WO2008016643A2 - Certain chemical entities, compositions, and methods - Google Patents

Certain chemical entities, compositions, and methods Download PDF

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Publication number
WO2008016643A2
WO2008016643A2 PCT/US2007/017186 US2007017186W WO2008016643A2 WO 2008016643 A2 WO2008016643 A2 WO 2008016643A2 US 2007017186 W US2007017186 W US 2007017186W WO 2008016643 A2 WO2008016643 A2 WO 2008016643A2
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optionally substituted
ethyl
methyl
amino
pyridin
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WO2008016643A3 (en
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Pu-Ping Lu
Xiangping Qian
Jeffrey T. Finer
Chihyan 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • substituted heterocycles including 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.
  • Myosin is present in all muscle and non-muscle cells. Of the ten distinct classes of myosin in human cells, myosin-l! 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 ⁇ oncovalently 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. [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
  • W 1 is chosen from N and CR 6 and W 2 is chosen from N and CR 4 , provided that both W 1 and W 2 are not N;
  • R 1 and R 4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodo
  • Z 1 is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , cyano, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted carbamimidoyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, sulfonyl, sulfinyl, and sulfanyl;
  • Z 2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
  • Z 3 is chosen from hydrogen, halogen, and optionally substituted alkyl
  • R 3 is chosen from hydrogen and optionally substituted alkyl
  • R 6 is chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl.
  • composition comprising at least one chemical entity described herein, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients.
  • kits for 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.
  • Boc tert-butoxycarbonyl cyclo
  • DIPEA N,N-diisopropylethylamine
  • HATU 0-(7-azabenzotriazol-1 -yl)- ⁇ /, N, N', N -tetramethyluron ium hexafluorophosphate
  • HBTU 0-(benzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium hexafluorophosphate
  • NMP N-Methyl-2-pyrrolidone
  • Ph phenyl
  • TBAF tetrabutylammonium fluoride
  • TBS TBDMS tert-butyldimethylsilyl
  • TES triethylsilyl or triethylsilane
  • TMS trimethylsilyl or trimethylsilane
  • 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
  • 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.
  • C 1 -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 Ci alkylene is a methylene group.
  • 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.
  • 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-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cyc!oprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1 -en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-e ⁇ -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, cyclobuta-1 ,3-dien-1-yl; and the like.
  • an alkenyl group has from 2 to 20 carbon atoms and in
  • 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-1-yl, prop-2-yn-1-yl; butynyls such as but-1 -y ⁇ -1-yl, but-i-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.
  • 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.
  • Tormyl refers to the group -C(O)H.
  • Carboxy and/or “carboxyl” refer to the group -C(O)OH.
  • a C 1 -C 6 alkoxycarbony] group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • amino is meant the group -NH 2 .
  • “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 C 1 -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 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, N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C r C 4 alkyl-, heteroaryKVC alkyl-, Ci-C 4 haloalkyl
  • 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, O, and S.
  • bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocycloalkyl ring.
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • Aryl does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • aryloxy refers to the group -O-aryl.
  • aralkyl refers to the group -alkyl-aryl.
  • -R a -OR 6 , optionally substituted amino (including -NR c COR b , -NR 0 CO 2 R 3 , -NR c CONR b R c , - NR b C(NR°)NR b R c , -NR b C(NCN)NR b R°, 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 c ), -OCOR b , -OCO 2 R 3 , -OCONR b R c , -OP(O)(O R b )OR c , sulfanyl
  • R is chosen from H, optionally substituted C- ⁇ -CQ alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and c
  • R is independently chosen from hydrogen and optionally substituted C1-C4 alkyl; or b c
  • 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 C 1 -C 4 alkyl, aryl, heteroaryl, aty ⁇ -C ⁇ C 4 alkyl-, heteroaryl-d-C4 alkyl-, C 1 -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 8 ⁇ yI)(C 1 -C 4 alkyl), -NH(C 1 -C 4 alkyl), -NH(C 1
  • 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:
  • 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.
  • 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 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.
  • 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, A- piperidyl, and 2,5-piperizinyl.
  • 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 ⁇ )alkyl), -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 ⁇ )alkyl), -S(0)-optionally substituted aryl), -S(O)-optionally substituted heteroaryl), -S(O)-(optionally substituted heterocycloalkyl); and -S(0)-(optionally substituted amino).
  • sulfonyl includes the groups: -S(O 2 )-(optionally substituted (CrC e )alkyl), -S( ⁇ 2 )-optionally substituted aryl), -S( ⁇ 2 )-optionally substituted heteroaryl), -S(O 2 )-(optionally substituted heterocycloalkyl) ,-S(O 2 )-(optio ⁇ ally substituted alkoxy), -S(O 2 )-optionally substituted aryloxy), -S(0 2 )-optionally substituted heteroaryloxy), -S(0 2 )-(optionally substituted heterocyclyloxy); and -S(0 2 )-(optionally substituted amino).
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic 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.
  • substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyi, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from:
  • -R a -OR
  • optionally substituted amino including -NR c COR b , -NR 0 CO 2 R 3 , -NR c CONR b R°, - 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°), -OCOR b , -OCO 2 R 3 , -OCONR b R c , -OP(O)(OR b )OR°, sulfanyl (such as
  • 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 1 -C 4 alkyl, aryl, heteroaryl, aryl-CrC 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, C 1 -C 4 haloalkyl, -OC 1 -C 4 alkyl,
  • substituted acyl refers to the groups (substituted alkyl)-C(O)-; (substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)-; and (substituted heterocycloalkyl)-C(O)-, wherein the 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:
  • alkoxycarbonyl such as -CO 2 R b
  • aminocarbonyl such as
  • R a is chosen from optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R b is chosen from H, optionally substituted CrC 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 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 Ci-C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-C 1 -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)(d-C 4
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e., - ⁇ -(substituted alkyl)) wherein “substituted alkyl” refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from:
  • -R a , -OR b 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°, 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°), -OCOR", -OCO 2 R 3 , -OCONR b R°, -OP(O)(OR b )OR c , sulfanyl (such as
  • -C 4 alkyl- C 1 -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 alkyl), -NH(C 1 -C 4 alkyl),
  • 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 c CONR b R c , - NR b C(NR°)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 3 , -OCONR b R°, -OP(O)(OR b )OR c , sulfanyl (such as SR b ), sulfinyl (such as -SOR a ), and sulfonyl (such as -SO 2 R 3 and -SO 2 NR b R°), where 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
  • 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, 817!-C 1 -C 4 alkyl-, heteroaryl-Crd alkyl-, C 1 -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-NHz, -N(C 1 -C 4 8 ⁇ yI)(
  • 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 acyi, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein R ⁇ 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 is chosen from optionally substituted C 1 -C 6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is chosen from H, optionally substituted CrC 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, 8FyI-C 1 -C 4 alkyl-, heteroaryl-CrCj alkyl-, C 1 -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)(Ci-C 4 alkyl), -NH(C 1 -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. 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.
  • 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. Where compounds of Formula X exists in various tautomeric forms, chemical entities of the present invention include all tautomeric forms of the compound.
  • Chemical entities of the present invention 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 ) n -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.
  • 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.
  • solvate refers to the chemical entity formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
  • chelate refers to the chemical entity formed by the coordination of a compound to a metal ion at two (or more) points.
  • non-covalent complex refers to the chemical entity formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule.
  • complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • 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.
  • 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.
  • Provided is at least one chemical entity chosen from compounds of Formula X
  • W 1 is chosen from N and CR 6 and W 2 is chosen from N and CR 4 , provided that both W 1 and W 2 are not N;
  • R 1 and R 4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
  • Z 1 is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , cyano, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted carbamimidoyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, sulfonyl, sulfinyl, and sulfanyl;
  • Z 2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
  • Z 3 is chosen from hydrogen, halogen, and optionally substituted alkyl
  • R 3 is chosen from hydrogen and optionally substituted alkyl; and R 6 is chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl.
  • W 1 is N and W 2 is CR 4 .
  • W 1 is CR ⁇ and W 2 is N.
  • R 1 and R 4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
  • Z 1 is chosen from optionally substituted aryl and optionally substituted heteroaryl
  • Z 2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
  • Z 3 is chosen from hydrogen and optionally substituted alkyl
  • R 3 is chosen from hydrogen and optionally substituted alkyl.
  • Z 1 is optionally substituted aryl.
  • Z 1 is optionally substituted heteroaryl.
  • Z 3 is optionally substituted alkyl.
  • Z 3 is chosen from optionally substituted aralkyl and optionally substituted heteroaralkyl.
  • R 1 and R 4 are independently chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
  • Z 1 is optionally substituted aryl
  • Z 2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, and optionally substituted aminocarbonyl;
  • Z 3 is chosen from optionally substituted aralkyl and optionally substituted heteroaralkyl
  • R 3 is chosen from hydrogen and optionally substituted alkyl.
  • Z 2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
  • Z 2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
  • Z 2 is chosen from (2-(N- acetylaminomethyl)piperidin-1-yl)carbonyl; (2-aminomethylpiperidin-1-yl)carbonyl; 1-hydroxy-2- amino-ethyl; 2-((methylsulfonamido)methyl)piperidin-1-ylcarbonyl; 2-
  • R 3 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula II, R 3 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula II, R 3 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula II, R 3 is hydrogen.
  • R 4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl. In certain embodiments of compounds of Formula II, R 4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl. In certain embodiments of compounds of Formula II, R 4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl. In certain embodiments of compounds of Formula II, R 4 is hydrogen.
  • Z 2 is -C(O)-NR 2 R 5 wherein R 2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R 5 is chosen from hydrogen and optionally substituted alkyl.
  • R 2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
  • R 2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
  • R 2 is chosen from (1-(2- aminoethyl)-1H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin- 3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyl; (1H-imidazol-2-yl)methyl; (1 H-pyrazol-3-yl)methyl; (1-methyl-1 H-pyrazol-3-yl)methyl; (1 -methyl- 1 H-pyrazol-5-yl)methyl; (2- (aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)carbonylmethyl;
  • Z 3 is chosen from -(CH 2 ) r R 20 wherein r is chosen from 1 , 2, and 3 and R 20 is chosen from optionally substituted aryl and optionally substituted heteroaryl.
  • compounds of Formula M 1 Z 3 is chosen from 2-(3- methylphenyl)ethyl, 2-(1 H-imidazol-4-yl)ethyl, 2-(1-methyl-1H-imidazol-4-yl)ethyl, 2-(2,3- difluorophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2- (2-methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-(trifluoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2-(
  • Z 3 is 2-(pyridin-2-yl)ethyl.
  • Z 1 is chosen from aryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamlmidoyl, and optionally substituted sulfonyl.
  • Z 1 is chosen from phenyl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, lower alkenyl, lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, lower acyl, dialkylamino, acetylamino, carbamimidoyl optionally substituted with cyano, aralkyl, and herteroaralkyl, and aminocarbonyl.
  • Z 1 is chosen from phenyl, 2-aminocarbonylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 2-cyanophenyl, 2-cyanomethylphenyl, 2-vinylphenyl, 2- formylphenyl, 3,4-difluorophenyl, 3-methylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3- cyanophenyl, 3-dimethylaminophenyl, 3-methoxyphenyl, 3-methoxymethylphenyl, 3- hydroxyphenyl, 3-trifluoromethylphenyl, 4-aminocarbonylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-hydroxymethylphenyl, A- trifiuoromethyl
  • R 1 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula II, R 1 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula II,
  • R 1 is chosen from hydrogen and methyl.
  • R 1 is hydrogen
  • R 1 and R 4 are independently chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
  • Z 1 is optionally substituted heteroaryl
  • Z 2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, and optionally substituted aminocarbonyl;
  • Z 3 is chosen from optionally substituted aralkyl and optionally substituted heteroaralkyl
  • R 3 is chosen from hydrogen and optionally substituted alkyl.
  • Z 1 is chosen from heteroaryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyi, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl.
  • Z 1 is chosen from 1 H-pyrazol-3-yl; 1 H-pyrazol-4-yl; 1 H-tetrazol-5-yl; 1-methyl-1 H-pyrazol-4-yl; 1-methyl-1 H-pyrazol-5-yl; 2- (hydroxymethyl)thiophen-3-yl; 2,2'-bipyridine; 2,3'-bipyridi ⁇ e; 2,4'-bipyridine; 2-cyanothiophen-3- yl; 2-formylthiophen-3-yl; 3-(hydroxymethyl)thiophen-2-yl; 3-cyano-1-methyl-1 H-pyrazol-4-yl; 3- formylthiophen-2-yl; 4-cyanothiophen-3-yl; 4-methylthiophen-2-yl; 4-methylthiophen-3-yl; 5-(1- hydroxyethyl)thiophen-2-yl; 5-(aminomethyl)thiophen-2-yl; 5-
  • Z 2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
  • Z 2 is chosen from 2- (methylamino)-2-oxoethyl, 2-amino-2-oxoethyl, 3-amino-3-oxopropyl, (2-(N- acetylaminomethyl)piperidin-1 -yl)carbonyl; (2-aminomethylpiperidin-1 -yl)carbonyl; 1 -hydroxy-2- amino-ethyl; 2-((methyIsulfonamido)methyl)piperidin-1-ylcarbonyl; 2-
  • R 3 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula III, R 3 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula III, R 3 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula III, R 3 is hydrogen.
  • R 4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl. In certain embodiments of compounds of Formula III, R 4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl. In certain embodiments of compounds of Formula III, R 4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxy methyl. In certain embodiments of compounds of Formula III, R 4 is hydrogen.
  • Z 2 is -C(O)NR 2 R 5 wherein R 2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R 5 is chosen from hydrogen and optionally substituted alkyl.
  • R 2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
  • R 2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
  • R 2 is chosen from (1-(2- aminoethyl)-1H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin- 3-yl)methyl; (1 -acetylpyrrolidin-2-yl)methyl; (1 H-imidazol-2-yl)methyl;
  • Z 3 is chosen from -(CH 2 ) r R 20 wherein r is chosen from 1 , 2, and 3 and R 20 is chosen from optionally substituted aryl and optionally substituted heteroaryl.
  • Z 3 is chosen from 2-(3- methylphenyl)ethyl, 2- ⁇ 1H-imidazol-4-yl)ethyl, 2-(1-methyl-1H-imidazol-4-yl)ethyl, 2-(2,3- difluorophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2- (2-methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-(trifluoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2- ⁇
  • Z 3 is chosen from 3- fJuorophenethyl, 3,5-difluorophenethyl, and 2-(pyridin-2-yl)ethyl. In certain embodiments of compounds of Formula III, Z 3 is 2-(pyridin-2-yl)ethyl.
  • R 1 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula III, R 1 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula III,
  • R 1 is chosen from hydrogen and methyl.
  • R 1 is hydrogen
  • R 1 and R 4 are independently chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
  • Z 1 is chosen from optionally substituted aryl and optionally substituted heteroaryl
  • Z 2 is chosen from hydrogen, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted amidino, and optionally substituted aminocarbonyl;
  • Z 3 is optionally substituted alkyl
  • R 3 is chosen from hydrogen and optionally substituted alkyl.
  • Z 1 is chosen from aryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted amino optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl, and heteroaryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alke ⁇ yl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted
  • Z 1 is chosen from aryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, optionally substituted lower acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and amino optionally substituted with alkyl, and heteroaryl optionally substituted by one or two groups selected from optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, optionally substituted lower acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optional
  • Z 1 is chosen from phenyl
  • Z 2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
  • Z 2 is chosen from carboxyl, optionally substituted pyridinylmethylcarbonyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
  • Z 2 is -C(O)NR 2 R 5 wherein
  • R 2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R 5 is chosen from hydrogen and optionally substituted alkyl.
  • R 2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
  • R 2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
  • R 2 is chosen from ⁇ 1-(2- aminoethyl)-1 H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin- 3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyl; (1 H-imidazol-2-yl)methyl; (1 H-pyrazol-3-yl)methyl; (1-rnethyl-1H-pyrazol-3-yl)methyl; (1-methyl-1H-pyrazol-5-yl)methyl; (2- (aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)car
  • R 2 is pyridin-3-ylmethyl.
  • R 5 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula IV, R 5 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula IV, R 5 is hydrogen.
  • Z 3 is chosen from optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl.
  • Z 3 is chosen from -(CH ⁇ J r R 20 wherein r is chosen from 1 , 2, and 3 and R 20 is chosen from optionally substituted heterocycloalkyl and optionally substituted cycloalkyl.
  • Z 3 is chosen from
  • R 1 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula IV, R 1 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula IV 1 R 1 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula IV, R 1 is hydrogen.
  • R 3 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula IV, R 3 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula IV, R 3 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula IV 1 R 3 is hydrogen.
  • R 4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl. In certain embodiments of compounds of Formula IV, R 4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl. In certain embodiments of compounds of Formula IV 1 R 4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl. In certain embodiments of compounds of Formula IV, R 4 is hydrogen. [0124] In certain embodiments, the compound of Formula I is chosen from

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Abstract

Chemical entities that modulate smooth muscle myosin and/or non-muscle myosin, and chemical entities, 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. 60/834,903, filed August 1, 2006, U.S. Provisional Patent Application No. 60/835,183, filed August 1, 2006, U.S. Provisional Patent Application No. 60/835,010, filed August 1, 2006, U.S. Provisional Patent Application No. 60/834,904, filed August 1, 2006, U.S. Provisional Patent Application No. 60/834,901, filed August 1, 2006, and U.S. Provisional Patent Application No. 60/835,236, filed August 2, 2006, each of which is incorporated herein by reference for all purposes.
[002] Provided are certain substituted heterocycles, including 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-l! 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 πoncovalently 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
W1 is chosen from N and CR6 and W2 is chosen from N and CR4, provided that both W1 and W2 are not N; R1 and R4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
Z1 is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , cyano, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted carbamimidoyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, sulfonyl, sulfinyl, and sulfanyl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is chosen from hydrogen, halogen, and optionally substituted alkyl;
R3 is chosen from hydrogen and optionally substituted alkyl; and
R6 is chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl.
[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. W
[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,N,N',N'-tetraacetic acid
Ac acetyl
APCI atmospheric pressure chemical ionization atm = atomosphere
Boc = tert-butoxycarbonyl 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
9 - gram GC = gas chromatograghy h or hr = hour
HATU = 0-(7-azabenzotriazol-1 -yl)-Λ/, N, N', N -tetramethyluron ium hexafluorophosphate
HBTU = 0-(benzotriazol-1 -yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate
HOBT = 1 -hydroxybenzotriazole
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 mL/g or L/Kg 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 C1-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 Ci 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-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cyc!oprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1 -en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-eπ-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, cyclobuta-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-1-yl, prop-2-yn-1-yl; butynyls such as but-1 -yπ-1-yl, but-i-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] The term "amidino" refers to the group -C(=NH)-NH2. The term "substituted amidino" refers to the formula -C(=NR')-NR"R" in which each of the R" groups is independently chosen from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, acyl, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl and R1 is chosen from hydrogen, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, acyl, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, provided that at least one R1 or R" group is not hydrogen.
[025] "Mono- and di-alkylcarboxamide" encompasses a group of the formula -(C=O)NR3Rb where Ra and Rb are independently chosen from hydrogen and alkyl groups of the indicated number of carbon atoms, provided that R3 and Rb are not both hydrogen. [026] "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)-. [027] Tormyl" refers to the group -C(O)H. [028] "Carboxy" and/or "carboxyl" refer to the group -C(O)OH.
[029] By "alkoxycarbonyl" is meant a group of the formula (alkoxy)(C=0)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a C1-C6 alkoxycarbony] 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 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 Ci-C4 alkyl; or Rband Rc taken together with the nitrogen to which they are bound, form an optionally substituted 5- to 7-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N, and S in the heterocycloalkyl ring; where each substituted group is independently substituted with one or more substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-CrC4 alkyl-, heteroaryKVC alkyl-, Ci-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyf-NH2, -N(C1-C4 alkyl)(CrC4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 3IRyI)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo
(as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl,
-CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(CrC4 alkyl),
-NHC(O)(phenyl), -N(C1-C4 3IkVl)C(O)(C1-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).
[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, O, and S.
For such fused, bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocycloalkyl ring. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
[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(=NR )-NR R where R , is chosen from: hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; f g 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 that at least one of Rβ, R , and R9 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, -OR6, optionally substituted amino (including -NRcCORb, -NR0CO2R3, -NRcCONRbRc, - NRbC(NR°)NRbRc, -NRbC(NCN)NRbR°, 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 -CONRbRc), -OCORb, -OCO2R3, -OCONRbRc, -OP(O)(O Rb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2R3 and -SO2NRbRc), where R is chosen from optionally substituted C-j-Cβ alkyl, optionally substituted aryl, and optionally substituted heteroaryl; b
R is chosen from H, optionally substituted C-\-CQ alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and c
R is independently chosen from hydrogen and optionally substituted C1-C4 alkyl; or b c
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 C1-C4 alkyl, aryl, heteroaryl, aty\-C^C4 alkyl-, heteroaryl-d-C4 alkyl-, C1-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 8^yI)(C1-C4 alkyl), -NH(C1-C4 alkyl),
-N(C1-C4 8^yI)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyiχCτ-0, alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(OXphenyl), -N(C1-C4 8^yI)C(O)(C1-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(CrC4 alkyl), -SO2(phenyl), -SO2(C1-C4 haloalkyl), -SO2NH2, -SO2NH(C1-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 S1 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, A- piperidyl, and 2,5-piperizinyl. 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-Cβ)alkyl), -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-Cβ)alkyl), -S(0)-optionally substituted aryl), -S(O)-optionally substituted heteroaryl), -S(O)-(optionally substituted heterocycloalkyl); and -S(0)-(optionally substituted amino). [049] The term "sulfonyl" includes the groups: -S(O2)-(optionally substituted (CrCe)alkyl), -S(θ2)-optionally substituted aryl), -S(θ2)-optionally substituted heteroaryl), -S(O2)-(optionally substituted heterocycloalkyl) ,-S(O2)-(optioπally substituted alkoxy), -S(O2)-optionally substituted aryloxy), -S(02)-optionally substituted heteroaryloxy), -S(02)-(optionally substituted heterocyclyloxy); and -S(02)-(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 (cycloalkyl)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, heterocycloalkyi, 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, -OR", optionally substituted amino (including -NRcCORb, -NR0CO2R3, -NRcCONRbR°, - 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 -SORa), and sulfonyl (such as -SO2R3 and -SO2NRbRc), where Ra is chosen from optionally substituted C1-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
Rband 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-CrC4 alkyl-, heteroaryl-Ci-C4 alkyl-, C1-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)(d-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(d-C4 alkylphenyl),
-NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 alkyl)(Ci-C4 alkyl), -CONH(Ci-C4 alkyl),
-CONH2, -NHC(O)(C1-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 8IkVl)C(O)(C1-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).
[052] The term "substituted acyl" refers to the groups (substituted alkyl)-C(O)-; (substituted cycloalkyl)-C(O)-; (substituted aryl)-C(O)-; (substituted heteroaryl)-C(O)-; and (substituted heterocycloalkyl)-C(O)-, wherein the 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, -NRcCO2Ra, -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), -OCORbi -OCO2R3, -OCONRbRc, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl
(such as -SORa), and sulfonyl (such as -SO2R3 and -SO2NR6R0), where Ra is chosen from optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; Rb is chosen from H, optionally substituted CrC6 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-Ci-C4 alkyl-, heteroaryl-C1-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)(d-C4 alkyl), -NH(C1-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)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(OXphenyl), -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)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(Ci-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., -©-(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, -NR0CO2R8, -NRcCONRbRc, - NRbC(NRc)NRbRc, -NRbC(NCN)NRbR°, 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°), -OCOR", -OCO2R3, -OCONRbR°, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2Ra and -SO2NRbR°), where Ra is chosen from optionally substituted C1-C6 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-Ci-C4 alkyl-, heteroaryl-C!-C4 alkyl-, C1-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(C1-C4 alkyl),
-N(C1-C4 8IKyI)(C1-C4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 8^yI)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 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)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). 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, -NRcCONRbRc, - NRbC(NR°)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, -OCO2R3, -OCONRbR°, -OP(O)(ORb)ORc, sulfanyl (such as SRb), sulfinyl (such as -SORa), and sulfonyl (such as -SO2R3 and -SO2NRbR°), 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 Rband 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, 817!-C1-C4 alkyl-, heteroaryl-Crd alkyl-, C1-C4 haloalkyl, -OC1-C4 alkyl, -OC1-C4 alkylphenyl, -C1-C4 alkyl-OH, -OC1-C4 haloalkyl, halo, -OH, -NH2, -C1-C4 alkyl-NHz, -N(C1-C4 8^yI)(C1-C4 alkyl), -NH(C1-C4 alkyl),
-N(C1-C4 8^yI)(C1-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)(Ci-C4 alkyl), -NHC(O)(phenyl), -N(C1-C4 alkyl)C(O)(d-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). [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 acyi, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein Rβ 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, -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)ORc, sulfanyl (such as SRb), sulfinyl
(such as -SORa), and sulfonyl (such as -SO2R3 and -SO2NRbRc), where Ra is chosen from optionally substituted C1-C6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rb is chosen from H, optionally substituted CrC6 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, 8FyI-C1-C4 alkyl-, heteroaryl-CrCj alkyl-, C1-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)(Ci-C4 alkyl), -NH(C1-C4 alkyl),
-N(C1-C4 alkyl)(CrC4 alkylphenyl), -NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO2H, -C(O)OC1-C4 alkyl, -CON(C1-C4 8IKyI)(C1-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -NHC(O)(C1-C4 alkyl), -NHC(OXphenyl), -N(C1-C4 alkyl)C(O)(d-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); 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 of the present invention include all tautomeric forms of the compound.
[058] Chemical entities of the present invention 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)n-COOH where n is 0-4, and like salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
[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-covalent complex" refers to the chemical entity formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). [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 imgf000022_0001
Formula X and pharmaceutically acceptable salts thereof wherein
W1 is chosen from N and CR6 and W2 is chosen from N and CR4, provided that both W1 and W2 are not N;
R1 and R4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
Z1 is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , cyano, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted carbamimidoyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, sulfonyl, sulfinyl, and sulfanyl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is chosen from hydrogen, halogen, and optionally substituted alkyl;
R3 is chosen from hydrogen and optionally substituted alkyl; and R6 is chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl.
[071] In some embodiments of compounds of Formula X, W1 is N and W2 is CR4. In some embodiments of compounds of Formula X1 W1 is CRβ and W2 is N. [072] Provided is at least one chemical entity chosen from compounds of Formula I
Figure imgf000023_0001
Formula I and pharmaceutically acceptable salts thereof, wherein
R1 and R4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
Z1 is chosen from optionally substituted aryl and optionally substituted heteroaryl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is chosen from hydrogen and optionally substituted alkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl. [073] In certain embodiments of compounds of Formula I, Z1 is optionally substituted aryl. [074] In certain embodiments of compounds of Formula I, Z1 is optionally substituted heteroaryl.
[075] In certain embodiments of compounds of Formula I, Z3 is optionally substituted alkyl.
[076] In certain embodiments of compounds of Formula I, Z3 is chosen from optionally substituted aralkyl and optionally substituted heteroaralkyl.
[077] Provided is at least one chemical entity chosen from compounds of Formula Il
Figure imgf000024_0001
Formula Il
and pharmaceutically acceptable salts thereof wherein
R1 and R4 are independently chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
Z1 is optionally substituted aryl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, and optionally substituted aminocarbonyl;
Z3 is chosen from optionally substituted aralkyl and optionally substituted heteroaralkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
[078] In certain embodiments of compounds of Formula II, Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl. In certain embodiments, Z2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl. In certain embodiments of compounds of Formula II, Z2 is chosen from (2-(N- acetylaminomethyl)piperidin-1-yl)carbonyl; (2-aminomethylpiperidin-1-yl)carbonyl; 1-hydroxy-2- amino-ethyl; 2-((methylsulfonamido)methyl)piperidin-1-ylcarbonyl; 2-
(methylaminocarbonyl)ethenyl; 2-(pyridin-3-ylmethyl)-2H-tetrazol-5-yl; aminomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ylcarbonyl. [079] In certain embodiments of compounds of Formula II, R3 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula II, R3 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula II, R3 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula II, R3 is hydrogen.
[080] In certain embodiments of compounds of Formula II, R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl. In certain embodiments of compounds of Formula II, R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl. In certain embodiments of compounds of Formula II, R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl. In certain embodiments of compounds of Formula II, R4 is hydrogen. [081] In certain embodiments of compounds of Formula II, Z2 is -C(O)-NR2R5 wherein R2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
[082] In certain embodiments of compounds of Formula II, R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[083] In certain embodiments of compounds of Formula II, R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[084] In certain embodiments of compounds of Formula II, R2 is chosen from (1-(2- aminoethyl)-1H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin- 3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyl; (1H-imidazol-2-yl)methyl; (1 H-pyrazol-3-yl)methyl; (1-methyl-1 H-pyrazol-3-yl)methyl; (1 -methyl- 1 H-pyrazol-5-yl)methyl; (2- (aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)carbonylmethyl; (2-(methylamino)ethylamino)carbonylmethyl; (2-(N- methyl-N-(t-butoxycarbonyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylmethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylamino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)methyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1 ,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- aminoethylamino)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)methyl; (6-(hydroxymethyl)pyridin-2-yl)methyl; (6-bromopyridin-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1-(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1 -(2-(tert-butoxycarbonylamtno)ethyl)-1 H- pyrazol-5-ylmethyl; 1-(aminocarbonyl)-2-(amino)-eth-1-yl; 1-(aminocarbonyl)-3-(amino)-propyl; 1-(aminocarbonyl)-4-(amino)-butyl; 1-(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1- (aminocarbonyl)-5-(amino)-pentyl; 1-(aminocarbonyl)eth-1-yl; 1-(carboxy)-2-(amino)-eth-1-yl; 1- (dimethylaminocarbonyl)-2-(amino)-eth-1 -yl; 1 -(hydroxy)-2-(aminocarbonylmethylamino)eth-1 -y I; 1-(hydroxy)-2-(ethoxycarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(pyridin-2-ylmethylamino)eth- 1-yl; 1-(methoxycarbonyl)-2-(amino)-eth-1-yl; 1-(methoxycarbonyl)-2-(t-butoxycarbonylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(arnino)-eth-1-yl (2 occ); 1- (methylaminocarbonyl)eth-i-yl; 1-aminocarbonyl-2-hydroxy-eth-1-yl; 1 -methoxycarbonyl-2- hydroxy-eth-1-yl; 2-(2-aminoethoxy)ethyl; 2-(2-aminoethyl)-pyridin-6-ylmethyl; 2-(2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-(acetylamino)ethyl; 2-(amino)ethyl; 2-(aminocarbonyl)-2- (acetylamino)-eth-i-yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamino)ethyl; 2- (dimethylaminocarbonyI)-2-(amino)-eth-1 -yl; 2-(ethoxycarbonyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamino)-eth-i-yl; 2-(methoxycarbonyl)-2-(amino)-eth-1-yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1 -yl; 2- (methylaminocarbonyl)-2-(amino)-eth-1-yl; 2-(methylsulfonamido)ethyl; 2-(methyoxycarbonyl)-2- (amino)-eth-i-yl; 2-(N-(t-butoxycarbony))-N-(methyl)-amino)ethyl; 2-(piperazin-1-yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridin-3-yimethyl; 2-(t-butoxycarbonyIaminomethyl)pyridin-6- ylmethyl; 2-(trifluoromethyl)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridin-5- ylmethyl; 2-chloropyridin-5-ylmethyl; 2-cyanopyridin-5-ylmethyl; 2-hydroxy-3-amino-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yl; 2-methoxypyridin-3-ylmethyl; 2-methoxypyridin-5-ylmethyl; 2- methylpyιϊdin-3-ylmethyl; 2-methylpyridin-5-ylmethyl; 2-methyipyridin-6-ylmethyl; 3-(2- aminoethyl)cyclohexyl)methyl; 3-{4-methylpiperazin-1 -yl)propyl; 3-(amino)-3- (methylaminocarbonyl)prop-i-yl; 3-(aminocarbonyl)propyl; 3-(aminomethyl)benzyl; 3- (aminomethyl)pyridin-2-ylmethyl; 3-(methoxycarbonyl)propyl; 3-(methylaminocarbonyl)propyl; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; 3-carbamoylcyclopentyl; 3-carboxy propyl; 3-hydroxypropyl; 3-methoxypropyl; 4- (aminomethyl)-pyridin-2-ylmethyl; 4-(N,N-dimethylamino)pyridin-3-ylmethyl; 4-{t- butoxycarbonylamino)-morpholinomethyl; 4-aminobutyl; 4-aminomethylpyridin-3-ylmethyl; 4- cyanobenzyl; 4-fluorobenzyl; 4-methylaminopyridin-3-ylmethyl; 4-methylbenzyl; 4- morpholinopyridin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5-
((bis(dimethylamino)methylamino)methyl)pyridin-3-ylmethyl; 5-(aminomethyl)pyridin-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethyl; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarbonylaminomethyl)-pyridin-2-ylmethyl; 5-(trifluoromethyl)-pyridin-2-ylmethyl; 5- aminopentyl; 5-aminopyridin-2-ylmethyl; 6-((bis(dimethylamiπo)methyleπeamiπo)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1 -yl)pyridin-3-ylmethyl); 6-(aminomethyl)pyridin-2-yl)methyl; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylaminocarbonylmethyl; isopropyl; isoxazo!-5-ylmethyl; methoxycarbonylmethyl; methyl; methylaminocarbonylmethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-yl methyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
[085] In certain embodiments of compounds of Formula II, Z3 is chosen from -(CH2)rR20 wherein r is chosen from 1 , 2, and 3 and R20 is chosen from optionally substituted aryl and optionally substituted heteroaryl.
[086] In certain embodiments of compounds of Formula M1 Z3 is chosen from 2-(3- methylphenyl)ethyl, 2-(1 H-imidazol-4-yl)ethyl, 2-(1-methyl-1H-imidazol-4-yl)ethyl, 2-(2,3- difluorophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2- (2-methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-(trifluoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethyl-1 H-pyrazol-1-yl)ethyl, 2-(3,5- dimethyl-1 H-pyrazol-4-yl)ethyl, 2-(3-carbamoylphenyl)ethyl, 2-(3-carboxyphenyl)ethyl, 2-(3- cyanophenyl)ethyl, 2-(3-fluorophenyl)-2-(hydroxy)-ethyl, 2-(3-fluorophenyl)ethyl, 2-(3- fluoropyridin-2-yl)ethyl, 2-(3-methoxycarbonylphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(3- methylphenyl)ethyl, 2-(4-aminophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2- (4-hydroxyphenyI)ethyl, 2-(benzo[d][1,3]dioxol-5-yl)ethyl, 2-(furan-2-yl)ethyl, 2-(hydroxy)-2- (phenyl)ethyl, 2-(phenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-phenylprop-1-yl, 3-{1H-imidazol-1-yl)prop-1-yI, 3-phenylpropyl, benzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, and thiophen-3-ylmethyl.
[087] In certain embodiments of compounds of Formula II, Z3 is 2-(pyridin-2-yl)ethyl. [088] In certain embodiments of compounds of Formula II, Z1 is chosen from aryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamlmidoyl, and optionally substituted sulfonyl. In certain embodiments of compounds of Formula II, Z1 is chosen from phenyl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, lower alkenyl, lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, lower acyl, dialkylamino, acetylamino, carbamimidoyl optionally substituted with cyano, aralkyl, and herteroaralkyl, and aminocarbonyl. In certain embodiments of compounds of Formula II, Z1 is chosen from phenyl, 2-aminocarbonylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 2-cyanophenyl, 2-cyanomethylphenyl, 2-vinylphenyl, 2- formylphenyl, 3,4-difluorophenyl, 3-methylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3- cyanophenyl, 3-dimethylaminophenyl, 3-methoxyphenyl, 3-methoxymethylphenyl, 3- hydroxyphenyl, 3-trifluoromethylphenyl, 4-aminocarbonylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-hydroxymethylphenyl, A- trifiuoromethylphenyl, 4-methoxycarbonylphenyl, 4-dimethylaminophenyl, 4-acetylphenyl, 4- carboxyphenyl, 4-ethylphenyl, 4-acetylaminophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 2,3- dimethylphenyl, 2,5-dimethylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4- dimethylphenyl, 2-chloro-4-fluoro-phenyl, 2-cyano-4-fluoro-phenyl, 2-chloro-6-fluoro-phenyl, 2- chloro-4-methoxy-phenyl, 2-cyano-4-methoxy-phenyl, 2-cyano-6-fluoro-phenyl, 2-chloro-5- fluoro-phenyl, 2-cyano-5-fluoro-phenyl, 2-chloro-4-methylphenyl, 2-chloro-4-hydroxymethyl- phenyl, 2-(N-(pyridin-3-ylmethyl)carbamimidoyl)phenyl, and 2-cyano-4-methylphenyl.
[089] In certain embodiments of compounds of Formula II, R1 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula II, R1 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula II,
R1 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula II,
R1 is hydrogen.
[090] Provided is at least one chemical entity chosen from compounds of Formula III
Figure imgf000029_0001
Formula III
and pharmaceutically acceptable salts thereof wherein
R1 and R4 are independently chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
Z1 is optionally substituted heteroaryl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, and optionally substituted aminocarbonyl;
Z3 is chosen from optionally substituted aralkyl and optionally substituted heteroaralkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
[091] In certain embodiments of compounds of Formula III, Z1 is chosen from heteroaryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyi, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl. [092] In certain embodiments of compounds of Formula III, Z1 is chosen from 1 H-pyrazol-3-yl; 1 H-pyrazol-4-yl; 1 H-tetrazol-5-yl; 1-methyl-1 H-pyrazol-4-yl; 1-methyl-1 H-pyrazol-5-yl; 2- (hydroxymethyl)thiophen-3-yl; 2,2'-bipyridine; 2,3'-bipyridiπe; 2,4'-bipyridine; 2-cyanothiophen-3- yl; 2-formylthiophen-3-yl; 3-(hydroxymethyl)thiophen-2-yl; 3-cyano-1-methyl-1 H-pyrazol-4-yl; 3- formylthiophen-2-yl; 4-cyanothiophen-3-yl; 4-methylthiophen-2-yl; 4-methylthiophen-3-yl; 5-(1- hydroxyethyl)thiophen-2-yl; 5-(aminomethyl)thiophen-2-yl; 5-(hydroxymethyl)thiopheπ-2-yl; 5- (hydroxymethyl)thiophen-3-yl; 5-acetylthiophen-2-yl; 5-cyano-1 H-pyrazol-4-yl; 5-cyano-1- methyl-1 H-pyrazol-4-yl; 5-cyanothiophen-2-yl; 5-formylthiophen-2-yl; 5-formylthiophen-3-yl; 3- (aminomethyl)thiophen-2-yl; isoxazol-4-yl; thiazol-2-yl; thiophen-2-yl; and thiophen-3-yl. [093] In certain embodiments of compounds of Formula III, Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
[094] In certain embodiments of compounds of Formula III, Z2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl. [095] In certain embodiments of compounds of Formula III, Z2 is chosen from 2- (methylamino)-2-oxoethyl, 2-amino-2-oxoethyl, 3-amino-3-oxopropyl, (2-(N- acetylaminomethyl)piperidin-1 -yl)carbonyl; (2-aminomethylpiperidin-1 -yl)carbonyl; 1 -hydroxy-2- amino-ethyl; 2-((methyIsulfonamido)methyl)piperidin-1-ylcarbonyl; 2-
(methylaminocarbonyl)ethenyl; 2-(pyridin-3-ylmethyl)-2H-tetrazol-5-yl; amiπomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ylcarbonyl. [096] In certain embodiments of compounds of Formula III, R3 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula III, R3 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula III, R3 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula III, R3 is hydrogen.
[097] In certain embodiments of compounds of Formula III, R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl. In certain embodiments of compounds of Formula III, R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl. In certain embodiments of compounds of Formula III, R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxy methyl. In certain embodiments of compounds of Formula III, R4 is hydrogen. [098] In certain embodiments of compounds of Formula III, Z2 is -C(O)NR2R5 wherein R2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
[099] In certain embodiments of compounds of Formula III, R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[0100] In certain embodiments of compounds of Formula III, R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[0101] In certain embodiments of compounds of Formula III, R2 is chosen from (1-(2- aminoethyl)-1H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin- 3-yl)methyl; (1 -acetylpyrrolidin-2-yl)methyl; (1 H-imidazol-2-yl)methyl;
(1 H-pyrazol-3-yl) methyl; (1 -methyl-1 H-pyrazol-3-yl)methyl; (1 -methyl-1 H-pyrazol-5-yl) methyl; (2- (aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylarnino)carbonylmethyl; (2- (hydroxy)ethylamino)carbonylmethyl; (2-(methylamino)ethylamino)carbonylmethyl; (2-(N- methyl-N-(t-butoxycarbonyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylmethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylamino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)methyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1 ,3-dioxoisorndolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- aminoethylamiπo)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)methyl; (6-(hydroxymethyl)pyridin-2-yl)methyl; (6-bromopyridin-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1-(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1-(2-(tert-butoxycarbonylamino)ethyl)-1 H- pyrazoI-5-ylmethyl; 1-(aminocarbonyl)-2-(amino)-eth-1-yl; 1-(aminocarbonyt)-3-(amino)-propyl; 1-(aminocarbonyl)-4-(amino)-butyl; 1-(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1- (aminocarbonyl)-5-(amino)-pentyl; 1-(aminocarbonyl)eth-1-yl; 1-(carboxy)-2-(amino)-eth-1-yl; 1- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 1-(hydroxy)-2-(aminocarbonylmethylamino)eth-1-yl; 1 -(hydroxy)-2-(ethoxycarbonylmethylamino)eth-1 -yl; 1 -(hydroxy)-2-(pyridin-2-ylmethylamino)eth- 1-yl; 1 -(methoxycarbonyl)-2-(amino)-eth-1-yl; 1-(methoxycarbonyl)-2-(t-butoxycarbonylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(amiπo)-eth-1-yl (2 occ); 1- (methylaminocarbonyl)eth-i-yl; i-aminocarbonyl-2-hydroxy-eth-i-yl; 1-methoxycarbonyl-2- hydroxy-eth-1-yl; 2-(2-aminoethoxy)ethyl; 2-(2-aminoethyl)-pyridin-6-ylmethyl; 2-(2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-(acetylamino)ethyl; 2-(amino)ethyl; 2-(aminocarbonyl)-2- (acetylamino)-eth-i-yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamino)ethyl; 2- (dimethylaminocarbonyl)-2-(amino)-eth-1 -yl; 2-(ethoxycarbonyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamrno)-eth-i-yl; 2-(methoxycarbonyl)-2-(amino)-eth-1-yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1-yl; 2- (methylaminocarbonyl)-2-(amino)-eth-1 -yl; 2-(methylsulfonamido)ethyl; 2-(methyoxycarbonyl)-2- (amino)-eth-i-yl; 2-(N-(t-butoxycarbonyl)-N-(methyl)-amino)ethyi; 2-(piperazin-1-yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridin-3-ylmethyl; 2-(t-butoxycarbonylaminomethyl)pyridin-6- ylmethyl; 2-(trifluoromethyl)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridin-5- ylmethyl; 2-chloropyridin-5-ylmethyl; 2-cyanopyridin-5-ylmethyl; 2-hydroxy-3-amino-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yl; 2-methoxypyridiπ-3-ylmethyl; 2-methoxypyridin-5-ylmethyl; 2- methylpyridin-3-ylmethyl; 2-methylpyrϊdin-5-ylmethyl; 2-methylpyridin-6-ylmethyl; 3-(2- aminoethyl)cyclohexyl)methyl; 3-(4-methylpiperazin-1 -yl)propyl; 3-(amino)-3- (methylaminocarbonyl)prop-i-yl; 3-(aminocarbonyl)propyl; 3-(aminomethyl)benzyl; 3- (aminomethyl)pyridin-2-ylmethyl; 3-(methoxycarbonyl)propyl; 3-(methylamiπocarbonyl)propyl; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; 3-carbamoylcyclopentyl; 3-carboxypropyl; 3-hydroxypropyl; 3-methoxypropyl; A- (aminomethyl)-pyridin-2-ylmethyl; 4-(N,N-dimethylamino)pyridin-3-ylmethyl; 4-(t- butoxycarbonylamino)-morpholinomethyl; 4-aminobutyl; 4-aminomethylpyridin-3-ylmethyl; A- cyanobenzyl; 4-fluorobenzyl; 4-methylaminopyridin-3-ylmethyl; 4-methylbenzyl; A- morpholinopyridin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5-
((bis(dimethylamino)methylamino)methyl)pyridin-3-ylmethyl; 5-(aminomethyl)pyridin-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethyl; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarbonylaminomethyl)-pyridin-2-ylmethyl; 5-(trifluoromethyl)-pyridin-2-ylmethyl; 5- aminopentyl; 5-aminopyridin-2-ylmethyl; 6-((bis(dimethylamino)methyleneamino)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1-yl)pyridin-3-ylmethyl); 6-(aminomethyl)pyridin-2-yl)methyI; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylaminocarbonylmethyl; isopropyl; isoxazol-5-ylmethyl; methoxycarboπylmethyl; methyl; methylaminocarbonylmethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-ylmethyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
[0102] In certain embodiments of compounds of Formula III, Z3 is chosen from -(CH2)rR20 wherein r is chosen from 1 , 2, and 3 and R20 is chosen from optionally substituted aryl and optionally substituted heteroaryl.
