hydroxy, carboxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl;
R8 and R14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; m is selected from 0, 1, 2 and 3; n is selected from 0, 1 , 2 and 3; p is selected from 0, 1 , 2, and 3; and q is selected from 0, 1 , 2 and 3.
73. At least one chemical entity of Claim 72 wherein W4 is
Figure imgf000181_0001
wherein W1a, W1b, and W1c are independently selected from -CH and N.
74. At least one chemical entity of Claim 73 wherein at least one of W 1a , l WA,1b and
W1c is N.
75. At least one chemical entity of Claim 73 wherein at least two of W 1a , . W..1b and
W1c are N.
76. At least one chemical entity of Claim 73 wherein W1a, W1b and W1care N.
77. At least one chemical entity of any one of Claims 72 to 5 wherein n is chosen from 1 and 2.
78. At least one chemical entity of Claim 78 wherein n is 1.
79. At least one chemical entity of any one of Claims 72 to 79 wherein each R3 and R4 is independently chosen from hydrogen, optionally substituted lower alkyl and lower alkoxycarbonyl.
80. At least one chemical entity of Claim 79 wherein each R3 and R4 is independently chosen from hydrogen, methyl, ethyl, isopropyl, hydroxy methyl, and methoxycarbonyl.
81. At least one chemical entity of Claim 80 wherein each R3 and R4 is hydrogen.
82. At least one chemical entity of any one of Claims 72 to 81 wherein p is chosen from 1 and 2.
83. At least one chemical entity of Claim 82 wherein p is 1.
84. At least one chemical entity of Claim 82 wherein each R10 is independently selected from cyano, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, hydroxymethyl, trifluoromethyl, methoxycarbonyl, phenoxy, trifluoromethoxy, methoxy, N,N-dimethyamino, and 1H-imidazolyl.
85. At least one chemical entity of Claim 84 wherein each R10 is chosen from methyl, ethyl, isopropyl, and CF3.
86. At least one chemical entity of Claim 84 wherein p is 1 and R10 is ethyl or isopropyl.
87. At least one chemical entity of any one of Claims 72 to 86 wherein R1 and R2 are independently chosen from hydrogen and lower alkyl.
88. At least one chemical entity of Claim 87 wherein R1 and R2 are independently chosen from hydrogen and methyl.
89. At least one chemical entity of Claim 88 wherein R1 and R2 are hydrogen.
90. At least one chemical entity of Claim 88 wherein R1 and R2 are methyl.
91. At least one chemical entity of Claim 88 wherein R1 is hydrogen and R2 is methyl.
92. At least one chemical entity of any one of Claims 72 to 91 wherein R1 and R2 are joined together to form a group selected from cycloalkyl and heterocycloalkyl.
93. At least one chemical entity of Claim 92 wherein R1 and R2 are joined together to form a group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, and 2H-3,4,5,6-tetrahydropyranyl, each of which is optionally substituted.
94. At least one chemical entity of Claim 93 wherein R1 and R2 are joined together to form a group selected from optionally substituted cyclopropyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, and optionally substituted 2H-3,4,5,6-tetrahydropyranyl.
95. At least one chemical entity of any one of Claims 72 to 94 wherein each R5 and R6 is independently chosen from hydrogen, optionally substituted lower alkyl and lower alkoxycarbonyl.
96. At least one chemical entity of Claim 95 wherein each R5 and R6 is independently chosen from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, and methoxycarbonyl.