[0103] In certain embodiments of compounds of Formula III, Z3 is chosen from 2-(3- methylphenyl)ethyl, 2-{1H-imidazol-4-yl)ethyl, 2-(1-methyl-1H-imidazol-4-yl)ethyl, 2-(2,3- difluorophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2- (2-methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-(trifluoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2-{3,5-difluorophenyl)ethyl, 2-(3,5-dimethyl-1 H-pyrazof-1-yl)ethyl, 2-(3,5- dimethyl-1H-pyrazol-4-yl)ethyl, 2-(3-carbamoylphenyl)ethyl, 2-(3-carboxyphenyI)ethyl, 2-(3- cyanopheπyOethyi, 2-(3-fluorophenyl)-2-(hydroxy)-ethyl, 2-(3-fludrophenyl)ethyl, 2-(3- fluoropyridin-2-yl)ethyl, 2-(3-methoxycarbonylphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(3- methylphenyl)ethyl, 2-(4-aminophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluoropheny!)ethyl, 2- (4-hydroxyphenyl)ethyl, 2-(benzo[d][1 ,3]dioxol-5-yl)ethyl, 2-(furan-2-yl)ethyl, 2-(hydroxy)-2- (phenyl)ethyl, 2-(phenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-phenylprop-1-yl, 3-(1 H-imidazol-1-yl)prop-1-yl, 3-phenylpropyl, benzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, and thiophen-3-ylmethyl. [0104] In certain embodiments of compounds of Formula III, Z3 is chosen from 3- fJuorophenethyl, 3,5-difluorophenethyl, and 2-(pyridin-2-yl)ethyl. In certain embodiments of compounds of Formula III, Z3 is 2-(pyridin-2-yl)ethyl.
[0105] In certain embodiments of compounds of Formula III, R1 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula III, R1 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula III,
R1 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula III,
R1 is hydrogen.
[0106] Provided is at least one chemical entity chosen from compounds of Formula IV
Figure imgf000034_0001
Formula IV and pharmaceutically acceptable salts thereof wherein
R1 and R4 are independently chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
Z1 is chosen from optionally substituted aryl and optionally substituted heteroaryl;
Z2 is chosen from hydrogen, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted amidino, and optionally substituted aminocarbonyl;
Z3 is optionally substituted alkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
[0107] In certain embodiments of compounds of Formula IV, Z1 is chosen from aryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted amino optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl, and heteroaryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkeπyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl. [0108] In certain embodiments of compounds of Formula IV, Z1 is chosen from aryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, optionally substituted lower acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and amino optionally substituted with alkyl, and heteroaryl optionally substituted by one or two groups selected from optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, optionally substituted lower acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and amino optionally substituted with alkyl.
[0109] In certain embodiments of compounds of Formula IV, Z1 is chosen from phenyl,
1 H-pyrazol-3-yl; 1H-pyrazol-4-yl; 1 H-tetrazol-5-yl; 1-methyl-1H-pyrazol-4-yl; 1-methyl-1H- pyrazol-5-yl; 2-aminomethylthiophen-5-yl; 2-cyanothiophen-3-yl; 2-formylthiophen-3-yl; 2- formylthiophen-4-yl; 2H-pyrrol-1(5H)-yl; 2-hydroxymethylthiophen-3-yl; 2- hydroxymethylthiophen-4-yl; 2-hydroxymethylthiophen-5-yl; 3-aminomethylthiophen-2yl; 3- cyano-1-methyl-1H-pyrazol-4-yl; 3-cyanothiophen-4-yl; 3-formylthiophen-2-yl; 3- hydroxymethylthiophen-2-yl; 4-methylthiophen-2-yl; 4-methylthiophen-3-yl; 5-(1-hydroxyeth-1- yl)-thiophen-2-yl; 5-acetylthiophen-5-yl; 5-cyano-1H-pyrazol-4-yl; 5-cyano-1-methyl-1H-pyrazol- 4-yl; 5-cyanothiophen-2-yl; 5-formylthiophen-2-yl; 5-hydroxymethylthiophen-2-yl; isoxazol-4-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; thiazol-2-yl;thiophen-2-yl; and thiophen-3-yl. In certain embodiments of compounds of Formula IV, Z1 is phenyl.
[0110] In certain embodiments of compounds of Formula IV, Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl. [0111] In certain embodiments of compounds of Formula IV, Z2 is chosen from carboxyl, optionally substituted pyridinylmethylcarbonyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
[0112] In certain embodiments of compounds of Formula IV1 Z2 is chosen from pyridin-
3-ylmethylcarbonyl, (2-(N-acetylaminomethyl)piperidin-1-yl)carbonyl; (2-aminomethylpiperidin-1- yl)carbonyl; 1-hydroxy-2-amino-ethyl; 2-({methylsulfonamido)methyl)piperidin-1-ylcarbonyl; 2- (methylaminocarbonyl)ethenyl; 2-(pyridin-3-ylmethyl)-2H-tetrazol-5-ylmethyl; amiπomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ytcarbonyl. [0113] In certain embodiments of compounds of Formula IV, Z2 is -C(O)NR2R5 wherein
R2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
[0114] In certain embodiments of compounds of Formula IV, R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[0115] In certain embodiments of compounds of Formula IV, R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[0116] In certain embodiments of compounds of Formula IV, R2 is chosen from {1-(2- aminoethyl)-1 H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin- 3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyl; (1 H-imidazol-2-yl)methyl; (1 H-pyrazol-3-yl)methyl; (1-rnethyl-1H-pyrazol-3-yl)methyl; (1-methyl-1H-pyrazol-5-yl)methyl; (2- (aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)carboπylmethyl; (2-(methylamino)ethylamino)carbonylmethyl; (2-(N- methyl-N-(t-butoxycarbonyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylmethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylamino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)methyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1 ,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- aminoethylamino)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)methyl; (6-(hydroxymethyl)pyridin-2-yl)methyl; (6-bromopyridiπ-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1-(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1-(2-(tert-butoxycarbonylamino)ethyl)-1H- pyrazol-5-ylmethyl; 1-(aminocarbonyl)-2-(amino)-eth-1-yl; 1-(aminocarbonyl)-3-(amino)-propyl; 1 -(aminocarbonyl)-4-(amino)-butyl; 1 -(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1 - (aminocarbonyl)-5-(amino)-pentyl; 1~(aminocarbonyl)eth-1-yl; 1-(carboxy)-2-(amino)-eth-1-yl; 1- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 1-(hydroxy)-2-(aminocarboπylmethylamino)eth-1-yl; 1-(hydroxy)-2-(ethoxycarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(pyridin-2-ylmethylamino)eth- 1-yl; 1-(methoxycarbonyl)-2-(amino)-eth-1-yl; 1-(methoxycarbonyl)-2-(t-butoxycarbonylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(amino)-eth-1-yl (2 occ); 1- (methylaminocarbonyl)eth-i-yl; i-aminocarbonyl-2-hydroxy-eth-i-yl; 1 -methoxycarbonyl-2- hydroxy-eth-1-yl; 2-(2-aminoethoxy)ethyl; 2-(2-amiπoethyl)-pyridin-6-ylmethyl; 2-(2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-(acetylamino)ethyl; 2-(amino)ethyl; 2-(aminocarbonyl)-2- (acetylamiπo)-eth-i-yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamino)ethyl; 2- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 2-(ethoxycarbonyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamino)-eth-i-yl; 2-(methoxycarboπyl)-2-(amino)-eth-1-yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1 -yl; 2- (methylamiπocarbony!)-2-(amiπo)-eth-1 -yl; 2-(methylsulfonamido)ethyl; 2-(methyoxycarbonyl)-2- (amino)-eth-i-yl; 2-(N-(t-butoxycarbonyl)-N-(methyl)-amino)ethyl; 2-(piperazin-1-yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridin-3-ylmethyl; 2-(t-butoxycarbonylaminomethyl)pyridin-6- ylmethyl; 2-(trifluoromethyl)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridin-5- ylmethyl; 2-chloropyridin-5-ylmethyl; 2-cyanopyridin-5-ylmethyl; 2-hydroxy-3-amino-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yl; 2-methoxypyridin-3-ylmethyl; 2-methoxypyridin-5-ylmethyl; 2- methylpyridin-3-yl methyl; 2-methylpyridin-5-ylmethyl; 2-methylpyridin-6-ylmethyl; 3-(2- aminoethyl)cyclohexyl)methyl; 3-(4-methylpiperazin-1 -yl)propyl; 3-(amino)-3- (methylamiπocarbonyl)prop-i-yl; 3-(aminocarbonyl)propyl; 3-(aminomethyl)benzyl; 3- (aminomethyI)pyridin-2-ylmethyl; 3-(methoxycarbonyl)propyl; 3-(methylaminocarbonyl)propyl; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; S-carbamoylcyclopentyl; 3-carboxy propyl; 3-hydroxypropyl; 3-methoxypropyl; 4- (aminomethyl)-pyridin-2-ylmethyl; 4-(N,N-dimethyfamino)pyridin-3-ylmethyl; 4-(t- butoxycarbonylamino)-morpholinomethyl; 4-aminobutyl; 4-aminomethylpyridin-3-ylmethyl; A- cyanobenzyl; 4-fluorobenzyl; 4-methyIamiπopyridin-3-ylmethyl; 4-methylbenzyl; 4- morpholinopyridin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5-
((bis(dimethylamino)methylamino)methyl)pyridin-3-ylmethyl; 5-(aminomethyl)pyridin-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethyl; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarbonylaminornethyl)-pyridin-2-ylmethyl; 5-(trifluoromethyl)-pyridin-2-ylmethyl; 5- aminopentyt; 5-aminopyridin-2-ylmethyl; 6-((bis(dimethylamino)methyleneamino)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1-yl)pyridin-3-ylmethyl); 6-(aminomethyl)pyridin-2-yl)methyl; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylaminocarbonylmethyl; isopropyl; isoxazol-5-ylmethyl; methoxycarbonylmethyl; methyl; methylaminocarbonyimethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-ylmethyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
[0117] In certain embodiments of compounds of Formula IV, R2 is pyridin-3-ylmethyl.
[0118] In certain embodiments of compounds of Formula IV, R5 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula IV, R5 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula IV, R5 is hydrogen.
[0119] In certain embodiments of compounds of Formula IV, Z3 is chosen from optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl. In certain embodiments of compounds of Formula IV1 Z3 is chosen from -(CH≥JrR20 wherein r is chosen from 1 , 2, and 3 and R20 is chosen from optionally substituted heterocycloalkyl and optionally substituted cycloalkyl.
[0120] In certain embodiments of compounds of Formula IV, Z3 is chosen from
(tetrahydrofuran-2-yl)methyl, 1-hydroxycyclohexylmethyl, 2-(1 ,3-dioxolan-2-yl)ethyl, 2-(1- methylpiperidin-4-yl)ethyl, 2-(2-oxoimidazolidin-1-yl)ethyl, 2-(2-oxopiperidin-1-yl)ethyl, 2-(2- oxopyrrolidin-1-yl)ethyl, 2-cyclohex-1-enylethyl, 2-cyclohexylethyl, and 2-morpholinoethyl. [0121] In certain embodiments of compounds of Formula IV, R1 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula IV, R1 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula IV1 R1 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula IV, R1 is hydrogen.
[0122] In certain embodiments of compounds of Formula IV, R3 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula IV, R3 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula IV, R3 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula IV1 R3 is hydrogen.
[0123] In certain embodiments of compounds of Formula IV, R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl. In certain embodiments of compounds of Formula IV, R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl. In certain embodiments of compounds of Formula IV1 R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl. In certain embodiments of compounds of Formula IV, R4 is hydrogen. [0124] In certain embodiments, the compound of Formula I is chosen from
COMPOUND CHEMICAL NAME
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- N-prop-2-enylcarboxamide
N-methyl(2-{[2-(3-methylphenyl)ethyl]amino}-6- phenyl(3-pyridyl))carboxamide
Figure imgf000039_0001
N-methyl{6-phenyl-2-[(2-ρhenylethyl)amino](3- pyridyl)}carboxamide {6-phenyl-2-[(2-phenylethyl)amino](3-pyridyl)}-N- prop-2-enylcarboxamide
(2-{[2-(3-methylphenyl)ethyl]amino}-6-phenyl(3- pyridyl))-N-prop-2-enylcarboxamide
N-methyl{6-phenyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-benzyl{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3- pyridyl)}carboxamide
{6-phenyl-2-[(2-phenylethyl)amino](3-pyridyl)}-N- (3-pyridylmethyl)carboxamide
N-(methylethyl){6-phenyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-
Figure imgf000040_0001
N-(2-pyridylmethyl)carboxamide
{6-phenyl~2-[(2-(2-pyridyl)ethyl)amino](3-pyιϊdyl)}- N-(4-pyridylmethyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- N-(3-pyridyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- N-(2-py ridyl)ca rboxam ide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- N-(4-pyridyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- N-(2-thienylmethyl)carboxamide
Figure imgf000041_0001
(6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- N-(3-thienylmethyl)carboxamide N-(oxolan-2-ylmethyl){6-phenyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[((2S)oxolan-2-yl)methyl]{6-phenyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide
tert-butyl 2-[({6-phenyl-2-[(2-(2- pyridyl)ethyl)amino]-3- pyridyl}carbonylamino)methyl]morpholine-4- carboxylate
N-[(1-acetyl(4-piperidyl))methyl]{6-phenyl-2-[(2- (2-pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[(1-acetyl(3-piperidyl))methyl]{6-phenyl-2-[(2- (2-py ridyl)ethy l)am i n o](3-pyridy l)}ca rboxa m ide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- N-(4-piperidylmethyl)carboxamide
{2-[(2-cyclohex-1 -enylethyl)amino]-6-phenyl(3- pyridyl)}-N-(3-pyridylmethyl)carboxamide
{6-phenyl-2-[(3-phenylpropyl)amino](3-pyridyl)}- N-(3-pyridy lmethy l)ca rboxam ide
{6-phenyl-2-[benzylamino](3-pyridyl)}-N-(3- pyridy lmethyl)ca rboxam ide
N-(1,3-oxazol-2-ylmethyl){6-phenyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-(imidazol-2-ylmethyl){6-phenyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[((2S)-1-acetylpyrrolidin-2-yl)methyl]{6-phenyl-
2-[(2-(2-pyridyl)ethyl)amino](3- pyridyl)}carboxamide
N-[((3R)-1-acetylpyrrolidin-3-yl)methyl]{6-phenyl-
Figure imgf000043_0001
2-[(2-(2-pyridyl)ethyl)amino](3- pyridyl)}carboxamide N-[((3S)-1-acetylpyrrolidin-3-yl)methyl]{6-phenyl-
2-[(2-(2-pyridyl)ethyl)amino](3- pyridyl)}carboxamide
methyl 2-({6-phenyl-2-[(2-phenylethyl)amino]-3- pyridyl}carbonylamino)acetate
[6-phenyl-2-(propylamino)(3-pyridyl)]-N-(3- pyridy lmethyl)carboxa m ide
{2-[(3-methylbutyl)amino]-6-phenyl(3-pyridyl)}-N- (3-pyridylmethyl)carboxamide
{2-[(2-cyclohexylethyl)amino]-6-phenyl(3- pyridyl)}-N-(3-pyridylmethyl)carboxamide
N-{[1-(methylsulfonyl)(3-piperidyl)]methylK6- phenyl-2-[(2-(2-pyridyl)ethyl)amino](3- pyridyl)}carboxamide
2-(aminomethyl)piperidyl 6-phenyl-2-[(2-(2-
Figure imgf000044_0001
pyridyl)ethyl)amino](3-pyridyl) ketone
N-{[1-({6-phenyl-2-[(2-(2-pyridyl)ethyl)amino]-3- pyridyl}carbonyl)-2-piperidyl]methyl}acetamide
2-{[(methylsulfonyl)amino]methyl}piperidyl 6- phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl) ketone
N-[(1-methylpyrazol-5-yl)methyl]{6-phenyl-2-[(2- (2-pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[(1-methylpyrazol-3-yl)methyI]{6-phenyl-2-[(2- (2-pyridyl)ethyl)amino](3-pyridyl)}carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- N-(pyrazol-3-ylmethyl)carboxamide
Figure imgf000045_0001
N-(isoxazol-5-ylmethyl){6-phenyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide N-[((3S)pyrrolidin-3-yl)methyl]{6-phenyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[((3R)pyrrolidin-3-yl)methyl]{6-phenyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide
{6-phenyl-2-[(2-phenylethyl)amino](3-pyridyl)}-N- (2-(2-pyridyl)ethyl)carboxamide
{6-phenyl-2-[(2-phenylethyl)amino](3-pyridyl)}-N- (2-(3-pyridyl)ethyl)carboxamide
N-methyl-2-({6-phenyl-2-[(2- phenylethyl)amino](3- pyridyl)}carbonylamino)acetamide
N,N-dimethyl-2-({6-phenyl-2-[(2- phenylethyl)amino](3- pyridyl)}carbonylamino)acetamide
N-(ca rbamoylmethyl){6-phenyl-2-[(2-
Figure imgf000046_0001
phenylethyl)amino](3-pyridyl)}carboxamide
(2-{[2-(2-oxopiperidyl)ethyl]amino}-6-phenyl(3- pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(1-methyl(4-piperidyl))ethyl]amino}-6- phenyl(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
{6-phenyl-2-[(2-(2-thienyl)ethyl)amino](3-pyιϊdyl)}- N-(3-pyridylmethyl)carboxamide
(2-{[2-(1-methylimidazol-4-yl)ethyl]amino}-6- phenyl(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
{2-[(2-(2-furyl)ethyl)amino]-6-phenyl(3-pyridyl)}-N- (3-pyridylmethyl)carboxamide
Figure imgf000047_0001
{2-[(oxolan-2-ylmethyl)amino]-6-phenyl(3- pyridyl)}-N-(3-pyridylmethyl)carboxamide {2-[(2-(1,3-dioxolan-2-yl)ethyl)amino]-6-phenyl(3- pyridyl)}-N-(3-pyridylmethyl)carboxamide
{2-[(3-imidazolylpropyl)amino]-6-phenyl(3- pyridyl)}-N-(3-pyridylmethyl)carboxamide
{2-[(2-morpholin-4-ylethyl)amino]-6-phenyl(3- pyridyl)}-N-(3-pyridylmethyl)carboxamide
{6-phenyl-2-[(2-phenoxyethyl)amino](3-pyridyl)}- N-(3-pyridylmethyl)carboxamide
{2-[(2-(2H-benzo[3,4-d]1,3-dioxolen-5- yl)ethyl)amino]-6-phenyl(3-pyridyl)}-N-(3- pyridylmethyl)carboxamide
(2-{[2-(2-oxoimidazolidinyl)ethyl]amino}-6- phenyl(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(2-{[2-(2-oxopyrrolidinyl)ethyl]amino}-6-phenyl(3-
Figure imgf000048_0001
pyridyl))-N-(3-pyridylmethyl)carboxamide
{2-[(2-imidazol-4-ylethyl)amino]-6-phenyl(3- pyridy1)}-N-(3-pyridylmethyl)carboxamide
(2-{[(hydroxycyclohexyl)methyl]amino}-6- phenyl(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(2-{[2-(3,5-dimethylpyrazol-4-yl)ethyl]amino}-6- phenyl(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(2-{[2-(3,5-dimethylpyrazolyl)ethyl]amino}-6- phenyl(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(2-{[2-(2-chlorophenyl)ethyl]amino}-6-(2- cyanophenyl)(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(2-
Figure imgf000049_0001
methylphenyl)ethyl]amino}(3-pyridyl))-N-(3- pyridylmethyljcarboxamide (6-(2-cyanopheny!)-2-{[2-(2- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(2- cyanophenyl)ethyl]amino}(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
{6-(2-cyanophenyl)-2-[(2-(2- thienyl)ethyl)amino](3-pyridyl)}-N-(3- pyridylmethyl)carboxamide
{6-(2-cyanophenyl)-2-[(2-(2-furyl)ethyl)amino](3- pyridyl)}-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluoro(2-pyridyl))ethyl]amino}-6- phenyl(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(2-{[2-(3-methylphenyl)ethyl]amino}-6-phenyl(3- pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(2-cyanσphenyl)-2-{[2-(2- hydroxyphenyl)ethyl]amino}(3-pyridyl))-N-(3-
Figure imgf000050_0001
pyridylmethyl)carboxamide
N-{[2-(aminornethyl)(3-pyridyl)]methyl}{6-pyrazol-
4-yl-2-[(2-(2-pyridyl)ethyl)amino](3- pyridyl)}carboxamide
N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)-2- hydroxyethyl]amino}-6-pyrazol-4-yl(3- pyridyl))carbonylamino]-isopropyl}-2-[(tert- butoxy)carbonylamino]acetamide
{5-fluoro-6-pyrazol-4-yl-2-[(2- pyrazolylethyl)amino](3-pyridyl)}-N-(3- pyridylmethyl)carboxamide
N-[(1R)-2-({5-fluoro-6-pyrazol-4-yl-2-[(2- pyrazolylethyl)amino](3-pyridyl)}carbonylamino)- isopropyl]-2-aminoacetamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[6-
(trifluoromethyl)(2-pyridyl)]methyl}carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000051_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[5-
(trifluoromethyl)(2-pyridyl)]methyl}carboxamide (6-(2-cyanophenyl)-2-{[2-(3- fluorophenyI)ethyl]amino}(3-pyridyl))-N-{[3-
(trifluoromethyl)(2-pyridyl)]methyl}carboxamide
N-[(6-chloro(3-pyridyl))methyl](6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyano(3-thienyl))-2-{[2-(3- fIuorophenyl)ethyl]amino}(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(2E)-3-(2-{[2-(3-fluorophenyl)ethyl]amino}-6- phenyl(3-pyridyl))-N-methylprop-2-enamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[6-
(methylamino)(3-pyridyl)]methyl}carboxamide
N-{[6-(dimethylamino)(3-pyridyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-4-
(hydroxymethyl)-6-phenyl(3-pyridyl))-N-(3-
Figure imgf000052_0001
pyridylmethyl)carboxamide
N-[(5-amino(2-pyrϊdyl))methyl](6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-5-
(hydroxymethyl)-6-phenyl(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl-5-[N-
(3-pyridylmethyl)carbamoyl](3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(5-(2-diazo-2-azavinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-
(3-pyridylmethyl)carboxamide
(5-(aminomethyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-
(3-pyridylrriethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Figure imgf000053_0001
methylpyrazol-3-yl)(3-pyridyl))-N-(3- pyridylmethyl)carboxamide N-({6-[3,3-bis(dimethylamino)-2-azaprop-2- enyl](2-pyridyl)}methyl)(6-(2-cyanophenyl)-2-{[2- (3-fl uoropheny l)ethyl]am ino}(3- pyridyl))carboxamide
tert-butyl 2-(6-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-3- pyridyl)carbonylamino]methyl}-2-pyridyl)acetate
N-{[4-(aminomethyl)(3-pyridyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridy1))carboxamide
N-{[3-(aminomethyl)(4-pyridyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(5-bromo-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrazol-4-yl(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(5-bromo-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(6-(5-cyanopyrazol-4-yl)-2-{[2-(3- fluorophenyl)ethyl]amiπo}(3-pyridyl))-N-(3-
Figure imgf000054_0001
pyridylmethyl)carboxamide
Figure imgf000055_0001
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-3- yl(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(3-cyano-1-methylpyrazol-4-yl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(6-(5-cyano-1-methylpyrazol-4-yl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-
4-yl(3-pyridyl))carbonylamino]-N- methylacetamide
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Figure imgf000055_0002
methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-N- methylacetamide
Figure imgf000056_0001
pyridylmethyl)carboxamide
N-{[6-(aminomethyl)(2-pyridyl)Jmethyl}(5-bromo-
Figure imgf000056_0002
2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3- pyridyl))carboxamide
rboxamide
Figure imgf000056_0003
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-3-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amiπo}(3-pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-5-yiJmethyl}(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000056_0004
yl)(3-pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3- pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(5-bromo-
2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-5-oxopyrrolidin-2-yl)methyl](6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2S)-5-oxopyrrolidin-2-yl)methyll(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{3-[(5S)-5-(2-diazo-2-azavinyl)-2- oxopyrrolidinyl]propyl}(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxam id e
N-[((2S)-1-{3-[(tert-butoxy)carbonylamino]propyl}- 5-oxopyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-2-
Figure imgf000057_0001
{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxamide N-{[(2S)-1-(2-aminoethyl)-5-oxopyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-1-(3-aminopropyl)-5-oxopyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{3-[(5S)-5-(aminomethyl)-2- oxopyrrolidinyl]propyl}(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxamide
N-{[(2R)-1-(2-aminoethyl)-5-oxopyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{3-[(5R)-5-(2-diazo-2-azavinyl)-2- oxopyrrolidinyl]propyl}(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxamide
N-{3-[(5R)-5-(aminomethyl)-2- oxopyrrolidinyl]propyl}(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxamide
N-{2-[(5S)-5-(aminomethyl)-2- oxopyrrolidinyl]ethyl}(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000058_0001
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{2-[(5R)-5-(aminomethyl)-2-
Figure imgf000059_0001
oxopyrrolidinyl]ethyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 412 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
Figure imgf000059_0002
rV N-[((2R)-5-oxopyrrolidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compound 413 pyridyl))carboxamide
N-[((2R)-5-oxopyrrolidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compou yl)(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-
Compou (pyrrolidin-2-ylmethyl)carboxamide
N-[((2R)-5-oxopyrrolidin-2-yl)methyl](2-{[2-(3-
Figure imgf000059_0003
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 420 pyridy l))carboxa m ide
}pyrrolidin-2- l)-2-{[2-(3-
Comp
Figure imgf000059_0004
-pyridyl))carboxamide lidin-2- (3-
Com
Figure imgf000060_0001
))carboxamide
N-{[1-(2-aminoethyl)pyrrolidin-2-yl]methyl}(6-(2-
Figure imgf000060_0002
cyanophenyl)-2-([2-(3-
Compound 424 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(4-aminobutyl)pyrrolidin-2-yl]methyl}(6-(2-
Figure imgf000060_0003
cyanophenyl)-2-{[2-(3-
Compound 425 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
methyl 2-({(2S)-2-amino-3-[(6-(2-cyanophenyl)-2-
Figure imgf000060_0004
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 428 pyridyl))carbonylamino]propyl}amino)acetate
2-({(2S)-2-amino-3-[(2-{[2-(3- henyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000060_0005
Compound 429 pyridyl))carbonylamino]propyl}amino)acetate
N-[((2S)-6-oxopiperazin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compoun pyridyl))carboxamide
N-[((2S)-6-oxopiperazin-2-yl)methyl](6-(2- cyanophenyl)-2-{[2-(3-
Figure imgf000060_0006
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 434
N-[((2R)-4-{3-[(tert-butoxy)carbonylamino]propyl}- 6-oxopiperazin-2-yl)methyl](6-(2-cyanophenyl)-2- {[2-(3-fluorophenyl)ethyl]arnino}(3-
Compoun pyridyl))carboxamide
N-[((2S)-6-oxopiperazin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compoun yl)(3-pyridyl))carboxamide
N-[((2S)-6-oxopiperazin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compoun pyridyl)) ca rboxam ide
N-{[(2R)-4-(3-aminopropyl)-6-oxopiperazin-2-
Figure imgf000061_0001
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 438 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-4-(2-aminoethyl)-6-oxopiperazin-2-
Figure imgf000061_0002
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 0 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-6-oxopiperazin-2-yl)methyl](6-(2-
Figure imgf000061_0003
cyanophenyl)-2-{[2-(3-
Compound 440 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[(2S)-4-(2-aminoethyl)-6-oxopiperazin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-4-(3-aminopropyl)-6-oxopiperazϊn-2-
Figure imgf000062_0001
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 452 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({(2R)-1 -[4-(1 ,3-dioxobenzo[c]a2olin-2-yl)butyl]- 5-oxopyrrolidin-2-yl}methyl)(6-(2-cyanophenyl)-2- {[2-(3-fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carboxamide
N-({(2R)-1-[5-(1 ,3-dioxobenzo[c]azoIin-2- yi)pentyll-5-oxopyrrolidin-2-yl}methyl)(6-(2-
Figure imgf000062_0002
cyanophenyl)-2-{[2-(3-
Compound 454 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
tert-butyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000062_0003
pyridyl))carbonylamino]methyl}pyrrolidinecarboxyl
Compound 455 ate
N-{[(2R)-1-(4-aminobuty!)-5-oxopyrrolidin-2-
Figure imgf000062_0004
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(5-aminopentyl)-5-oxopyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000062_0005
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 2
N-[((2R)pyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-
Figure imgf000063_0001
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 3 pyridyl))carboxamide
Figure imgf000063_0002
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
Compound 459 yl(3-pyridyl))-N-(pyrazol-3-ylmethyl)carboxamide
ΛTΎ (2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
"TΛJ methylpyrazol-4-yl)(3-pyridyl))-N-(pyrazol-3-
Compound 460 ylmethyl)carboxamide
Figure imgf000063_0003
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-3-
Compound 461 yl(3-pyridyl))-N-(pyrazol-3-ylmethyl)carboxamide
N-[((2R)-1-{4-[(tert- butoxy)carbonylamino]butanoyl}pyrrolidin-2-
Figure imgf000063_0004
yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
Compound 462 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)pyrrolidin-2-
Figure imgf000063_0005
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 464 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[1-(3-aminopropyl)pyrazol-3-yl3methyl}(6-(2-
Figure imgf000064_0001
cyanophenyl)-2-{[2-(3-
Compound 466 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-3-yl]methyl}(2-{[2-
Figure imgf000064_0002
(3-fluorophenyJ)ethyljamino}-6-(1-methylpyrazol-
Compound 467 4-yl)(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-3-yl]methyl}(2-{[2-
Figure imgf000064_0003
(3-fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compound 468 pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-5-yl]methyl}(2-{[2-
Figure imgf000064_0004
(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-
Compound 469 4-yl)(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-5-yl]methyl}(2-{[2-
Figure imgf000064_0005
(3-fiuorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compound 470 pyridyl))carboxarn id e
N-[((2R)-1-{2-[(tert- butoxy)carbonylamino]ethyl}pyrrolidin-2-
Figure imgf000064_0006
yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
Compound 471 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-{3-[(tert- butoxy)carbonylamino]propyl}pyrrolidin-2- yl)methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000064_0007
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 472
N-{[(2R)-1-(2-aminoethyl)pyrrolidin-2-
Figure imgf000065_0001
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 473 fluorophenyl)ethyl]amino}(3-pyridy!))carboxamide
N-{[(2R)-1-(3-aminopropyl)pyrrolidin-2-
Figure imgf000065_0002
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 474 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
o]ethyl}pyrazol-3- orophenyl)ethyl]amino}-6-
Com
Figure imgf000065_0003
))carboxamide
N-{[1-(2-aminoethyl)pyrazol-3-yl]methyl}(2-{[2-(3-
Figure imgf000065_0004
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 480 pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-3-yl]methyl}(2-{[2-(3-
Figure imgf000065_0005
fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compound 481 pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-5-yl]methyl}(2-{[2-(3-
Figure imgf000065_0006
fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compound 482 pyridyl))carboxamide N-{[1-<2-aminoethyl)pyrazol-3-yl]methyl}(2-{[2-(3-
Figure imgf000066_0001
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 483 yl)(3-pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-5-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compou yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-6-oxopiperazin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-6-oxopiperazin-2- yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compou methylpyrazol-4-yl)(3-pyridyI))carboxamide
N-{[(2R)-1-(3-aminopropyl)-6-oxopiperazin-2- yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compou pyrazol-4-yl(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-6-oxopiperazin-2-
Figure imgf000066_0002
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 488 pyrazol-3-yl(3-pyridyl))carboxamide
N-[((2R)-1-acetylpyrrolidin-2-yl)methyl](6-(2- cyanophenyl)-2-{[2-(3-
Figure imgf000066_0003
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 489
N-{l(2R)-1-(methylsulfonyl)pyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-methylpyrrolidin-2-yl)methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1 , 1 -dimethylpyrrolidin-2-yl)methyl](6-(2-
Figure imgf000067_0001
cyanophenyl)-2-{[2-(3-
Compound 492 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-{[3-(1 ,3-dioxobenzo[c]azolin-2- yl)propyl]sulfonyl}pyrrolidin-2-yI)methyl](6-(2-
Figure imgf000067_0002
cyanophenyl)-2-{[2-(3-
Compound 494 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({(2R)-1-[(2-aminoethyl)sulfonyl]pyrrolidin-2-
Figure imgf000067_0003
yl}methyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compound 495 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({(2R)-1-[(3-aminopropyl)sulfonyl]pyrrolidin-2-
Figure imgf000067_0004
yl}methyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compound 496 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[1-(3-aminopropyl)pyrazol-3-yl]methyl}(2-{[2-
Figure imgf000068_0001
(3-fluorophenyl)ethyl]amino}-6~pyrazol-4-yl(3-
Compound 497 pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-5-yl]methyl}(2-{[2-
Figure imgf000068_0002
(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 498 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}- 5-oxopyrrolidin-2-yl)methy[](2-{[2-(3-
Figure imgf000068_0003
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 520 yl)(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)-5-oxopyrrolidin-2- yl]methyl}(6-{1-
[(dimethylamino)(dimethylylidene)methyl]pyrazol-
Figure imgf000068_0004
4-yl}-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 522 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-
Figure imgf000068_0005
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 523 methylpyrazol-4-yl)(3-pyrldyl))carboxamide -methylpyrazol-4- }pyrrolidinecarboxyl
Compo
Figure imgf000068_0006
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2- yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Figure imgf000068_0007
pyrazol-4-yl(3-pyridyl))carboxamide Compound 526
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}- 5-oxopyrrolidϊn-2-yl)methyl](6-(2-cyanophenyl)-2-
Figure imgf000069_0001
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 528 pyιϊdyl))carboxamide
N-(2-amino-2-methylpropyl)(6-(2-cyanophenyl)-2-
{[2-(3-fIuorophenyl)ethyl]amino}(3-
Compou pyridyl))carboxamϊde
N-[((2R)pyrrolidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amJno}-6-pyrazol-4-yl(3-
Compou pyridyl))carboxamide
N-[((2R)pyrrolidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compou yl)(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000069_0002
fluoropheπyl)ethyl]amino}(3-pyridyl))-N-{2-methyl-
Compound 537 2-[(methylsulfoπyl)amiπo]propyl}carboxamide
N-[((2R)-1-{2-[(tert- butoxy)carbonylamino]acetyl}pyrrolidin-2-
Figure imgf000069_0003
yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(1-
Compound 538 methylpyrazol-4-yl)(3-pyridyl))carboxamide N-[((2R)-1-{3-[(tert- butoxy)carbonylamino]propanoyl}pyrrolidin-2-
Figure imgf000070_0001
yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 539 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-1-{4-[(tert- butoxy)carbonylamino]butanoyl}pyrrolidin-2-
Figure imgf000070_0002
yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 540 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2-
Figure imgf000070_0003
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 541 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)pyrrolidin-2-
Figure imgf000070_0004
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 542 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-
Figure imgf000070_0005
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 543 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-((2S)-2-aminopropyl)(6-(2-cyanophenyl)-2-{[2-
Figure imgf000070_0006
(3-fluorophenyl)ethyl]amino}(3-
Compound 544 py ridyl))ca rboxam ide
2-[(tert-butoxy)carbonylamino]-N-{2-[(6-(2- cyanophenyl)-2-{[2-(3- fluoropheπyl)ethyl]amino}(3-
Figure imgf000070_0007
pyridyl))carbonylamino]-tert-butyl}acetamide Compound 545
4-[(tert-butoxy)carbonylamino]-N-{2-[(6-(2- cyanophenyl)-2-{[2-(3-
Figure imgf000071_0001
fluorophenyl)ethyl]amino}(3-
Compound 546 pyridyl))carbonylamino]-tert-butyl}butanamide
N-{(1S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000071_0002
pyridyl))carbonylamino]-isopropyl}-4-[(tert-
Compound 547 butoxy)carbonylamino]butanamide
N-[((2R)-1-{5-[(tert- butoxy)carbonylamino]pentanoyl}pyrrolidin-2-
Figure imgf000071_0003
yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
Compound 548 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-amino-N-{2-[{6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000071_0004
fluorophenyl)ethyl]amino}(3-
Compound 549 pyridyl))carbonylamino]-tert-butyl}acetamide
4-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000071_0005
fluorophenyl)ethyl]amino}(3-
Compound 550 pyridyl))carbonylamino]-tert-butyl}butanamide
N-{[(2R)-1-(N-methylcarbamoyl)pyrrolidin-2-
Figure imgf000071_0006
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 551 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide methyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000072_0001
pyridyl))carbonylamino]methyl}pyrrolidinecarboxyl
Compound 552 ate
N-{(1S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amiπo}(3-
Figure imgf000072_0002
pyridyl))carbonylamino]-isopropyl>-2-
Compound 555 aminoacetamide
N-{(1S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000072_0003
pyridyl))carbonylamino]-isopropyl}-3-
Compound 556 aminopropanamide
N-{[(2R)-1-(5-aminopentanoyl)pyrrolidin-2-
Figure imgf000072_0004
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 557 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{(2S)-2-[(methylsulfonyl)amino]propyl}(6-(2-
Figure imgf000072_0005
cyanophenyl)-2-{[2-(3-
Compound 558 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-aminoethyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3-
Figure imgf000072_0006
pyridyl))carbonylamino]methyl}pyrrolidinecarboxyl
Compound 602 ate
N-[(2S)-2-(methylamino)propyl](6-(2- cyanophenyl)-2-{[2-(3-
Figure imgf000072_0007
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 603
N-((2R)-2-aminopropyl)(6-(2-cyanophenyl)-2-{[2-
(3-fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carboxamide
N-[(2R)-2-(methylamino)propyl](6-(2-
Figure imgf000073_0001
cyanophenyl)-2-{[2-(3-
Compound 605 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
ino]propyl}(6-(2-
Compo
Figure imgf000073_0002
3-pyridyl))carboxamide
N-{(2R)-2-[(methylsulfonyl)amino]propyl}(6-(2-
Figure imgf000073_0003
cyanophenyl)-2-{[2-(3-
Compound 607 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
ino]propyl}(6-(2-
Compo
Figure imgf000073_0004
3-pyridyl))carboxamide
N-{(1R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000073_0005
pyridyl))carbonylamino]-isopropyl}-2-[(tert-
Compound 609 butoxy)carbonylamino]acetamide N-{(1 R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000074_0001
pyridyl))carbonylamino]-isopropyl}-2-[(tert-
Compound 610 butoxy)carbonylamino]-N-methylacetamide
N-{(1R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000074_0002
pyridyl))carbonylamino]-isopropyl}-4-[(tert-
Compound 611 butoxy)carbonylamino]butanamide
N-{(1R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000074_0003
pyridyl))carbonylamino]-isopropyl}-4-[(tert-
Compound 612 butoxy)carbonylamino]-N-methylbutanamide
N-{(1S)-2-[(6-(2-cyanophenyl)-2-{t2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000074_0004
pyridyl))carbonylamino]-isopropyl}-2-amino-N-
Compound 613 methylacetamide
N-{(1S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyljamino}(3-
Figure imgf000074_0005
pyridyl))carbonylamino]-isopropyl}-4-amino-N-
Compound 614 methylbutanamide
N-{(1 R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000074_0006
pyridyl))carbonylamino]-isopropyl}-2-
Compound 615 aminoacetamide
N-{(1 R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]-isopropyl}-4-
Figure imgf000074_0007
aminobutanamide Compound 616
N-{(1R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000075_0001
pyridyl))carbonylamino]-isopropyl}-4-amino-N-
Compound 617 methylbutanamide
N-{(1 R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000075_0002
pyridyl))carbonylamino]-isopropyl}-2-amino-N-
Compound 618 methylacetamide
(5-fluoro-2-{[2-(3-fluoropheπyl)ethyl]amiπo}-6-(1-
Figure imgf000075_0003
methylpyrazol-4-yl)(3-pyridyl))-N-(3-
Compound 619 pyridylmethyl)carboxamide
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2-
Figure imgf000075_0004
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 463 fluorophenyl)ethyl]arnino}(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-
Figure imgf000075_0005
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 465 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-
Figure imgf000075_0006
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 410 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
Compoun yl(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
{6-(3-methylphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(3-fluorophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(3-cyanophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(3-methoxypheny])-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(3-hydroxyphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(3-chlorophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Figure imgf000076_0001
pyridylmethyl)carboxamide Compound 7
{2-[(2-(2-pyridyl)ethyl)amino]-6-[3-
(trifluoromethyl)phenyl](3-pyridyl)}-N-(3- pyridylmethyl)carboxamide
{6-[3-(dimethylamino)phenyl]-2-|;(2-(2-
Figure imgf000077_0001
pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compound 11 pyιϊdylmethyl)carboxamide
{6-(2-fluorophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(2-chlorophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(2-methylphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(2-methoxyphenyl)-2-[(2-(2-
Figure imgf000077_0002
pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compound 15 pyridylmethyl)carboxamide {6-(2-cyanophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-(2-thienyl)(3-
Compoun pyridyl)}-N-(3-pyridylmethyl)carboxamide
Figure imgf000078_0001
{2-[(2-(2-pyridyl)ethyl)amino]-6-(3-thienyl)(3-
Compound 58 pyridyl)}-N-(3-pyridylmethyl)carboxamide
{6-(4-hydroxyphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compou pyridylmethyl)carboxamide
{6-(2-hydroxyphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compou pyridylmethyl)carboxamide
{6-(4-ethylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-
Compound 26 pyridyl)}-N-(3-pyridylmethyl)carboxamide
N-(4-{6-[(2-(2-pyridyl)ethyl)amino]-5-[N-(3- pyridylmethyl)carbamoyl]-2-
Figure imgf000078_0003
pyridyl}phenyl)acetamide Compound 861
{6-(4-methyl(2-thienyl))-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(4-methyl(3-thienyl))-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(2,3-dimethylphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(2,5-dinnethylphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(2,4-dimethylphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamtde
{6-(3,5-dimethylphenyl)-2-[(2-(2-
Figure imgf000079_0001
pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compound 33 pyridylmethyl)carboxamide {6-(3,4-dimethylphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyιϊdyl)}-N-(3-
Compou pyridylmethyl)carboxamide
(2-{[2-(4-fluorophenyl)ethyl]amino}-6-phenyl<3-
Compou pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(4-chlorophenyl)ethyl]amino}-6-phenyl(3-
Compou pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-chlorophenyl)ethyl]amino}-6-phenyl(3-
Compou pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-methoxyphenyl)ethyl]amino}-6-pheny!(3-
Compou pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3-
Compou pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(2-chlorophenyl)ethyl]amino}-6-phenyl(3-
Figure imgf000080_0001
pyridyl))-N-(3-pyridylmethyl)carboxamide Compound 70
(2-{[2-(2-methoxyphenyl)ethyl]amino}-6-phenyl(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(2-methylphenyl)ethyl]amino}-6-phenyl(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(2-fluorophenyl)ethyl]amino}-6-phenyl(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(2,6-difluorophenyl)ethyl]amino}-6- phenyl(3-pyridyI))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6- phenyl(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(3,4-difluorophenyl)ethyl]amino}-6-
Figure imgf000081_0001
pheny!(3-pyridyl))-N-(3-
Compound 84 pyridylmethyl)carboxamide <2-{I2-(2,5-difluorophenyl)ethyl]amino}-6- phenyl(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxarnide
[6-phenyl-2-({2-[3-
(trifluoromethyl)phenyl]ethyl}amino)(3-pyridyl)]-N-
Compoun (3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-methyl(2- thienyl))(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(3- thienyl)(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(2-cyanophenyl)ethyl]amino}-6-phenyl(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-cyanophenyl)ethyl]amino}-6-phenyl(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(4-hydroxyphenyl)ethyl]amino}-6-phenyl(3-
Figure imgf000082_0001
pyridyl))-N-(3-pyridylmethyl)carboxamide Compound 91
(2-{[2-(2-hydroxyphenyl)ethyl]amino}-6-phenyi(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(4-aminophenyl)ethyl]amino}-6-phenyl(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