97. At least one chemical entity of Claim 96 wherein each R5 and R6 is hydrogen.
98. At least one chemical entity of any one of Claims 72 to 97 wherein R7 is Cl, F, methyl, or CF3.
99. At least one chemical entity of Claim 98 wherein R7 is Cl.
100. At least one chemical entity of any one of Claims 72 to 99 wherein m is 1 or 2.
101. At least one chemical entity of Claim 100 where an R7 is positioned at 2 or 3- position.
102. At least one chemical entity of Claim 73 wherein the compound of Formula Il is chosen from
N-[(2-chlorophenyl)methyl]({[5-(4-ethylphenyl)(1 ,2,3,4-tetraazol-2- yl)]methyl}cyclopropyl)carboxamide
N-[(2-chlorophenyl)methyl](1-{[5-(4-ethylphenyl)(1I2,3>4-tetraazol-2- yl)]methyl}cyclopent-3-enyl)carboxamide
N-[(2-chlorophenyl)methyl]({[5-(4-ethylphenyl)(1 ,2,3,4-tetraazol-2- yl)]methyl}cyclobutyl)carboxamide
N-[(2-chlorophenyl)methyl]-3-[5-(4-ethylphenyl)(1 ,2,3,4-tetraazol-2-yl)]-2,2- dimethylpropanamide
N-^.S-dichlorophenyOmethyll^^-dimethyl-S^δ-μ-CmethylethyOpheny^i^.S^- tetraazol-2-yl)}propanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 , 2,3,4- tetraazol-2-yl)}propanamide
S^S-H-CdimethylaminoJpheny^i ^.S^-tetraazol^-yl^-N-Ka-chlorophenyOmethyl]- 2,2-dimethylpropanamide
3-[5-(4-bromophenyl)(1 ,2,3,4-tetraazol-2-yl)]-N-[(2-chlorophenyl)methyl]-2,2- dimethylpropanamide
N-[(2-chlorophenyl)methyl]-3-[5-(4-methoxyphenyl)(1 ,2,3,4-tetraazol-2-yl)]-2,2- dimethylpropanamide methyl 4-[2-(2-{N-[(2-chlorophenyl)methyl]carbamoyl}-2-methylpropyl)-1, 2,3,4- tetraazol-5-yl]benzoate
N-[(2-chloro-4-fluorophenyl)methyl]-2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 , 2,3,4- tetraazol-2-yl)}propanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}-N-[(2- methylphenyl)methyl]propanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-[5-(4-methylphenyl)(1 ,2,3,4-tetraazol-2- yl)]propanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{5-[4-(trifluoromethoxy)phenyl](1 ,2,3,4- tetraazol-2-yl)}propanamide N-[(2-chlorophenyl)methyl]-3-[5-(4-imidazolylphenyl)(1 ,2,3,4-tetraazol-2-yl)]-2,2- dimethylpropanamide
N-[(2-fluorophenyl)methyl]-2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 , 2,3,4- tetraazol-2-yl)}propanamide
N-[(2-chlorophenyl)methyl](4-{[5-(4-ethylphenyl)(1,2I3,4-tetraazol-2-yl)]methyl}(2H-
3,4,5,6-tetrahydropyran-4-yl))carboxamide
N-[(2-chlorophenyl)methyl](1-{[5-(4-ethylphenyl)(1,2l3,4-tetraazol-2-yl)]methyl}-3,4- dihydroxycyclopentyl)carboxamide
N-[1-(2-chlorophenyl)-2-hydroxypropyl]-2,2-dimethyl-3-{5-[4-
(methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}propanamide
3-[5-(4-chlorophenyl)(1,2,3,4-tetraazol-2-yl)]-N-[(2-chlorophenyl)methyl]-2>2- dimethylpropanamide
{[(2-chlorophenyl)methyl]amino}-N-{2-[5-(4-ethylphenyl)(1(2,3t4-tetraazol-2-yl)]ethyl}-
N-methylcarboxamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{5-[4-(trifluoromethyl)phenyl](1 ,2,3,4- tetraazol-2-yl)}propanamide
Not Available
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-[5-(4-phenoxyphenyl)(1 ,2,3,4-tetraazol-2- yl)]propanamide
N-[(2-chlorophenyl)methyl]-3-{5-[4-(methylethyl)phenyl](1,2,3l4-tetraazol-2- yl)}propanamide
N-[(2,4-dichlorophenyl)methyl]-2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 ,2,3,4- tetraazol-2-yl)}propanamide
(2S)-N-[(2-chlorophenyl)methyl]-2-methyl-3-[5-(4-methylphenyl)(1 ,2,3,4-tetraazol-2- yl)]propanamide
3-[5-(3-chlorophenyl)(1 ,2,3,4-tetraazol-2-yl)]-N-[(2-chlorophenyl)methyl]-2,2- dimethylpropanamide
3-{5-[4-(tert-butyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}-N-[(2-chlorophenyl)methyl]-2l2- dimethylpropanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-{2-[4-(methylethyl)phenyl](1 , 2,3,4- tetraazol-5-yl)}propanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}-N- benzylpropanamide
N-[(2-chlorophenyl)methyl]-2,2-dimethyl-3-[5-(3-methylphenyl)(1,2,3,4-tetraazol-2- yl)]propanamide
N-[(3-fluorophenyl)methyll-2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 ,2,3,4- tetraazol-2-yl)}propanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}-N-(2- pyridylmethyl)propanamide