3-[2-{{6-phenyl-3-[N-(3-pyridylmethyl)carbamoyl]-
Compoun 2-pyridyl}amino)ethyl]benzamlde
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-(3- thienyl)(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-(4- methyl(2-thieπyl))(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-(2-
Figure imgf000083_0001
cyanophenyI)(3-pyridyl))-N-(3-
Compound 99 pyridylmethyl)carboxamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2- thienyl)(3-pyridyl))-N-(3-
Compound pyridylmethyl)carboxamide
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-(2- thienyl)(3-pyridyl))-N-(3-
Compound pyridylmethyl)carboxamide
methyl 3-[2-({6-phenyl-3-[N-(3- pyridylmethyl)carbamoyl]-2-
Compoun pyridyl}amino)ethyl]benzoate
Figure imgf000084_0001
2-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Compound 108 pyridylmethyl)carbamoyl]-2-pyridyl)benzamide
(6-(4-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
3-[2-({6-phenyl-3-[N-(3-pyridylmethyl)carbamoyl]-
Compoun 2-pyridyl}amino)ethyl]benzoic acid
(6-(2-chloro-4-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Figure imgf000084_0002
pyridylmethyl)carboxamide Compound 156
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-(4- fluorophenyl)(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(6-(2-cyano-4-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(6-(2-chloro-6-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-(2-chloro-5-methoxyphenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-(2-cyano-5-methoxyphenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-(2-cyano-6-fluorophenyl)-2-{[2-(3-
Figure imgf000085_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 206 pyridylmethyl)carboxamide (6-(2-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(2,3-difluorophenyl)ethyl]amino}-6-(2- cyanophenyl)(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-(2-chloro-5-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridy!))-N-(3-
Compou pyridylmethyl)carboxamide
(6-(2-cyano-5-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-(3-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-[2-(cyanomethyl)phenyl]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[3-
(hydroxymethyl)(2-thienyl)](3-pyridyl))-N-(3-
Figure imgf000086_0001
pyridylmethyl)carboxamide Compound 263
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(5-formyl(3- thienyl))(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[5-
(hydroxymethyl)(3-thienyl)](3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(6-(2-chloro-4-methylphenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(6-(2-cyano-4-methylphenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[3-
Figure imgf000087_0001
(hydroxymethyl)phenyl](3-pyridyl))-N-(3-
Compound 281 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[3-
Figure imgf000087_0002
(methoxymethyl)phenyl](3-pyridyl))-N-(3-
Compound 282 pyridylmethyl)carboxamide (6-(1 H-1 ,2,3,4-tetraazol-5-yl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-[2-chloro-5-(hydroxymethyl)phenyl]-2-{[2-(3-
Figure imgf000088_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 289 pyridylmethyl)carboxamide
(2R)-2-amino-4-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000088_0002
fluorophenyl)ethyl]amino}(3-
Compound 290 pyridyl))carbonylamino]-N-methylbutanamide
(2S)-2-amino-4-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000088_0003
fluorophenyl)ethyl]amino}(3-
Compound 294 pyridyl))carbonylamino]-N-methylbutanamide
N-(3-amino-2-hydroxypropyl)(6-(2-cyanophenyl)-
Figure imgf000088_0004
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 295 pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3- boc fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-phenyl(3-
Figure imgf000088_0005
pyridyl))carboxamide Compound 399
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compou pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-3-
Compou yl)(3-pyridyl))carboxamide
N-[((3R)(3-piperidyl))methyl](6-(2-cyanophenyl)-
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(4-
Compou piperidylmethyl)carboxamide
N-{[1-(2-aminoacetyl)(4-piperidyl)]methyl}(6-(2-
Figure imgf000089_0001
cyanophenyl)-2-{[2-(3-
Compound 505 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropanoyl)(4-piperidyl)]methyl}(6-
Figure imgf000089_0002
(2-cyanophenyl)-2-{[2-(3-
Compound 506 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[(3S)-1-(2-aminoacetyl)(3-piperidyl)]methyl}(6-
Figure imgf000090_0001
(2-cyanophenyl)-2-{[2-(3-
Compound 507 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(3S)-1-(3-aminopropanoyl)(3-
Figure imgf000090_0002
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 508 fluorophenyl)ethyl]amino}(3-pyridy!))carboxamide
N-l(1-acetyl(4-piperidyl))methyl](6-(2-
Figure imgf000090_0003
cyanophenyl)-2-{[2-(3-
Compound 509 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((3S)-1-acetyl(3-piperidyl))methyl](6-(2-
Figure imgf000090_0004
cyanophenyl)-2-{[2-(3-
Compound 510 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(4-aminobutanoyl)(4-piperidyl)]methyl}(6-(2-
Figure imgf000090_0005
cyanophenyl)-2-{[2-(3-
Compound 553 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
methyl 4-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-3- pyridyl)carbonylamino]methyl}p(peridinecarboxyla
Compou te
N-[((2R)(2-piperidyl))methyl](6-(2-cyanophenyl)-
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Figure imgf000090_0006
pyridyl))carboxamide Compound 559
N-{[(2R)-1-(2-aminoacetyl)(2-piperidyl)]methyl}(6-
Figure imgf000091_0001
(2-cyanophenyl)-2-{[2-(3-
Compound 560 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)(2-
Figure imgf000091_0002
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 561 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-{4-aminobutanoyl)(2-
Figure imgf000091_0003
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 562 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-acetyl(2-piperidyl))methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
methyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000091_0004
pyridyl))carbonylamino]methyl}piperidinecarboxyl
Compound 564 ate
N-({(2R)-1-[(3-aminopropyl)sulfonyl](2-
Figure imgf000091_0005
piperidyl)}methyl)(6-(2-cyaπopheπyl)-2-{[2-(3-
Compound 597 fluorophenyl)ethyl]amiπo}(3-pyridyl))carboxamide N-[((2R)-1-methyl(2-piperidyl))methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-((2R)-2,3-diaminopropanoyl)(2-
Figure imgf000092_0001
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 599 fiuorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-((2R)-2,4-diaminobutanoyl)(2-
Figure imgf000092_0002
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 600 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-((2R)-2,5-diaminopentanoyl)(2-
Figure imgf000092_0003
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 601 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({(2R)-1-[(2-aminoethyl)sulfonyl](2-
Figure imgf000092_0004
piperidyl)}methyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compound 626 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-((2S)-2,5-diaminopentanoyl)(2-
Figure imgf000092_0005
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 627 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-((2S)-2-aminopropanoyl)(2- piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000092_0006
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 628
N-{[(2R)-1-((2R)-2-aminopropanoyl)(2- piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-chloroethyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3-
Figure imgf000093_0001
pyridyl))carbonylamino]methyl}piperidinecarboxyl
Compound 630 ate
2-aminoethyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3-
Figure imgf000093_0002
pyridyl))carbonylamino]methyl}piperidinecarboxyl
Compound 631 ate
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-
Figure imgf000093_0003
yl]methyl}(2-{[2-(3,5-difluorophenyl)ethyl]amino}-
Compound 637 6-(2-cyanophenyl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-
Figure imgf000093_0004
yl]methyl}{6-(2-cyanophenyl)-2-[(2-cyclohex-1-
Compound 638 enylethyl)amino](3-pyridyl)}carboxamide
3-{[3-(N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-
Figure imgf000093_0005
yl]methyl}carbamoyl)-6-(2-cyanophenyl)(2-
Compound 639 pyridyl)]amino}-N,N-dimethylpropanamide N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-
Figure imgf000094_0001
yl]methyl}{6-(2-cyanophenyl)-2-[(2-
Compound 673 phenylethyl)amino](3-pyridyl)}carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2- yl]methylX6-(2-cyanophenyl)-2-[(2-(2H-3,4,5,6-
Figure imgf000094_0002
tetrahydropyran-4-yl)ethyl)amino](3-
Compound 674 pyridyl)}carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2- yl]methyl}{6-(2-cyanophenyl)-2-[(2-(2H-3,4,5,6-
Figure imgf000094_0003
tetrahydropyran-2-yl)ethyl)amino](3-
Compound 681 pyridyl)}carboxamide
N-{[(2R)-1-((2S)-2,3-diaminopropanoyl)pyrrolidin-
Figure imgf000094_0004
2-yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 689 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1 -((2S)-2-amino-3- methoxypropanoyl)pyrrolidin-2-yl]methyl}(6-(2-
Figure imgf000094_0005
cyanophenyl)-2-{[2-(3-
Compound 690 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1 -((2S)-2-amino-3- hydroxypropanoyl)pyrrolidin-2-yl]methyl}(6-(2-
Figure imgf000094_0006
cyaπophenyl)-2-{[2-(3-
Compound 691 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2- {[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Figure imgf000094_0007
pyridyl))carboxamide Compound 772
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000095_0001
fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compound 773 pyridyl))carboxamide
N-{[(2R)-1 -((2S)-2-amino-3- hydroxypropanoyl)pyrrolidin-2-yl]methyl}(5-fluoro-
Figure imgf000095_0002
2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-3-
Compound 774 yl(3-pyridyl))carboxamide
N-{[(2R)-1-((2S)-2-aminopropanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000095_0003
fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compound 775 pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000095_0004
fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
Compound 776 pyridyl))carboxamide
{6-(2-cyaπophenyl)-2-[(2-oxolan-2- ylethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
N-((2R)-2-aminopropyl)(5-fluoro-2-{[2-(3-
Figure imgf000095_0005
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 778 yl)(3-pyridyl))carboxamide N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000096_0001
yl)(3-pyridyl))carbonylamino]-isopropyl}~2-[(tert-
Compound 779 butoxy)carbonylamino]acetamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000096_0002
yl)(3-pyridyl))carbonylamino]-isopropyl}-2-
Compound 780 aminoacetamide
N-[((2R)-5-oxopyrrolidin-2-yl)methyl](5-fluoro-2-
Figure imgf000096_0003
{[2-(3-flυorophenyl)ethyl]amino}-6-(1-
Compound 787 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{(1 S)-2-[(5-fluoro-2~{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000096_0004
yl)(3-pyridyl))carbonylamino]-isopropyl}-2-
Compound 808 aminoacetamide
N-{{1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000096_0005
yl)(3-pyridyl))carbonylamino]-isopropyl}-2-
Compound 812 hydroxyacetamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000096_0006
yl)(3-pyridyl))carbonylamino]-isopropyl}-4-[(tert-
Compound 813 butoxy)carbonylamino]butanamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methy!pyrazol-4- yl)(3-pyridyl))carbonylamino]-isopropyl}-4-
Figure imgf000096_0007
aminobutanamide Compound 814
N-{(2R)-2-[(2-methoxyethyl)amino]propyl}(5-
Figure imgf000097_0001
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 830 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{(2R)-2-[(tert-butoxy)carbonylamino]propyl}(5-
Figure imgf000097_0002
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}~6-
Compound 831 pyrazol-4-y!(3-pyridyl))carboxamide
N-((2R)-2-aminopropyl)(5-fluoro-2-{[2-(3-
Figure imgf000097_0003
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 832 pyridyl))carboxamide
6 N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 833 yl)(3-pyridyl))carbonylamino]-isopropyl}acetamide
N-{(2R)-2-[(methylsulfonyl)amino]propyl}(5-
Figure imgf000097_0004
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 834 methy!pyrazol-4-yl)(3-pyridyl))carboxamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000097_0005
pyridyl))carbonylamino]-isopropyl}-2-
Compound 835 aminoacetamide (5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Figure imgf000098_0001
pyrazol-4-yl(3-pyridyl))-N-(2-
Compound 836 pyridylmethyl)carboxamide
N-{(2R)-2-[(2-hydroxyethyl)amino]propyl}(5-
Figure imgf000098_0002
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 837 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{(2R)-2-[(carbamoylmethyl)amino]propyl}(5-
Figure imgf000098_0003
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 847 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000098_0004
yl)(3-pyridyl))carbonylamino]-isopropyl}-2-
Compound 848 (dimethylamino)acetamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4- yl)(3-pyridyl))carbonylamino]-isopropyl}(2S)-2-
Figure imgf000098_0005
[(tert-butoxy)carbonylamino]-3-
Compound 849 hydroxypropanamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000098_0006
yl)(3-pyridyl))carbonylamino]-isopropyl}(2S)-2-
Compound 850 amino-3-hydroxypropanamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4- yl)(3-pyridyl))carbonylamino]-isopropyl}-2-amino-
Figure imgf000098_0007
2-methylpropanamide Compound 851
N-((1 R)-1-{[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amiπo}-6-(1-methylpyrazol-4-
Figure imgf000099_0001
yl)(3-pyridyl))carbonylamino]methyl}propyl)-2-
Compound 871 [(tert-butoxy)carbonylamino]acetamide
N-((1 R)-H[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000099_0002
yl)(3-pyridyl))carbonylamino3methyl}propyl)-2-
Compound 872 aminoacetamide
N-((1 R)-1-{[(5-ftuoro-2-{[2-(3- fluorophenyi)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000099_0003
pyridyl))carbonylamino]methyl}propyl)-2-[(tert-
Compound 873 butoxy)carbonylamino]acetamide
N-((1 R)-1-{[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000099_0004
pyridyl))carbonylamino]methyl}propyl)-2-
Compound 874 aminoacetamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3- fluorophenyl)ethylJamino}-6-(1-methylpyrazol-4-
Figure imgf000099_0005
yl)(3-pyridyl))carbonylamino]-isopropyl}(2S)-2-
Compound 877 aminopropanamide
N-((2R)-3-hydroxy-2-methylbutyl)(5-fluoro-2-{[2-
Figure imgf000099_0006
(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-
Compound 878 4-yl)(3-pyridyl))carboxamide N-{[2-(aminomethyl)(3-pyιϊdyl)]methyl}(6-(2- cyanophenyI)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compou pyridyl))carboxamide
(6-(2-cyan oph eny l)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-
Compou N-(3-pyridylmethyl)carboxamide
{6-(3,4-difluorophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compou pyridy lmethyl)ca rboxam ide
{6-(4-fluorophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compou pyridylmethyl)ca rboxam ide
{6-(4-chlorophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Figure imgf000100_0001
pyridylmethyl)carboxamide Compound 24
{6-(4-methylphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(4-cyanophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(4-methoxyphenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3- Compoun pyridylmethyl)carboxamide
{6-[4-(hydroxymethyl)phenyl]-2-[(2-(2-
Figure imgf000101_0001
pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compound 18 pyridylmethyl)carboxamide
CwO {6-(3,4-dichlorophenyl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compound 13 pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-[4-
Figure imgf000101_0002
(trifluoromethyl)phenyll(3-pyridyl)}-N-(3-
Compound 4 pyridylmethyl)carboxamide methyl 4-{6-[(2~(2-pyridyl)ethyl)amino]-5-[N-(3-
Compound pyridylmethyl)carbamoyl]-2-pyridyl}benzoate
{6-[4-(dimethylamino)phenyl]-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compound pyridylmethyl)carboxamide
{6-(4-acetylphenyl)-2-[(2-(2-
Figure imgf000102_0001
pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compound 2 pyridylmethyl)carboxamide
{6-phenyl-2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}-
Compoun N-(3-pyridylmethyl)carboxamide
4-{6-[(2-(2-pyridyl)ethyl)amino]-5-[N-(3-
Compoun pyridylmethyl)carbamoyl]-2-pyridyl}benzoic acid
N-(3-pyridylmethyl){6-(3-pyridyl)-2-[(2-(2-
Compoun pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-(3-pyridylmethyl){6-(4-pyridyl)-2-[(2-(2-
Figure imgf000102_0002
pyridyl)ethyl)amino](3-pyridyl)}carboxamide Compound 8
N-(3-pyridylmethyl){6-(2-pyridyl)-2-[(2-(2-
Compoun pyridyl)ethyl)amino](3-pyridyl)}carboxamide
4-{6-[(2-(2-pyridyl)ethyl)amino]-5-[N-(3-
Compoun pyridyl methyl) ca rbam oy l]-2-pyridyl}benzamide
{2-[(2-hydroxy-2-phenylethyl)amino]-6-phenyl(3-
Compoun pyridyl)}-N-(3-pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-(2-vinylphenyl)(3-
Compoun pyridyl)}-N-(3-pyridylmethyl)carboxamide
{6-[2-(methoxymethyl)phenyl]-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
{6-(2-formylphenyl)-2-[(2-(2-
Figure imgf000103_0001
pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compound 102 pyridylmethyl)carboxamide (2-{[2-(3-fluorophenyl)-2-hydroxyethyl]amino}-6- phenyl(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)-2- hydroxyethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-(1 ,3-thiazol-2-
Compoun yl)(3-pyridyl)}-N-(3-pyridylmethyl)carboxamide
{6-(1-methylpyrazol-4-yl)-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
[3-(aminomethyl)-6-phenyl(2-pyridyl)][2-(3-
Compou fluorophenyl)ethyl]amine
(6-(3,4-difluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{3-
Compou pyridylmethyl)carboxamide
(6-(5-cyano(2-thienyl))-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Figure imgf000104_0001
pyridylmethyl)carboxamide Compound 274
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(5-formyl(2- th ienyl))(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-formyl(2- thienyl))(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2-formyl(3- thienyl))(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
[2-{[2-(3-fluorophenyl)ethyl]amino}-6-(6-{[2-(3- fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))(3-pyridyl)]-N-
Compou (3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[2-
(hydroxymethyl)(3-thienyl)](3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
Figure imgf000105_0001
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-isoxazol-4-
Compound 214 yl(3-pyridyl))-N-(3-pyridylmethyl)carboxamide (6-(5-acetyl(2-thienyl))-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyιϊdyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-[3-(aminomethyl)(2-thienyl)]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[5-
(hydroxyethyl)(2-thienyl)](3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-(4-cyano(3-thienyl))-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-[5-(aminomethyl)(2-thienyl)]-2-{[2-(3-
Figure imgf000106_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 241 pyridylmethyl)carboxamide
N-{[5-(aminomethyl)(3-pyridyl)]methyl}(6-(2-
Figure imgf000106_0002
cyanophenyl)-2-{[2-(3-
Compound 306 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[5-
Figure imgf000106_0003
(hydroxymethyl)(3-pyridyl)]rnethyl}carboxamide Compound 307
N-({5-[3,3-bis(dimethylamino)-2-azaprop-2- enyl](3-pyridyl)}methyl)(6-(2-cyanophenyl)-2-{[2-
Figure imgf000107_0001
(3-fluorophenyl)ethyljamino}(3-
Compound 314 pyridyl))carboxamide
N-{[3-(aminomethyl)(2-pyridyl)]methyl}(6-(2-
Figure imgf000107_0002
cyanophenyl)-2-{[2-(3-
Compound 315 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(3-{[(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000107_0003
pyridyl))carbonylamino]methyl}(2-
Compound 316 pyridyl))methyl]carboxamide
Figure imgf000107_0004
N-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3-
Compound 331 pyridyl))methyl](3-pyridylamino)carboxamide
(5-chloro-6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(5-bromo-6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000107_0005
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 368 py ridylmethy l)carboxam ide (5-cyano-6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
N-[(2-chloro(3-pyridyl))methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({2-[(2-aminoethyl)amino](3-pyridyl)}methyl)(6-
(2-cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-5-
Figure imgf000108_0001
oxoindeno[3,2-b]pyridin-3-yl)-N-(3-
Compound 404 pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000108_0002
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(6-oxo(2-
Compound 408 piperidyl))methyl]carboxannide
N-[(1-{3-[(tert-butoxy)carbonylamino]propyl}-6- oxo(2-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-
Figure imgf000108_0003
(3-fluorophenyl)ethyl]amino}(3-
Compound 430 pyridyl))carboxamide
N-{[1 -(3-aminopropyl)-6-oxo(2- piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000108_0004
flυorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 431
N-[((2S)(2-piperidyl))methyl](6-(2-cyanophenyl)-
Figure imgf000109_0001
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 432 pyridyl))carboxamide
N-[((2S)-1-{2-[(tert- butoxy)carbonylamino]acetyl}(2-
Figure imgf000109_0002
piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
Compound 445 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-1-(2-aminoacetyl)(2-piperidyl)]methyl}(6-
Figure imgf000109_0003
(2-cyanophenyl)-2-{[2-(3-
Compound 446 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2S)-1-{3-[(tert- butoxy)carbonylamino]propanoyl}(2-
Figure imgf000109_0004
piperidyl))nnethyl](6-(2-cyanopheπyl)-2-{[2-(3-
Compound 448 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-1-(3-aminopropanoyl)(2-
Figure imgf000109_0005
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 450 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-1-(methylsulfonyl)(2-piperidyl)]methyl}(6-
Figure imgf000109_0006
(2-cyanophenyl)-2-{[2-(3-
Compound 479 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-[((2R)-6-oxo(2-piperidyl))methyl](6-(2-
Figure imgf000110_0001
cyanophenyl)-2-{[2-(3-
Compound 511 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}- 6-oxo(2-piperidyl))methyl](6-(2-cyanophenyl)-2-
Figure imgf000110_0002
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 512 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-6-oxo(2-
Figure imgf000110_0003
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 513 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((3S)(3-piperidyl))methyl](6-(2-cyanophenyl)-
Figure imgf000110_0004
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 516 pyridyl))carboxamide
N-[((3R)-1-acetyl(3-piperidyl))methyl](6-(2-
Figure imgf000110_0005
cyanophenyl)-2-{[2-(3-
Compound 518 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
methyl (3R)-3-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000110_0006
pyridyl))carbonylamino]methyl}piperidinecarboxyl
Compound 519 ate
N-[((3R)-1-{2-[(tert- butoxy)carbonylamino]acetyl}(3- piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000110_0007
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 521
N-[((3R)-1-{3-[(tert- butoxy)carbonylamino]propanoyl}(3-
Figure imgf000111_0001
ρiperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
Compound 524 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((3R)-1-{4-[(tert- butoxy)carboπylamino]butanoyl}(3-
Figure imgf000111_0002
piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
Compound 527 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(3R)-1-(2-aminoacetyl)(3-piperidyl)]methyl}(6-
Figure imgf000111_0003
(2-cyanophenyl)-2-{[2-(3-
Compound 529 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(3R)-1-(3-aminopropanoyl)(3-
Figure imgf000111_0004
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 532 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(3R)-1 -(4-aminobutanoyl)(3-
Figure imgf000111_0005
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 533 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({(2R)-1-[4-(1 ,3-dioxobenzo[c]azolin-2-yl)butyl]- 6-oxo(2-piperidyl)}methyl)(6-(2-cyanophenyl)-2-
Figure imgf000111_0006
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 535 pyridyl))carboxamide N-{[(2R)-1-(4-aminobutyl)-6-oxo(2-
Figure imgf000112_0001
piperidyl)]methyl}(6-(2-cyanophenyl)-2-{j;2-(3-
Compound 536 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((3S,4S,2R,5R)-3,4,516-tetrahydroxy(2H- 3,4,5,6-tetrahydropyran-2-yl))methyl](6-(2-
Figure imgf000112_0002
cyanophenyl)-2-{[2-(3-
Compound 596 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-[5-(N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-
Figure imgf000112_0003
2-yl]methyl}carbamoyl)-6-{[2-(3-
Compound 667 fluorophenyl)ethyl]amino}-2-pyridyl]benzamide
N-[2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3-
HΑrx O fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]methyl}pyrrolidinyl)(1 S)-1 ■
Compound 668 methyl-2-oxoethyl](tert-butoxy)carboxamide
N-{[(2R)-1-((2S)-2-aminopropanoyl)pyrrolidin-2-
Figure imgf000112_0004
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 669 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(1R)-2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000112_0005
pyridyl))carbonylamino]methyl}pyrrolidiπyl)-1-
Compound 670 methyl-2-oxoethyl](tert-butoxy)carboxamide
N-{[(2R)-1-((2R)-2-aminoproρanoyl)pyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000112_0006
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 671
N-{[(2R)-1-((2S)-2,5-diaminopentanoyl)pyrrolidin-
Figure imgf000113_0001
2-yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 672 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(2-chloro(3-pyridyl))methyl](2-{[2-(3-
Figure imgf000113_0002
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 696 yl)(3-pyridyl))carboxamide
N-({2-[(3-aminopropyl)amino](3- pyridyl)}methyl)(2-{[2-(3-
Figure imgf000113_0003
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 699 py ridy I)) ca rboxam ide
N-({2-[(2-aminoethyl)amino](3-pyridyl)}methyl)(2-
Figure imgf000113_0004
{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 711 pyridyl))carboxamide
ylpyrazol-4-
Figure imgf000113_0005
lidinecarboxyl
Compound 712 ate
N-[((2R)pyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000113_0006
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 713 yl)(3-pyridyl))carboxamide N-[((2R)-1-{2-[(tert- butoxy)carbonylamino]acetyl}pyrrolidin-2- yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000114_0001
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 714 yl)(3-pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
Figure imgf000114_0002
yl(3-pyridyl))-N-({2-[(2-hydroxyethyl)amino](3-
Compound 717 pyridyl)}methyl)carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- ρyridyl))methyl](5-fluoro-2-{[2-(3-
Figure imgf000114_0003
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 745 pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2-
Figure imgf000114_0004
{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 746 py ridy I) ) ca rboxa m ide
N-[((2R)-1-{2-[(tert- butoxy)carbonylamino]acetyl}pyrrolidin-2- yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000114_0005
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 747 pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000114_0006
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 748 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert- butoxy)carbonylamino]propanoyl}pyrrolidin-2- yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000114_0007
pyridyl))carboxamide Compound 749
N-{[(2R)-1-(3-aminopropanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000115_0001
fluorophenyl)ethylJamino}-6-pyrazol-4-yl(3-
Compound 750 py ridyl))carboxam id e
N-[((2R)-1-{4-[(tert- butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000115_0002
fluoropheny0ethyl]amino}-6-pyrazol-4-yl(3-
Compound 751 pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000115_0003
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 752 pyridyl))carboxamide
N-[((2R)pyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000115_0004
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 753 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}- 5-oxopyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000115_0005
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 757 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2- yl]methyl}(5-fIuoro-2-{[2-(3-
Figure imgf000115_0006
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 758 py ridyl)) ca rboxam ide N-(carbamoylmethyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compou pyridyl))carboxamide
2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Figure imgf000116_0001
pyrazol-4-yl(3-pyridyl))carbonylamino]-N-
Compound 760 methylacetamide
N-[((2R)-1-{(2S)-2-[(tert-butoxy)carbonylamino]-3- hydroxypropanoyl}pyrrolidin-2-yl)methyl](5-fluoro-
Figure imgf000116_0002
2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
Compound 761 yl(3-pyridyl))carboxamide
N-{[(2R)-1 -((2S)-2-amino-3- hydroxypropanoyl)pyrrolidin-2-yl]methyl}(5-fluoro-
Figure imgf000116_0003
2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
Compound 762 yl(3-pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- pyridyl))methyl](5-fluoro-2-{[2-(3-
Figure imgf000116_0004
fluorophenyl)ethyl]amino}-6-(2-pyridyl)(3-
Compound 806 pyridyl))carboxamide
N-([2-(am[nomethyl)(3-pyridyl)]methyl}(5-fluoro-2-
{[2-(3-fluorophenyl)ethyl]amino}-6-(2-pyridyl)(3-
Compou pyridyl))carboxamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))-N-(2-hydroxy-2-
Figure imgf000116_0005
methy lpropyl)carboxam id e Compound 869
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Figure imgf000117_0001
methylpyrazol-4-yl)(3-pyridyl))-N-(3-hydroxy-2,2-
Compound 870 dimethylpropyl)carboxamide
N-((2R)-2-methyl-3-oxobutyl)(5-fluoro-2-{[2-(3-
Figure imgf000117_0002
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 879 yl)(3-pyridyl))carboxamide
N-((2R)-3-hydroxy-2,3-dimethylbutyl)(5-fluoro-2-
Figure imgf000117_0003
{[2-(3-fluorophenyl)ethyllamino}-6-(1-
Compound 880 methylpyrazol-4-yl)(3-pyridyl))carboxamide
2-((2R)-2-{[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4- yl)(3-pyridyl))carbonylamino]methyl}azetidinyl)-2- b oxoethyl 2-[(tert-butoxy)carbonylamino]acetate
2-((2R)-2-{[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000117_0004
yl)(3-pyridyl))carbonylamino]methyl}azetidinyl)-2-
Compound 908 oxoethyl 2-aminoacetate
2-((2R)-2-{[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000117_0005
yl)(3-pyridyl))carbonylamino]methyl}azetidinyl)-2-
Compound 909 oxoethyl dimethyl phosphate (2-{[2-(3-fluorophenyl)ethyl]amino}-6-[5-
(hydroxymethyl)(2-thienyl)](3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
N-({2-[(3-aminopropyl)amino](3- pyridyl)}methyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Figure imgf000118_0001
pyrazol-4-yl(3-pyridyl))-N-(3-
Compound 695 py ridy lmethy l)ca rboxam ide
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000118_0002
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 715 yl)(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-4-methyl(3-pyridyl))-N-
Compoun (3-pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(6-
Compoun morpholin-4-yl(3-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(6-
Figure imgf000118_0003
pyrrolidinyl(3-pyridyl))methyl]carboxamide Compound 217
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(6-
Compoun piperazinyl(3-pyridyl))rnethyl]carboxamide
N-{[6-(4-acetylpiperazinyl)(3-pyridyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(6-bromo(2-pyridyl))methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridy!))carboxannide
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[5- (hydroxy methyl) (2-th ienyl)](3-
Compoun pyridyl))carbonylamino]-N-methylacetamide
N-(2-carbamoylethyl)(2-{[2-(3- fluorophenyl)ethyl]amino}-6-[5- (hyd roxym ethy l)(2-thieπy I)] (3-
Compoun pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[5-
Figure imgf000119_0001
(hydroxymethyl)(2-thienyl)](3-pyridyl))-N-(2-
Compound 268 pyridylmethyl)carboxamide N-(carbamoyl methyl) (2-{[2-{3- fluorophenyl)ethyl]amino}-6-[5- (hydroxymethyl)(2-thienyl)](3-
Compou pyridyl))carboxamide
2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]-N-
Compou (methylsulfonyl)acetamide
N-{[3-(aminomethyl)cyclohexyl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
3-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000120_0001
fluorophenyl)ethyl]amino}-3-
Compound 325 pyridyl)carbonylamino]cyclopentanecarboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000120_0002
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(2-
Compound 339 piperazinylethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000120_0003
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(2-
Compound 340 pyrazin-2-ylethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amlno}(3-pyridyl))-N-(pyrazin-
Figure imgf000120_0004
2-ylm ethyl)ca rboxamide Compound 341
N-((1S)-5-amino-1-carbamoylpentyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(3-amino-1-carbamoylpropyl)(6-(2-
Figure imgf000121_0001
cyanophenyl)-2-{[2-(3-
Compound 350 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{(1 R)- 1 -carbamoyl-5- [<phenylmethoxy)carbonylamino]pentyl}(6-(2-
Figure imgf000121_0002
cyanophenyl)-2-{[2-(3-
Compound 351 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(4-amino-1-carbamoylbutyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((1 R)-5-amiπo-1 -carbamoylpentyl)(6-(2- cyaπopheπyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({6-[(2-aminoethyl)amino](2-pyridyl)}methyl)(6-
Figure imgf000121_0003
(2-cyanophenyl)-2-{[2-(3-
Compound 356 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-({6-[(3-aminopropyl)amino](2-
Figure imgf000122_0001
pyridyl)}methyl)(6-(2-cyan.ophenyl)-2-{[2-(3-
Compound 357 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{(4R)-4-carbamoyl-4-[(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3-
Figure imgf000122_0002
pyridyl))carbonylamino]butyl}(phenylmethoxy)car
Compound 401 boxamide
N-((1 S)-4-amino-1 -carbamoylbutyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((1 R)-4-amino-1 -carbamoylbutyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluoropheπyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluoropheπyl)ethyl]amino}(3-pyridyl))-N-
Compoun (pyrrolidin-3-ylmethyl)carboxamide
N-{[1-(2-aminoacetyl)pyrrolidin-3-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropanoyl)pyrrolidin-3- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000122_0003
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 442
N-{[1-(4-aminobutanoyl)pyrrolidin-3-yl]methyl}(6-
Figure imgf000123_0001
(2-cyanophenyl)-2-{[2-(3-
Compound 443 flυorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(1-acetylpyrrolidin-3-yl)methyl](6-(2-
Figure imgf000123_0002
cyanophenyl)-2-{[2-(3-
Compound 444 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrrolidin-3-yl]methyl}(6-(2- cyanopheny!)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(3-amino-2-carbamoylpropyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Figure imgf000123_0003
methylpyrazol-4-yl)(3-pyridyl))-N-[(6-
Compound 499 oxopiperazin-2-yl)methyl]carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
Figure imgf000123_0004
yl(3-pyridyl))-N-[(6-oxopiperazin-2-
Compound 500 yl)methyl]carboxamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-5- yl(3-pyιϊdyl))-N-[(6-oxopiperazin-2-
Compou yl)methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[4- (methylsulfonyl)-6-oxopiperazin-2-
Compou yl]methyl}carboxarnide
N-[(4-acetyl-6-oxopiperazin-2-yl)methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000124_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(4-
Compound 517 methyl-6-oxopiperazin-2-yl)methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000124_0002
fluorophenyl)ethyl]amino}(3-pyridyl))-N-{2-
Compound 581 [(methylamino)carbonylamino]ethyl}carboxamide
N-(2-{[(2-aminoethyl)sulfonyl]amino}ethyl)(6-(2-
Figure imgf000124_0003
cyanophenyl)-2-{[2-(3-
Compound 582 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2S)pyrrolidiη-2-yl)methyl](6-(2-cyanophenyl)-
2-{[2-(3-fIuorophenyl)ethyl]amino}(3-
Figure imgf000124_0004
pyridyl))carboxamide Compound 583
2-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000125_0001
fluorophenyl)ethyl]amino}(3-
Compound 584 pyridyl))carbonylamino]ethyl}acetamide
3-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000125_0002
fluorophenyl)ethyl]amino}(3-
Compound 585 pyridyl))carbonylamino]ethyl}propanamide
4-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000125_0003
fluorophenyl)ethyl]amino}(3-
Compound 586 pyridyl))carbonylamino]ethyl}butanamide
2-[(tert-butoxy)carbonylamino]-N-{2-[(6-(2- cyanophenyl)-2-{[2-(3-
Figure imgf000125_0004
fluorophenyl)ethyl]amino}(3-
Compound 587 pyridyl))carbonylamino]ethyl}-N-methylacetamide
4-[(tert-butoxy)carbonylamino]-N-{2-[(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000125_0005
pyridyl))carbonylamino]ethyl}-N-
Compound 588 methylbutanamide
N-{[(2S)-1-(2-aminoacetyl)pyrrolidin-2-
Figure imgf000125_0006
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 589 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[(2S)-1-(3-aminopropanoyl)pyrrolidin-2-
Figure imgf000126_0001
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 590 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-1-(4-amiπobutanoyl)pyrrolidin-2-
Figure imgf000126_0002
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 591 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000126_0003
fluorophenyl)ethyl]amino}(3-
Compound 592 pyridyl))carbonylamino]ethyl}-N-methylacetamide
3-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000126_0004
pyridyl))carbonylamino]ethyl}-N-
Compound 593 methylpropanamide
4-amino-N-{2-[(6-(2-cyanopheπyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000126_0005
pyridyl))carbonylamino]ethyl}-N-
Compound 594 methylbutanamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{2-
Compo [methyl(methylsulfonyl)amino]ethyl}carboxamide
3-amino-N-(2-aminoethyl)-2-{[(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000126_0006
pyridyl))carbonylamino]methyl}propanamide Compound 632
N-(2-carbonylamino-2-methylpropyl)(6-(2-
Figure imgf000127_0001
cyanophenyl)-2-{[2-(3-
Compound 633 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((2S)-2-amino-3-hydroxypropyl)(6-(2-
Figure imgf000127_0002
cyaπophenyl)-2-{[2-(3-
Compound 634 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((1S)-1-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000127_0003
pyridyl))carbonylamino]methyl}-2-hydroxyethyl)-
Compound 635 2-aminoacetamide
(2S)-2-(2-aminoacetylamino)-3-[(6-(2- cyanophenyl)-2-{[2-(3-
Figure imgf000127_0004
fluorophenyl)ethyl]amino}(3-
Compound 636 pyridyl))carbonylamino]propyl 2-aminoacetate
N-((1 R)-1-{[(6-(2-cyaπophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000127_0005
pyridyl))carbonylamino]methyl}-2-methylpropyl)-
Compound 643 2-hyd roxyacetam ide
N-((1R)-H[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000127_0006
pyridyl))carboπylamino]methyl}-2-methylpropyl)-
Compound 644 2-aminoacetamide N-((2R)-2-amino-4-methylpentyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((1R)-1-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]methyl}-3-methylbutyl)-2-
Compou hydroxyacetamide
N-((1R)-1-{[(6-(2-cyanophenyl)-2-{[2-(3- fluoropheπyl)ethyl]amino}(3-
Figure imgf000128_0001
pyridyl))carbonylamino]methyl}-3-methylbutyl)-2-
Compound 666 aminoacetamide
N-((1 R)-2-amino-1 -{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000128_0002
pyridyl))carbonylamino]methyl}ethyl)-2-
Compound 692 aminoacetamide
N-((1 R)-2-amino-1 -{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000128_0003
pyridyl))carbonylamino]methyl}ethyl)-2-
Compound 693 hydroxyacetamide
N-((3R)-2-oxo(3-piperidyl))(6-(2-cyanophenyl)-2-
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compoun pyridyl))carboxamide
{2-[((2R)-2-phenylpropyl)amino]-6-phenyl(3-
Figure imgf000128_0004
pyridyl)}-N-(3-pyridylmethyl)carboxamide Compound 103
N-(carbamoylethyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((1R)-1-carbamoylethyl)(6-(2-cyanophenyl)-2-
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compoun py ridy l))carboxam ide
methyl (2S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]propanoate
methyl (2R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]propanoate
methyl 2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000129_0001
fluorophenyl)ethyl]amino}-3-
Compound 133 pyridyl)carbonylamino]acetate
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000129_0002
fluorophenyl)ethyllamino}(3-pyridyl))-N-(2-
Compound 134 hydroxyethyl)carboxamide (6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(2-
Compou methoxyethyl)carboxamide
N-[2-(dimethylamino)ethyl](6-(2-cyanophenyl)-2-
Figure imgf000130_0001
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 136 pyridyl))carboxamide
N-{2-[(tert-butoxy)-N- methylcarbonylamino]ethyl}(6-(2-cyanophenyl)-2-
Figure imgf000130_0002
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 137 pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000130_0003
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[2-
Compound 138 (methylamino)ethyl]carboxamide
Figure imgf000130_0004
N-(3-aminopropyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compound 139 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compoun pyridyl))carbonylamino]-N-methylpropanamide
(2R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000130_0005
pyridyl))carbonylamino]-N-methylpropanamide Compound 292
N-{2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000131_0001
fluorophenyl)ethyl]amino}-3-
Compound 291 pyridyl)carbonylamino]ethyl}acetamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000131_0002
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[2-
Compound 143 (methoxycarbonylamino)ethyljcarboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000131_0003
fluorophenyl)ethyl]amino}(3-pyridyl))-N-{2-
Compound 144 [(methylsulfonyl)amino]ethyl}carboxamide ethyl 3-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000131_0004
fluorophenyl)ethyl]amino}-3-
Compound 145 pyridyl)carbonylamino]propanoate methyl 4-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000131_0005
fluorophenyl)ethyl]amino}-3-
Compound 287 pyridyl)carbonylamino]butanoate
3-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000131_0006
fluorophenyl)ethyl]amino}(3-
Compound 286 pyridyl))carbonylamino]-N-methylpropanamide 4-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000132_0001
fluorophenyl)ethyl]amino}(3-
Compound 148 pyridyl))carbonylamino]-N-methylbutanamide
N-(3-carbamoylpropyl)(6-(2-cyanophenyJ)-2-{[2-
Figure imgf000132_0002
(3-fluorophenyl)ethyl]amino}(3-
Compound 149 pyridyl))carboxamide
4-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000132_0003
fiuorophenyl)ethyl]amino}-3-
Compound 283 pyridyl)carbonylamiπo]butanoic acid
N-(2-aminoethyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanoρhenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(4-
Compou fluorophenyl)methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(4-
Compou cyanophenyl)methyl]carboxamide
N-[(3,4-difluorophenyl)methyl](6-(2-cyanophenyl)-
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Figure imgf000132_0004
pyridyl))carboxamide W
Compound 279
N-((1S)-1-carbamoyl-2-hydroxyethyl)(6-(2-
Figure imgf000133_0001
cyanophenyf)-2-{[2-(3-
Compound 155 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000133_0002
fiuorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 167 hydroxypropyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000133_0003
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 168 methoxypropyl)carboxamide
methyl (2S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compoun pyridyl))carbonylamino]-3-hydroxypropanoate
methyl (2R)-2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000133_0004
fluorophenyl)ethyl]amino}(3-
Compound 170 pyridyl))carbonylamino]-3-hydroxypropanoate
(2S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000133_0005
pyridyl))carbonylamino]-3-hydroxy-N-
Compound 262 methylpropanamide (2R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]-3-hydroxy-N-
Compoun methylpropanamide
(6-(2-cyanoρhenyl)-2-{[2-(3-
Figure imgf000134_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(2-
Compound 173 pyridylmethyl)carboxamide
(6-(2-cyanoρhenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(4-