N-[2-(2-chlorophenyl)ethyl]-2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 , 2,3,4- tetraazol-2-yl)}propanamide
N-[(2-chlorophenyl)methyl]-3-{3-[4-(methylethyl)phenyl](1 ,2I4-oxadiazol-5- yl)}propanamide
N-[(2-chlorophenyl)methyl]-3-{5-[4-(hydroxymethyl)phenyl](1 I2,3,4-tetraazol-2-yl)}-
2,2-dimethylpropanamide
N-[(2-chlorophenyl)methyl]-2-methyl-3-{2-[4-(methylethyl)phenyl](1 ,2,3,4-tetraazol-5- yl)}propanamide
N-[(2-chlorophenyl)methyl]-3-[5-(4-cyanophenyl)(1 ,2,3,4-tetraazol-2-yl)]-2,2- dimethylpropanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 ,2,3,4-tetraazol-2-yl)}-N-(3- thienylmethyl)propanamide
N-[(6-chloro-2-fluorophenyl)methyl]-2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 , 2,3,4- tetraazol-2-yl)}propanamide
2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1 ,2l3I4-tetraazol-2-yl)}-N-(1 ,3-oxazol-2- ylmethyl)propanamide and
4-[(2,2-dimethyl-3-{5-[4-(methylethyl)phenyl](1,2,3,4-tetraazol-2- yl)}propanoylamino)methyl]benzoic acid.
103. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier and at least one chemical entity of any one of Claims 1 to 102.
104. A pharmaceutical composition of Claim 103 wherein the composition is formulated in a form chosen from tablets, capsules, powders, liquids, suspensions, suppositories and aerosols.
105. A packaged pharmaceutical composition comprising a pharmaceutical composition of Claim 103 or 104 and instructions for using the composition to treat a patient suffering from a disease associated with smooth muscle myosin or non-muscle myosin.
106. The packaged pharmaceutical composition of Claim 105 wherein the disease associated with smooth muscle myosin is selected from hypertension, asthma, chronic obstructive pulmonary disease (copd) asthma, bronchoconstrictive disease, glaucoma and other ocular indications, incontinence and other bladder disfunctions, irritable bowel syndrome, pre-term labor, esophogial dysmotility, strokes, subarachnoid hemmorhages, pre-menstrual cramps, erectile dysfunction and other acute and chronic diseases and conditions associated with smooth muscle myosin and/or non-muscle myosin.
107. A method of treating or ameliorating a disease associated with smooth muscle myosin or non-muscle myosin in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity of any one of Claims 1 to 103.
108. A method of Claim 107 wherein the disease associated with smooth muscle myosin is selected from hypertension, asthma, chronic obstructive pulmonary disease (copd) asthma, bronchoconstrictive disease, glaucoma and other ocular indications, incontinence and other bladder disfunctions, irritable bowel syndrome, pre-term labor, esophogial dysmotility, strokes, subarachnoid hemmorhages, pre-menstrual cramps, erectile dysfunction and other acute and chronic diseases and conditions associated with smooth muscle myosin and/or non-muscle myosin.
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US20190352294A1 (en) * 2016-11-18 2019-11-21 Merck Sharp & Dohme Corp. Factor XIIa Inhibitors
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US8759374B2 (en) 2007-08-15 2014-06-24 Cytokinetics, Inc. Certain chemical entities, compositions, and methods
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EP3541375A4 (en) * 2016-11-18 2020-05-13 Merck Sharp & Dohme Corp. FACTOR XIIA INHIBITORS
US20190352294A1 (en) * 2016-11-18 2019-11-21 Merck Sharp & Dohme Corp. Factor XIIa Inhibitors
US10875851B2 (en) * 2016-11-18 2020-12-29 Merck Sharp & Dohme Corp. Factor XIIa inhibitors
WO2021064189A3 (en) * 2019-10-02 2021-05-20 Domain Therapeutics Prostaglandin e2 (pge2) ep4 receptor antagonists
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US12527779B2 (en) 2019-10-02 2026-01-20 Domain Therapeutics Prostaglandin E2 (PGE2) EP4 receptor antagonists
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US12522593B2 (en) 2022-06-13 2026-01-13 Alivexis, Inc. Azacycloalkyl carbonyl cyclic amine compound

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