Compou methylphenyl)methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(6-
Compou methyl(3-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000134_0002
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(6-
Compound 176 methyl(2-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000134_0003
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(2-(2-
Compound 177 pyridyl)ethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(2-(3-
Figure imgf000134_0004
pyridyl)ethyl)carboxamide Compound 178
N-[(6-amino(3-pyridyl))methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethy!]amino}(3-pyridyl))-N-[(6-
OMe methoxy(3-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(2-
Compou methyl(3-pyridyl))methyl]carboxamide
N-[(2-amino(3-pyridyl))methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(2-
Compou methoxy(3-pyridyl))methyl]carboxamide
(6-{2-cyanophenyl)-2-{[2-(3-
Figure imgf000135_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(1-
Compound 200 hydroxy(2-pyridyl))methyl]carboxamide (6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000136_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(1-
Compound 201 hydroxy(3-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000136_0002
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[3-(4-
Compound 202 methylpiperazinyl)propyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000136_0003
fluorophenyl)ethyl]amino}(3-pyridyl))-N-
Compound 203 (cyclopropylmethyl)carboxamide
N-[2-(dimethylamino)ethyl]-2-[(6-(2- cyanophenyl)-2-{[2-(3-
Figure imgf000136_0004
fluorophenyl)ethyl]amino}(3-
Compound 219 pyridyl))carbonylamino]acetamide
2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000136_0005
pyridyl))carbonylamino]-N-(2-
Compound 220 hydroxyethyl)acetamide
N-(2-carbamoylethyl)-2-[(6-(2-cyanophenyl)-2-{[2-
Figure imgf000136_0006
(3-fluorophenyl)ethyl]amino}(3-
Compound 221 pyridyl))carbonylamjno]acetamide -(3- mino}propanoic
Figure imgf000136_0007
Compound 222
N-{3-[(tert-butoxy)carbonylamino]propyl}-2-[(6-(2- cyanophenyl)-2-{[2-(3-
Figure imgf000137_0001
fluorophenyl)ethyl]amino}(3-
Compound 223 pyridyl))carbonylamino]acetamide
N-[3-(dimethylamino)propyl]-2-[(6-(2- cyanophenyl)-2-{[2-(3-
Figure imgf000137_0002
fluorophenyl)ethyl]amino}(3-
Compound 224 pyridyl))carbonylamino]acetamide
2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000137_0003
pyridyl))carbonylamino]-N-(3-
Compound 225 hydroxypropyl)acetamide
N-{2-[(tert-butoxy)-N-methylcarbonylamino]ethyl}- 2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000137_0004
fluorophenyl)ethyl]amino}(3-
Compound 232 pyridyl))carbonylamino]acetamide
2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000137_0005
pyridyl))carbonylamino]-N-[2-
Compound 233 (methylamino)ethyl]acetamide
methyl (2S)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-
Figure imgf000137_0006
(3-fluorophenyl)ethyl]amino}(3-
Compound 234 pyridyl))carbonylamino]propanoate N-((1S)-2-amino-1-carbamoylethyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2S)-3-[(tert-butoxy)carbonylamino]-2-[(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]propanoic acid
(2S)-3-[(tert-butoxy)carbonylamino]-2-[(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]-N-methylpropanamide
(2S)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]-N-methylpropanamide
(2S)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]-N,N-
Compou dimethylpropanamide
(2S)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]propanoic acid
methyl (2S)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-
(3-fluorophenyl)ethyl]amino}(3-
Figure imgf000138_0001
pyridyl))carbonylamino]propanoate Compound 245
methyl (2S)-2-(acetylamino)-3-[(6-(2- cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]propanoate
N-((2S)-2-amino-2-carbamoylethyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{(1 S)- 1 -carbamoyl-2-[(6-(2-cyanophenyl)-2-{[2-
(3-fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]ethyl}acetamide
(2S)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]-N-methylpropanamide
(2S)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]-N, N-
Compou dimethylpropanamide
(2S)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compound 251 pyridyl))carbonylamino]propanoic acid (2S)-2-(acetylamino)-3-[(6-(2-cyanophenyl)-2-{[2-
(3-fluorophenyl)ethyl]amino}(3-
Compoun pyridyl))carbonylamino]-N-methylpropanamide
methyl (2R)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-
(3-fIuorophenyl)ethyl]amino}(3-
Compoun pyridyl))carbonylamino]propanoate
N-((1 R)-2-amino-1 -carbamoylethyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2R)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000140_0001
fluorophenyl)ethyl]amino}(3-
Compound 257 pyridyl))carbonylamino]-N-methylpropanamide
methyl (2R)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-
(3-fluorophenyl)ethyl]amino}(3-
Compou pyridyl))carbonylamino]propanoate
N-((2R)-2-amino-2-carbamoylethyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(1 ,3-
Figure imgf000140_0002
oxazol-2-ylmethyl)carboxamide Compound 260
N-[(6-cyano(3-pyridyl))methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-phenyl(3-
Compou pyridyl))carboxamide
N-{[6-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-phenyl(3-
Compou pyridyl))carboxamide
Figure imgf000141_0001
2-amino-1-(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 288 phenyl(3-pyridyl))ethan-1 -ol
N-{[4-(aminomethyl)(2-pyridyl)]methyl}(6-(2-
Figure imgf000141_0002
cyanophenyl)-2-{[2-(3-
Compound 293 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(5-{[(tert-butoxy)carbonylamino]methyl}(2-
Figure imgf000141_0003
pyridyl))methyl](6-(2-cyanophenyl)-2-{(2-(3-
Compound 297 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[5-(aminomethyl)(2-pyridyl)]methyl}(6-(2-
Figure imgf000141_0004
cyanophenyl)-2-{[2-(3-
Compound 298 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[4-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000142_0001
fluorophenyl)ethyl]amino}-6-phenyl(3-
Compound 299 pyridyl))carboxamide
N-{[5-(amiπomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000142_0002
fluorophenyl)ethyl]amino}-6-phenyl(3-
Compound 300 pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000142_0003
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(isoxazol-
Compound 301 5-ylmethyl)carboxamϊde
2-{[2-(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Figure imgf000142_0004
phenyl(3-pyridyl))-2-
Compound 302 hydroxyethyl]amino}acetamide
Figure imgf000142_0005
ethyl 2-{[2-(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 305 phenyl(3-pyridyl))-2-hydroxyethyl]amino}acetate
Figure imgf000142_0006
1-(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3-
Compound 313 pyridyl))-2-[(2-pyridylmethyl)amino]ethan-1-ol
N-(4-aminobutyl)(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000142_0007
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 317
Figure imgf000143_0001
N-{5-aminopentyl)(6-(2-cyaπophenyl)-2-{[2-(3-
Compound 318 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
Figure imgf000143_0002
N-(6-aminohexyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compound 319 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{2-[6-(aminomethyl)(2-pyridyl)]ethyl}(6-(2-
Figure imgf000143_0003
cyanophenyl)-2-{[2-(3-
Compound 320 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{2-[6-(aminomethyl)(2-pyridyl)]ethyl}(2-{[2-(3-
Figure imgf000143_0004
fluorophenyl)ethyl]amino}-6-phenyl(3- Compound 321 pyridyl))carboxamide
N-{[6-(2-aminoethyl)(2-pyridyl)]methyl}(6-(2-
Figure imgf000143_0005
cyanophenyl)-2-{[2-(3-
Compound 322 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[6-(2-aminoethyl)(2-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000143_0006
fluorophenyl)ethyl]amino}-6-phenyl(3-
Compound 323 py ridyl))ca rboxam ide N-[2-(2-aminoethoxy)ethyl](6-(2-cyanophenyl)-2-
Figure imgf000144_0001
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 327 pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000144_0002
fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[6-
Compound 342 (hydroxymethyl)(2-pyridyl)]methyl}carboxamide
N-{[3-(aminomethyl)phenyl]methyl}(6-(2-
Figure imgf000144_0003
cyanophenyl)-2-{[2-(3-
Compound 343 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000144_0004
fluorophenyl)ethyl]amino}(3-
Compound 347 pyridyl))carbonylamino]-N,N-dimethylacetamide
N-{2-[(2-aminoethyl)amino]ethyl}(6-(2- cyanophenyl)-2-{[2-(3-
Comp fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000144_0005
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(2-oxo(3-
Compound 355 piperidyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyrrdyl))-N-(pyrazol-
Figure imgf000144_0006
3-ylmethyl)carboxam ide Compound 364
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000145_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(1-
Compound 365 methylpyrazol-3-yl)rnethyl]carboxamide
N-{[4-(aminomethyl)phenyl]methyl}(6-(2-
Figure imgf000145_0002
cyanophenyl)-2-{[2-(3-
Compound 366 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(6-{[(2-aminoethyl)amino]methyl}(2-
Figure imgf000145_0003
pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
Compound 367 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
methyl 6-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-3-
Figure imgf000145_0004
pyridyl)carbonylamino]methyl}pyridine-2-
Compound 376 carboxylate
6-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-3-
Figure imgf000145_0005
pyridyl)carbonylamino]methyl}pyridine-2-
Compound 377 carboxylic acid
6-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-3-
Figure imgf000145_0006
pyridyl)carbonylamino]methyl}pyridine-2-
Compound 378 carboxamide W
(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000146_0001
fluoropheπyl)ethyl]amiπo}(3-pyridyl))-N-[(1-
Compound 379 methylpyrazol-5-yl)methyl]carboxamide
N-(1-{2-[(tert-butoxy)carbonylamino]ethyl}-2-
Figure imgf000146_0002
oxo(3-piperidyl))(6-(2-cyanophenyl)-2-{[2-(3-
Compound 380 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[1-(2-aminoethyl)-2-oxo(3-piperidyl)](6-(2-
Figure imgf000146_0003
cyanophenyl)-2-{[2-(3-
Compound 381 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(2-{2-oxo- ridyl}θthyl)c
Co
Figure imgf000146_0004
N-[2-(3-amino-2-oxopiperidyl)ethyl](6-(2-
Figure imgf000146_0005
cyanophenyl)-2-{[2-(3-
Compound 383 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[2-(aminomethyl)phenyl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyf]amino}(3-pyridyl))-N-[(2-
Figure imgf000146_0006
oxopyrrolidin-3-yl)methyl]carboxamide Compound 397
N-[(2-{2-[(tert-butoxy)carbonylamino]ethyl}(3-
Figure imgf000147_0001
pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
Compound 415 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[2-(2-aminoethyl)(3-pyridyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{2-[3-(aminomethyl)(2-pyridyl)]ethyl}(6-(2- , cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((3S)-2-oxopyrrolidin-3-yl)(6-(2-cyanophenyl)-
Figure imgf000147_0002
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 418 pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[1-(2-
Figure imgf000147_0003
hyd roxyethy l)-2-oxo(3-
Compound 447 piperidyl)]methyl}carboxamide
N-{[1-(2-aminoethyl)-2-oxo(3-piρeridyl)]methyl}(6-
Figure imgf000147_0004
(2-cyanophenyl)-2-{[2-(3-
Compound 449 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide (6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[1-(3-
Figure imgf000148_0001
diazo-3-azaprop-3-enyl)-2-oxo(3-
Compound 477 pi peridyl)]methy l}carboxam ide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[3-(3- diazo-3-azaprop-3-enyl)-2-oxo(3-
Compoun piperidyl)]methyl}carboxamide
N-[((2R)piperazin-2-yl)methyl](6-(2-cyaπophenyl)-
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compoun pyridyl))carboxamide
N-[((2R)-1-methylpiperazin-2-yl)methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-acetylpiperazin-2-yl)methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(ethylsulfonyl)piperazin-2-yl]methyl}(6-
Figure imgf000148_0002
(2-cyanophenyl)-2-{[2-(3-
Compound 568 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide -(2-cyanophenyl)-2-{[2-(3- ]amino}(3- mino]methyl}piperazinecarboxyl
Figure imgf000148_0003
Compound 569
N-[((2S)-1-acetyl-4-methy1piperazin-2- yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
methyl (2S)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000149_0001
pyridyl))carbonylamino]methyl}-4-
Compound 571 methylpiperazineca rboxylate
N-{[(2R)-1-(2-aminoacetyl)piperazin-2-
Figure imgf000149_0002
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 572 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)piperazin-2-
Figure imgf000149_0003
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 573 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)piperazin-2-
Figure imgf000149_0004
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 574 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-1-(2-aminoacetyl)-4-methylpiperazin-2-
Figure imgf000149_0005
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 575 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[(2S)-1-(3-aminopropanoyl)-4- methylpiperazin-2-yl]methyl}(6-(2-cyanophenyl)-
Figure imgf000150_0001
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 576 pyridyl))carboxamide
N-{[(2S)-1-(4-aminobutanoyl)-4-methylpiperazin-
Figure imgf000150_0002
2-yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 577 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-4-(2-aminoacetyl)piperazin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{ϊ(2S)-4-(3-aminopropanoyl)piperazin-2-
Figure imgf000150_0003
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 579 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-4-(4-aminobutanoyl)piperazin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{{(2S)-4-(2-aminoacetyl)-1-methylpiperazin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-4-(3-aminopropanoyl)-1- methylpiperazin-2-yl]methyl}(6-(2-cyanophenyl)- 2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Figure imgf000150_0004
pyridyl))carboxam«de Compound 621
N-{[(2S)-4-(4-aminobutanoyl)-1-methylpiperazin-
2-yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)acetamide
N-[((2S)-1,4-diacetylpiperazin-2-yl)methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2S)-4-methylpiperazin-2-yl)methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compou fluoropheπyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)azetidin-2-yl)methyl](6-(2-cyanophenyl)-
Figure imgf000151_0001
2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 640 pyridyl))carboxamide
methyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000151_0002
pyridyl))carbonylamino]methyl}azetidinecarboxyla
Compound 641 te (2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))-N-[(2-
Compou oxopyrrolidin-3-yl)methyl]carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
Figure imgf000152_0001
yl(3-pyridyl))-N-[(2-oxopyrrolidin-3-
Compound 646 yl)methyl]carboxamide
N-{[(2R)-1-(2-hydroxyacetyl)pyrrolidin-2-
Figure imgf000152_0002
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 647 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
methyl 4-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000152_0003
pyridyl))carbonylamino]methyl}pyrrolidinyl)-4-
Compound 648 oxobutanoate
N-{[(2R)-1-(4-hydroxybutanoyl)pyrrolidin-2-
Figure imgf000152_0004
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 649 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(2-hydroxyacetyl)pyrrolidin-2-
Figure imgf000152_0005
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(1-
Compound 650 methylpyrazol-4-yl)(3-pyridyl))carboxamide
methyl 4-((2R)-2-{[(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4- yl)(3-pyridyl))carbonylamino]methyl}pyrrolidinyl)-
Figure imgf000152_0006
4-oxobutanoate Compound 651
N-{[(2R)-1-(4-hydroxybutanoyl)pyrrolidin-2-
Figure imgf000153_0001
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 652 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-1-acetylazetidin-2-yl)methyl](6-(2-
Figure imgf000153_0002
cyanophenyl)-2-{[2-(3-
Compound 653 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(methylsulfonyl)a2etidin-2-
Figure imgf000153_0003
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 654 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)azetidin-2-yl]methyi}(6-
Figure imgf000153_0004
(2-cyanophenyl)-2-{[2-(3-
Compound 655 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)azetidin-2-
Figure imgf000153_0005
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 656 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)azetidin-2-
Figure imgf000153_0006
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 657 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2-
Figure imgf000154_0001
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 658 f luoropheny l)ethyl]a m i no}(3-py ridyl))carboxam ide
methyl 4-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Figure imgf000154_0002
pyridyl))carbonylamino]methyl}azetidinyl)-4-
Compound 659 oxobutanoate
N-{[(2R)-1-(4-hydroxybutanoyl)azetidin-2-
Figure imgf000154_0003
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 660 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(azaperhydroepin-2-ylmethyl)(6-(2- cyanophβnyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(2-aminoacetyl)azaperhydroepin-2-
Figure imgf000154_0004
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 662 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropanoyl)azaperhydroepin-2-
Figure imgf000154_0005
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 663 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(4-aminobutanoyl)azaperhydroepin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-{3-
Figure imgf000154_0006
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 664
N-[(1-{3-[(tert-butoxy)carbonylamino]propyl}-2- oxopyrrolidin-3-yl)methyl](6-(2-cyanophenyl)-2-
Figure imgf000155_0001
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 675 pyridyl))carboxamide
N-{[1-(3-aminopropyl)-2-oxopyrro!idin-3-
Figure imgf000155_0002
yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 676 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(1-{3-[(tert-butoxy)carbonylamino]propyl}-2- oxopyrrolidin-3-yl)methyl](2-{[2-(3-
Figure imgf000155_0003
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 677 pyridyl))carboxamide
N-{[1-(3-aminopropyl)-2-oxopyrrolidin-3-
Figure imgf000155_0004
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 678 pyrazol-4-yl(3-pyridyl))carboxamide
N-[(1-{3-[(tert-butoxy)carbonylamino]propyl}-2- oxopyrrolidin-3-yl)methyl](2-{[2-(3-
Figure imgf000155_0005
fluorop he ny l)ethy l]amino}-6-( 1 -m ethylpyrazol-4-
Compound 679 y I) (3-pyιϊdyl))car boxam ide
N-{[1-(3-aminoproρyl)-2-oxopyrrolidin-3-
Figure imgf000155_0006
yl]methyl}(2-{[2-(3-fluoropheny!)ethyl]amino}-6-(1-
Compound 680 methylpyrazol-4-yl)(3-pyridyl))carboxamide tert-butyl (2R)-2-{[(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000156_0001
pyridyl))carbonylamino]methyl}pyrrolidinecarboxyl
Compound 682 ate
N-{[(2 R)- 1 -(2-hyd roxyacety l)pyrrolid i n-2-
Figure imgf000156_0002
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 683 pyrazol-4-yl(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyrϊdyl))-N-[(7-
Compou oxoazaperhydroepin-2-yl)methyl]carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4- yl(3-pyridyl))-N-[(7-oxoazaperhydroepin-2-
Compou yl)methyl]carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Figure imgf000156_0003
methylpyrazol-4-yl)(3-pyridyl))-N-[(7-
Compound 686 oxoazaperhydroepin-2-yl)methyl]carboxamide
N-[(1-{3-[(tert-butoxy)carbonylamino]propyl}-7- oxoazaperhydroepin-2-yl)methyl](6-(2-
Figure imgf000156_0004
cyanophenyl)-2-{[2-(3-
Compound 687 fluoropheπyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)-7-oxoazaperhydroepin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000156_0005
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 688
N-{[(2R)-1-(4-hydroxybutanoyl)pyrrolidin-2-
Figure imgf000157_0001
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 694 pyrazol-4-yl(3-pyridyl))carboxamide
N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2- yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[5-
Figure imgf000157_0002
(hydroxymethyl)(2-thienyl)](3-
Compound 697 pyridyl))carboxamide
N-{[(2R)-1-(2,3-dihydroxypropanoyl)azetidin-2-
Figure imgf000157_0003
yl]methyl}(6-(2-cyanoρhenyl)-2-{[2-(3-
Compound 698 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
tert-butyl (2R)-2-{[(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000157_0004
pyridyl))carbonylamino]methyl}azetidinecarboxyla
Compound 700 te
N-[((2R)azetidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compou pyridyl))carboxamidθ
N-[2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]methyl}azetidinyl)(1S)-1-
Figure imgf000157_0005
(hydroxymethyl)-2-oxoethyl](tert-
Compound 702 butoxy)carboxamide W
N-{[(2R)-1-((2S)-2-amino-3- hydroxypropanoyl)azetidin-2-yl]methyl}(6-(2-
Figure imgf000158_0001
cyanophenyl)-2-{[2-(3-
Compound 703 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(1R)-2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]methyl}azetidinyl)-1-
Figure imgf000158_0002
(hydroxymethyl)-2-oxoethyl](tert-
Compound 704 butoxy)carboxamide
N-{[(2R)-1 -((2R)-2-amino-3- hydroxypropanoyl)azetidin-2-yl]methyl}(6-(2-
Figure imgf000158_0003
cyanophenyl)-2-{[2-(3-
Compound 705 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]methyl}azetidinyl)(1S)-1-
Figure imgf000158_0004
(3-aminopropyl)-2-oxoethyl](tert-
Compound 706 butoxy)carboxamide
N-{[(2R)-1-((2S)-2,5-diaminopentanoyl)azetidin-
Figure imgf000158_0005
2-yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Compound 707 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2-
Figure imgf000158_0006
yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 708 pyrazol-4-yl(3-pyridyl))carboxamide
N-[((2R)-1-{2-[(tert- butoxy)carbonylamino]acetyl}azetidin-2- yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Figure imgf000158_0007
pyrazol-4-yl(3-pyridyl))carboxamide Compound 709 •
N-{[(2R)-1-(2-aminoacetyl)azetidin-2-yl]methyl}(2-
Figure imgf000159_0001
{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 710 pyridyl))carboxamide
N-[(6-bromo(2-ρyridyl))methyl](2-{[2-(3-
Figure imgf000159_0002
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 718 pyridyl))carboxamide
N-({6-[(3-aminopropyl)amino](2- pyridyl)}methyl)(2-{[2-(3-
Figure imgf000159_0003
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 719 pyridyl))carboxamide
N-({6-[(2-a m inoethyl)a m ino] (2-py ridyl)}methyl)(2-
Figure imgf000159_0004
{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 720 pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
Figure imgf000159_0005
yl(3-pyridyl))-N-({6-[(2-hydroxyethyl)amino](2-
Compound 721 pyridyl)}methyl)carboxamide
methyl (2R)-2-{[(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000159_0006
pyridyl))carbonylamino]methyl}azetidinecarboxyla
Compound 722 te N-[((2R)-1-{3-[(tert- butoxy)carbonylamino]propanoyl}pyrrolidin-2- yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000160_0001
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 723 y I) (3-py ridy l))carboxam ide
N-{[(2R)-1-(3-aminopropanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000160_0002
fIuorophenyl)ethyl]amino}-6-(1-methylpyra2oI-4-
Compound 724 yl)(3-pyridyl))carboxamide
N-[((2R)-1-{4-[(tert- butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000160_0003
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 725 yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000160_0004
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 726 yl)(3-pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- pyridyl))methyl](5-fluoro-2-{[2-(3-
Figure imgf000160_0005
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 727 yl)(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2-
Figure imgf000160_0006
{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 728 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}- 5-oxopyrro(idin-2-yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000160_0007
yl)(3-pyridyl))carboxamide Compound 729
N-{[(2 R)-1 -(3-am inopropy l)-5-oxopyrrol id i n-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000161_0001
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 730 yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(2,3-dihydroxypropanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000161_0002
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 731 yl)(3-pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[1-(2-
Figure imgf000161_0003
hydroxyethyl)pyrazol-4-yl](3-pyridyl))-N-(3-
Compound 732 pyridylmethyl)carboxamide
tert-butyl (2R)-2-{[(6-(2-cyaπopheπyl)-5-fluoro-2- {[2-(3-fluorophenyl)ethyl]amino}(3-
Figure imgf000161_0004
pyridyl))carbonylamino]methyl}pyrrolidinecarboxyl
Compound 733 ate
N-[((2 R)pyrrolid i n-2-yl)methy I] (6-(2-cyanopheny I)-
Figure imgf000161_0005
5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 734 pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- pyridyl))methyl](2-{[2-(3-
Figure imgf000161_0006
fluorophenyl)ethyl]amino}-6-[1-(2-
Compound 735 hydroxyethyl)pyrazol-4-yl](3-pyridyl))carboxamide "0V5 N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-[1-(2-
Compound 736 hydroxyethyl)pyrazol-4-yl](3-pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- pyridyl))methyl](6-(2-cyanophenyl)-5-fluoro-2-{[2-
Figure imgf000162_0001
(3-fluorophenyl)ethyl]amino}(3-
Compound 737 pyridyl))carboxamrde
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(6-(2-
Figure imgf000162_0002
cyanophenyl)-5-fluoro-2-{[2-(3-
Compound 738 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-{2-[(tert- butoxy)carbonylamino]acetyl}pyrrolidin-2-
Figure imgf000162_0003
yl)methyl](6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
Compound 739 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2-
Figure imgf000162_0004
yl]methyl}(6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
Compound 740 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-{3-[(tert- butoxy)carbonylamino]propanoyl}pyrrolidin-2-
Figure imgf000162_0005
yl)methyl](6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
Compound 741 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)pyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
Figure imgf000162_0006
fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide Compound 742
N-[((2R)-1-{4-[(tert- butoxy)carbonylamino]butanoyl}pyrrolidin-2-
Figure imgf000163_0001
yl)methyl](6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
Compound 743 fluorophenyl)ethyl]amino}(3-pyridyJ))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-
Figure imgf000163_0002
yl]methyl}(6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
Compound 744 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}- 5-oxopyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-5-
Figure imgf000163_0003
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 754 pyridyl))ca rboxam ide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-
Figure imgf000163_0004
yl]methyl}(6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
Compound 755 fiuorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(2,3-dihydroxypropanoyl)pyrrolidin-2-
Figure imgf000163_0005
yl]methyl}(6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
Compound 756 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide luoro-2-{[2-(3- ]amino}-6-(1-methylpyrazol-4- mino]methyl}pyrrolidiπyl)(1S)-1-
Comp
Figure imgf000163_0006
](tert-butoxy)carboxamide N-{[(2R)-1-((2S)-2-aminopropanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000164_0001
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 765 yl)(3-pyridyl))carboxamide
N-[((2R)-H(2S)-2,5-bis[(tert- butoxy)carbonylamino]pentanoyl}pyrrolidin-2- ό~ yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 766 yl)(3-pyridyl))carboxamide
N-{[(2R)-1-((2S)-2,5-diaminopentanoyl)pyrrolidin- 2-yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000164_0002
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 767 yl)(3-pyridyl))carboxamide ol-4- 1S)-1-
Com
Figure imgf000164_0003
N-{[(2R)-1-((2S)-2-amino-3- hydroxypropanoyl)pyrrolidin-2-yl]methyl}(5-fluoro-
Figure imgf000164_0004
2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(1-
Compound 769 methylpyrazol-4-yl)(3-pyridyl))carboxamide
methyl 4-((2R)-2-{[(5-fIuoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000164_0005
yl)(3-pyridyl))carbonylamino]methyl}pyrrolidinyl)-
Compound 770 4-oxobutanoate
N-{[(2R)-1-(4-hydroxybutanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000164_0006
yl)(3-pyridyl))carboxamide Compound 771
N-[(2-{[(tert-butoxy)carbonylaminojmethyl}(3- pyridyl))methyl](5-cyano-2-{[2-(3-
Figure imgf000165_0001
fluorophenyl)ethyl]amino}-6-(1-methylpyrazo!-4-
Compound 781 yl)(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyriclyl)]methyl}(5-cyano-
Figure imgf000165_0002
2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 782 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[3-((5R)-5-{[(5-cyano-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000165_0003
yl)(3-pyridyl))carbonylamino]methyl}-2-
Compound 783 oxopyrrolidinyl)propyl](tert-butoxy)carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2- yl]methyl}(5-cyano-2-{[2-(3-
Figure imgf000165_0004
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 784 yl)(3-pyridyl))carboxamide
l-4- boxyl
Compo
Figure imgf000165_0005
N-[((2R)pyrrolidin-2-yl)methyll(5-cyano-2-{[2-(3-
Figure imgf000165_0006
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 786 yl)(3-pyridyl))carboxamide N-[((2R)-1-{4-[(tert- butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](5-cyano-2-{[2-(3-
Figure imgf000166_0001
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 788 yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2- yl]methyl}(5-cyano-2-{|;2-(3-
Figure imgf000166_0002
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 789 yl)(3-pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- pyridyl))methyl](2-{[2-(3-
Figure imgf000166_0003
fluorophenyl)ethyl]amino}-5-methyl-6-(1-
Compound 790 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000166_0004
fluorophenyl)ethyl]amino}-5-methyl-6-(1-
Compound 791 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}- 5-oxopyrrolidiπ-2-yl)methyl](2-{[2-(3-
Figure imgf000166_0005
fluorophenyl)ethyl]amino}-5-methyl-6-(1-
Compound 792 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2- yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-5-
Figure imgf000166_0006
methy l-6-( 1 -methylpyrazol-4-y I) (3-
Compound 793 pyridyl))carboxamide yl-6-( 1 - rrolidinecarboxyl
Figure imgf000166_0007
Compound 794
N-[((2R)pyrrolidin-2-yl)methyl](2-{[2-(3-
Figure imgf000167_0001
fluorophenyl)ethyl]amino}-5-methyl-6-(1-
Compound 795 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-1-{4-[(tert- butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyI](2-{[2-(3-fluorophenyl)ethyl]amino}-5-
Figure imgf000167_0002
methyl-6-(1-methylpyrazol-4-yl)(3-
Compound 796 pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyI)pyrrolidin-2- yl]methyl}(2-{[2-(3-fluorophenyl)ethyl]amino}-5-
Figure imgf000167_0003
methyl-6-(1-methylpyrazol-4-yl)(3-
Compound 797 pyridyl))carboxamide
tert-butyl (2R)-2-{[(5-cyano-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000167_0004
pyridyl))carbonylamino]methyl}pyrrolidinecarboxyl
Compound 798 ate
N-[((2R)pyrrolidin-2-yl)methyl](5-cyano-2-{[2-(3-
Figure imgf000167_0005
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 799 pyridyl))carboxamide
N-[((2R)-1-{4-[(tert- butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](5-cyano-2-{[2-(3-
Figure imgf000167_0006
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 800 pyridyl))carboxamide N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2- yl]methyl}(5-cyano-2-{[2-(3-
Figure imgf000168_0001
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 801 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamiπo]propyl}- 5-oxopyrrolidin-2-yl)methyfJ(5-cyano-2-{[2-(3-
Figure imgf000168_0002
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 802 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2- yl]methyl}(5-cyano-2-{[2-(3-
Figure imgf000168_0003
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 803 pyridyl))carboxam ide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- pyridyl))methyl](5-cyano-2-{[2-(3-
Figure imgf000168_0004
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 804 pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-cyaπo-
Figure imgf000168_0005
2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
Compound 805 yl(3-pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000168_0006
fluorophenyl)ethyl]amino}-5-methyl(3-
Compound 809 pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-
Figure imgf000168_0007
5-methyl(3-pyridyl))carboxamide Compound 810
N-[3-<(5R)-5-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-5-methyl(3-
Figure imgf000169_0001
pyridyl))carbonylamino]methyl}-2-
Compound 811 oxopyrrolidinyl)propyl](tert-butoxy)carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000169_0002
fluorophenyl)ethyl]amino}-5-methyl(3-
Compound 815 pyridyl))carboxamide
methyl 5-chloro-2-{[2-(3-
Figure imgf000169_0003
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 816 yl)pyridine-3-carboxylate
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3- pyridyl))methyl](5-chloro-2-{[2-(3-
Figure imgf000169_0004
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 817 yl)(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-chloro-
Figure imgf000169_0005
2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 818 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}- 5-oxopyrrolidin-2-yl)methyl](5-chloro-2-{[2-(3-
Figure imgf000169_0006
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 819 yl)(3-pyridyl))carboxamide N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2- yllmethyl}(5-chloro-2-{[2-(3-
Figure imgf000170_0001
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 820 yl) (3-pyridyl)) ca rlDoxamide
ylpyrazol-4- lidinecarboxyl
Comp
Figure imgf000170_0002
N-[((2R)pyrrolidin-2-yl)methyl](5-chloro-2-{[2-(3-
Figure imgf000170_0003
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 822 yl)(3-pyridyl))carboxamide
N-[((2R)-1-{4-[(tert- butoxy)carbonylamiπo]butanoyl}pyrrolidin-2- yl)methyl](5-chloro-2-{[2-(3-
Figure imgf000170_0004
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 823 yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2- yl]methyl}(5-chloro-2-{[2-(3-
Figure imgf000170_0005
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 824 yl)(3-pyridyl))carboxamide
N-{3-[(tert-butoxy)carbonylamino]propyl}(5-fluoro-
Figure imgf000170_0006
2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 826 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-(3-aminopropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000170_0007
yl)(3-pyridyl))carboxamide Compound 827
methyl (2R)-3-[(5-fluoro-2-{[2-(3-
Figure imgf000171_0001
fluorophenyl)ethyl]amino}-6-(1-rnethylpyrazol-4-
Compound 828 yl)(3-pyridyl))carbonylamino]-2-methylpropanoate
(2R)-3-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000171_0002
yl)(3-pyridyl))carbonylamino]-2-methylpropanoic
Compound 829 acid
2-[(tert-butoxy)carbonylamino]-N-{3-[(5-fluoro-2- {[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Figure imgf000171_0003
methylpyrazol-4-yl)(3-
Compound 838 pyridyl))carbonylamino]propyl}acetamide
2-amino-N-{3-[(5-fluoro-2-{[2-(3-
Figure imgf000171_0004
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 839 yl)(3-pyridyl))carbonylamino]propyl}acetamide
N-{3-[(5-fluoro-2-{[2-(3-fluorophenyl)ethylJamiπo}-
Figure imgf000171_0005
6-(1 -methylpyrazol-4-yl)-3-
Compound 840 pyridyl)carbonylamino]propyl}acetamide
N-((2R)-3-hydroxy-2-methylpropyl)(5-fluoro-2-{[2-
Figure imgf000171_0006
(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-
Compound 841 4-yl)(3-pyridyl))carboxamide N-((2R)-2-carbamoylpropyl)(5-fluoro-2-{[2-(3-
Figure imgf000172_0001
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 842 yl)(3-pyridyl))carboxamide
(2R)-3-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000172_0002
yl)(3-pyridyl))carbonylamino]-2-methyl-N-
Compound 843 methylpropanamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrazol-4-yl(3-pyridyl))-N-(pyrazol-3-
Compou ylmethyl)carboxamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Figure imgf000172_0003
methylpyrazol-4-yl)(3-pyridyl))-N-(pyrazol-3-
Compound 845 ylmethyl)carboxamide
N-((2R)-4-diazo-2-methyl-4-azabut-4-enyl)(5-
Figure imgf000172_0004
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 853 rnethylpyrazol-4-yl)(3-pyridyl))carboxamide
5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Figure imgf000172_0005
methylpyrazol-4-yl)(3-pyridyl) 3-methylazetidinyl
Compound 854 ketone
N-((2S)-3-amino-2-methylpropyl)(5-fluoro-2-{[2-
(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-
Figure imgf000172_0006
4-yl)(3-pyridyl))carboxamide Compound 855
N-{(2R)-3-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000173_0001
yl)(3-pyridyl))carbonylamino]-2-methylpropyl}-2-
Compound 856 [(tert-butoxy)carbonylamino]acetamide
N-{(2R)-3-[(5-fluoro-2-{[2-(3- fluoropheny0ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000173_0002
yl)(3-pyridyl))carbonylamino]-2-methylpropyl}-2-
Compound 857 aminoacetamide
N-{(2R)-3-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Figure imgf000173_0003
yl)(3-pyridyl))carbonylamino]-2-methylpropyl}-2-
Compound 858 hyd roxyaceta m ide
Figure imgf000173_0004
» a pyridyl))carbonylamiπo]methyl}azetidinecarboxyla
Compound 862 te
N-[((2R)azetidin-2-yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000173_0005
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 863 yl)(3-pyridyl))carboxamide
N-[((2R)-1-{2-[(tert- butoxy)carbonylamino]acetyl}azetidin-2- yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000173_0006
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 864 yl)(3-pyridyl))ca rboxam ide N-{[(2R)-1-(2-aminoacetyl)azetidin-2-yl]methyl}(5-
Figure imgf000174_0001
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 865 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-1-{4-[(tert- butoxy)carbonylamino]butanoyl}azetidin-2- yl)methyl](5-fJuoro-2-{[2-(3-
Figure imgf000174_0002
fluorophenyl)ethyl]arnino}-6-(1-methylpyrazol-4-
Compound 866 yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)azetidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000174_0003
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 867 yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000174_0004
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 868 yl)(3-pyridyl))carboxamide
methyl (2S)-3-[(5-fluoro-2-{[2-(3-
Figure imgf000174_0005
fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 875 yl)(3-pyridyl))carbonylamino]-2-methylpropanoate
N-((2S)-3-hydroxy-2-methylpropyl)(5-fluoro-2-{[2-
Figure imgf000174_0006
(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-
Compound 876 4-yl)(3-pyridyl))carboxamide
N-((2R)-3-hydroxy-2-methylpropyl)(5-fluoro-2-{[2-
(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000174_0007
pyridyl))carboxamide Compound 881
methyl (2R)-3-[(5-fluoro-2-{[2-(3-
Figure imgf000175_0001
fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 882 pyridyl))carbonylamino]-2-methylpropanoate
methyl (2R)-3-[(6-(2-cyanophenyl)-2-{[2-(3-
Figure imgf000175_0002
fluorophenyl)ethyljamino}(3-
Compound 883 pyridyl))carbonylamino]-2-methylpropanoate
N-((2R)-3-hydroxy-2-methylpropyl)(6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}{3-pyridyl))carboxamide
N-[(2,2-dimethyl(1,3-dioxan-5-yl))methyl3(5- fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compou methylpyrazol-4-yl)(3-pyridyl))carboxamide
(5-fluoro-2-{[2-(3-fluoroρhenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))-N-[3-hydroxy-2-
Compou (hydroxymethyl)propyl]carboxamide
N-[(2,2-dimethyl(1 ,3-dioxan-5-yl))methyl](5-
Figure imgf000175_0003
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 887 pyrazol-4-yl(3-pyridyl))carboxamide (5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrazol-4-yl(3-pyridyl))-N-[3-hydroxy-2-
Compou (hydroxymethyl)propyl]carboxamide
N-[(2,2-dimethyl(1,3-dioxaπ-5-yl))methyl](6-(2- cyanophenyl)-2-{[2-(3-
Compou fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[3-
Compou hydroxy-2-(hydroxymethyl)propyl]carboxamide
methyl (2R)-2-{[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compou yl)(3-pyridyl))carbonylamino]methyl}i3utanoate
N-((2R)-2-ethyl-3-hydroxypropyl)(5-fluoro-2-{[2-
(3-fluoropheny[)ethyl]amino}-6-(1-methylpyrazol-
Compou 4-yl)(3-pyridyl))carboxamide
methyl (2R)-2-{[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compou pyridyl))carbonylamino]methyl}butanoate
N-((2R)-2-ethyl-3-hydroxypropyl)(5-fluoro-2-{[2-
(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000176_0001
pyridyl))carboxamide W
Compound 894
methyl (2R)-2-[(tert-butoxy)carbonylamino]-3-[(5- fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-
Compou pyridyl))carbonylamino]propanoate
methyl (2R)-2-amino-3-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazoI-4-
Compou yl)(3-pyridyl))carbonylamino]propanoate
N-((1 R)-1-{[(5-fluorp-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4- yl)(3-pyridyl))carbonylamino]methyJ}-2-
Compou hydroxyethyl)(tert-butoxy)carboxamide
N-((2R)-2-amino-3-hydroxypropyl)(5-fluoro-2-{[2- (3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-
Compou 4-yl)(3-pyridyl))carboxamide
N-((1 R)-H[(5-fiuoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3- pyridyl))carbonylamino]methyl}-2-
Compou hydroxyethyl)(tert-butoxy)carboxamide
N-((2R)-2-amino-3-hydroxypropyl)(5-fluoro-2-{[2-
Figure imgf000177_0001
(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Compound 900 pyridyl))carboxamide rr N-(2,3-dihydroxypropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
Compound 901 yl)(3-pyridyl))carboxamide
N-(2,3-dihydroxypropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyf]amino}-6-pyrazol-4-yl(3-
Compou pyridyl))carboxamide
methyl (2R)-3-{[2-amiπo-5-fluoro-6-(1-
Figure imgf000178_0001
methylpyrazol-4-yl)(3-pyridyl)]carbonylamino}-2-
Compound 903 methylpropanoate
N-{[(2R)-1 -(2-hydroxy-2- methylpropanoyl)azetidin-2-yl]methyl}(5-fluoro-2-
Figure imgf000178_0002
{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
Compound 904 methylpyrazol-4-yl)(3-pyridyl))carboxamide
tert-butyl (2R)-2-{[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000178_0003
pyridyl))carbonylamino]methyl}azetidinecarboxyla
Compound 905 te
N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2- yl]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000178_0004
fluorophenyl)ethyl]amino}-6-pyrazoI-4-yl(3-
Compound 906 pyridyl))carboxamide
N-[((2R)azetidin-2-yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
Figure imgf000178_0005
pyridyl))carboxamide Compound 907
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyljamino}-6-phenyl(3-
Compoun pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-
Compoun fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
Figure imgf000179_0001
N-(carbamoylmethyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compound 126 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
Figure imgf000179_0002
N-(2-carbamoylethyl)(6-(2-cyanophenyl)-2-{[2-(3-
Compound 127 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
Compoun pyridyl))carbonylamino]-N-methylacetamide
N-((3S)-2-oxo(3-piperidyl))(6-(2-cyanophenyl)-2-
Figure imgf000179_0003
{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 396 pyridyl))carboxam ide [0125] Provided is at least one chemical entity chosen from compounds of Formula V
Figure imgf000180_0001
Formula V and pharmaceutically acceptable salts thereof wherein
R1 is selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
Z1 is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , cyano, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted carbamimidoyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, sulfonyl, sulfinyl, and sulfanyl,
Z2 is selected from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is selected from optionally substituted alkyl and optionally substituted heterσaralkyl;
R3 is chosen from hydrogen and optionally substituted alkyl; and
R6 is chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl. [0126] In certain embodiments of compounds of Formula V1 Z1 is chosen from phenyl substituted with one, two or three groups chosen from halo, alkyl, alkoxy, cyano, and optionally substituted acyl. In certain embodiments of compounds of Formula V1 Z1 ischosen from 3,4- difluorophenyl and 2-cyanophenyl.
[0127] In certain embodiments of compounds of Formula V, Z2 is chosen from methylaminocarbonyl, methylaminocarbonylmethylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and isopropylaminocarbonyl, wherein the methyl, ethyl, propyl, and isopropyl group is optionally substituted with one, two or three groups independently selected from optionally substituted methoxy, optionally substituted ethoxy, optionally substituted phenyl, and optionally substituted pyridinyl. In certain embodiments of compounds of Formula V1 Z2 is chosen from methylaminocarbonylmethylaminocarbonyl, 2-methoxyeth-1-ylaminocarbonyl, benzylaminocarbonyl, isopropylaminocarbonyl, pyridin-3-ylmethylaminocarbonyl, and pyridin-4- ylmethylaminocarbonyl.
[0128] In certain embodiments of compounds of Formula V, Z3 is chosen from ethyl, methyl and propyl substituted with one, two or three groups independently selected from optionally substituted aryl and optionally substituted heteroaryl. In certain embodiments of compounds of Formula V, Z3 is chosen from ethyl and methyl substituted with a group selected from optionally substituted phenyl and optionally substituted pyridinyl. In certain embodiments of compounds of Formula V, Z3 is chosen from 2-(3-fluorophenyl)ethyl, 2-(3-methylphenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(3-methylpheny!)ethyl and pyridin-2-ylmethyl.
[0129] In certain embodiments of compounds of Formula V, R1 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula V1 R1 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula V, R1 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula V1 R1 is hydrogen.
[0130] Mn certain embodiments of compounds of Formula V, R3 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula V. R3 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula V, R3 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula V, R3 is hydrogen.
[0131] In certain embodiments of compounds of Formula V1 Rβ is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl. In certain embodiments of compounds of Formula V, Rβ is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl. In certain embodiments of compounds of Formula V, RB is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl. In certain embodiments of compounds of Formula V, R6 is hydrogen. [0132] In certain embodiments, the compound of Formula V is chosen from
COMPOUND CHEMICAL NAME
Figure imgf000182_0001
(6-(2-cyanophenyl)-4-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 0 pyrϊdylmethyl)carboxamide
Figure imgf000182_0002
2-l(6-(2-cyaπophenyl)-4-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 1 pyridyl))carbonylamino]-N-methylacetarnide
Figure imgf000182_0003
[4-{[2-(3-fluorophenyl)ethyl]amino}-6-(2-{imino[(3-
Compound 2 pyridylmethyl)amino]methyl}phenyl)(3-pyridyl)]-N-(3-pyridytmethyl)carboxamide
[0133] Provided is at least one chemical entity chosen from compounds of Formula Vl
Figure imgf000182_0004
Formula Vl
and pharmaceutically acceptable salts thereof wherein R1 and R4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
Z1 is chosen from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is chosen from halo and optionally substituted alkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
[0134] In certain embodiments of compounds of Formula Vl1 Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
[0135] In certain embodiments of compounds of Formula Vl1 Z2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
[0136] In certain embodiments of compounds of Formula Vl, Z2 is chosen from (2-(N- acetylaminomethyl)piperidin-1-yl)carbonyl; (2-aminomethylpiperidin-1-yl)carbonyl; 1-hydroxy-2- amino-ethyl; 2-((methylsulfonamido)methyl)piperidin-1 -ylcarbonyl; 2-
(methylaminocarbonyl)ethenyl; 2-(pyridin-3-ylmethyl)-2H-tetrazol-5-yl; aminomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ylcarbonyl.
[0137] In certain embodiments of compounds of Formula Vl, R3 is chosen from hydrogen and optionally substituted lower alkyl.
[0138] In certain embodiments of compounds of Formula Vl, R3 is chosen from hydrogen and lower alkyl.
[0139] In certain embodiments of compounds of Formula Vl, R3 is chosen from hydrogen and methyl. [0140] In certain embodiments of compounds of Formula Vl, R3 is hydrogen.
[0141] In certain embodiments of compounds of Formula Vl, Z2 is -C(O)NR2R5 wherein R2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
[0142] In certain embodiments of compounds of Formula Vl, R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl.
[0143] In certain embodiments of compounds of Formula Vl, R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl.
[0144] In certain embodiments of compounds of Formula Vl1 R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl.
[0145] In certain embodiments of compounds of Formula Vl1 R4 is hydrogen.
[0146] In certain embodiments of compounds of Formula Vl, R5 is chosen from hydrogen and lower alkyl.
[0147] In certain embodiments of compounds of Formula Vl, R5 is chosen from hydrogen and methyl
[0148] In certain embodiments of compounds of Formula Vl, R5 is hydrogen.
[0149] In certain embodiments of compounds of Formula Vl, R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[0150] In certain embodiments of compounds of Formula Vl, R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[0151] In certain embodiments of compounds of Formula Vl, R2 is chosen from (1-(2- aminoethyl)-1H-pyrazol-3-yl)methyI; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin- 3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyt; (1 H-imidazol-2-yl)methyl;
(1 H-pyrazol-3-yl)methyl; (1-methyl-1 H-pyrazol-3-yl)methyl; (1 -methyl-1 H-pyrazol-5-yl)methyl; (2- (aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)carbonylmethyl; (2-(methylamino)ethylamino)carbonylmethyl; (2-(N- methyl-N-(t-butoxycarbonyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylmethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylamino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)methyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1 ,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- arninoethylarnino)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)methyl; (6-(hydroxymethyl)pyridin-2-yl)methyl; (6-bromopyridin-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1-(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1 -(2-(tert-butoxycarbonylamino)ethyl)-1 H- pyrazol-5-ylmethyl; 1-(aminocarbonyl)-2-(amino)-eth-1-yl; 1-(aminocarbonyl)-3-(amino)-propyl; 1 -(aminocarbonyl)-4-(amino)-butyl; 1 -(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1 - (aminocarbonyl)-5-(amino)-pentyl; 1-(aminocarbonyl)eth-1-yl; 1-(carboxy)-2-(amino)-eth-1-yl; 1- (dimethylaminocarbonyl)-2-(amino)-eth-1 -yl; 1 -(hydroxy)-2-(aminocarbonylmethylamino)eth-1 -yl; 1-(hydroxy)-2-(ethoxycarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(pyridin-2-ylmethylamino)eth- 1-yl; 1-(methoxycarbonyl)-2-(amino)-eth-1-yl; 1-(methoxycarbonyl)-2-(t-butoxycarbonylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(amino)-eth-1-yl (2 occ); 1- (methylaminocarbonyl)eth-i-yl; 1-aminocarbonyl-2-hydroxy-eth-1 -yl; 1-methoxycarbonyl-2- hydroxy-eth-1-yl; 2-(2-aminoethoxy)ethyl; 2-(2-aminoethyl)-pyridin-6-ylmethyl; 2-(2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-(acetylamino)ethyl; 2-(amino)ethyl; 2-(aminocarbonyl)-2- (acetylamino)-eth-i-yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamino)ethyl; 2- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 2-(ethoxycarbonyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamino)-eth-i-yl; 2-(methoxycarbonyl)-2-(amino)-eth-1-yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1-yl; 2- (methylaminocarbonyl)-2-(amino)-eth-1-yl; 2-(methylsulfonamido)ethyl; 2-(rηethyoxycarbonyl)-2- (amino)-eth-i-yl; 2-(N-(t-butoxycarbonyl)-N-(methyl)-amino)ethyl; 2-(piperazin-1-yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridin-3-ylmethyl; 2-(t-butoxycarbonylaminomethyl)pyridin-6- ylmethyl; 2-(trifluoromethyl)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridin-5- ylmethyl; 2-chloropyridin-5-ylmethyl; 2-cyanopyridin-5-ylmethyl; 2-hydroxy-3-amiπo-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yl; 2-methoxypyridin-3-ylmethyl; 2-mβthoxypyridin-5-ylmethyl; 2- methylpyridin-3-ylmethyl; 2-methylpyridin-5-ylmethyl; 2-methylpyridiπ-6-ylmethyl; 3-(2- aminoethyl)cyclohexyl)methyl; 3-(4-methylpiperazin-1 -yl)propyl; 3-(amino)-3- (methylamiπocarbonyl)prop-i-yl; 3-(amiπocarboπyl)propyl; 3-(aminomethyl)benzyl; 3- (aminomethyl)pyridin-2-ylmethyl; 3-(methoxycarbonyl)propyl; 3-(methylaminocarbonyl)propyl; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; S-carbamoylcyclopentyl; 3-carboxypropyl; 3-hydroxypropyl; 3-methoxypropyl; A- (aminomethyl)-pyridin-2-ylmethyl; 4-(N,N-dimethylamino)pyridin-3-ylmethyl; 4-(t- butoxycarbonylamino)-morpholinomethyl; 4-aminobutyl; 4-aminomethylpyridin-3-ylmethyl; A- cyanobenzyl; 4-fluorobenzyl; 4-methylaminopyridin-3-ylmethyl; 4-methylbenzyl; A- morpholinopyridin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5-
((bis(dimethylamino)methylamino)methyl)pyridin-3-ylmethyl; 5-(aminomethyl)pyridin-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethyl; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarbonylaminomethyl)-pyridin-2-ylmethyl; 5-(trifluoromethyl)-pyridin-2-ylmethyl; 5- aminopentyl; 5-aminopyridiπ-2-ylmethyl; 6-((bis(dimethylamino)methyleneamino)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1 -yl)pyridin-3-ylmethyl); 6-(aminomethyl)pyridin-2-yl)methyl; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylaminocarbonylmethyl; isopropyl; isoxazol-5-ylmethyl; methoxycarbonylmethyl; methyl; methylaminocarbonylmethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-ylmethyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
[0152] In certain embodiments of compounds of Formula Vl, Z3 is chosen from halo and optionally substituted lower alkyl.
[0153] In certain embodiments of compounds of Formula Vl1 Z3 is chosen from halo, optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl wherein the methyl, ethyl and propyl groups are optionally substituted with one or two groups selected from hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, and optionally substituted aryloxy.
[0154] In certain embodiments of compounds of Formula Vl1 Z3 is chosen from 2-(3- methylphenyl)ethyl, (tetrahydrofuran-2-yl)methyl, 1-hydroxycyclohexylmethyl, 2-(1 ,3-dioxolan-2- yl)ethyl, 2-(1 H-imidazol-4-yl)ethyl, 2-(1-methyl-1H-imidazol-4-yl)ethyl, 2-(1-methylpiperidin-4- yl)ethyl, 2-(2,3-difluorophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2- (2-methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(2-oxoimidazolidiπ-1-yl)ethyl, 2-(2- oxopiperidin-1-yl)ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 2-(3-(trif!uoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl, 2-(3,5- dimethyl-1 H-pyrazol-4-yl)ethyl, 2-(3-carbamoylphenyl)ethyl, 2-(3-carboxyphenyl)ethyl, 2-(3- cyanophenyl)ethyl, 2-(3-fluorophenyl)-2-(hydroxy)-ethyl, 2-(3-fluorophenyl)ethyl, 2-(3- fluoropyridin-2-yl)ethyl, 2-(3-methoxycarbonylphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(3- methylphenyl)ethyl, 2-(4-aminophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2- (4-hydrσxyphenyl)ethyl, 2-(benzo[d][1 ,3]dioxol-5-yl)ethyl, 2-(furan-2-yl)ethyl, 2-(hydroxy)-2- (phenyl)ethyl, 2-(phenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-cyclohex-1-enylethyl, 2-cyclohexylethyl, 2-morpholinoethyl, 2-phenoxyethyl, 2-phenylprop-1- yl, 3-(1H-imidazol-1-yl)prop-1-yl, 3-phenylpropyl, benzyl, chloro, isopentyl, propyl, pyridin-2- ylmethyl, pyridin-3-ylmethyl, and thiophen-3-ylmethyl.
[0155] In certain embodiments of compounds of Formula Vl, Z3 is chosen from 2-(3- fluorophenyl)ethyl and 2-(pyridin-2-yl)ethyl.
[0156] In certain embodiments of compounds of Formula Vl, Z1 is chosen from cycloalkyl and heterocycloalkyl, where each group is optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl.
[0157] In certain embodiments of compounds of Formula Vl, Z1 is chosen from cycloalkyl and heterocycloalkyl, where each group is optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl.
[0158] In certain embodiments of compounds of Formula Vl, Z1 is chosen from 1-(2H)-(methoxycarbonyl)-3,4-dihydropyridin-4-yl; 1-(2H)-(methoxycarbonyl)-5,6-dihydropyridin-4-yl; 1-(2H)-(methoxymethyl)-5,6-dihydropyridin4-yl; 1-(2H)-(t-butoxycarbonyl)-5,6-dihydropyridin-4-yl; 1-(2H)-5,6-dihydropyridin-4-yl; 1-(acetyl)-4,5-dihydroimidazo-2-yl; 1-(dimethylcarbamoyl)-1 ,2,3,6-tetrahydropyridin-4-yl; 1-(methoxymethyl)-4,5-dihydroimida2O-2-yl; 1-cyano-4,5-dihydro-1H-imidazol-2-yl; 1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl; 2-(acetylaminomethyl)pyrrolidin-1-yl; 2-(hydroxymethyl)morpholino; 2-(hydroxymethyl)pyrrolidin-1-yl; 2-(methoxymethyl)pyrrolidiπ-1-yl; 2H-pyrrol-1(5H)-yl; 2-hydroxymorpholino;
2-methyl-4-(t-butoxycarbonyl)-piperazin-1-yl; 2-oxo-5-hydroxy-piperidinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl;
3-(3,3-dimethylureido)pyrrolidin-1-yl; 3-(aminomethyl)-pyrrolidin-1-yl; 3-(carboxymethyl)-pyrrolidinyl; 3-(dimethylamino)pyrrolidin-1-yl; 3-(dimethylaminomethyl)-pyrrolidin-1-yl; 3-(hydroxymethyl)pyrrolidin-1-yl; 3-(methoxycarbonylamino)-pyrrolidinyl; 3-(methylsulfonyl)pyrrolidin-1-yl; 3-(N-acetyl-N-methyl)-aminomethyl)-pyrrolidin-1-yl; -(pyridin-4-yl)pyrrolidin-1 -yl; -(t-butoxycarbonylamino)-pyrrolidinyl;
3-(trifluoromethyl)pyrrolidin-1-yl;
3,3-difluoropyrrolidinyl;
3-acetylaminopyrrolidinyl;
3-aminopyrrolidin-1 -yl;
3-fluoropyrrolidin-1 -yl;
3-hydroxymethylpyrrolidin-1-yl;
3-hydroxypyrrolidin-1 -yl;
3-methoxymethylpyrrolidin-1 -yl;
3-methylamino-pyrrolidinyl;
3-oxopiperazin-1 -yl; -(acetyl)-piperazin-1 -yl; -(aminomethyl)piperidin-1-yl; -(ethoxycarbonyl)-piperazin-1-yl;
4-(ethoxycarbonyl)-piperidinyl;
4-(methoxycarbonyl)-piperazin-1-yl;
4-(methylsulfonyl)cyclohex-1-enyl;
4-(N, N-dimethylaminocarbonyl)-piperazin-1 -yl;
4-(t-butoxycarbonylamino)-piperidin-1-yl;
4-(t-butoxycarbonylaminomethyl)-piperidin-1-yl;
4,5-dihydro-1 H-imidazol-2-yl;
4,5-dihydrooxazol-2-yl;
4-hydroxy-4-phenylpiperidin-1-yl;
4-hydroxyethyl-piperidin-yl;
4-hydroxym ethyl-pi perid i n-yl ;
4-hydroxypiperidinyl;
4-methylaminocarboπyl-piperidiπyl;
4-methylpiperazin-1-yl;
4-methylpiperidinyl;
4-oxocyclohex-1 -enyl;
5,6-dihydropyridin-i (2H)-yl; azetidinyl; cyclohex-1 -enyl; cyclohexyl; cyclopent-1-enyl; cyclopentyl; morpholino; piperazinyl; piperidinyl; pyrrolidinyl; and thiomorpholino.
[0159] In certain embodiments of compounds of Formula Vl, R1 is chosen from hydrogen and optionally substituted lower alkyl.
[0160] In certain embodiments of compounds of Formula Vl, R1 is chosen from hydrogen and lower alkyl.
[0161] In certain embodiments of compounds of Formula Vl, R1 is chosen from hydrogen and methyl.
[0162] In certain embodiments of compounds of Formula Vl, R1 is hydrogen.
[0163] In certain embodiments, the compound of Formula Vl is chosen from COMPOUND Chemical Name
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-piperidyl(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
N-{[(3S)-1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-
Compou yl]methyl}acetamide
(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3-
Figure imgf000190_0001
fluoropnenyl)ethyl]arnino}(3-pyridyl))-N-
Compound 2 (carbamoylmethyl)carboxamide W
2-[(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
Compoun methylacetamide
(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3-
Figure imgf000191_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N,N-
Compound 4 dimethylcarboxamide
N-(carbamoylmethyl)(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compou pyrrolidinyl(3-pyridyl))carboxamide
(6-[(3R)-3-(hydroxymethyl)pyrrolidinyl]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-{(3S)-3-[(methylamino)methyl]pyrrolidiπyl}-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
N-{[(3R)-1-(6-{[2-(3-fiuorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-yl]methyl}-N-
Compou methylacetamide
(6-{(3S)-3-[(dϊmethylamino)methyl]pyrrolidinyl}-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Figure imgf000191_0002
pyridylmethyl)carboxamide Compound 9
(2-{[2-(3-fluorophenyl)ethyljamino}-6-(2-oxopiperidyl)(3-
Compoun pyridyl))-N-(3~pyridylmethyl)carboxamide
(6-[(3S)-3-(aminomethyl)pyrrolidinyl]-2-{[2-(3-
Figure imgf000192_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 11 pyridylmethyl)carboxamide
N-[(6-amino(3-pyridyl))methyl](2-{[2-(3-
Figure imgf000192_0002
fIuorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compound 12 pyridyl))carboxamide
)ethyl]amino}-6-
Figure imgf000192_0003
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2-oxopyrrolidinyl)(3-
Compound 15 pyridyl))-N-(3-pyridylmethyl)carboxamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-pyridyl))-N-
Compou (3-pyridylmethyl)carboxamide
(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridy!))-N-(2-
Compou carbamoylethyl)carboxamide
(6-((3S)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[4-
(hydroxymethyl)piperidyl](3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(5-hydroxy-2-
Compou oxopiperidyl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-oxopiperazinyl)(3-
Compou pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-methylpiperazinyl)(3-
Figure imgf000193_0001
pyridyl))-N-(3-pyridylmethyl)carboxamide Compound 22
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[4-(2- hydroxyethyl)piperidyl](3-pyridyl))-N-(3-
Compoun pyridylmethyljcarboxamide
tert-butyl 4-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))-3-
Compoun oxopiperazlnecarboxylate
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2-oxopiperazinyl)(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2-oxopiperidyl)(3-
Compoun pyridyl))-N,N-dimethylcarboxamide
(6-[(3S)-3-(hydroxymethyl)pyrrolidinyl]-2-{[2-(3-
Figure imgf000194_0001
fIuorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 27 pyridylmethyl)carboxamide
Figure imgf000194_0002
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compound 28 pyridyl))carbonylamino]-N-methylacetamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-pyrrolinyl)(3-pyridyl))-
Compou N-(3-pyridylmethyl)carboxarnide
(6-((3S)-3-aminopyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
N-[(3R)-1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-
Compou yl](dimethylamino)carboxamide
Figure imgf000195_0001
(6-azetidinyl-2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-
Compound 32 (3-pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-pyrrolidinyl(3-pyridyl)}-N-(3-
Compoun pyridylmethyl)carboxamide
Figure imgf000195_0002
{6-(4-methylpiperidyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-
Compound 34 N-(3-pyridylmethyl)carboxam ide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1,3-oxazolin-2-yl)(3-
Figure imgf000195_0003
pyridyl))-N-(3-pyridy!methyl)carboxamide Compound 35
<6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[2-(aminomethyl)(3- Compou pyridyl)]methyl}carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(6-cyclopent-1-eπyl-2-
Compou {[2-(3-fIuorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-((3S)-3-fluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl)amino}(3-pyridyl))-N-{[2-(aminomethyl)(3-
Compou pyridyl)]methyl}carboxamide
(6-((3R)-3-fluoropyrrolidinyl)-2-{[2-{3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[2-(aminomethyl)(3-
Compou pyridyl)]methyl}carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3-
Compou fIuorophenyl)ethyl]amino)-6-piperidyl{3-pyridyl))carboxamide
N-{[2-(amiπomethyl)(3-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000196_0001
fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compound 41 pyridyl))carboxamide N-[(3S)-1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-
Compoun yljmethoxyca rboxam ide
methyl 4-(6-{[2-( 3-fIuorophenyl)ethyl]amino}-5-{N-[(N- methylcarbamoyl)methyl]carbamoyl}-2-pyridyl)-1 , 2,5,6-
Compoun tetrahydropyridiπecarboxylate
N-[(3R)-1-(6-{[2-(3-fIuorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-
Compoun yl]methoxycarboxamide
{6-piperidyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-<3-
Compou pyridylmethyl )ca rboxam ide
(6-((3R)-3-aminopyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-{1 ,2,5,6-
Compoun tetrahydropyridyl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(5-chloro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Figure imgf000197_0001
pyridyl))-N-(3-pyridylmethyl)carboxamide Compound 48
(5-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
methyl 2-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Compoun pyridylmethyl)carbamoyl]-2-pyridyl)-2-imidazolinecarboxylate
(6-(1-cyano(2-imidazo!in-2-yl))-2-{[2-(3-
Figure imgf000198_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 51 pyridylmethyl)carboxamide
N-[[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(5-
Figure imgf000198_0002
fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compound 52 pyridyl))carboxamide
(6-((3R)-3-fluoropyrrolidinyl)-5-fluoro-2-{[2-(3-
Figure imgf000198_0003
fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[2-(aminomethyl)(3-
Compound 53 pyrιdyl)]methyl}carboxamide
(6-((3R)-3-hydroxypyrrolidinyl)-5-fluoro-2-{[2-(3-
Figure imgf000198_0004
fluorophenyl)ethylJamino}(3-pyridyl))-N-[(2-{[(tert-
Compound 54 butoxy)carbonylamino]methyl}(3-pyridyl))methyl]carboxamide (6-((3R)-3-hydroxypyrrolidinyl)~5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}{3-pyridyl))-N-{[2-(aminomethyl)(3-
Compou pyridyl)]methyl}carboxamide
(6-(1-acetyl(4-1 ,2,5,6-tetrahydropyridyl))-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-1 ,2,5,6-
Compou tetrahydropyridyl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
tert-butyl 4-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Figure imgf000199_0001
pyridylmethyl)carbamoyl]-2-pyridyl)-1 ,2,5,6-
Compound 58 tetrahydropyridinecarboxylate
Compou
Figure imgf000199_0002
<6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound pyridylmethyl)carboxamide
methyl 4-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl]-2-pyridyl)-1,2,5,6-
Figure imgf000199_0003
tetrahydropyridinecarboxylate Compound 61
Figure imgf000200_0001
(6-cyclopent-1-enyl-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 62 pyridyl))-N-(3-pyridylmethyl)carboxamide
N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Figure imgf000200_0002
pyrrolidinyl(3-pyridyl))carbonylarnino]-isopropyl}-2-[(tert-
Compound 63 butoxy)carbonylamino]acetatπide
Figure imgf000200_0003
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-{4-oxocyclohex-1-
Compound 64 enyl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-((3R)-3-fluoropyrrolidinyl)-5-fluoro-2-{[2-(3-
Figure imgf000200_0004
fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(2-{[(tert-
Compound 65 butoxy)carbonylamino]methyl}(3-pyridyl))methyl]carboxamide
Figure imgf000200_0005
(6-cyclohexyl-2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-
Compound 66 (3-pyridylmethyl)carboxamide
Compoun
Figure imgf000200_0006
N-[((2R)-1-{3-[(tert-butoxy)carbonylamtno]propyl}-5- oxopyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000201_0001
fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compound 68 pyridyl))carboxamide
{6-[1-(N,N-dimethylcarbamoyl)(4-1,2,5,6-tetrahydropyridyl)]-2-
{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridytmethyl)carboxamide
(5-bromo-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compoun pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1 -methy!(4-1 ,2,5,6-
Compoun tetrahydropyridyl))(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
methyl 4-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl]-2-pyridyl)-1 ,4,5,6-
Compou tetrahydropyridinecarboxylate
Figure imgf000201_0002
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2-imidazolin-2-yl){3-
Compound 73 pyridyl))-N-(3-pyridylmethyl)carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(5-fluoro-2-
{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Figure imgf000201_0003
pyridyl))carboxamide Compound 74
N-[((2R)-1-{4-[(tert-butoxy)carbonylamino]butanoyl}pyrrolidin-
Figure imgf000202_0001
2-yl)methyl](5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 75 pyrrolidinyl(3-pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl}(5-fluoro-2-
Figure imgf000202_0002
{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compound 76 pyridyl))carboxamide
N-[((2R)-1-{2-[(tert-butoxy)carbonylamino]acetyl}pyrrolidin-2-
Figure imgf000202_0003
yl)methyl](5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
Compound 77 pyrrolidinyl(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2-{[2-(3-
Figure imgf000202_0004
fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compound 78 pyridyl))carboxamide
N-[((2R)pyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3-
Figure imgf000202_0005
fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compound 79 pyridyl))carboxamide
tert-butyl (2R)-2-{t(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-
Figure imgf000202_0006
6-pyrrolidinyl(3-
Compound 80 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate Comp
Figure imgf000203_0001
Figure imgf000203_0002
N-{(1R)-2-[(5-fIuoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrrolidinyl(3-pyridyl))carbonylamino]-isopropyl}-2-
Compound 82 aminoacetamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[1-(methylsulfonyl)(4-
1l2,5,6-tetrahydropyridyl)](3-pyridyl))-N-(3-
Compound pyridylmethyl)carboxamide
[4-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pipera2inyl]-N,N-
Compound dimethylcarboxamide
methyl 4-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Compound pyridylmethyl)carbamoyl]-2-pyridyl)piperazinecarboxylate
(6-(3-aminopyrrolidinyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{f2-(3-fluorophenyl)ethyl]amiπo}-6-morpholiπ-4-yl(3-
Figure imgf000203_0003
pyridyl))-N-(3-pyridylmethyl)carboxamide Compound 87
<6-[(2R)-2-(hydroxymethyl)pyrrolidinyl]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
2-[(6-((3S)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
Compoun methylacetamide
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-hydroxypiperidyI)(3-
Compoun pyridyl))carbonylamino]-N-methylacetamide
(tert-butoxy)-N-[1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-
Compoun yljcarboxamide
(6-[(3R)-3-(dimethylamino)pyrrolidinyl]-2-{[2-(3- fluoropnenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compoun pyridylmethyl)carboxamide
2-[(6-((3S)-3-fluoropyrrolidinyl)-2-{[2-(3-
Figure imgf000204_0001
fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
Compound 93 methylacetamide 2-[(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3-
Figure imgf000205_0001
fluorophenyl)ethyI]amino}(3-pyιϊdyl))carbonylamino]-N-
Compound 94 methylacetamide eft
2-[1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Compound pyridylmethyl)carbamoyl]-2-pyridyl)pyrrolidin-3-yl]acetic acid
Figure imgf000205_0002
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-(4-
Compound 96 pyridyl)pyrrolidinyl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
2-[(6-(3,3-difluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N- methylacetamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000205_0003
fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
Compound 98 pyridyl))carboxamide
(2-{[2-{3-fluorophenyl)ethyl]amino}-6-[3-
(trifluoromethyl)pyrrolidinyl](3-pyridyl))-N-(3-
Compound pyridylmethyl)carboxamide
(6-(3,3-difluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethy!]amino}(3-pyridyl))-N-(3-
Figure imgf000205_0004
pyridylmethyl)carboxamide Compound 100
Compo
Figure imgf000206_0001
rboxamide
(6-((3S)-3-hydroxypyrrolidinyl)-2-{[2-(3-
Figure imgf000206_0002
fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[6-(aminomethyl)(2- Compound 102 pyridyl)]methyl}carboxamide
-(aminomethyl)(2-
Compo
Figure imgf000206_0003
(6-((3R)-3-fluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 1 pyridylmethyl)carboxamϊde
(6-[4-{aminomethyl)piperidyl]-2-{[2-(3-
Figure imgf000206_0004
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 1 pyridylmethyl)carboxamide
Figure imgf000206_0005
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-piperidyl(3-
Compound 106 pyridyl))carbonylamino]-N-methylacetamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-[3-
(methylsulfonyl)pyrrolidinyl](3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(6-[(2S)-2-(methoxymethyl)pyrrolidinyl]-2-{[2-(3- fluorophenyl)ethyl]amino}{3-pyridyl))-N-(3-
Compou pyridylmethyl)carboxamide
(tert-butoxy)-N-{[ 1 -{6-{[2-(3-f luorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl)){4-
Compou piperidyl)]methyl}carboxamide
(tert-butoxy)-N-[1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Compou pyridylmethyl)carbamoyl](2-pyridyl))(4-piperidyl)]carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-hydroxy-4-
Compou phenylpiperidylJCS-pyridylJJ-N-CS-pyridylmethyQcarboxamide
ethyl 1 -(6-{[2-(3-fIuorophenyl)ethyl]amino}-5-[N-(3-
Compou pyridylmethyl)carbamoyl]-2-pyridyl)piperidine-4-carboxylate
(6-((3S)-3-fluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridy)))-N-(3-
Figure imgf000207_0001
pyιϊdylmethyl)carboxamide Compound 113
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[4-(N- methylcarbamoyl)piperidyl](3-pyridyl))-N-(3-
Compound pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-hydroxypiperidyl)(3-
Compound pyridyl))-N-(3-pyridylmethyl)carboxamide
{2-{[2-(3-fluorophenyl)ethyl]amino}-6-piperazinyl(3-pyridyl))-N-
Compound {3-pyridylmethyl)carboxamide
(6-((3S)-3-hydroxypiperidyl)-2-{[2-(3-
Figure imgf000208_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 117 pyridylmethyl)carboxamide
N-[1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl]-2-pyridyl)pyrrolidin-3-yl]acetamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[2-
Figure imgf000208_0002
(hydroxymethyl)morpholin-4-yl](3-pyridyl))-N-(3-
Compound 119 pyridylmethyl)carboxamide (6-[(3S)-3-(methylamino)pyrro!idinyl]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound pyridylmethyljcarboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1,4-thiazaperhydroin-4-
Compound yl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(1,1-dioxo(1,4-thiazaperhydroin-4-yl))-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound pyridylmethyl)carboxamide
(6-(4-acetylpiperazinyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-piperidylpiperidyl)(3-
Compound pyridyl))-N-(3-pyridylmethyl)carboxamide
Figure imgf000209_0001
ethyl 4-(6-{[2-(3-fluorophenyl)ethyl]am ino}-5-[N-(3-
Compound 125 pyridylmethyl)carbamoyl]-2-pyridyl)piperazinecarboxylate
[0164] Provided is at least one chemical entity chosen from compounds of Formula VII
Figure imgf000210_0001
Formula VII
and pharmaceutically acceptable salts thereof wherein
R1 and R4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
Z1 is chosen from hydrogen, cyano, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted carbamimidoyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, sulfonyl, sulfinyl, and sulfanyl;
Z2 is chosen from hydrogen, optionally substituted amidiπo, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is chosen from optionally substituted alkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl. [0165] In certain embodiments of compounds of Formula VII, Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
[0166] In certain embodiments of compounds of Formula VII1 Z2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
[0167] In certain embodiments of compounds of Formula VII, Z2 is chosen from (2-(N- acetylaminomethyl)piperidin-1-yl)carbonyl; (2-aminomethylpiperidin-1-yl)carbonyl; 1-hydroxy-2- amino-ethyl; 2-((methylsulfonamido)methyl)piperidin-1-ylcarbonyl; 2- (methylaminocarbonyl)ethenyl; 2-(pyridin-3-ylmethyl)-2H-tetrazol-5-ylmethyl; aminomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ylcarbonyl.
[0168] In certain embodiments of compounds of Formula VII1 R3 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments, R3 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula VII, R3 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula VII, R3 is hydrogen.
[0169] In certain embodiments of compounds of Formula VII, R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl. In certain embodiments of compounds of Formula VII, R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl. In certain embodiments of compounds of Formula VII1 R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl. In certain embodiments of compounds of Formula VII, R4 is hydrogen.
[0170] In certain embodiments of compounds of Formula VII, R5 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula VII, R5 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula VII, R5 is hydrogen.
[0171] In certain embodiments of compounds of Formula VII, Z2 is -C(O)-NR2R5 wherein R2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
[0172] In certain embodiments of compounds of Formula VII, R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopeπtyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[0173] In certain embodiments of compounds of Formula VII, R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
[0174] In certain embodiments of compounds of Formula VII, R2 is chosen from (1-(2- aminoethyl)-1H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin- 3-yl)methyl; (1 -acetylpyrrolidin-2-yl)methyl; (1 H-imidazol-2-yl)methyl; (1 H-pyrazol-3-yl)methyl; (1-methyl-1 H-pyrazol-3-yl)methyl; (1-methyl-1 H-pyrazol-5-yl)methyl; (2- (aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)carbonylmethyl; (2-(methylamino)ethylamino)carbonylmethyl; (2-(N- methyl-N-(t-butoxycarbonyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylmethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylamino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)methyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1 ,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- amiπoethylamino)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)methyl; (6-(hydroxymethyl)pyridin-2-yl)methyl; (6-bromopyridin-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1-(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1-(2-(tert-butoxycarbonylamino)ethyl)-1 H- pyrazol-5-ylmethyl; 1 -(aminocarbonyl)-2-(amino)-eth-1 -yl; 1 -(aminocarbonyl)-3-(amino)-propyl; 1-(aminocarbonyl)-4-(amino)-butyl; 1-(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1- (aminocarbonyl)-5-(amino)-pentyl; 1-(aminocarbonyl)eth-1-yl; 1-(carboxy)-2-(amino)-eth-1-yl; 1- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 1-(hydroxy)-2-(aminocarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(ethoxycarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(pyridin-2-ylmethylamino)eth- 1 -yl; 1 -(methoxycarbonyl)-2-(amino)-eth-1 -yl; 1 -(methoxycarbonyl)-2-(t-butoxycarbonylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(amino)-eth-1-yl (2 occ); 1- (methylamiπocarbonyl)eth-i-yl; i-amiπocarbonyl-2-hydroxy-eth-i-yl; 1-methoxycarbonyl-2- hydroxy-eth-1-yl; 2-(2-aminoethoxy)ethyl; 2-(2-aminoethyl)-pyridin-6-ylmethyl; 2-(2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-{acetylamino)ethyl; 2-{amino)ethyl; 2-(aminocarbonyl)-2- (acetylamino)-eth-i-yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamiπo)ethyl; 2- (dimethylaminocarbonyl)-2-(amino)-eth-1 -yl; 2-(ethoxycarbonyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamino)-eth-i -yl; 2-(methoxycarbonyl)-2-(amino)-eth-1 -yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1 -yl; 2- (methylaminocarbonyl)-2-(amino)-eth-1-yl; 2-(methylsulfonamido)ethyl; 2-(methyoxycarbonyl)-2- (amino)-eth-i-yl; 2-(N-(t-butoxycarbonyl)-N-(methyl)-amino)ethyl; 2-(piperazin-1-yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridin-3-ylmethyl; 2-(t-butoxycarbonylaminomethyl)pyridin-6- ylmethyl; 2-(trifluoromethyl)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridin-5- ylmethyl; 2-chloropyridin-5-ylmethyl; 2-cyanopyridin-5-ylmethyl; 2-hydroxy-3-amino-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yl; 2-methoxypyridin-3-ylmethyl; 2-methoxypyridin-5-ylmethyl; 2- methylpyridin-3-ylmethyl; 2-methylpyridin-5-ylmethyl; 2-methylpyridin-6-ylmethyl; 3-(2- amiπoethyl)cyclohexyl)methyl; 3-{4-methylpiperazin-1 -yl)propyl; 3-(amino)-3- (methylaminocarbonyl)prop-i-yl; 3-(aminocarbonyl)propyl; 3-(aminomethyl)benzyl; 3- (aminomethyl)pyridin-2-ylmethyl; 3-(methoxycarbonyl)propyl; 3-(methylaminocarbonyl)propyl; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; 3-carbamoylcyclopentyl; 3-carboxypropyl; 3-hydroxypropyl; 3-methoxypropyl; 4- (aminomethyl)-pyridin-2-ylmethyl; 4-(N,N-dimethylamino)pyridin-3-ylmethyl; 4-(t- butoxycarbonylamino)-morpholinomethyl; 4-aminobutyl; 4-aminomethylpyridin-3-ylmethyl; 4- cyanobenzyl; 4-fluorobenzyl; 4-methylaminopyridin-3-ylmethyl; 4-methylbenzyl; A- morpholinopyridin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5-
((bis(dimethylamino)methylamino)methyl)pyridin-3-ylmethyl; 5-(aminomethyl)ρyridin-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethyl; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarbonylaminomethyl)-pyridin-2-ylmethyl; 5-(trifluoromethyl)-pyridin-2-ylmethyl; 5- aminopentyl; 5-aminopyridin-2-ylmethyl; 6-((bis(dimethylamino)methyleneamino)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1 -yl)pyridin-3-ylmethyl); 6-(aminomethyl)pyridin-2-yl)methyl; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylaminocarbonylmethyl; isopropyl; isoxazol-5-ylm ethyl; methoxycarbonylmethyl; methyl; methylaminocarbonylmethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-ylmethyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
[0175] In certain embodiments of compounds of Formula VII, Z3 is chosen optionally substituted lower alkyl.
[0176] In certain embodiments of compounds of Formula VII, Z3 is chosen from optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl wherein the methyl, ethyl and propyl groups are optionally substituted with one or two groups selected from hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, and optionally substituted arylσxy.
[0177] In certain embodiments of compounds of Formula VII, Z3 is chosen from 2-(3- methylphenyl)ethyl, (tetrahydrofuran-2-yl)methyl, 1-hydroxycyclohexylmethyl, 2-(1 ,3-dioxolan-2- yl)ethyl, 2-(1H-imidazol-4-yl)ethyl, 2-(1-methyl-1H-imidazoI-4-yl)ethyl, 2-(1-methylpiperidin-4- yl)ethyl, 2-(2,3-difludrophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2- (2-methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(2-oxoimidazolidin-1-yl)ethyl, 2-(2- oxopiperidin-1 -yl)ethyl, 2-(2-oxopyrrolidin-1 -yl)ethyl, 2-(3-(trifluoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl, 2-(3,5- dimethyl-1 H-pyrazol-4-yl)ethyl, 2-(3-carbamoylphenyl)ethyl, 2-(3-carboxyphenyl)ethyl, 2-(3- cyanophenyl)ethyl, 2-(3-fluorophenyl)-2-(hydroxy)-ethyl, 2-{3-fluorophenyl)ethyl, 2-(3- fluoropyridin-2-yl)ethyl, 2-(3-methoxycarbonylphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(3- methylphenyl)ethyl, 2-(4-aminophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2- (4-hydroxyphenyl)ethyl, 2-(benzo[d][1,3]dioxol-5-yl)ethyl, 2-(furan-2-yl)ethyl, 2-(hydroxy)-2- (phenyl)ethyl, 2-(phenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-cyclohex-1-enylethyl, 2-cyclohexylethyl, 2-morpholinoethyl, 2-phenoxyethyl, 2-phenylprop-1- yl, 3-(1H-imidazol-1-yl)prop-1-yl, 3-phenylpropyl, benzyl, chloro, isopentyl, propyl, pyridin-2- ylmethyl, pyridin-3-ylmethyl, and thiophen-3-ylmethyl.
[0178] In certain embodiments of compounds of Formula VII, Z3 is chosen from 2-(3- fluorophenyl)ethyl and 2-(pyridin-2-yl)ethyl.
[0179] In certain embodiments of compounds of Formula VII, Z1 is chosen from cyano, halo, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted amino, optionally substituted aminocarbonyl, and optionally substituted carbamimidoyl.
[0180] In certain embodiments of compounds of Formula VII1 Z1 is chosen from acyl, alkenyl, alkoxycarbonyl, alkyl, amino, aminocarbonyl, and carbamimidoyl, where each group is optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl.
[0181] In certain embodiments of compounds of Formula VII, Z1 is chosen from (5- oxo-tetrahydrofuran-2-yl)methylamino; (E)-N'-cyano-N, N-dimethylcarbamimidoyl; (Z)-4-(N-(2- hydroxyethyl)-N,N'-bis(methoxycarbonyl)carbamimidoyl); (Z)-but-2-en-2-yl; 1-ethoxyeth-1-yl; 1- ethoxyvinyl;2-hydroxyeth-1 -ylamino 2-methoxyeth-1 ylamino;2-methylprop-1 -enyl; 3- (methoxycarbonyl)-prop-2-en-2-yl; 3-(N,N-dimethylamino)carbonyl-prop-1 -ylamino; 3- aminocarbonyl-prop-1 -ylamino; 3-hydroxyprop-1 -ylamino; 3-methoxy-prop-1 -enyl; 3- methoxyprop-1 -ylamino; 3-methoxypropyl; 3-methylbut-2-eπ-2-yl; 4-((pyridin-3- ylmethyl)aminocarbonyl)butylamino; 4-(N, N-dimethylamino)carbonyl-but-1 -ylamino; 4-(N- methylamino)carbonyl-but-1 -ylamino; 4-aminocarbonyl-but-1 -ylamino; acetyl; aminocarbonyl; carbamimidoyl; chloro; cyano; dimethylamino; ethoxycarbonyl; hydrogen; methoxycarbonyl; methylamino; N-(2-hydroxyethyl)-N-(acetyl)-amino; N-(2-hydroxyethyl)-N-(methyl)-amino; N-(2- hydroxyprop-1-yl)-N-(methyl)-amino; N-(methyl)-aminocarbonyl; N-(pyridin-2-ylmethyl)amino; N- (pyridin-3-ylmethyl)amiπo; N-(pyridin-4-ylmethyl)amino; N, N-dimethylcarbamimidoyl; N- cyanocarbamimidoyl; N-methyl-N-acetylamino; and prop-1-enyl.
[0182] In certain embodiments of compounds of Formula VII, R1 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments of compounds of Formula VIJ, R1 is chosen from hydrogen and lower alkyl. In certain embodiments of compounds of Formula VII, R1 is chosen from hydrogen and methyl. In certain embodiments of compounds of Formula VII, R1 is hydrogen.
[0183] In certain embodiments, the compound of Formula VII is chosen from Compound Chemical Name N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000216_0001
fluorophenyl)ethyl]amino}-5-(3-pyridyl)(3-
Compound 0 pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000216_0002
fluorophenyl)ethyl]amino}-5-(4-pyridyl)(3-
Compound 1 pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000216_0003
fluorophenyl)ethyl]amino}-5-(1-methylpyrazol-4-yl)(3-
Compound 2 py ridyl))ca rboxam ide
Figure imgf000216_0004
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(5-(2-cyanophenyl)-
Compound 3 2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
Figure imgf000216_0005
(5-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-
Compound 4 (2-pyridylmethyl)carboxamide
Figure imgf000216_0006
(5-bromo-2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-
Compound 5 [(6-methyl(2-pyridyl))methyl]carboxamide
Figure imgf000217_0001
(δ-bromo-δ-chloro-Z-fp-CS-fluorophenylJethyllaminoXS-
Compound 6 pyridyl))-N-(2-pyridylmethyl)carboxamide
Figure imgf000217_0002
5-bromo-2-{[2-(3-fluorophenyl)ethyl]amino}pyridine-3-
Compound 7 carboxylic acid
Figure imgf000217_0003
methyl 5-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}pyridine-
Compound 8 3-carboxylate
N-({6-[(1 ,3-dioxobenzo[c]azolin-2-yl)methyl](2-
Figure imgf000217_0004
pyridyl)}methyl)(5-bromo-2-{[2-(3-
Compound 9 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
Figure imgf000217_0005
(5-bromo-2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-
C 10 (2-py ridylmethyl)ca rboxam ide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(5-bromo-2-{[2-(3- Compound 11 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
Figure imgf000218_0001
fluorophenyl)ethyl]amino}-5-(2-pyridyl)(3-
Compound 12 pyridyl))carboxamide
Figure imgf000218_0002
methyl 6-[(4-carbamoylbutyl)amino]-2-{[2-(3-
Compound 13 fluorophenyl)ethyl]amino}pyridine-3-carboxylate
5-[(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Figure imgf000218_0003
pyridylmethyl)carbamoyl](2-pyridyl))amino]-N,N-
Compound 14 dimethylpentaπamide
5-[(6-{[2-(3-fluoroρhenyl)ethyl]amino}-5-[N-(3-
Figure imgf000218_0004
pyridylmethyl)carbamoyl](2-pyridyl))amino]-N-
Compound 15 methylpentanam ide
(6-[(4-carbamoyl b utyl)am ino]-2-{[2-(3-
Figure imgf000218_0005
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 16 pyridylmethyl)carboxamidθ
4-[(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Figure imgf000218_0006
pyridylmethyl)carbamoyl](2-pyridyl))am ino]-N , N-
Compound 17 dimethylbutanamide (6-[(3-carbamoylpropyl)amino]-2-{[2-(3-
Figure imgf000219_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 18 pyridylmethyl)carboxamide
Figure imgf000219_0002
(6-(dimethylamino)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 19 pyridyl))-N-(3-pyridylmethyl)carboxamide
5-[(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Figure imgf000219_0003
pyridylmethyl)carbamoyl](2-pyridyl))amino]-N-(3-
Compound 20 pyridylmethyl)peπtanamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(methylamino)(3- pyridyl))-N-(3-pyridylmethyl)carboxamide
Figure imgf000219_0004
N-(6-{[2-(3-fluorophenyI)ethyl]amino}-5-[N-(3-
Compound 22 pyridylmethyl)carbamoyl](2-pyridyl))-N-methylacetamide
N-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Figure imgf000219_0005
pyridylmethyl)carbamoyl](2-pyridyl))-N-(2-
Compound 23 hydroxyethyl)acetamide
Figure imgf000220_0001
6-{[2~(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Compound 24 pyridylmethyl)carbamoyl]pyridine-2-carboxamide
Figure imgf000220_0002
(6-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-
Compound 25 (3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(3-
Figure imgf000220_0003
pyridylmethyl)amino](3-pyridyl))-N-(3-
Compound 26 pyridylmethyl)carboxamide
(6-[(cyanoamino)iminomethyl]-2-{[2-(3-
Figure imgf000220_0004
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 27 pyridylmethyl)carboxamide
(6-((1 Z)-1-methylprop-1 -enyl)-2-{[2-(3-
Figure imgf000220_0005
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 28 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(N-
Figure imgf000220_0006
methylcarbamoyl)(3-pyridyl))-N-(3-
Compound 29 pyridylmethyl)carboxamide
Figure imgf000221_0001
methyl 6-{[2-(3-fluoroρhenyl)ethyl]amino}-5-[N-(3-
Compound 30 pyridylmethyl)carbamoyl]pyιϊdine-2-carboxylate
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2-
Figure imgf000221_0002
pyridylmethyl)amino](3-pyridyl))-N-(3-
Compound 31 pyridylmethyl)carboxamide
(6-((1 E)prop-1 -enyl)-5-bromo-2-{[2-(3-
Figure imgf000221_0003
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 32 pyridylmethyl)carboxamide
Figure imgf000221_0004
methyl (2E)-3-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Compound 33 pyridylmethyl)carbamoyl](2-pyridyl))but-2-enoate
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(4-
Figure imgf000221_0005
pyridylmethyl)amino](3-pyridyl))-N-(3-
Compound 34 pyridylmethyl)carboxam»de
Figure imgf000221_0006
ethyl 6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Compound 35 pyridylmethyl)carbamoyl]pyridine-2-carboxylate
Figure imgf000222_0001
(6-((1 E)prop-1 -enyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 36 pVridyl))-N-(3-pyridylmethyl)carboxamide
(6-((1E)prop-1-enyl)-5-cyano-2-{[2-(3-
Figure imgf000222_0002
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 37 pyridylmethyl)carboxamide
Figure imgf000222_0003
(2-{[2-{3-fluorophenyl)ethyl]amino}-6-(2-methylprop-1-
Compound 38 enyl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-[(dimethylamino)iminomethyl]-2-{[2-(3-
Figure imgf000222_0004
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3- Compound 39 pyridylmethyl)carboxamide
(6-[(1 E)-1 -(dimethylamino)-2-cyano-2-azavinyl]-2-{[2-(3-
Figure imgf000222_0005
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 40 pyridylmethyl)carboxamide
Figure imgf000222_0006
6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
Compound 41 pyridylmethyl)carbamoyl]pyridine-2-carboxamidine
Figure imgf000223_0001
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-5-phenyl(3-
Compound 42 pyridyl))carbonylamino]-N-methylacetamide
(6-((1 E)prop-1 -enyl)-2-{[2-(3-f luorophenyl)ethyl]amino}(3-
Figure imgf000223_0002
pyridyl))-N-{[2-(aminomethyl)(3- boc pyridyl)]methyl}carboxamide
Figure imgf000223_0003
2-[(5-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 43 pyridyl))carboπylamino]-N-methylacetamide
(6-((1E)-3-methoxyprop-1-enyl)-2-{[2-(3-
Figure imgf000223_0004
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 44 pyridylmethyl)carboxamide
Figure imgf000223_0005
(6-(ethoxyethyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
Compound 45 pyridyl))-N-(3-pyridylmethyl)carboxamlde
Figure imgf000223_0006
(6-acetyl-2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-
Compound 46 (3-pyridylmethyl)carboxamide (6-((1 E)prop-1 -enyl)-5-f luoro-2-{[2-(3-
Figure imgf000224_0001
fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[2-
Compound 47 (aminomethyl)(3-pyridyl))methyl}carboxamide
(6-((1E)prop-1-enyl)-5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(2-{[(tert-
Figure imgf000224_0002
butoxy)carbonylamino]methyl}(3-
Compound 48 pyrid y l))methyl]carboxam ide
Figure imgf000224_0003
Compound 49 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
Figure imgf000224_0004
(2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 50 pyridylmethyl)carboxamide
(6-(1 ,2-dimethylprop-1 -enyl)-2-{[2-(3-
Figure imgf000224_0005
fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
Compound 51 pyridylmethyl)carboxamide
Figure imgf000224_0006
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-methoxypropyl)(3- Compound 52 pyridyl))-N-(3-pyridylmethyl)carboxamide (6-(1-ethoxyvinyI)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2-
Figure imgf000225_0001
hydroxyethyl)amino](3-pyridyl))-N-(3-
Compound 54 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2-
Figure imgf000225_0002
hydroxyethyl)methylamino](3-pyridyl))-N-(3-
Compound 55 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2- methoxyethyl)amino](3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2-
Figure imgf000225_0003
hydroxypropyl)methylamino](3-pyridyl))-N-(3-
Compound 57 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(3-
Figure imgf000225_0004
methoxypropyl)amino](3-pyridyl))-N-(3-
Compound 58 pyridylmethyl)carboxamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(3-
Figure imgf000226_0001
hydroxypropyl)amino](3-pyridyl))-N-(3- Compound 59 pyridylmethyl)carboxamide
[0184] The compounds described herein can be synthesized utilizing techniques well known in the art from commercially available starting materials and reagents. For example, the compounds can be prepared as described below.
Figure imgf000226_0002
[0185] Referring to Reaction Scheme 1, Step 1, to a solution of a compound of Formula 101 and an excess (such as about 1.1 equivalents) of a compound of formula Z3NH2 in a polar solvent such as DMF is added a base such as potassium carbonate at room temperature. The product, a compound of Formula 103, is isolated and optionally purified.
[0186] Referring to Reaction Scheme 1, Step 2, to a mixture of a compound of Formula 103, an excess (such as about 2 equivalents) of a compound of formula Z1B(OH)2, and a base such as potassium carbonate in a polar solvent such as DMF is added about 0.1 equivalent of PdCI2. dppf. The reaction mixture is stirred at about 1000C for about 4 h. The product, a compound of Formula 105, is isolated and optionally purified. [0187] Referring to Reaction Scheme 1 , Step 2, to a solution of a compound of Formula 105 and an excess (such as about 1.4 equivalents) of a compound of Formula R10NH2 in a nonpolar solvent such as toluene is added an excess (such as about 1.5 equivalents) of AIMe3 at r.t.. The reaction mixture is stirred at about 70 0C overnight until completion. The product, a compound of Formula 107 wherein Z2 is aminocarbonyl, is isolated and optionally purified.
[0188] Unless specified to the contrary, for each gram of the limiting reagent, one cc (or ml.) of solvent constitutes a volume equivalent.
[0189] 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 in the Example. However, other equivalent separation or isolation procedures can, of course, also be used. [0190] 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. [0191] 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. [0192] 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.
[0193] 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 can be applied to cells or administered to individuals afflicted or subject to impending affliction with any one of these disorders or states.
[0194] 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.
[0195] 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. [0196] 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).
[0197] 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.
[0198] 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.
[0199] 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 Pharmacol 1970 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. [0200] 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.
[0201] 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.
[0202] 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.
[0203] 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 -200C, 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 ATP1 7 mM MgCI2, 55 mM KCI, 1 μM Calmodulin, and 10 mM EGTA. Free calcium will be controlled by addition of various amounts of CaCI2, 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.
[0204] 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.
[0205] 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 schedufe 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. [0206] 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, transdermal^, 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. [0207] 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 controlled-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.
[0208] 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 crosscarmellose, 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. 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.
[0209] 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.
[0210] 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. [0211] 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. [0212] Compositions comprising at least one chemical entity may be administered intraocularly (including intraocular, periocular, and retrobulbar injection and perfusion). When adminsitered 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. [0213] 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.
[0214] 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.
[0215] 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
[0216] 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 1 :
Figure imgf000234_0001
6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-iV-(pyridin-3-ylinethyl)nicotinamide
Method A:
Figure imgf000234_0002
[0217J To a solution of 2,6-dichloronicotinic acid (5Og, 0.26 mol) in methanol (250 ml_) was added thionyl chloride (22.7 mL, 0.312 mol) slowly. The mixture was refluxed for 4 hours and concentrated to give methyl 2,6-dichloronicotinate as a white solid in quantitative yield.
Figure imgf000234_0003
[0218] A mixture of methyl 2,6-dichloronicotinate (53.3g, 0.26mol), 3-fluorophenethyl amine (37.3 ml_, 0.29 mol), K2CO3 (72 g 0.52 mol) and NMP (150 mL) was stirred at 1000C for 10 hrs. The mixture was diluted with ethyl acetate (2 X 300 mL) and washed with brine. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography using hexane-EtOAc (9:1) as eluant to give methyl 6-chloro-2-(3- fluorophenethylamino)nicotinate as an off-white solid (44 g, 54%). LRMS (M+H+) m/z 309.0.
Figure imgf000235_0001
[0219] A mixture of chloride methyl 6-chloro-2-(3-fluorophenethylamino)nicotinate (30.8 g, 0.1 mol), 2-cyanophenyl boronic acid (17.6 g, 0.12 mol), PdCI2(dppf)2 (3.6 g, 5.0 mmol), K2CO3 (41.4 g, 0.3 mol) and anhydrous DMF (100 mL) was degassed with nitrogen for 30min. The mixture was then stirred at 100°C for 2 hrs. The mixture was filtered through the Celite and washed with EtOAc. The filtrate was diluted with EtOAc, washed with brine and concentrated to dryness. The residue was purified by silica gel flash chromatography using hexane-EtOAc (4:1) as eluant to give the desired product methyl 6-(2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinate as a yellow solid (31 g, 82%). LRMS (M+H+) m/z 376.1.
Figure imgf000235_0002
[0220] To a mixture of methyl ester methyl 6-(2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinate (15 g, 40 mmol), methanol (80 mL) and THF (80 mL) was added 3N NaOH (40 mL). The mixture was stirred at room temperature for 16 hrs. The mixture was adjusted to pH 7 with 2N HCI. After concentration, the residue in the aqueous solution was acidified to pH 3 with 2N HCI (10 ml_) to give the yellow precipitates. The yellow solid was filtered, washed with water and dried to afford 6-(2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinic acid (14.5 g, 100%). LRMS (M+H+) m/z 362.1.
Figure imgf000236_0001
[0221] To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (2.8 g, 7.76 mmol) in DMF (28 mL) was added HBTU (5.88 g, 15.51 mmol), HOBt (2.1 g, 15.51 mmol), then 3-aminomethyl pyridine (1.68 g, 15.51 mmol). The reaction mixture was stirred at room temperature for 1 hr. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-N-(pyridin-3- ylmethyl)nicotinamide as a pale yellow solid (3.0 g, 86%). LRMS (M+H+) m/z 452.2.
Method B:
Figure imgf000236_0002
[0222] A mixture of acid 2,6-dichloronicotinic acid (19.2 g, 0.1 mol), N.N'-carbonyldiimidazole (CDI, 17.8 g, 0.11 mmol) and THF (1 L) was stirred at 6O0C for 30 min and cooled to room temperature. To the mixture was added 3-aminomethyl pyridine (10.2 mL, 0.1 mol) and DIEA (21 ml_, 0.12 mol). The reaction mixture was stirred at room temperature for 4 hrs, and diluted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4. Concentration of the organic solution gave 2,6-dichloro-N-(pyridin-3-ylmethyl)nicotinamide (20.5 g, 73%). LRMS (M+H+) m/z 282.0; (M+2+H+) m/z 283.9.
Figure imgf000237_0001
[0223] A mixture of 2,6-dichloro-N-(pyridin-3-ylmethyl)nicotinamide (20.4 g, 72.3 mmol), 3- fluorophenethyl amine (11.1 g, 79.5 mmol), K2CO3 (20 g 145 mmol) and DMF (200 ml_) was stirred at 1000C for 10 hours. The mixture was diluted with ethyl acetate (2 X 300 mL) and washed wjth saturated ammonium chloride, sodium bicarbonate and brine. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography to give 6-chloro-2-(3-fluorophenethyIamino)-N-(pyridin-3-ylmethyl)nicotinamide (12.6 g, 46%). LRMS (M+H+) m/z 385.1.
Figure imgf000237_0002
[0224] A mixture of 6-chloro-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (1.0 g, 2.6 mmol), 2-cyanophenyl boronic acid (460 mg, 3.12 mmol), PdCI2(dppf)2 (140 mg, 0.26 mmol), K2CO3 (1.08 g, 7.8 mmol) and anhydrous DMF (8 mL) was degassed with nitrogen for 10 min. The mixture was then stirred at 1250C for 1 hr. The mixture was filtered through the silica gel pad and washed with EtOAc. The filtrate was concentrated to dryness and purified by silica gel flash chromatography to give the desired product 6-(2-cyanophenyl)-2-(3- fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide as a pale yellow solid (740 mg, 63%). LRMS (M+H+) m/z 452.1.
Example 2:
Figure imgf000238_0001
II
/V-((2-(aminomethyl)pyridin-3-yI)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide
Figure imgf000238_0002
[0225] To a mixture of 2-bromoπicotiπaldehyde (50 g, 0.27 mol), methanol (250 mL) and THF (250 mL) in a 3-necked round bottom flask at O0C was added sodium borohydride (10.3 g, 0.27 mol) portion wise. The reaction mixture was stirred at O0C for 1 hr and warmed up to room temperature. The reaction mixture was adjusted to pH 7 with 2N HCI (120 mL), and concentrated to remove methanol and THF. The resulting mixture was partitioned between EtOAc and brine three times. The organic layer was combined and washed with brine, dried over Na2SO4, and concentrated to give (2-bromopyridin-3-yl)methanol (51 g), which was used without further purification. LRMS (M+H*) m/z 187.9.
Figure imgf000239_0001
[0226] To a mixture of (2-bromopyridin-3-yl)methanol (51 g, 0.27 mol), phthalimide (47.6 g, 0.32 mol), triphenylphosphine (83.8 g, 0.32 mol) and THF (60 ml_) at O0C was added DIAD (62 ml_, 0.32 mol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. The formed precipitate was filtered and washed with EtOAc (50 ml_). The obtained solid 2-((2-bromopyridin-3-yl)methyl)isoindoline-1 ,3-dione (50.2 g, 59%) was used for next step without further purification. LRMS (M+H+) m/z 317.1.
Figure imgf000239_0002
[0227] A mixture of bromide 2-((2-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (50 g, 0.16 mol), Zn(CN)2 (37.4 g, 0.32 mol), Pd(PPh3J4 (18.5 g, 16 mmol) and DMF (160 ml_) was degassed with nitrogen for 10 min and then stirred at 1000C for 3 hrs. The mixture was filtered through the Celite and washed with DMF. The combined filtrate was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and concentrated. The residue was triturated with dichloromethane to give the desired product 3-((1,3-dioxoisoindolin-2-yl)methyl)picolinonitrile as an off-white solid (35 g, 83%). LRMS (M+H+) m/z 264.0.
Figure imgf000240_0001
[0228] To a mixture of 3-((1 ,3-dioxoisoindolin-2-yl)methyl)picolinonitrile (10 g, 38 mmol) and methanol (80 ml_) was added cone. HCI (6.5 mL, 76 mmol) and 10% Pd/C (1 g). The mixture was stirred vigorously under 50 Psi H2 for 6 hrs. The mixture was filtered through the Celite pad and washed with methanol. The combined filtrate was concentrated to give the 2-((2- (aminomethyl)pyridin-3-yl)methyl)isoindoline-1 ,3-dione as a white solid in quantitative yield. LRMS (M+H+) m/z 268.1.
Figure imgf000240_0002
[0229] To a mixture of 2-((2-(aminomethyl)pyridin-3-yl)methyl)isoindoline-1 ,3-dione HCI salt (44.5 g, 0.13 mol), THF (230 mL) and H2O (230 mL) at O0C was added NaHCO3 (36 g, 0.43 mol), then Boc2O (31.4 g, 0.144 mol). The mixture was allowed to warm to room temperature and stirred for 2 hrs. The mixture was diluted with ethyl acetate (200 mL), washed with water, brine, dried and concentrated. The residue was triturated with EtOAc (150 mL) to give the desired product as a white solid (30 g, 63%). The EtOAc solution was purified by silica gel flash chromatography using hexane-EtOAc (1 :1) as eluant to give the second portion of tert-butyl (3- ((1 ,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methylcarbamate (13.5 g, 28%). LRMS (M+H+) m/z 368.1.
Figure imgf000241_0001
[0230] To a solution of tert-butyl (3-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-2- yl)methylcarbamate (30 g, 81 mmol) in MeOH (450 mL) at 00C was added hydrazine (25 mL, 810 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The precipitate was filtered off, and the filtrate was concentrated to dryness. The residue was triturated with dichloromethane (500 mL) and filtered. Concentration of the filtrate afforded tert- butyl (3-(aminomethyl)pyridin-2-yl)methylcarbamate in quantitative yield (18.7g). LRMS (M+H+) m/z 238.1.
Figure imgf000241_0002
[0231] To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (0.60 g, 1.66 mmol) in DMF (3 mL) was added DIEA (0.329 mL, 2.53 mmol), HBTU (0.756 g, 2.00 mmol), then tert-butyl (3-(aminomethyl)pyridin-2-yl)methylcarbamate (0.473 g, 2.11 mmol). The reaction mixture was stirred at room temperature for 1 hr. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give tert-butyl (3-((6-(2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbarnate as a pale yellow solid (545 mg, 57%). LRMS (M+H*) m/z 581.3.
Figure imgf000242_0001
II
[0232] To a solution of tert-butyl (3-((6-(2-cyaπophenyl)-2-(3- fluorophenethyIamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate (737 mg, 1.27 mmol) in methanol (6 ml_) at O0C was added a solution of 4M HCI in 1,4-dioxane (3 ml_). The mixture was warmed to room temperature and stirred for 2 hrs. Concentration of the mixture followed by the purification on RP-HPLC using a mixture of acetonitrile and H2O gave N-((2- (aminomethyl)pyridin-3-yl)methyl)-6-{2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinamide as a pale yellow solid (545 mg, 89%). LRMS (M+H+) m/z 481.2.
Example 3:
Figure imgf000242_0002
III
Λ^-(2-amino-2-oxoethyI)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide
Figure imgf000243_0001
[0233] Compound N-(2-amino-2-oxoethyl)-6-(2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinamide was prepared from 6-(2-cyanophenyl)-2-(3- f!uorophenethylamino)nicotinic acid and the appropriate amine 2-aminoacetamide according to the procedure (Method A) of preparation of Example 1. LRMS (M+H+) m/z 418.1.
Example 4:
Figure imgf000243_0002
IV
(/?)-/V-((l-(4-aminobutanoyI)pyrrolidin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluoropheπethylamino)nicotinamide
Figure imgf000243_0003
[0234] To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (510 mg, 1.41 mmol), (R)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (424 mg, 2.11 mmol), HOBT (285 mg, 2.11 mmol), and HBTU (800 mg, 2.11 mg) in RB flask was added DMF and the mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete and the mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (R)-tert- butyl 2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyrrolidine-1- carboxylate (695.1 mg, 91%). LRMS (M +H+) m/z 544.2.
Figure imgf000244_0001
[0235] To a solution of (R)-tert-butyl 2-((6-(2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinamido)methyl)pyrrolidine-1τcarboxylate (680 mg, 1.25 mmol) in MeOH (20 mL) was added HCI (2.0 mL, 8 mmol, 4 M in dioxane). The reaction was stirred at r.t. for 2 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-N- (pyrrolidin-2-ylmethyl)nicotinamide hydrochloride which was used for next step without further purification. LRMS (M +H+) m/z 444.2.
Figure imgf000245_0001
[0236] To a mixture of 6-(2-cyanopheπyl)-2-(3-fluoropheπethylamino)-N-(pyrrolidiπ-2- ylmethyl)nicotinamide hydrochloride (95 mg, 0.2 mmol), 4-(tert-butoxycarbonylamino)butanoic acid {61 mg, 0.3 mmol), HOBT (41 mg, 0.3 mmol), and HBTU (114 mg, 0.3 mmol) were added DMF (1.0 ml_) and DIEA (0.1 ml_, 0.6 mmol). The reaction mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete. The reaction mixture was then filtered and the filtrate was purified on RP-HPLC using a mixture of acetonitrile and water to give tert-butyl 4-(2- ((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4- oxobutylcarbamate (81.2 mg, 65%). LRMS (M +H+) m/z 629.2.
Figure imgf000245_0002
IV
[0237] To a solution of tert-butyl 4-(2-((6-(2-cyanophenyl)-2-(3- fluorophenethylaminoJnicotinamidoJmethylJpyrrolidin-i-yO^-oxobutylcarbamate (71 mg, 0.11 mmol) in MeOH (5.0 mL) was added HCI (1.0 mL, 4 mmol, 4 M in dioxane). The reaction mixture was stirred at r.t. for 2 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and the crude was purified on RP-HPLC using a mixture of acetonitrile (0.1% TFA) and water (0.1% TFA) to give N-((i-(4- aminobutanoyl)pyrrolidin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3- fluorophenethyIamino)nicotinamJde as a pale yellow solid (57.1 mg, 68%). LRMS (M +H+) m/z 529.2.
Example 5:
Figure imgf000246_0001
(R)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)-Λ/-((5-oxopyrrolidin-2-yl)methyl)nicotinamide
H DIAD, PPh3 HN3, THF N3 X ■■<y°
[0238] To (R)-5-(hydroxymethyl)pyrrolidin-2-one (660 mg, 5.73 mmol), hydrogen azide (10.8 mL, 8.60 mmol, 0.8 M in toluene), and PPh3 (2.25 g, 8.60 mmol) in THF was added DIAD dropwise. The mixture was stirred at rt for 1 h. LCMS indicated the completion of the reaction. The mixture was partially concentrated, filtered, and purified by RP-HPLC to give (R)-5- (azidomethyl)pyrrolidin-2-one (730 mgt 87%, 90% pure). LRMS (M +H+) m/z 141.1.
Figure imgf000246_0002
[0239] To (R)-5-(azidomethyl)pyrrolrdin-2-one (150 mg, 1.07 mmol) in MeOH was added Pd/C. The mixture was the placed into an autoclave, degasses three times, charged with 30 psi of H2 and stirred at rt for 30 min. The mixture was the filtered and the filtrate was concentrated under reduced pressure to give (R)-5-(aminomethyl)pyrrolidin-2-one (92 mg, 75%). LRMS (M +H+) m/z 115.1.
Figure imgf000247_0001
[0240] To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (110 mg, 0.30 mmol), (R)-5-(aminomethyl)pyrrolidin-2-one (52 mg, 0.46 mmol), HOBT (62 mg, 0.46 mmol), and HBTU (174 mg, 0.46 mg) in RB flask was added DMF and the mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete and the mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (R)-6-(2-cyanophenyl)-2- (3-fluorophenethylamiπo)-N-((5-oxopyrrolidiπ-2-yl)methyl)nicotinamide (91.6 mg, 67%). LRMS (M +H+) m/z 458.1.
Example 6:
Figure imgf000248_0001
(^-^((I^S-amiπopropylJ-δ-oxopyrrolidin^-ypmethyO-e^-cyaπophenyO^-fS- fluorophenethylamino)nicotinamide
Figure imgf000248_0002
[0241] To NaH (128 mg, 3.21 mmol) in DMF (5.0 ml_) was added (R)-5-(azidomethyl)pyrrolidin- 2-one (300 mg, 2.14 mmol) in DMF (5.0 ml_) and stirred at rt for 30 min followed by addition of tert-butyl 3-bromopropylcarbamate. The mixture was heated to 60 0C for 2 h and quenched with sat. NH4CI solution. The aqueous layer was extracted with EtOAc (50 ml_ x 2) and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-tert-butyl 3-(2-(azidomethyl)-5-oxopyrrolidin-1- yl)propylcarbamate (358 mg of crude), which was used for next step without purification. LRMS (M +H+-BoC) m/z 198.1.
Figure imgf000248_0003
[0242] To (R)-tert-butyl 3-(2-(azidomethyl)-5-oxopyrrolidin-1-yl)propylcarbamate (300 mg, 1.01 mmol) in MeOH was added Pd/C. The mixture was the placed into an autoclave, degasses three times, charged with 30 psi of H2 and stirred at rt for 30 min. The mixture was the filtered and the filtrate was concentrated under reduced pressure to give (R)-tert-butyl 3-(2- (aminomethyl)-5-oxopyrrolidin-1-yl)propylcarbamate (180 mg of crude). LRMS (M +H+) m/z 198.1.
Figure imgf000249_0001
[0243] To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (110 mg, 0.30 mmol), (R)-tert-butyl 3-(2-(aminomethyl)-5-oxopyrrolidin-1-yl)propylcarbamate (125 mg, 0.46 mmol), HOBT (107 mg, 0.46 mmol), and HBTU (174 mg, 0.46 mg) in RB flask was added DMF and the mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete and the mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (R)-tert-butyl 3-(2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)-5- oxopyrrolidin-1-yl)propylcarbamate (72 mg, 39%). LRMS (M +H+) m/z 615.2.
Figure imgf000249_0002
[0244] To a solution of (R)-tert-butyl 3-(2-((6-(2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinamido)methyl)-5-oxopyrrolidin-1-yl)propylcarbamate (72 mg, 0.12 mmol) in MeOH (5.0 mL) was added HCI ( 1.0 ml_, 4 mmol, 4 M in dioxane). The reaction mixture was stirred at r.t. for 2 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give (R)-N-((1-(3-aminopropyl)-5- oxopyrrolidin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide hydrogen chloride (75 mg, quantitative). LRMS (M +H+) m/z 515.1.
Example 7:
Figure imgf000250_0001
VII yV-((6-(3-aminopropylamino)pyridin-2-yl)methyl)-6-(2-cyaπophenyI)-2-(3-fluorophenethyIamino)nicotinamide
Figure imgf000250_0002
[0245]To a solution of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (582mg, 1.61 mmol) and 6-bromo-pyridin-2yl-methylamine (300mg, 1.61 mmol) in DMF was added CDI (261 mg, 1.61 mmol). The reaction mixture was stirred at r.t. for 2 h. The reaction mixture was purified on RP-HPLC to give N-((6-bromopyridin-2-yl)methyl)-6-(2- cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide (700mg, 82%) LRMS (M+H+) m/z 530.1.
Figure imgf000251_0001
VII
[0246] A solution of N-((6-bromopyridin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinamide (50 mg, 0.095 mmol,) and propane-1 ,3-diamine (396ul, 4.75mmol) in NMP was stirred in microwave at 150C for 15min. The reaction mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O gave N-((6-(3- aminopropylamino)pyridin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3- fluorophenethylamino)nicotinamide (28 mg, 56 %). LRMS (M+H+) m/z 524.1.
Example 8:
Figure imgf000251_0002
VIII
2-(3-fluorophenethylamino)-6-(l//-pyrazol-4-yl)-Λ^-(pyridin-3-yImethyl)nicotinamide
Method A:
Figure imgf000252_0001
[0247] To a mixture of ester methyl 6-chloro-2-(3-fluorophenethylamino)nicotinate (3.08 g, 10 mmol), methanol (20 ml_) and THF (20 mL) was added 3N NaOH (10 ml_, 30 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture was concentrated to remove methanol and THF and adjusted pH to 3 with 2N HCI. The precipitate was filtered and washed with water to give the 6-chloro-2-(3-fluorophenethylamino)nicotinic acid in quantitative yield. LRMS (M+H+) m/z 295.1.
Figure imgf000252_0002
[0248] A mixture of 6-chloro-2-(3-fluorophenethylamino)nicotinic acid (10.6 g, 36 mmol), borolane (12.72 g, 43 mmol), Pd(PPh3J4 (4.2 g, 3.6 mmol), K2CO3 (14.9 g, 108 mmol) and anhydrous DMF (50 mL) was degassed with nitrogen for 10 min. The mixture was then stirred at 120 0C in microwave for 2 hrs. The mixture was filtered through the Celite and washed with DMF. The filtrate was adjusted to pH 4 with 2N HCI (28 mL), and diluted with EtOAc. The organic layer was washed with brine twice and concentrated to dryness. The residue was triturated with dichloromethane (300 mL). Filtration followed by washed with EtOAc (20 mL) gave 2~(3-fluorophenethylamino)-6-(1 H-pyrazol-4-yl)nicotinic acid as a yellow solid (7.1 g, 61%). LRMS (M+H+) m/z 327.1.
Figure imgf000253_0001
[0249] To a mixture of 2-(3-fluorophenethylamino)-6-(1 H-pyrazol-4-yl)nicotinic acid (prepared according to example 1, method A) (1.0 g, 3.07 mmol) in DMF (10 ml.) was added HBTU (1.75 g, 4.6 mmol), HOBt (0.62 g, 4.6 mmol), then amine 7 (0.66 g, 6.13 mmol). The reaction mixture was stirred at room temperature for 2 hr. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-fluorophenethyIamino)-6-(1H-pyrazol-4-yl)-N- (pyridin-3-ylmethyl)nicotinamide as a pale yellow solid (0.79 g, 62%). LRMS (M+H+) m/z 417.1.
Method B:
Figure imgf000253_0002
VIII
[0250] A mixture of 6-chloro-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (prepared according to example 1, method B) (152 mg, 0.39 mmol), borolane (139 mg, 0.47 mmol), Pd(PPh3J4, and K2CO3 in DMF was heated at microwave reactor at 1250C for 1 h. The mixture was filtered on a silica gel plug using EtOAc as eluent. The filtrate was concentrated and purified on RP-HPLC using a mixture of acetonitrile and water to give 2-(3- f luorophenethylamino)-6-(1 H-pyrazol-4-yl)-N-(pyridin-3-ylmethyl)nicotinamide (60.5 mg,
37%). LRMS (M +H+-BoC) m/z 417.1.
Example 9:
Figure imgf000254_0001
Λf-((2-(aminomethyl)pyridin-3-yl)methyl)-2-(3-fluorophenethylamino)-6-(l//-pyrazol-4-yl)nicotinamide
Figure imgf000254_0002
[0251] To a mixture of 6-chloro-2-(3-fluorophenethylamino)nicotinic acid (prepared from example 8, method A) (0.72 g, 2.21 mmol) in DMF (5 mL) was added DIEA (0.417 mL, 2.53 mmol), HBTU (0.84 g, 2.21 mmol), HOBt (0.30 g, 2.21 mmol), then amine tert-butyl (3- (aminornethyl)pyridin-2-yl)methylcarbamate (preparations accordint to example 2) (0.50 g, 2.11 mmol). The reaction mixture was stirred at room temperature for 1 hr. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give tert-butyl (3-((2-(3- fluorophenethylamino)-6-(1 H-pyrazol-4-yl)nicotinamido)methyl)pyridin-2-yl)methylcarbamate as a pale yellow solid (737 mg, 60%). LRMS (M+H+) m/z 546.3.
Figure imgf000255_0001
[0252] To a solution of tert-butyl (3-((2-(3-fluorophenethylamino)-6-(1H-pyrazol-4- yl)nicotinamido)rnethyl)pyridin-2-yl)methylcarbamate (737 mg, 1.27 mmol) in methanol (6 ml_) at O0C was added a solution of 4M HCI in 1 ,4-dioxane (3 ml_). The mixture was warmed to room temperature and stirred for 2hrs. Concentration of the mixture followed by the purification on RP-HPLC using a mixture of acetonitrile and H2O gave N-((2-(aminomethyl)pyridin-3- yl)methyl)-2-(3-fluorophenethylamino)-6-(1 H-pyrazol-4-yl)nicotinamide compound with methanol (1:1) as a pale yellow solid (545 mg, 89%). LRMS (M+H+) m/z 446.2.
Example 10:
Figure imgf000255_0002
Λ^-((2-(aminomethyl)pyridin-3-yI)methyl)-5-fluoro-2-(3-fluorophenethylamino)-6-(l//-pyrazoI-4-yl)nicotinamide
Figure imgf000256_0001
[0253] A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.26 g, 6.0 mmol), 3-fluorophenethyl amine (1.25 ml_, 9.0 mmol), DIEA (3.14 ml_, 18 mmol) and MeCN (6 ml.) was refluxed for 48 hrs and concentrated. The residue was dissolved in EtOAc (120 ml_) and washed with saturated citric acid, water, brine, dried and concentrated. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6-chloro-5-fluoro-2-(3-fluorophenethylamino)nicotinic acid as a solid (920 mg, 49%). LRMS (M+H+) m/z 313.0.
Figure imgf000256_0002
[0254] A mixture of 6-chloro-5-fluoro-2-(3-fluorophenethylamino)nicotinic acid (2.2 g, 7.04 mmol), 4,4,5,5-tetramethyl-2-(1 H-pyrazol-4-yl)-1,3,2-dioxoborolane (2.04 g, 10.56 mmol), Pd(PPh3)4 (0.81 g, 0.71 mmol), K2CO3 (2.92g, 21.1 mmol) and anhydrous DMF (10 mL) was degassed with nitrogen for 10 min. The mixture was then stirred at 150 0C in microwave for 3 hrs. The mixture was filtered through the Celite and washed with DMF (50 mL). The filtrate was adjusted to pH 4 with 2N HCI (5 mL), and diluted with EtOAc (150 mL). The organic layer was washed with saturated ammonium chloride, brine and concentrated to dryness. The residue was triturated with dichloromethane (30 mL). Filtration followed by washed with EtOAc (5 mL) gave 5-fluoro-2-(3-fluorophenethylamino)-6-(1 H-pyrazol-4-yl)nicotinic acid as a yellow solid (2.1 g, 87%). LRMS (M+H+) m/z 345.3.
Figure imgf000257_0001
[0255] Compound X was prepared from 5-fluoro-2-(3-fluorophenethylamino)-6-(1 H-pyrazol-4- yl)nicotinic acid and amine tert-butyl (3-(aminomethyl)pyridin-2-yl)methylcarbamate according to the procedure of preparation of Example 9. LRMS (M+H+) m/z 464.1 ,
Example 11:
Figure imgf000257_0002
Xl
(R)-5-fluoro-2-(3-fluorophenethylamino)-/V-((1-(2-hydro>^acetyl)azetidin-2-yl)methyl)-6-(1-methyl-1H- pyrazol-4-yl)nicotinamide
Figure imgf000257_0003
[0256] A mixture of 6-chloro-5-fluoro-2-(3-fluorophenethylamino)nicotinic acid (see example 10) (15.6g, 50 mmol), borolaπe (12.5g, 60 mmol), Pd(PPh3)4 (5.8 g, 5 mrnol), K2CO3 (20.7g, 150 mmol) and anhydrous DMF (100 ml_) was degassed with nitrogen for 10 min. The mixture was then stirred at 1250C in microwave for 2 hrs. The mixture was filtered through the Celite and washed with DMF. The filtrate was adjusted to pH 4 with 2N HCI, and diluted with EtOAc. The organic layer was washed with brine twice and concentrated to dryness. The residue was triturated with EtOAc (200 ml_). Filtration followed by washed with EtOAc (20 ml_) gave 5-fluoro- 2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinic acid as a yellow solid (14.5 g, 85%). LRMS (M+H+) m/z 359.0.
H
Figure imgf000258_0001
[0257] To a mixture of D-azetidine-carboxylic acid (20 g, 200 mmol), H2O (200 mL) and dioxane (200 ml) at 00C was added a solution of BoC2O in dioxane (100 mL) with an additional funnel. The mixture was stirred at r.t for 1 hour. After concentration, 200 mL ether and 200 mL H2O were added to the residue. The aqueous layer was acidified with 2N HCI to pH 3-4, and then extracted with 200 mL EtOAc. The organic layer was dried and concentrated to give (R)-1- (tert-butoxycarbonyl)azetidine-2-carboxylic acid in quantitative yield (4Og). LRMS (M-100+H*) m/z 102.1.
Figure imgf000258_0002
[0258] To a solution of 2M LiBH4 (200 ml, 400mmol) in THF at 00C was added TMSCI (101ml, 800 mmol) slowly. The mixture was warmed up to r.t and stirred at r.t. for 30 min. To the mixture at 0 0C was added a solution of (R)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (4Og, 200 mmol) in 200 ml THF with an additional funnel over 1 hour. The mixture was warmed up to r.t and stirred at r.t. for 2 hours. The mixture was cooled down to 0 0C and then treated with 32 mL MeOH followed by 40 mL H2O. After removal of THF, the residue was extracted with 300 mL EtOAc and washed with 300 ml_ brine. The organic layer was dried and concentrated to give (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate as a colorless oil (32.5g, 87%). LRMS (M-100+H+) m/z 132.1.
NjΛ Qw Ml-Boc
Figure imgf000259_0001
[0259] To a mixture of (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (32.5g, 173 mmol) and Et3N (27 mL, 191mmol) in THF (650 mL) at 0 0C was added methane sulfonylchloride (14.9 ml, 191 mmol) dropwise. The mixture was stirred for 10 min. The precipitation was filtered off and the filtrate was concentrated. The residue was then dissolved with DMF (200 mL). Sodium azide (34g, 519 mmol) was then added. The mixture was stirred at 65 0C for 6 hours. 300 mL EtOAc and 300 mL brine were then added to the reaction mixture. The organic layer was dried and concentrated. The residue was purified by Biotage silica gel chromatography (EtOAc: Hexane 1 :4) to give (R)-tert-butyl 2-(azidomethyl)azetidine-1- carboxylate as a colorless oil (32g, 87% yield). LRMS (M-100+H*) m/z 113.1.
Figure imgf000259_0002
[0260] A mixture of (R)-tert-butyl 2-(azidomethyl)azetidine-1-carboxylate (17g, 80 mmol), 10% Pd/C (2g) and MeOH (15OmL) was stirred under 45 psi hydrogen for 1 hour. The catalyst was filtered off and the filtrate was concentrated to give (R)-tert-butyl 2-(aminomethyl)azetidine-1- carboxylate (14.9 g, yield 100%). LRMS (M+H+) m/z 187.3.
Figure imgf000259_0003
[0261] To a mixture of 5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H-pyrazol-4-yl)nicotinic acid (14.3 g, 40 mmol) and DMF (30OmL) was added of HBTU (18.2 g, 48 mmol) and HOBT (6.49 g, 48 mmol). The mixture was cooled down to 00C, 8.93 g (48 mmol) of (R)-tert-butyl 2- (aminomethyl)azetidine-i-carboxylate was added, followed by 13.9 ml of DIEA (80mmol). The mixture was stirred at r.t for 1 hour and extracted with 300 mL EtOAc. The organic layer was washed with 500 mL brine, dried over MgSO4 and then concentrated. The residue was purified by Biotage silica gel chromatography using EtOAc:Hex (1:1) as eluant. (R)-tert-butyl 2-((5- fluoro^-tS-fluorophenethylaminoJ-e-ti-methyl-IH-pyrazoM-ylJnicotinamidoJmethyOazetidine-i- carboxylate was obtained as a yellow solid (16.5 g, yield 80%). LRMS (M+H+) m/z 527.1.
Figure imgf000260_0001
Xl
[0262] To a mixture of (R)-tert-butyl 2-<(5-fluoro-2-(3-fluorophenethylamino)-6-(1-methyl-1H- pyrazol-4-yl)nicotinamido)methyl)azetidine-1-carboxylate (16.5g, 31.4mmol) in 100 mL DCM at 00C was added trifluoroacetic acid (24 mL, 314 mmol) slowly. The mixture was stirred at r.t for 2 hours until the Boc protection group was completely removed. The mixture was then concentrated. The residue was dissolved in 100 mL DMF and cooled down to 0 0C. To the mixture was added a mixture of glycolic acid (2.86g, 38mmol), HBTU (14.3g, 38mmol), HOBT (5.1g, 38mmol) and DIEA (16.4ml, 94mmol). The mixture was warmed up to r.t and stirred at r.t. for 2 hours. The mixture was extracted with EtOAc. The organic layer was further washed with 1N NaOH (300ml) and brine, dried and concentrated. The residue was subjected to a Biotage silica gel chromatography using gradient 0-40% B as eluant (A = dichloromethane, B = 10% MeOH in dichloromethane) to give the crude product. The yellow solid was further tritirated with 100 mL EtOAc. (R)-5-fluoro-2-(3-fluorophenethylamino)-N-((1-(2- hydroxyacetyl)azetidin-2-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide was obtained as a pale yellow solid (12.7g, 83% yield). LRMS (M+H+) m/z 485.1. Example 12:
Figure imgf000261_0001
xπ
Λ^-(((Λ)-l-(4-aminobutanoyI)pyiτolidin-2-y])πiethyl)-6-(2-cyanophenyl)-2-(2-(tetrahydro-2//-pyran-2-yl)ethylaniino)
Figure imgf000261_0002
iii. TFA/ CH2CI2
[0263] A mixture of 2,6-dichloronicotinic acid (1.0 g, 5.21 mmol), N,N'-carbonyldiimidazole (CDI, 1.01g, 6.25 mmol) and THF (10 mL) was stirred at 600C for 30 min and cooled to room temperature. To the mixture was added (R)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (1.04 g, 6.25 mmol) and DIEA (1.03 mL, 5.21 mmol). The reaction mixture was stirred at room temperature for 4 hrs, and diluted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4. Concentration of the organic solution followed by treatment with 30% TFA in dichloromethane (10 mL) gave (R)-2,6-dichloro-N-(pyrrolidin-2-ylmethyl)nicotinamide TFA salt as a white solid (1.7 g, 84%). LRMS (M+H+) m/z 274.0.
Figure imgf000262_0001
[0264] To a mixture of 4-(benzyloxycarbonylamino)butanoic acid (1.29 g, 5.45 mmol) in DMF (4 mL) was added HBTU (2.07 g, 5.45 mmol), DIEA (3.0 mL, 18.17 mmol), then amine (R)-2,6- dichloro-N-(pyrrolidin-2-ylmethyl)nicotinamide (1.7 g, 4.54 mmol). The reaction mixture was stirred at room temperature for 1 hr. The crude mixture was purified by silica gel chromatography using a mixture of EtOAC-MeOH (19:1) to give (R)-benzyl 4-(2-((2,6- dichloronicotinamidoJmethylJpyrrolidin-i-yO^-oxobutylcarbamate (1.9 g, 85%). LRMS (M+H+) m/z 493.4.
Figure imgf000262_0002
[0265] A mixture of chloride (R)-benzyl 4-(2-((2,6-dichloronicotinamido)methyl)pyrrolidin-1-yl)-4- oxobutylcarbamate (150 mg, 0.304 mmol), 2-(tetrahydro-2H-pyran-2-yl)ethanamine HCI salt (76 mg, 0.459 mmol), K2CO3 (125 mg, 0.905 mmol) and DMF (1 mL) was stirred at 10O0C for 10 hrs. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give benzyl 4-((R)-2-((6-chloro-2-(2-(tetrahydro-2H-pyran-2- yl)ethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (62 mg, 35%). LRMS (M+H+) m/z 586.3.
Figure imgf000263_0001
[0266] A mixture of benzyl 4-((R)-2-((6-chloro-2-(2-(tetrahydro-2H-pyran-2- yl)ethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (62 mg, 0.101 mmol), 2- cyanophenyl boronic acid (23 mg, 0.156 mmol), PdCI2(dppf)2 (11 mg, 0.02 mmol), K2CO3 (92 g, 0.667 mmol) and anhydrous DMF (1 ml_) was stirred at 1250C for 1 hr. The mixture was filtered through the silica gel pad and washed with EtOAc. The filtrate was concentrated to dryness and purified on RP-HPLC using a mixture of acetonitrile and H2O to give benzyl 4-((R)-2-((6-(2- cyanophenyl)-2-(2-(tetrahydro-2H-pyran-2-yl)ethyfamino)nicotinamido)methyl)pyrrolidin-1-yl)-4- oxobutylcarbamate (50 mg, 77%). LRMS (M+H+) m/z 653.3.
Figure imgf000263_0002
XII
[0267] To a solution of benzyl 4-((R)-2-((6-(2-cyanophenyl)-2-(2-(tetrahydro-2H-pyran-2- yl)ethylamino)nicotinamido)methyl)pyrrolidin-1-yl)-4-oxobutylcarbamate (47 mg, 0.072 mmol) in MeCN (1 mL) at 00C was added TMSI (72 mg, 0.36 mmol). The mixture was stirred at room temperature for 2 hrs and purified on RP-HPLC using a mixture of acetonitrile and H2O to give N-({(R)-1-(4-aminobutanoyl)pyrrolidin-2-yl)methyl)-6-(2-cyanophenyl)-2-(2-(tetrahydro-2H- pyran-2-yl)ethylamino)nicotinamide (36 mg, 77%). LRMS (M+H+) m/z 519.3.
Example 13
[0268] Using procedures similar to those described herein, the compounds in the following table were synthesized and tested. IC50
Arithmetic
Mean Ion m/z CHEMICAL NAME
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-prop-2-
3.123 M+H 359.2 enylcarboxamide
N-methyl(2-{[2-(3-methylpheπyl)ethyl]amino}-6-phenyl(3-
6.747 M+H 346.2 pyridyl))carboxamide
N-methyl{6-phenyl-2-[(2-phenylethyl)amino](3-
18.628 M+H 332.2 pyridyl)}carboxamide
{6-phenyl-2-[(2-phenylethyl)amino](3-pyridyl)}-N-prop-2-
1.062 M+H 358.2 enylcarboxamide
(2-{[2-(3-methylphenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-
3.74 M+H 372.3 prop-2-enylcarboxamide
N-methyl{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-
27.729 M+H 333.2 pyridyl)}carboxamide
N-benzyl{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-
1.564 M+H 409.2 pyridyl)}carboxamide
{6-phenyl-2-[(2-phenylethyl)amiπo](3-pyridyl)}-N-(3-
0.151 M+H 409.2 pyridylmethyl)carboxamide
N-(methylethyl){6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-
13.296 M+H 361.3 pyridyl)}carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(2-
0.463 M+H 410.1 pyridylmethyijcarboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(4-
1.29 M+H 410.2 pyridylmethyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyϊ)ethyl)amino](3-pyridyl)}-N-(3-
5.373 M+H 396.2 pyridyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(2-
7.189 M+H 396.2 pyridyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(4-
5.209 M+H 396.2 pyridyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(2-
1.721 M+H 415.2 thienylmethyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(3-
0.683 M+H 415.2 thienylmethyl)carboxamide
N-(oxolan-2-ylmethyl){6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-
11.022 M+H 403.3 pyridyl)}carboxamide
N-[((2S)oxolan-2-yl)methyl]{6-pheπyl-2-[(2-(2-
6.821 M+H 403.2 pyridyl)ethyl)amino](3-pyridyl)}carboxamide tert-butyl 2-[({6-phenyl-2-[(2-(2-pyridyl)ethyl)amino]-3-
65.098 M+H 518.2 pyridyl}carbonylamino)methyl]morpholine-4-carboxylate
N-[(1-acetyl(4-piperidyl))methyl]{6-phenyl-2-I(2-(2-
96.68 M+H 458.3 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[( 1 -acetyl(3-piperidyl))methy l]{6-phenyl-2-[(2-(2-
48.434 M+H 458.3 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(4-
43.709 M+H 416.3 piperidylmethyl)carboxamide
^-^-cyclohex-i-enylethyOaminoJ-e-phenylCS-pyridylJJ-N^S-
0.532 M+H 413.2 pyridylmethyl)carboxamide
{6-phenyl-2-[(3-phenylpropyl)amino](3-pyridyl)}-N-(3-
5.689 M+H 423.3 pyridylmethyl)carboxamide
{6-phenyl-2-lbenzylamino](3-pyridyl)}-N-(3-
2.792 M+H 395.2 pyridy!methyl)carboxamide
4.897 M+H 400.2 N-(1 ,3-oxazol-2-ylmethyl){6-pheπyl-2-[(2-(2- pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-(imidazol-2-ylmethyl){6-phenyl-2-[(2-(2-
6.148 M+H 399.1 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[((2S)-1-acetylpyrrolidiπ-2-yl)methyl]{6-phenyl-2-[(2-(2-
15.715 M+H 444.3 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[((3R)-1-acetylpyrrolidin-3-yl)methyl]{6-phenyl-2-[(2-(2-
26.904 M+H 444.3 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[((3S)-1-acetylpyrrolidin-3-yl)methyl]{6-phenyl-2-[(2-(2-
25.159 M+H 444.3 pyridyl)ethyl)amino](3-pyridyl)}carboxamide methyl 2-({6-phenyl-2-[(2-phenylethyl)amino]-3-
1.335 M+H 390.2 pyridyljcarbonylami no)acetate
[6-phenyl-2-(propylamino)(3-pyridyl)]-N-(3-
11.377 M+H 347.1 pyridylmethyl)carboxamide
{2-[(3-methylbutyl)amino]-6-phenyl(3-pyridyl)}-N-(3-
2.484 M+H 375.2 pyridylmethyl)carboxamide
{2-[(2-cyclohexylethyl)amino]-6-phenyl(3-pyridyl)}-N-{3-
1.854 M+H 415.3 pyridylmethyl)carboxamide
N-{[1-(methylsulfonyl)(3-piperidyl)]methyl}{6-phenyl-2-[(2-(2-
20.292 M+H 494.3 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
2-(aminomethyl)piperidyl 6-phenyl-2-[(2-(2-
18.23 M+H 416.3 pyridyl)ethyt)amino](3-pyridyl) ketone
N^[1-({6-phenyl-2-[(2-(2-pyridyl)ethyl)amino]-3-
21.154 M+H 458.3 pyridyl}carbonyl)-2-piperidyl]methyl}acetamide
2-{[(methylsulfonyl)amino]methyl}piperidyl 6-pheπyl-2-[(2-(2-
22.226 M+H 494.3 pyridyl) ethyl)ami no](3-pyridy I) keton e
N-[(1-methylpyrazol-5-yl)methyl]{6-phenyl-2-[(2-(2-
1.298 M+H 413.2 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[(1-methylpyrazol-3-yl)methyl]{6-phenyl-2-[(2-(2-
2.733 M+H 413.2 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(pyrazol-3-
0.711 M+H 399.2 ylmethyl)carboxamide
N-(isoxazol-5-ylmethyl){6-pheny!-2-[(2-(2-
0.836 M+H 400.2 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[((3S)pyrrolidin-3-yl)methyl]{6-phenyl-2-[(2-(2-
62.553 M+H 402.3 pyridyl)ethyl)amino](3-pyridyl)}carboxamide
N-[((3R)pyrrolidin-3-yl)methyl]{6-pheπyl-2-[(2-(2-
53.616 M+H 402.3 pyridyl)ethyl)amiπo](3-pyridyl)}carboxamide
{6-phenyl-2-[(2-phenylethyl)amino](3-pyridyl)}-N-(2-(2-
5.245 M+H 423.3 pyridyl)ethyl)carboxamide
{6-phenyl-2-[(2-phenylethyl)amino](3-pyridyl)}-N-(2-(3-
3.093 M+H 423.2 pyridyl)ethyl)carboxamide
N-methyl-2-({6-phenyl-2-[(2-phenylethyl)amino](3-
0.486 M+H 389.2 pyridyl)}carbonylamino)acetamide
N,N-dimethyl-2-({6-phenyl-2-[(2-phenylethyl)amino](3-
30.309 M+H 403.3 pyridyl)}carbonylamino)acetamide
N-(carbamoylmethyl){6-pheπyl-2-[(2-phenylethyl)amino](3-
0.81 M+H 375.2 pyridyl)}carboxamide
(2-{[2-(2-oxopiperidyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3-
22.145 M+H 430.3 pyridylmethyl)carboxamide
(2-{[2-(1-methyl(4-piperidyl))ethyl]amino}-6-phenyl(3-pyridyl))-
20.145 M+H 430.3 N-(3-pyridylmethyl)carboxamide
{6-phenyl-2-[(2-(2-thienyl)ethy!)amino](3-pyridyl)}-N-(3-
0.149 M+H 415.2 pyridylmethyl)carboxamide
32.174 M+H 413.2 (2-{t2-(1-methylimidazol-4-yl)ethyl]amino}-6-pheny!(3-pyridyl))- N-(3-pyridylmethyl)carboxamide
{2-[(2-(2-furyl)ethyl)amiπo]-6-pheπyl(3-pyridyl)}-N-(3- 0.294 M+H 399.2 pyridylmethyljcarboxamide
{2-[(oxolan-2-ylmethyl)amino]-6-phenyl(3-pyridyl)}-N-(3- 4.835 M+H 389.2 pyridylmethyl)carboxamide
{2-[(2-( 1 , 3-dioxolan-2-yl)ethyl)amino]-6-phenyl(3-pyridyl)}-N-(3- 7.122 M+H 405.2 pyridylmethyl)carboxamide
{2-[(3-imidazolylpropyl)amino]-6-phenyl(3-pyridyl)}-N-(3- 30.307 M+H 413.3 pyridylmethyljcarboxamide
{2-[(2-morpholin-4-ylethyl)amino]-6-pheπyl{3-pyridyl)}-N-(3- 37.33 M+H 418.3 pyridylmethyl)carboxamide
{6-phenyl-2-[(2-phenoxyethyl)amino](3-pyridyl)}-N-(3- 20.164 M+H 425.2 pyridylmethyl)carboxamide
{2-[(2-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)ethyl)amino]-6- 28.307 M+H 453.2 phenyl(3-pyridyl)}-N-(3-pyridylmethyl)carboxamide
(2-{[2-(2-oxoimidazolidinyl)ethyl]amino}-6-phenyl(3-pyridyl))-N- 70.65 M+H (3-pyridylmethyl)carboxamide
(2-{[2-(2-oxopyrrolidinyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3- 10.62 M+H 416.2 pyridylmethyl)carboxamide
{2-[(2-imidazol-4-ylethyl)amino]-6-phenyl(3-pyridyl)}-N-(3- 9.766 M+H 399.2 pyridylmethyl)carboxamide
(^-{[(hydroxycyclohexylJmethyllaminoJ-β-phenyKS-pyridyOJ-N- 7.811 M+H 417.3 (3-pyridylmethyl)carboxamide
(2-{[2-(3,5-dimethylpyrazol-4-yl)ethyl]amino}-6-phenyl(3- 5.941 M+H 427.2 pyridyI))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3,5-dimethylpyrazolyI)ethyl]amino}-6-phenyl(3-pyridyl))- 6.833 M+H 427.2 N-(3-pyridylmethyl)carboxamide
(2-{[2-(2-chlorophenyl)ethyl]amino}-6-(2-cyanophenyl)(3- 0.028 M+H 468.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(2-methylphenyl)ethyl]amino}(3- 0.076 M+H 448.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(2-fluorophenyl)ethyl]amino}(3- 0.028 M+H 452.2 pyridyI»-N-(3-pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(2-cyanophenyl)ethyl]amino}(3- 0.044 M+H 458.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
{6-(2-cyanophenyl)-2-[(2-(2-thienyl)ethyl)amiπo](3-pyridyl)}-N- 0.029 M+H 440.2 (3-pyridylmethyl)carboxamide
{6-(2-cyanophenyl)-2-[(2-(2-furyl)ethyl)amino](3-pyridyl)}-N-(3- 0.065 M+H 424.2 pyridylmethyl)carboxamide
(2-{[2-(3-fluoro(2-pyridyl))ethyl]amino}-6-prιenyl(3-pyridyl))-N- 1.479 M+H (3-pyridylmethyl)carboxamide
^-(P-O-methylphenyOethyllaminoJ-θ-phenylCS-pyridyOJ-N-CS- 0.45 M+H 423.3 pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(2-hydroxyphenyl)ethyl]amino}(3- 0.38 M+H 450.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methylK6-pyrazol-4-yl-2-[(2-(2- 1.238 M+H 429.1 pyridyl)ethyl)amino3(3-pyridyl)}carboxamide
N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)-2- hydroxyethyl]amino}-6-pyrazol-4-yl(3-pyridyl))carbonylamino]- 14.214 M+H 574.3 isopropyl}-2-[(tert-butoxy)carbonylamino]acetamide
{5-fluoro-6-pyrazol-4-yl-2-[(2-pyrazolylethyl)amino](3-pyridyl)}- 0.211 M+H 407.3 N-(3-pyridylmethyl)carboxamide
N-[( 1 R)-2-({5-fluoro-6-pyrazol-4-yl-2-[(2- 4.635 M+H 430.3 pyrazolylethyl)amino](3-pyridyl)}carbonylamino)-isopropyl]-2- aminoacetamide
(6-(2-cyanophenyl)-2-{[2-(3-flubrophenyl)ethyl]amino}(3- 0.604 M+H 520.1 pyridyl))-N-{[6-(trifluoromethyl)(2-pyridyl)]methyl}carboxarriide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 1.497 M+H 520.1 pyridyl))-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.603 M+H 520.1 pyridyl))-N-{[3-(trifluoromethyl)(2-pyridyl)]methyl}carboxamide
N-[(6-chloro(3-pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3- 1.789 M+H 486.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyano(3-thienyl))-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.033 M+H 458.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2E)-3-(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))- 57.378 M+H 376.1 N-methylprop-2-enamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethy!]amino}(3- 0.298 M+H 481.2 pyridyl))-N-{[6-(methylamino)(3-pyridyl)]methyl}carboxamide
N-{[6-(dimethylamino)(3-pyridyl)]methyl}(6-(2-cyanophenyl)-2- 30.234 M+H 495.2 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2-{[2-(3-fluoropheπyl)ethyl]amino}-4-(hydroxymethyl)-6- 59.114 M+H 457.2 phenyl(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
N-[(5-amino(2-pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3- 0.021 M+H 467.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2-{[2-(3-fIuorophenyl)ethyl]amino}-5-(hydroxymethyl)-6- 0.625 M+H 457.1 phenyl(3-pyridyl))-N-(3-pyridyImethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl-5-[N-(3- pyridylmethyl)carbamoyl](3-pyridyl))-N-(3- 55.988 M+H 561.2 pyridylmethyl)carboxamide
(5-(2-diazo-2-azavinyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-6- 0.428 M+H 482.2 phenyl(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(5-(aminomethyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-6- 8.904 M+H 456.1 phenyl(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-3-yl)(3- 0.04 M+H 431.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
N-({6-[3, 3-bis(dimethylamino)-2-azaprop-2-enyl](2- pyridyl)}methyl)(6-(2-cyanophenyl)-2-{[2-(3- 0.285 M+H 579.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide tert-butyl 2-(6-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-3-pyridyI)carboπylamino]methyl}-2- 1.189 M+Na 603.2 pyridyl)acetate
N-{[4-(aminomethyl)(3-pyridyl)]methyl}(6-(2-cyanophenyl)-2- 0.401 M+H 481.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[3-(aminomethyl)(4-pyridyl)]methyl}(6-(2-cyanophenyl)-2- 0.056 M+H 481.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(5-bromo-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3- 0.021 M+H 497.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(5-bromo-2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(1- 0.023 M+H 509.1 methylpyra2ol-4-yl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
{6-(5-cyanopyrazol-4-yl)-2-{[2-(3-fluorophenyl)ethyl]arnino}(3- 0.105 M+H 442.1 pyridyl))-N-(3-pyridylmethyl)carboxa.mide
(5-cyano-2-[[2-(3-fluorophenyl)ethyl]amino}-6-(1- 0.021 M+H 456.1 methylpyrazol-4-yl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyra∑ol-3-yl(3-pyridyl))-N- 0.124 M+H 417.1 (3-pyridylmethyl)carboxamide
(6-(3-cyano-1-methylpyrazol-4-yl)-2-{[2-(3- 0.047 M+H 456.1 fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
(6-(5-cyano-1-methylpyrazol-4-yl)-2-{[2-(3- fluorophenyl)ethy]]amino}(3-pyridyl))-N-(3-
0.02 M+H 456.1 pyridylmethyl)carboxamide
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.328 M+H 397.0 pyridyl))carbonylamino]-N-methy1acetamide
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
0.35 M+H 411.1 yl)(3-pyridyl))carbonylamino]-N-methylacetamide
(δ-chloro^-tP-CS-fluorophenyOethyllaminoJ-δ-CI-
0.021 M+H 465.1 methylpyrazol-4-yl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]tnethyl}(5-bromo-2-{[2-(3-
0.604 M+H 536.1 fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))carboxamide
N-[(1-{2-[(tert-butoxy)carboπylamino]ethyl}pyrazol-3- yl)rnethyl](6-(2-cyanophenyl)-2-{[2-(3-
2.725 M+Na 606.1 fluorophenyl)ethyl]amino}(3-pyridy1))carboxamide
N-[(1-{2-[(tert-butoxy)carbonylamino]ethyl}pyrazol-5- yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
2.2 M+H 584.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-{2-aminoethyl)pyrazol-3-yl]methyl}(6-(2-cyanophenyl)-2-
0.296 M+H 484.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-5-yl]methyl}(6-(2-cyanophenyl)-2-
0.032 M+H 484.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.136 M+H 460.1 pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.121 M+H 446.1 pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(5-bromo-2-{[2-(3- fIuoropheπyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.027 M+H 539.1 pyridyl))carboxamide
N-[((2R)-5-oxopyrro!idin-2-yl)methyl](6-(2-cyanophenyl)-2-{[2-
0.013 M+H 458.1 (3-fiuorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2S)-5-oxopyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-2-{[2-
0.133 M+H 458.1 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{3-[(5S)-5-(2-diazo-2-azavinyl)-2-oxopyrrolidinyl]propyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
16.552 M+H 541.1 pyridyi))carboxam ide
N-[((2S)-1-{3-[(tert-butoxy)carbonylamino]propyl}-5- oxopyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-2-{{2-(3-
4.516 M+H 615.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{t(2S)-1-(2-aminoethyl)-5-oxopyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-([2-(3-fluorophenyl)ethyl]amino}(3-
0.917 M+H 501.1 pyridyl))carboxamide
N-{[(2S)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.431 M+H 515.2 pyridyl))carboxamide
N-{3-[(5S)-5-(aminomethyl)-2-oxopyrrolidinyl]propyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
11.658 M+H 515.1 pyridyl))carboxamide
N-{[(2R)-1-(2-aminoethyl)-5-oxopyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amiπo}(3-
0.11 M+H 501.1 pyridyl))carboxamide
5.621 M+H 541.2 N-{3-[(5R)-5-(2-diazo-2-azavinyl)-2-oxopyrrolidinyl]propyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxamide
N-{3-[(5R)-5-(aminomethyl)-2-oxopyrrolidinyl]propyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
4.951 M+H 515.1 pyridyl))carboxamide
N-{2-[(5S)-5-(aminomethyl)-2-oxopyrrolidinyl]ethyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
17.87 M+H 501.1 pyridyl))carboxamide
N-{2-[(5R)-5-(aminomethyl)-2-oxopyrrolidinyl]ethyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
19.454 M+H 501.1 pyridyl))carboxamide
N-[((2R)-5-oxopyrrolidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
0.355 M+H 423.1 pyridyl))carboxamide
N-[((2R)-5-oxopyrrolidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.156 M+H 437.1 pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.439 M+H 444.0 pyridyl))-N-(pyrrolidin-2-ylmethyl)carboxamide N-[((2R)-5-oxopyrrolidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.119 M+H 423.1 pyridyl))carboxamide
N-[(1-{2-[(tert-butoxy)carbonylamiπo]ethyl}pyrrolidin-2- yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
4.834 M+H 587.1 f luorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-[(1-{3-[(tert-butoxy)carbonyIamino]propyl}pyrrolidin-2- yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
2.082 M+H 601.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[1-(2-aminoethyl)pyrrolidin-2-yl]methyl}(6-(2-cyanophenyl)-
0.758 M+H 487.1 2-{t2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamϊde N-{[1-(4-aminobutyl)pyrrolidin-2-yl]methyl}(6-(2-cyanophenyl)-
3.502 M+H 501.2 2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide methyl 2-({(2S)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
0.913 M+H 505.1 pyridyl))carbonylamino]propyl}amino)acetate methyl 2-({(2S)-2-amino-3-[(2-{[2-(3-fluorophenyl)ethyl]amino}-
M+H 6-(1-methylpyrazol-4-yl)(3-
10.852 OMe 452.3 pyridyl))carbonylamino]propyl}amino)acetate N-[((2S)-6-oxopiperazin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
16.026 M+H 438.2 pyridyl))carboxamide N-[((2S)-6-oxopiperazin-2-yl)methylj(6-(2-cyanophenyl)-2-{[2-
0.819 M+H 473.1 (3-fIuorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-[((2R)-4-{3-[(tert-butoxy)carbonylamino]propyl}-6-
M+H oxopiperazin-2-yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
9.536 Boc 530.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-[((2S)-6-oxopiperazin-2-yl)methyl](2-{t2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
13.056 M+H 452.1 pyridyl))carboxamide
N-[((2S)-6-oxopiperazin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
6.391 M+H 438.1 pyridyl))carboxamide N-{[(2R)-4-(3-aminopropyl)-6-oxopiperazin-2-yl]methyl}(6-(2-
4.522 M+H 530.2 cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxam ide
N-{[(2R)-4-(2-aminoethyl)-6-oxopiperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 8.4722 M+H 516.2 pyridyl))carboxamide
N-[((2R)-6-oxopiperazin-2-yl)methyl]{6-(2-cyanopheπyl)-2-{[2- 0.155 M+H 473.1 (3-fluoropheny1)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-4-(2-aminoethyl)-6-oxopiperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.623 M+H 515.2 pyridyl))carboxamide
N-{[(2S)-4-(3-aminopropyl)-6-oxopiperazirv2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorOphenyl)ethyl]amino}(3- 2.809 M+H 530.2 pyridyl))carboxamide
N-({(2R)-1-[4-(1,3-dioxobenzo[c]azolin-2-yl)butyl]-5- oxαpyrrolidin-2-yl}methyl)(6-(2-cyanophenyl)-2-{[2-(3- 0.376 M+H 659.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({(2R)-1-[5-(1 ,3-dioxobenzo[c]azolin-2-yl)pentyl]-5- oxopyrrolidin-2-yl}methyl)(6-(2-cyanophenyl)-2-{[2-(3- 0.266 M+H 673.2 fluorophenyl)ethyl)amino}(3-pyridyl))carboxamide tert-butyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- 1.933 M+H 544.2 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate
N-{[(2R)-1-(4-aminobutyl)-5-oxopyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.0517 M+H 529.2 pyridyl))carboxamide
N-{[(2R)-1-(5-aminopentyl)-5-oxopyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.039 M+H 543.2 pyridyl))carboxamide
N-[((2R)pyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-2-{[2-(3- 0.1738 M+H 444.1 fluorophenyl)ethyl]amiπo}(3-pyridyl))carboxamide
(2-{[2-{3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-pyridyl))-N- 0.034 M+H 406.1 (pyrazol-3-ylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 0.031 M+H 420.1 pyridyl))-N-(pyrazol-3-ylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-pyridyl))-N- 0.092 M+H 406.1 (pyrazol-3-ylmethyl)carboxamide
N-[((2R)-H4-[(tert-butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](6-(2-cyanophenyl)-2-{[2-(3- 0.432 M+H 629.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{t(2R)-1-(3-aminopropanoyl)pyrrolidiπ-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.047 M+H 515.2 pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-3-yl]methyl}(6-(2-cyanophenyl)-2- 0.065 M+H 498.2 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[i-(3-aminopropyl)pyrazol-3-yl]methyl}(2-{[2-(3- f luorophenyl)ethyl]amiπo}-6-( 1 -methylpyrazol-4-yl)(3- 2.686 M+H 477.1 pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-3-yl]methyl}(2-{[2-(3- fluorophenyI)ethyl]amiπo}-6-pyrazol-3-yl(3- 3.764 M+H 463.2 pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazo!-5-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazoi-4-yl)(3- 0.228 M+H 477.2 pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-5-yl]methyl}(2-{[2-(3- 0.462 M+H 463.2 fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3- pyridyl))carboxamide
N-[((2R)-1-{2-[(tert-butoxy)carbonylamino]ethyl}pyrrolidin-2- yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
3.691 M+H 587.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}pyrrolidin-2- yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
1.341 M+H 601.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamidβ
N-{[(2R)-1-(2-aminoethyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl )ethy l]am ino}( 3-
0.705 M+H 487.2 py ridy l))carboxam ide
N-{[(2R)-1-(3-aminopropyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
1.389 M+H 501.2 pyridyl))carboxamide
N-[(1-{2-[(tert-butoxy)carbonylamino]ethyl}pyrazol-3- yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
11.966 M+H 549.2 pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-3-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
1.488 M+H 449.1 pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-3-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
5.506 M+H 449.2 pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-5-yl]methyl}(2-{t2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
0.634 M+H 449.2 pyridyl))carboxamide
N-{[1-(2-aminoethyl)pyrazol-3-yl3methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-{1-methylpyrazol-4-yl)(3-
1.862 M+H 463.2 pyridyl))carboxamide
N-{[1-(2-amiπoethyl)pyrazol-5-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-( 1 -methylpyrazol-4-yl)(3-
0.313 M+H 463.3 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-6-oxopiperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.318 M+H 530.3 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-6-oxopiperazin-2-yl]methyl}(2-{I2-
(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
3.562 M+H 509.3 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-6-oxopiperazin-2-yl]methyl}(2-{[2-
(3-fiuorophenyl)ethyi]amino}-6-pyrazol-4-yl(3-
2.343 M+H 495.3 pyridyl))carboxamide
N-{[(2R)-1-(3-amiπopropyl)-6-oxopiperazin-2-yl]methyl}(2-{[2-
(3-fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
9.627 M+H 495.3 pyridyl))carboxamide
N-[((2R)-1-acetylpyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-2-
0.119 M+H 486.2 {[2-(3-fluorophenyl)ethyl]amiπo}(3-pyridyl))carboxamide
N-{[(2R)-1-(methylsulfonyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
1.448 M+H 522.2 pyridyl))carboxamide
N-[((2R)-1-methylpyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-2-
0.214 M+H 458.3 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1,1-dimethylpyrrolidin-2-yl)nnethyl](6-{2-cyanophenyl)-
2.049 M 472.2 2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-{[3-(1 ,3-dioxobenzo[c]azolin-2-
11.341 M+H 695.3 yl)propyl]sulfonyl}pyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-2- {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({(2R)-1-[(2-aminoethyl)sulfonyl]pyrrolidin-2-yl}methyl)(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.071 M+H 551.3 pyridyl))carboxamide
N-({(2R)-1-[(3-aminopropyl)sulfonyl]pyrrolidin-2-yl}methyl)(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.234 M+H 565.3 pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-3-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl<3-
1.406 M+H 463.1 pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrazol-5-yl]methyl}(2-{[2-(3- fluorophenyl)ethy]]amino}-6-pyrazol-4-yl(3-
0.095 M+H 463.1 pyridyl))carboxamide
N-[((2R)-1-{3-[{tert-butoxy)carbonylamino]propyl}-5- oxopyrrolidin-2-yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-6-
1.342 M+H 594.3 (1-methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(6-{1- [(dimethylamino)(dimethylylidene)methyl]pyrazol-4-yl}-2-{[2-(3-
2.127 M+H 578.4 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{t(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(2-{[2- (3-fluorophenyl)ethyl]amino}-6-(1-rrιethylpyrazol-4-yl)(3- 0.29 M+H 494.3 pyridyl))carboxamide tert-butyl (2R)-2-{[(2-{[2-(3-fluoropheny!)ethyl]amino}-6-(1 - methylpyrazol-4-yl){3- 4.64 M+H 523.3 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(2-{[2- (3-fiuorophenyl)ethyl]amino}-6-pyrazo!-4-yl(3-
0.966 M+H 480.2 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}-5- oxopyrro!idin-2-yl)methyl](6-(2-cyanophenyl)-2-[[2-(3-
0.518 M+H 615.3 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(2-amino-2-methylpropyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.666 M+H 432.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)pyrrolidir»-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
4.746 M+H 409.2 pyridyl))carboxamide
N-[((2R)pyrrolidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
3.185 M+H 423.2 pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{t2-(3-fIuorophenyl)ethyl]amino}(3- pyridyl))-N-{2-methyl-2-
1.473 M+H 510.3 [(methylsulfonyl)amino]propyl}carboxamide
N-[((2R)-1-{2-[(tert-butoxy)carbonylamino]acetyl}pyrrolidin-2- yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
5.532 M+H 580.3 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carboπyIamino]propanoyl}pyrrolidin- 2-yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
5.026 M+H 594.3 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[((2R)-1-{4-[(tert-butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
3.651 M+H 608.3 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{t(2R)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.581 M+H 480.3 pyridyl))carboxamide N-{[(2R)-1-(3-aminopropanoyl)pyrrolidiπ-2-yl]methyl}(2-{[2-(3- f luorophenyl)ethyl]amino}-6-( 1 -methylpyrazol-4-yl)(3-
0.587 M+H 494.3 pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.351 M+H 508.3 pyridyl))carboxamide N-((2S)-2-aminopropyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.515 M+H 418.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide 2-[(tert-butoxy)carbonylamino]-N-(2-[(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-tert-
9.572 M+H 589.4 butyl}acetamide
4-[(tert-butoxy)carbonylamino]-N-{2-[(6-(2-cyanophenyl)-2-{[2- (3-fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-tert-
0.194 M+H 617.4 butyljbutanamide
N-{(1S)-2-[(6-(2-cyanophenyl)-2-{[2-(3. fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-isopropyl}-
2.019 M+H 603.3 4-[(tert-butoxy)carbonylamino]butanamide N-[((2R)-1-{5-[(tert-butoxy)carbonylamino]pentanoyl}pyrrolidin- 2-yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
2.94 M+H 643.4 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide 2-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyljamino}(3-pyridyl))carbonylamino]-tert-
0.32 M+H 489.3 butyljacetamide
4-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-tert-
0.277 M+H 517.3 butyl}butanamide
N-{[(2R)-1-(N-methylcarbamoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-flυoropheπyl)ethyI]amino}(3-
0.307 M+H 501.1 pyridyl))carboxamide methyl (2R)-2-{[(6-(2-cyaπophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
0.101 M+H 502.2 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate N-{(1S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amiπo}(3-pyridyl))carbonylamino]-isopropyl}-
1.459 M+H 475.2 2-aminoacetamide
N-{(1S)-2-[(6-(2-cyanophenyl)-2-{t2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-isopropyl}-
3.56 M+H 503.2 3-aminopropanamide
N-{[(2R)-1-(5-aminopeπtanoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.099 M+H 543.3 pyridyl))carboxamide N-{(2S)-2-[(methylsulfonyl)amino]propyl}<6-(2-cyanophenyl)-2-
1.215 M+H 496.1 {[2-(3-fluorophenyl)ethyl]amino}(3-py ridyl))carboxamide 2-aminoethyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amiπo}(3-
0.027 M+H 531.2 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate M+H N-[{2S)-2-(methylamino)propyl](6-(2-cyanophenyl)-2-{[2-(3- 0.944 Me 432.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-((2R)-2-aminopropyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.399 M+H 418.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(2R)-2-(methylamino)propyl](6-(2-cyanophenyl)-2-{[2-(3-
1.89 M+H 432.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{(2S)-2-[methyl(methylsulfonyl)amiπo]propyl}(6-(2-
5.84 M+H 510.2 cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]annino}(3- pyridyl))carboxamide
N-{(2R)-2-[(methylsulfonyl)amino]propyl}(6-(2-cyanophenyl)-2-
1.333 M+H 496.2 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{(2R)-2-[methyl(methylsulfonyl)amino]propyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amiπo}(3-
7.071 M+H 510.2 pyridyi))carboxamide
N-{(1R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluoropheπyl)ethyl]amino}(3-pyridyl))carbonylamino]-isopropyl}-
2.312 M+H 575.3 2-[(tert-butoxy)carbonylamino]acetamide
N-{(1R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-isopropyl}-
5.916 M+H 589.3 2-[(tert-butoxy)carbonylamino]-N-methylacetamide
N-{( 1 R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-isopropyl}-
0.049 M+H 603.3 4-[(tert-butoxy)carbonylamino]butanamide
N-{(1R)-2-[(6-(2-cyanophenyl)-2-{[2-<3- fluorophenyl)ethyl]amiπo}(3-pyridyl))carboπylamiπo]-isopropyl}-
3.677 M+H 617.4 4-[(tert-butoxy)carbonylamino]-N-methylbutanamide
N-{( 1 S)-2-[(6-(2-cyanopheπyl)-2-{[2-(3- fluoropheπyl)ethyl]amino}(3-pyridyl))carbonylamino]-isopropyl}-
3.246 M+H 489.2 2-amino-N-methylacetamide
N-{( 1 S)-2-[(6-(2-cyanophenyl)-2-fl2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-isopropyl}-
6.826 M+H 517.3 4-amino-N-methylbutanamide
N-{(1R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-isopropyl}-
0.041 M+H 475.2 2-aminoacetamide
N-{(1R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino)-isopropyl}-
0.204 M+H 503.2 4-aminobutanamide
N-{( 1 R)-2-[(6-(2-cyanophenyl)-2~[[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-isopropyl}-
0.71 M+H 517.2 4-amino-N-methylbutanamide
N-{( 1 R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyljamino}{3-pyridyl))carbonylamino]-isopropyl}-
0.152 M+H 489.2 2-amino-N-methylacetamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-
0.012 M+H 449.1 4-yl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.025 M+H 501.2 pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.029 M+H 528.2 pyridyl))carboxamide
N-{[(2R)-1 -(3-aminopropyl)-5-oxopyrrolid in-2-yl]methy l}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.042 M+H 515.2 pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-pyridyl))-N-
0.044 M+H 417.1 (3-pyridylmethyl)carboxamide
{6-(3-methylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-
6.265 M+H 424.2 (3-pyridylmethyl)carboxamide
{6-(3-fluorophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-
0.915 M+H 428.2 (3-pyridylmethyl)carboxamide 2.992 M+H 435.2 {6-(3-cyanophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- (3-pyridylmethyl)carboxamide
{6-(3-methoxyphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 14.933 M+H 440.2 N-(3-pyridylmethyl)carboxamide
{6-(3-hydroxyphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 0.79 M+H 426.1 (3-pyridylmethyl)carboxamide
{6-(3-chlorophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 1.967 M+H 444.1 (3-pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-[3-(trifluoromethyl)phenyl](3- 5.927 M+H 478.1 pyridyl)}-N-(3-pyridylmethyl)carboxamide
{6-[3-(dimethylamino)phenyl]-2-[(2-(2-pyridyl)ethyl)amino](3- 12.404 M+H 453.2 pyridyl)}-N-(3-pyridylmethyl)carboxamide
{6-(2-fluorophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 1.321 M+H 428.1 (3-pyridylmethyl)carboxamide
{6-(2-chlorophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 4.438 M+H 444.1 (3-pyridylmethyl)carboxamide
{6-(2-methylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 11.031 M+H 424.2 (3-pyridylmethyl)carboxamide
{6-(2-methoxyphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 17.936 M+H 440.2 N-(3-pyridylmethyl)carboxamide
{6-(2-cyanophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyi)}-N- 0.46 M+H 435.2 (3-pyridylmethyl)carboxamide
{2-t(2-(2-pyridyl)ethyl)amino]-6-(2-thienyl)(3-pyridyl)}-N-(3- 0.797 M+H 416.1 pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-(3-thienyl)(3-pyridyl)}-N-(3- 0.414 M+H 416.1 pyridylmethyl)carboxamide
{6-(4-hydroxyphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 0.586 M+H 426.1 (3-pyridylmethyl)carboxamide
{6-(2-hydroxyphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 2.17 M+H 426.1 (3-pyridylmethyl)carboxamide
{6-(4-ethylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(3- 2.792 M+H 438.2 pyridylmethyl)carboxamide
N-(4-{6-[(2-(2-pyridyl)ethyl)amino]-5-[N-(3- 1.221 M+H 467.2 pyridylmethyl)carbamoyl]-2-pyridyl}phenyl)acetamide
{6-(4-methyl(2-thienyl))-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 0.344 M+H 430.1 N-(3-pyridylmethyl)carboxamide
{6-(4-methyl(3-thienyl))-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 4.063 M+H 430.1 N-(3-pyridylmethyl)carboxamide
{6-(2,3-dimethylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 6.945 M+H 438.2 N-(3-pyridylmethyl)carboxamide
{6-(2,5-dimethylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 13.588 M+H 438.2 N-(3-pyridylmethyl)carboxamide
{6-(2,4-dimethylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 3.964 M+H 438.2 N-(3-pyridylmethyl)carboxamide
{6-(3,5-dimethylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 10.138 M+H 438.2 N-(3-pyridylmethyl)carboxamide
{6-(3,4-dimethylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 3.38 M+H 438.2 N-(3-pyridylmethyl)carboxamide
(2-{[2-(4-fIuorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3- 1.609 M+H 427.2 pyridylmethyl)carboxamide
(2-{[2-(4-chlorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3- 6.677 M+H 443.1 pyridylmethyl)carboxamide
(2-{[2-(3-chlorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3- 0.349 M+H 443.1 pyridylmethyl)carboxamide
0.269 M+H 439.1 (2-{[2-(3-methoxyphenyl)ethyl]amino}-6-pheny!(3-pyπdyl))-N- (3-pyridylmethyl)carboxamide
<2-{[2-{3-fluorophenyl)ethylJamino}-6-phenyl(3-pyridyl))-N-(3-
0.063 M+H 427.1 pyιϊdylmethyl)carboxamide
(2-{[2-(2-chlorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3-
0.16 M+H 443.1 pyridylmethyl)carboxamide
(2-{[2-{2-methoxyphenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-
0.98 M+H 439.1 (3-py ridylm ethy l)carboxam ide
(2-{[2-(2-methylphenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3-
0.326 M+H 423.1 pyridylmethyl)carboxamide
(2-{[2-(2-fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3-
0.107 M+H 427.1 pyridylmethyl)carboxamide
(2-{[2-(2,6-difluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-
0.288 M+H 445.1 (3-pyridylmethyl)carboxamide
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-
0.055 M+H 445.1 (3-pyridylmethyl)carboxamide
(2-{[2-(3,4-difluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-
0.521 M+H 445.2 (3-pyridylmethyl)carboxamide
(2-{[2-(2,5-difluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-
0.079 M+H 445.2 (3-pyridylmethyl)carboxam ide
[6-phenyl-2-({2-[3-(trifluoromethyl)phenyl]ethyl}amiπo)(3-
8.254 M+H 477.2 pyιϊdyl)]-N-(3-pyridylmethy1)carboxamide
(2-{[2-(3-fIuorophenyl)ethyl]amino}-6-(4-methyl(2-thienyl))(3-
0.148 M+H 447.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-thienyl)(3-pyridyl))-N-
0.048 M+H 433.1 (3-pyridylmethyl)carboxamide
(2-{[2-(2-cyanophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3-
0.26 M+H 443.1 pyridylmethyl)carboxamide
(2-{[2-(3-cyanophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3-
4.649 M+H 434.1 pyridylmethyl)carboxamide
(2-{[2-(4-hydroxyphenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3-
36.722 M+H 425.1 pyridylmethyl)carboxamide
(2-{[2-(2-hydroxyphenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3-
2.431 M+H 425.1 pyridylmethyl)carboxamide
(2-{[2-(4-aminophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-N-(3-
27.106 M+H 424.1 pyridylmethyl)carboxamide
3-[2-({6-phenyl-3-[N-(3-pyridylmethyl)carbamoyl]-2-
11.492 M+H 452.1 pyridyl}amino)ethyl]benzamide
(2-{[2-(3,5-difIuorophenyl)ethyl]amino}-6-(3-thienyl)(3-pyridyl))-
0.04 M+H 451.1 N-(3-pyridylmethyl)carboxamide
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-(4-methyl(2-
0.119 M+H 465.1 thienyI))(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-(2-cyanophenyl)(3-
0.041 M+H 470.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{t2-(3-fluorophenyl)ethyl]amino}-6-(2-thienyl)(3-pyridyl))-N-
0.137 M+H 433.1 (3-pyridylmethyl)carboxamide
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-(2-thienyl)(3-pyridyl))-
0.097 M+H 451.1 N-(3-pyridylmethyl)carboxamide methyl 3-[2-({6-phenyl-3-[N-(3-pyridylmethyl)carbamoyl]-2-
28.097 M+H 467.2 pyridyl}amino)ethyl]benzoate
2-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
16.384 M+H 470.2 pyridylmethyl)carbamoyl]-2-pyridyl)benzamide
(6-(4-fluorophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.198 M+H 445.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
21.862 M+H 453.2 3-[2-({6-phenyl-3-[N-(3-pyridylmethyl)carbamoyl]-2- pyridyl}amino)ethyl]benzoic acid
(6-(2-chloro~4-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
1.383 M+H 479.1 pyridylmethyl)carboxamide
(2-{[2-(3,5-difluorophenyl)ethyl]amino}-6-(4-fluorophenyl)(3-
0.138 M+H 463.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(2-cyano-4-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.038 M+H 470.1 pyridylmethyl)carboxamide
(6-(2-chloro-6-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3- 0.54 M+H 479.1 pyridylmethyl)carboxamide
(6-(2-chloro-5-methoxyphenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
2.005 M+H 491.1 pyrϊdylmethyl)carboxamide
(6-(2-cyano-5-methoxyphenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.041 M+H 482.1 pyridylmethyl)carboxamide
(6-(2-cyano-6-fluorophenyl)-2-{[2-(3- fIuorophenyl)ethyl]arτiino}(3-pyridyl))-N-(3-
0.086 M+H 470.1 pyridylmethyl)carboxamide
(6-(2-fluorophenyl)-2-{t2-(3-fluorophenyl)ethyl]amino}(3-
0.139 M+H 445.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(2,3-difluorophenyl)ethyl]amino}-6-(2-cyanophenyl)(3-
0.022 M+H 470.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(2-chloro-5-fluorophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
1.327 M+H 479.1 pyridylmethyl)carboxamide
(6-(2-cyano-5-fluoropheπyl)-2-{[2-{3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.053 M+H 470.1 pyridylmethyl)carboxamide
(6-(3-fluorophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.157 M+H 445.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-[2-(cyanomethyl)phenyl]-2-{[2-(3- fluorophenyl)ethyl]amir»o}(3-pyridyl))-N-(3- 16.392 M+H 466.2 pyridylmethyl)carboxamide
(2-{t2-(3-fluorophenyl)ethyl]amino}-6-[3-(hydroxymethyl)(2-
2.245 M+H 463.1 thienyl)](3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(5-formyl(3-thienyl))(3-
0.098 M+H 461.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluoropheπyl)ethyl]amino}-6-[5-(hydroxymethyl)(3-
0.073 M+H 463.1 thienyl)](3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(2-chloro-4-methylphenyl)-2-{[2-(3- fluoropheπyl)ethyl]amino}(3-pyridyl))-N-(3-
2.078 M+H 475.1 pyridylmethyl)carboxamide
(6-(2-cyano-4-methylphenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.996 M+H 466.2 pyιϊdylmethyl)carboxamide
(2-{[2-(3-fluoropheπyl)ethyl]amino}-6-[3- (hydroxymethyl)phenyl](3-pyridyl))-N-(3-
0.281 M+H 457.1 pyridylmethyl)carboxamide
(2-{[2-{3-fluorophenyl)ethyl]amino}-6-[3- (methoxymethyl)phenyl](3-pyridyl))-N-(3-
5.719 M+H 471.2 pyridylmethyl)carboxamide (6-(1 H-1 ,2,3,4-tetraazol-5-yl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
78.064 M+H 419.1 pyridylmethyl)carboxamide
(6-[2-chloro-5-(hydroxymethyl)phenyl]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
1.185 M+H 491.1 pyridylmethyl)carboxamide
(2R)-2-amino-4-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]~N-
12.904 M+H 475.2 methylbutanamide
(2S)-2-amino-4-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
5.022 M+H 475.2 methyibutaπamide
N-(3-amino-2-hydroxypropyl)(6-(2-cyanophenyl)-2-{[2-(3-
4.812 M+H 434.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3-pyridyl))methyl](6-
(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
1.209 M+H 581.2 pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3-
0.008 M+H 456.1 fluorophenyl)ethy!]amino}-6-phenyl(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- fIuorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
0.043 M+H 446.1 pyridyl))carboxamide
N-{[2-(amiπomethyl)(3-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-3-yl)(3-
0.032 M+H 460.1 pyridyl))carboxamide
N-[((3R)(3-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
2.148 M+H 458.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.336 M+H 458.2 pyridyl))-N-(4-piperidylmethyl)carboxamide
N-{[1-(2-aminoacetyl)(4-piperidyl)]methyl}(6-(2-cyanophenyl)-2-
0.572 M+H 515.2 {[2-(3-fIuorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropanoyl)(4-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
3.874 M+H 529.2 pyridyl))carboxamide
N-{[(3S)-1-(2-aminoacetyl)(3-piperidyl)3methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluoropheny])ethyl]amino}(3-
0.755 M+H 515.2 pyridyi))carboxamide
N-{[(3S)-1-(3-aminopropanoyl)(3-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluoropheπyl)ethyl]amiπo}(3-
1.261 M+H 529.2 pyridyl))carboxamide
N-[(1-acetyl(4-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
1.696 M+H 500.3 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((3S)-1-acetyl(3-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-
10.729 M+H 500.3 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(4-aminobutanoyl)(4-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
6.009 M+H 543.3 pyridyl))carboxamide methyl 4-{[(6-(2-cyanophenyl)-2-{[2-( 3- fluorophenyl)ethyl]amino}-3-
2.13 M+H 516.3 pyridyl)carbonylamino]methyl}piperidinecarboxylate
N-[((2R)(2-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
1.159 M+H 458.3 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)(2-piperidyl)]methyl}(6-(2-
0.092 M+H 515.3 cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)(2-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyt)ethyl]amino}(3-
0.155 M+H 529.2 pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)(2-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.083 M+H 543.2 pyridyl))carboxamide
N-[((2R)-1-acetyl(2-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-
2.676 M+H 500.2 (3-fluoropheπyl)ethyl]amino}(3-pyridyl))carboxamide methyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
4.282 M+H 516.3 pyridyl))carbonylamino]methyl}piperidinecarboxylate
N-({(2R)-1-[(3-aminopropyl)sulfonylj(2-piperidyl)}methyl)(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amiπo}(3-
0.37 M+H 579.2 pyridyl))carboxamide
N-[((2R)-1-methyl(2-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-
0.488 M+H 472.2 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-((2R)-2,3-diaminopropanoyl)(2-piperidyl)]methyl}(6-
(2-cyanophenyl)-2-{[2-(3-fIuorophenyl)ethyl]amino}(3-
0.161 M+H 544.3 pyridyl))carboxamide
N-{[(2R)-1-((2R)-2,4-diaminobutanoyl)(2-piperidyl)]methyl}(6-
(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyt]amino}(3-
0.399 M+H 558.3 pyridyl))carboxamide
N-{[(2R)-1-((2R)-2,5-diaminopentanoyl)(2-piperidyl)]methytK6-
(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.456 M+H 572.2 pyridyl))carboxamide
N-({(2R)-1-[(2-aminoethyl)sulfonyl](2-piperidy!)}methyl)(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.178 M+H 565.2 pyridyl))carboxamide
N-{[(2R)-1-((2S)-2,5-diaminopentanoyl)(2-piperidyI)]methyl}(6-
(2-cyanopheπyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.048 M+H 572.3 pyridyl))carboxamide
N-{[(2R)-1-((2S)-2-aminopropanoyl)(2-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.052 M+H 529.3 pyridyl))carboxamide
N-{[(2R)-1 -((2 R)-2-aminopropanoyl)(2-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.261 M+H 529.2 pyridyl))carboxamide
2-chloroethyl (2R)-2-{t(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
2.691 M+H 564.1 pyridyl))carboπylamiπo]methyl}piperidinecarboxylate
2-aminoethyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
0.091 M+H 545.2 pyridyl))carbonylamino]methyl}piperidinecarboxylate
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(2-{[2-(3l5- difluorophenyl)ethyl]amino}-6-(2-cyanophenyl)(3-
0.023 M+H 547.2 pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}{6-(2- cyanophenyl)-2-[(2-cyclohex-1-enylethyl)amino](3-
0.133 M+H 515.3 pyridyl)}carboxamide
3-{[3-(N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2- yl]methyl}carbamoyl)-6-(2-cyanophenyl)(2-pyridyl)]amino}-N,N-
3.56 M+H 506.2 dimethylpropanamide 0.062 M+H 511.2 N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methylK6-(2- cyanophenyl)-2-[(2-phenylethyl)amino](3-pyridyl)}carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methylK6-(2- cyanophenyl)-2-[(2-(2H-3,4,5,6-tetrahydropyran-4-
8.767 M+H 519.2 yl)ethyl)amiπo](3-pyridyl)}carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}{6-(2- cyanophenyl)-2-[(2-(2H-3,4,5,6-tetrahydropyran-2-
2.038 M+H 519.2 yl)ethyl)amino](3-pyridyl)}carboxamide
N-{[(2R)-1-((2S)-2,3-diaminopropanoyl)pyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
0.059 M+H 530.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-((2S)-2-amino-3-methoxypropanoyl)pyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
0.193 M+H 545.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-((2S)-2-amino-3-hydroxypropanoyl)pyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
0.173 M+H 531.2 fluoropheny!)ethyl]amino}(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
0.014 M+H 464.1 pyridyl))carboxamide
N-([(2R)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl}(5-fluoro-2-{t2- (3-fluorophenyl)ethyl]arnino}-6-pyrazol-3-yl(3-
0.108 M+H 484.1 pyridyl))carboxamide
N-{[(2R)-1-((2S)-2-amino-3-hydroxypropanoyl)pyrro1idin-2- yl]methyl}(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-
0.269 M+H 514.1 3-yl(3-pyridyl))carboxamide
N%2R)-1-((2S)-2-aminopropanoyl)pyrro1idin-2-yl]methyl}(5- fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
0.314 M+H 498.2 pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(5-fluoro-2- {[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-3-yl(3-
0.169 M+H 512.1 pyridyl))carboxamide
{6-(2-cyanophenyl)-2-[(2-oxolan-2-ylethyl)amino](3-pyridyl)}-N- 0.92 M+H 428.1 (3-pyridylmethyl)carboxamide
N-((2R)-2-aminopropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.398 M+H 415.1 pyridyl))carboxamide
N-{( 1 R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]annino}-6-(1 - methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-isopropyl}-2-
1.754 M+H 572.2 [(tert-butoxy)carbonylamino]acetamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-isopropyl}-2-
0.076 M+H 472.3 aimirtoacetamide
N-[((2R)-5-oxopyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.027 M+H 455.1 pyridyl))carboxamide
N-^IS^-tCS-fluoro^-iP-CS-fluorophenyOethyllamino^θ^i- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-isopropyl}-2-
1.804 M+H 472.3 aminoacetamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1 - methyl py razol-4-y I) (3-py ridyl))ca rbony lam ino]-isop ropy l}-2-
0.197 M+H 473.1 hydroxyacetamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl)amiπo}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-isopropyl}-4- 0.1 M+H 600.2 [(tert-butoxy)carbonylamino]butanamide N-{(1 R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1 - methylpyrazo]-4-yl)(3-pyridyl))carbonylamino]-isopropyl}-4-
0.116 M+H 500.3 aminobutanamide
N-{(2R)-2-[(2-methoxyethyl)amino]propyl}(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
2.328 M+H 473.1 pyridyl))carboxamide
N-{(2R)-2-[(tert-butoxy)carbonylamino]propyl}(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
8.211 M+H 501.1 pyridyl))carboxamide
N-((2R)-2-aminopropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl{3-
0.443 M+H 401.1 pyridyl))carboxamide
N-{(1 R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1 - methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-
0.251 M+H 457.1 isopropyl}acetamide
N-{(2R)-2-[(methylsulfonyl)amino]propyl}(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
1.002 M+H 493.1 pyridyl))carboxamide
N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrazol-4-yl(3-pyridyl))carbonylamino]-isopropyl}-2-
0.122 M+H 459.1 aminoacetamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.024 M+H 435.1 pyridyl))-N-(2-pyridylmethyl)carboxamide
N-{(2R)-2-[(2-hydroxyethyl)amino]propyl}(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-{1-methylpyrazol-4-yl)(3-
0.648 M+H 459.2 pyridyl))carboxamide
N-{(2R)-2-[(carbamoylmethyl)amino]propyl}(5-fluoro-2-{[2-{3- fluorophenyl)ethyl]amino}-6-{1-methylpyrazol-4-yl)(3-
0.636 M+H 472.1 pyridyl))carboxamide
N-{(1R)-2-[(5-fIuoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-isopropyl}-2-
0.121 M+H 500.2 {dimethylamino)acetamide
N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-isopropyl}(2S)-2-
2.264 M+H 602.2 [(tert-butoxy)carbonylamino]-3-hydroxypropanamide
N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-isopropyl}(2S)-2-
0.115 M+H 502.2 amino-3-hydroxypropanamide
N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamiπo]-isopropyl}-2-
0.285 M+H 500.2 amino-2-methylpropanamide
N-(( 1 R)-1 -{[(5-fluoro-2-{[2-(3-f luorophenyl)ethyl]amino}-6-( 1 - methylpyrazol-4-yl)(3-pyridyl))carbonylamino]methyl}propyl)-2-
3.04 M+H 586.3 [(tert-butoxy)carbonylamino]acetamide
N-((1R)-H[(5-fluoro-2-{t2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]methyl}propyl)-2-
0.131 M+H 486.2 aminoacetamide
N-((1R)-1-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrazol-4-yl(3-pyridyl))carbonylamino]methyl}propyl)-2-[(tert-
4.323 M+H 572.3 butoxy)carbonylamino]acetamide
N-((1R)-1-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrazol-4-yl(3-pyridyl))carbonylamino]methyl}propyl)-2-
0.16 M+H 472.2 aminoacetamide 0.131 M+H 486.2 N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylarniπo]-isopropyl}(2S)-2- aminopropanamide
N-((2R)-3-hydroxy-2-methylbutyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-rnethylpyrazol-4-yl)(3- 0.283 M+H 444.2 pyrϊdyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(6-(2-cyanophenyl)-2- 0.006 M+H 481.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl»carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}<2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3- 0.024 M+H 446.3 pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.024 M+H 452.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
{6-phenyl-2-[(2-(2-pyridyl)ethy1)amino](3-pyridyl)}-N-(3- 0.512 M+H 410.1 pyridylmethyl)carboxamide
{6-(3,4-difluorophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyrϊdyl)}- 1.206 M+H 446.1 N-(3-pyridylmethyl)carboxamide
{6-(4-fluorophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 1.045 M+H 428.2 (3-pyridylmethyl)carboxamide
{6-(4-chlorophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 0.629 M+H 444.1 (3-pyridylmethyl)carboxamide
{6-(4-methylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 0.677 M+H 424.2 (3-pyιϊdylmethy])carboxamide
{6-(4-cyanophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 1.935 M+H 435.1 <3-pyridylmethyl)carboxamide
{6-(4-methoxyphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 1.063 M+H 440.1 N-(3-pyridylmethyl)carboxamide
{6-[4-(hydroxymethyl)phenyl]-2-[(2-(2-pyridyl)ethyl)amino](3- 2.43 M+H 440.2 pyridyl)>-N-(3-pyridylmethyl)carboxamide
{6-(3,4-dichlorophenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}- 3.375 M+H 478.1 N-(3-pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-[4-(trifluoromethyl)pheπyl](3- 2.285 M+H 478.1 pyridyl)}-N-(3-pyridylmethyl)carboxamide methyl 4-{6-[(2-{2-pyridyl)ethyl)amino]-5-[N-(3- 0.989 M+H 468.1 pyridylmethyl)carbamoyl]-2-pyridyl}benzoate
{6-[4-(dimethylamino)phenyl]-2-[(2-<2-pyridyl)ethyl)amino](3- 0.809 M+H 453.2 pyridyl)}-N-(3-pyridylmethyl)carboxamide
{6-(4-acetylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N- 2.133 M+H 452.1 (3-pyridylmethyl)carboxamide
{6-phenyl-2-[(2-(3-pyridyl)ethyl)amino](3-pyridyl)}-N-(3- 2.187 M+H 410.1 pyridylmethyl)carboxamide
4-{6-[(2-(2-pyridyl)ethyl)amino]-5-[N-(3- 18.274 M+H 454.1 pyridylmethyl)carbamoyl]-2-pyridyl}ben∑oic acid
N-(3-pyridylmethyl){6-(3-pyridyl)-2-[(2-(2-pyridyl)ethyl)amino](3- 19.129 M+H 411.1 pyridyl)}carboxamide
N-(3-pyridylmethyl){6-(4-pyridyl)-2-[(2-(2-pyridyl)ethyl)amino](3- 6.557 M+H 411.1 pyridyl)}carboxamide
N-(3-pyridylmethyl){6-(2-pyridyl)-2-[(2-{2-pyridyl)ethyl)amino](3- 5.379 M+H 411.2 pyridyl)}carboxamide
4-{6-[(2-(2-pyridyl)ethyl)amino]-5-[N-(3- 2.538 M+H 453.1 pyridylmethyl)carbamoyl]-2-pyridyl}benzannide
^-^-hydroxy^-phenylethylJaminol-β-phenyKS-pyridyl^-N-CS- 1.942 M+H 425.1 pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-(2-vinylphenyl)(3-pyridyl)}-N-(3- 5.342 M+H 436.1 pyridylmethyl)carboxamide {6-[2-(methoxymethyl)phenyl]-2-[(2-(2-pyridyl)ethyl)amino](3-
84.495 M+H 454.2 pyridyl)}-N-(3-pyridylmethyl)carboxamide
{6-(2-formylphenyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-
8.751 M+H 438.2 (3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)-2-hydroxyethyl]amino}-6-phenyl(3-
0.559 M+H 443.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)-2- nydroxyethyl)amino}(3-pyridyl))-N-(3-
0.339 M+H 468.2 pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-(1,3-thiazol-2-yl)(3-pyridyl)}-N-
8.662 M+H 417.1 (3-pyridylmethyl)carboxamide
{6-(1-methylpyrazol-4-yl)-2-[(2-(2-pyridyl)ethyl)amino](3-
2.53 M+H 414.2 pyridyl)}-N-(3-pyridylmethyl)carboxamide
[3-(aminomethyl)-6-phenyl(2-pyridyl)][2-(3-
39.528 M+H 322.1 fluorophenyl)ethyl]amine
(6-(3,4-difluorophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.534 M+H 463.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(5-cyano(2-thienyl))-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.28 M+H 458.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(5-formyl(2-thieπyl))(3-
0.052 M+H 461.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fIuorophenyl)ethyl]amino}-6-(3-formyl(2-thienyl))(3-
0.783 M+H 461.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]annino}-6-(2-formyl(3-thienyl))(3-
1.482 M+H 461.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
[2-{[2-(3-fluorophenyl)ethyl]amino}-6-(6-{[2-(3- fluorophenyl)ethyl]amino}-5-[N-(3-pyridylmethyl)carbamoylI(2-
30.616 M+H 699.2 pyridyl))(3-pyridyl)]-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[2-(hydroxymethyl)(3-
1.567 M+H 463.1 thienyl)](3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-isoxazol-4-yl(3-pyridyl))-
49.792 M+H 418.1 N-(3-pyridyl methyl)carboxamide
(6-(5-acetyl(2-thienyl))-2-{[2-(3-fluorophenyl)ethyl]atτiino}(3-
0.178 M+H 475.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-[3-(aminomethyl)(2-thienyl)]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
55.694 M+H 462.1 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[5-(hydroxyethyl)(2-
0.415 M+H 477.1 thienyl)](3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-(4-cyano(3-thienyl))-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.014 M+H 458.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-[5-(aminomethyl)(2-thienyl)]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
2.698 M+H 462.1 pyridylmethyl)carboxamide
N-{[5-(aminomethyl)(3-pyridyl)]methyl}(6-(2-cyanophenyl)-2-
0.323 M+H 481.2 {[2-(3-fIuorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.081 M+H 482.1 pyridyOJ-N^IS-ChydroxymethylJCS-pyridyOlmethylJcarboxamide
N-({5-[3,3-bis(dimethylannino)-2-azaprop-2-enyl](3- pyridyl)}methyl)(6-(2-cyanophenyl)-2-{[2-(3-
2.715 M+H 579.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[3-(amiπomethyl)(2-pyridyl)]methyl}(6-(2-cyanophenyl)-2-
0.624 M+H 481.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2.437 M+H 824.3 (6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))-N-[(3-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]methyl}(2- pyridyl))methyl]carboxamide N-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3-
70.994 M+H 442.1 pyridyl))methyl](3-pyridylamino)carboxamide
(5-chloro-δ-(2-cyanophenyl)-2-{[2-(3- fluoraphenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.512 M+H 486.1 pyιϊdylmethyl)carboxamide
(5-bromo-6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
2.653 M+H 531 pyridylmethyl)carboxamide
(5-cyano-6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.318 M+H 477.1 pyridylmethyl)carboxamide
N-[(2-chloro(3-pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
0.072 M+H 486.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({2-[(2-aminoethyl)amino](3-pyridyl)}methyl)(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.013 M+H 510.1 pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-5-oxoindeno[3,2-b]pyridin-
0.088 M+H 453.1 3-yl)-N-(3-pyridylmethyl)carboxamide
{6-(2-cyaπophenyl)-2-([2-(3-fluorophenyl)ethyl]amino}(3-
0.029 M+H 472 pyridyl))-N-[(6-oxo(2-piperidyl))methyl]carboxamide
N-[{1-{3-[(tert-butoxy)carboπylamino]propyl}-6-oxo(2- piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
0.877 M+H 629.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)-6-oxo(2-piperidyl)]methyl}(6-(2- cyanophenyI)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.025 M+H 529.2 pyridyl)}carboxamide
N-[((2S)(2-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
1.024 M+H 458.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2S)-1-{2-[(tert-butoxy)carbonylamino]acetyl}(2- piperidyl))methyl](6-(2-cyanophenyl)-2-{I2-(3- 16.979 M+H 615.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-1-(2-aminoacetyl)(2-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.074 M+H 515.2 pyridyl))carboxamide
N-[((2S)-1-{3-[(tert-butoxy)carbonylamino]propanoyl}(2- piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
8.636 M+H 629.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-1-(3-aminopropanoyl)(2-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.109 M+H 529.2 pyridyl))carboxamide
N-{[(2S)-1-(methylsulfonyl)(2-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
1.632 M+H 536.3 pytϊdyl))carboxamide
N-[((2R)-6-oxo(2-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
0.015 M+H 472.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-H[3-[(tert-butoxy)carboπylamino]propyl}-6-oxo(2- piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-{3-
0.392 M+H 629.4 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-6-oxo(2-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.026 M+H 529.2 pyridyl))carboxamide N-[((3S)(3-piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
1.974 M+H 458.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((3R)-1-acetyl(3-piperidyl))methyl]{6-(2-cyanophenyl)-2-{[2-
0.696 M+H 500.3 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide methyl (3R)-3-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
0.718' M+H 516.3 pyridyl))carbonylamino]methyl}piperidinecarboxylate
N-KPRJ-i-^-tCtert-butoxyJcarbonylaminoJacetylKS- piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
0.199 M+H 615.4 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((3R)-H3-[(tert-butoxy)carbonylamino]propanoyl}(3- piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
3.79 M+H 629.4 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((3R)-1-{4-Ktert-butoxy)carbonylamino]butanoyl}(3- piperidyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
6.161 M+H 643.4 fluorophenyl)ethyl]amino}(3-pyridyl))carboxarnide
N-{[(3R)-1-(2-aminoacetyl)(3-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.246 M+H 615.4 pyridyi))carboxamide
N-{[(3R)-1-(3-aminopropanoyl)(3-piperidyl)]methyl}(6-(2- cyaπophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.173 M+H 629.5 py ridyl))carboxam ide
N-{[(3R)-1-(4-amiπobutanoyl)(3-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethy]]amino}(3-
0.512 M+H 543.3 pyridyl))carboxamide
N-({(2R)-1 -[4-(1 ,3-dioxobenzo[c]azolin-2-yl)butyl]-6-oxo(2- piperidyl)}methyl)(6-(2-cyaπophenyl)-2-{[2-(3-
0.791 M+H 673.3 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutyl)-6-oxo(2-piperidyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.032 M+H 543.2 pyridyl) )carboxam ide
N-[((3S,4S,2R,5R)-3,4,5,6-tetrahydroxy(2H-3,4,5,6- tetrahydropyraπ-2-yl))methyl](6-(2-cyaπophenyl)-2-{[2-(3-
5.537 M+H 523.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-[5-(N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2- yl]methyl}carbamoyl)-6-{[2-(3-fluorophenyl)ethyl]amino}-2-
13.202 M+H 533.2 pyridyljbenzamide
N-[2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]methyl}pyrrolidinyl)(1 S)-1 -methyl-2-
3.262 M+H 615.2 oxoethyl](tert-butoxy)carboxamide
N-{[(2R)-1-((2S)-2-aminopropanoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.053 M+H 515.2 pyridyl))carboxamide
N-[( 1 R)-2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamiπo]methyl}pyrro!idinyl)-1-methyl-2-
3.94 M+H 615.2 oxoethyl](tert-butoxy)carboxamide
N-{[(2R)-1-((2R)-2-amiπopropaπoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fIuorophenyl)ethyl]amino}(3-
0.166 M+H 515.2 pyridyl))carboxamide
N-{[(2R)-1-((2S)-2,5-diaminopentanoyl)pyrrolidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
0.052 M+H 558.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-[(2-chloro(3-pyridyl))methyl](2-{[2-(3- fiuorophenyl)ethyl]arnino}-6-(1-methylpyrazol-4-yl)(3-
0.046 M+H 451.1 pyridyl))carboxamide
N-({2-[(3-aminopropyl)amino](3-pyridyl)}methyl)(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.129 M+H 489.2 pyridyl))carboxamide
N-({2-[(2-aminoethyl)amino](3-pyridyl)}methyl)(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.122 M+H 475.1 pyridyl))carboxamide tert-butyl (2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}- 6-(1 -methylpyrazol-4-yl)(3-
1.459 M+H 541.3 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate
N-[((2R)pyrralidin-2-yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.275 M+H 441.1 pyridyl))carboxamide
N-[((2R)-1-{2-[(tert-butoxy)carbonylamiπo]acetyl}pyrrolidiπ-2- yl)methyl](5-fluoro-2-{[2-(3-fIuorophenyl)ethyl]amino}-6-(1-
0.625 M+H 598.3 methylpyrazol-4-yl)(3-pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-pyridyl))-N-
0.065 M+H 476.1 ({2-[(2-hydroxyethyl)amino](3-pyridyl)}methyl)carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3-pyridyl))methyl](5- fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.488 M+H 564.2 pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.012 M+H 464.1 pyridyl))carboxamide
N-[((2R)-1-{2-[(tert-butoxy)carbonylamino]acetyl}pyrrolidin-2- yl)methyl](5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-
1.079 M+H 584.2 4-yl(3-pyridyl))carboxamide
N^[[(2R)-1-(2-aπninoacetyl)pyrrolidin-2-yl]methyl}(5-fluoro-2-{[2- (3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.061 M+H 484.1 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propanoyl}pyrrolidin- 2-yl)methyl](5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- 0.98 M+H 598.3 pyrazol-4-yl(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)pyrrolidin-2-yl]methyl}(5-fluoro- 2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3- 0.09 M+H 498.2 pyridyl))carboxamide
N-[((2R)-1-{4-[(tert-butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](5-fiuoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol- 0.75 M+H 612.2 4-yl(3-pyridyl))carboxamide
N-[[(2R)-1-(4-amiπobutanoyl)pyrrolidin-2-yl]methyl}(5-fIuoro-2- {[2-(3-fluoropheπyl)ethyl]amiπo}-6-pyrazol-4-yl(3-
0.047 M+H 512.2 pyridyl))carboxamide
N-[((2R)pyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3- fluoropheπyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.394 M+H 427.1 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}-5- oxopyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amiπo}-6-pyrazol-4-yl(3-
0.354 M+H 598.2 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(5- fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.066 M+H 498.1 pyridyl))carboxamide N-(carbamoylmethyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.14 M+H 401.1 pyridy l))carboxam ide
2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.065 M+H 415 pyridyl))carbonylamino]-N-methylacetamide
N-[((2R)-H<2S)-2-[(tert-butoxy)carbonylamino]-3- hydroxypropanoyl}pyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
1.001 M+H 614.3 pyridyl))carboxamide
N-{[(2R)-1-((2S)-2-amtno-3-hydroxypropaπoyl)pyrrolidin-2- yl]methyl}(5-fIuoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-
0.059 M+H 514.1 4-y!(3-pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3-pyridyl))methyl](5- fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2-pyridyl)(3-
3.665 M+H 575.2 pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2-{[2-(3-
0.066 M+H 475.1 fluorophenyl)ethyl]amino}-6-(2-pyridyl)(3-pyridyl))carboxamide
(5-fluoro-2-{[2-(3-fluoropnenyl)ethyl]amino}-6-(1-methylpyrazol-
0.381 M+H 430.1 4-yl)(3-pyridyl))-N-(2-hydroxy-2-methylpropyl)carboxamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-( 1 -methylpyrazol-
0.224 M+H 444.1 4-yl)(3-pyridyl))-N-(3-hydroxy-2,2-dimethylpropyl)carboxamide
N-((2R)-2-methyl-3-oxobutyl)(5-fluoro-2-{[2-(3- fluoropheπyl)ethyl]amino}-6-(1-methylpyra2θl-4-yl)(3-
0.109 M+H 442.2 pyridyl))carboxamide
N-((2R)-3-hydroxy-2,3-dimethylbutyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
1.225 M+H 458.1 pyridyl))carboxamide
2-((2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3- pyridyl))carbonylamino]methyl}azetidinyl)-2-oxoethyl 2-[(tert-
0.191 M+H 642.2 butoxy)carbonylamino]acetate
2-((2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3- pyridyl))carbonylamino]methyl}azetidinyl)-2-oxoethyl 2-
0.045 M+H 542.2 aminoacetate
2-((2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3- pyridyl))carbonylamino]methyl}azetidinyl)-2-oxoethyl dimethyl
0.4 M+H 593.2 phosphate
(2-{[2-(3-fluoropheπyl)ethylJamino}-6-[5-(hydroxymethyl)(2-
0.041 M+H 463.1 thienyl)](3-pyridyl))-N-(3-pyridylmethyl)carboxamide
N-({2-[(3-amiπopropyl)amino](3-pyridyl)}methyl)(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.017 M+H pyridyl))carboxamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.018 M+H pyridyl))-N-(3-pyridylmethyl)carboxamide
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl}(5-fluoro-2-{[2-
(3-fiuorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.066 M+H pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-4-
1.076 M+H 466.2 methyl(3-pyridyl))-N-(3-pyridy]methyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
16.894 M+H 537.2 pyridyl))-N-[(6-morpholin-4-yl(3-pyridyl))methyl]carboxamide
66.631 M+H 521.2 (6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))-N-[(6-pyrrolidinyl(3-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 1.752 M+H 536.2 pyridyl))-N-[(6-piperazinyl(3-pyridyl))methyl]carboxamide
N-{[6-(4-acetylpiperazinyl)(3-pyridyl)]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 7.747 M+H 578.2 pyridyl))carboxamide
N-[(6-bromo(2-pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3- 0.233 M+H 530.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-[(2-{[2-{3-fluorophenyl)ethyl]amino}-6-[5-(hydroxymethyl)(2- 0.254 M+H 443.1 thienyl)](3-pyridyl))carbonylamiπo]-N-methylacetamide
N-(2-carbamoylethyl)(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[5- 0.549 M+H 443.1 {hydroxymethyl)(2-thienyl)](3-pyridyl))carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[5-(hydroxymethyl)(2- 0.045 M+H 463.1 thienyl)](3-pyridyl))-N-(2-pyridylmethyl)carboxamide
N-(carbamoylmethyl)(2-{[2-(3-fluorophenyl)ethyi]amiπo}-6-[5- 0.496 M+H 429.1 (hydroxymethyl)(2-thienyl)](3-pyridyl))carboxamide
2-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 24.88 M+H 496.1 pyridyOJcarbonylaminoJ-N-CnnethylsulfonylJacetamide
N-{[3-(aminomethyl)cyclohexyl]methyl}(6-(2-cyanophenyl)-2- 0.352 M+H 486.2 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
3-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-3- 11.631 M+H 472.1 pyridyl)carbonylamino]cyclopentanecarboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 16.178 M+H 473.2 pyridyl))-N-(2-piperaziπylethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.266 M+H 467.1 pyridyl))-N-(2-pyrazin-2-ylethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.026 M+H 453.1 pyridyl))-N-(pyrazin-2-ylmethyl)carboxamide
N-((1S)-5-amino-1-carbamoylpentyl)(6-(2-cyanophenyl)-2-{[2- 4.421 M+H 489.1 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(3-amino-1-carbamoylpropyl)(6-(2-cyanophenyl)-2-{[2-(3- 1.906 M+H 461.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{(1R)-1-carbamoyl-5-
[(phenylmethoxy)carbonylamino]pentyl}(6-(2-cyanophenyl)-2- 58.8 M+H 623.2 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(4-amino-1-carbamoylbutyl)(6-(2-cyanophenyl)-2-{[2-(3- 0.59 M+H 475.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((1 R)-5-amiπo-1 -carbamoylpeπtyl)(6-(2-cyanophenyl)-2-([2- 1.28 M+H 489.1 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-({6-[(2-aminoethyl)amino](2-pyridyl)}methyl)(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.007 M+H 510.1 pyridyl))carboxamide
N-({6-[(3-amiπopropyl)amiπo](2-pyridyl)}methyl){6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.005 M+H 524.2 pyridyl))carboxamide
N-{(4R)-4-carbamoyl-4-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- 19.6 M+H 609.1 pyridyl))carbonylamino]butyl}(phenylmethoxy)carboxamide
N-((1S)-4-amino-1-carbamoylbutyl)(6-(2-cyanophenyl)-2-{[2-(3- 5.404 M+H 475.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((1 R)-4-amino-1-carbamoylbutyl)(6-(2-cyanophenyl)-2-{[2- 7.413 M+H 475.1 (3-fluoropheπyl)ethyl]amino}(3-pyridyl))carboxamide
(θ^-cyanophenyO^-fP-CS-fluoropheπyOethyllaminoXS- 0.963 M+H 444.1 pyridyl))-N-(pyrrolidin-3-ylmethyl)carboxamide N-{[1-(2-aminoacetyl)pyrrolidin-3-yl]methyl}(6-(2-cyaπopheπyl)-
0.203 M+H 501.1 2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropanoyl)pyrrolidin-3-yl]methyl}(6-{2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.27 M+H 515.1 pyridyl))carboxamide
N-{[1-(4-aminobutanoyl)pyrrolidin-3-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fIuorophenyl)ethyl]amino}(3-
0.433 M+H 529.1 pyridyl))carboxamide
N-[(1-acetylpyrrolidin-3-yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
0.334 M+H 486.1 fluorophenyl)ethyl]amiπo}(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)pyrrolidin-3-yl]methyl}(6-(2-cyanophenyl)-
4.787 M+H 501.2 2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(3-amino-2-carbamoylpropyl)(6-(2-cyanophenyl)-2-{[2-(3-
6.654 M+H 460.5 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2-{[2-(3-fluoropheny!)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
1.236 M+H 452.3 pyridyl))-N-[(6-oxopiperazin-2-yl)rnethyl]carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-pyridyl))-N-
0.973 M+H 438.3 [(6-oxopiperazin-2-yl)methyl]carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-5-yl(3-pyridyl))-N-
6.954 M+H 438.3 [(6-oxopiperazin-2-yl)methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))-N-{[4-(methyIsulfonyl)-6-oxopiperazin-2-
2.565 M+H 551.1 yl]methyl}carboxamide
N-[(4-acetyl-6-oxopiperazin-2-yl)methyt](6-(2-cyanophenyl)-2-
1.635 M+H 515.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.037 M+H 487.1 pyridyl))-N-[(4-methyl-6-oxopiperazin-2-yl)methyI]carboxamide
{6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.866 M+H 461.2 pyridyl))-N-{2-[(methylamino)carbonylamino]ethyl}carboxamide
N-(2-{[(2-aminoethyl)sulfonyl]amino}ethyl)(6-(2-cyanophenyl)-
1.548 M+H 511.2 2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[{(2S)pyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
4.569 M+H 444.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
1.23 M+H 461.2 pyridyl))carbonylamino]ethyl}acetamide
3-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
4.325 M+H 475.2 pyridyl))carbonylamino]ethyl}propanamide
4-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
1.265 M+H 489.2 pyridyl))carbonylamino]ethyl}butanamide
2-[(tert-butoxy)carbonylamino]-N-{2-[(6-(2-cyanophenyl)-2-{[2-
(3-fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]ethyl}-N-
15.303 M+H 575.3 methylacetamide
4-[(tert-butoxy)carbonylamino]-N-{2-[(6-(2-cyaπopheπyl)-2-{[2-
(3-fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]ethyl}-N-
3.883 M+H 603.3 methylbutanamide
N-{t(2S)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl3amino}(3-
0.995 M+H 501.2 pyridyl))carboxamide
N-{[(2S)-1-(3-aminopropanoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluoropnenyl)ethyl]amino}(3-
1.856 M+H 515.2 pyridyl))carboxamide N-{[(2S)-1-(4-aminobutaπoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 1.27 M+H 529.3 pyridyl))carboxamide
2-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyljamino}(3-pyridyl))carbonylamino]ethyl}-N-
1.374 M+H 475.2 methylacetamide
3~amino-N-{2-[<6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amiπo}(3-pyridyl))carboπylamino]ethyl}-N-
1.775 M+H 489.2 methylpropanamide
4-amino-N-{2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]ethyt}-N- 1.2 M+H 503.2 methylbutanamide
(6-(2-cyanophenyl)-2-{[2-(3-fluoropheny!)ethyl]amino}(3-
1.385 M+H 496.2 pyridyl))-N-{2-[methyl(methylsulfonyl)amino]ethyl}carboxamide
3-amino~N-(2-aminoethyl)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- 13.725 M+H 504.2 pyridyl))carbonylamino]methyl}propanamide
N-(2-carbonylamino-2-methylpropyl)(6-(2-cyanophenyl)-2-{[2-
0.151 M+H 460.2 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((2S)-2-amino-3-hydroxypropyl)(6-(2-cyanophenyl)-2-{[2-(3-
1.588 M+H 434.3 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{( 1 S)-1 -{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]methyl}-2-
0.249 M+H 491.1 hydroxyethyl)-2-aminoacetamide
(2S)-2-(2-aminoacetylamino)-3-[(6-(2-cyanophenyl)-2-{t2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]propyl 2-
5.705 M+H 548.3 aminoacetate
N-((1R)-1-{t(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]methyl}-2-
0.441 M+H 504.2 methylpropyl)-2-hydroxyacetamide
N-((1R)-1-{[(6-(2-cyanophenyl)-2-{[2-(3- fIuoropheπyl)ethyl]amino}(3-pyridyl))carbonylamino]methyl}-2- 0.939 M+H 503.3 methylpropyl)-2-aminoacetamide
N-((2R)-2-amino-4-methylpentyl)(6-(2-cyanophenyl)-2-{[2-(3- 1.237 M+H 460.3 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((1 R)-1-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]methyl}-3- 1.169 M+H 518.2 methylbutyl)-2-hydroxyacetamide
N-((1R)-1-{t(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]methyl}-3- 0.913 M+H 517.2 methylbutyl)-2-aminoacetamide
N-(( 1 R)-2-amino-1 -{[<6-(2-cyanopheny l)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- 12.554 M+H 490.2 pyridyl))carbonylamino]methyl}ethyl)-2-aminoacetamide
N-(( 1 R)-2-amino-1 -{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}{3- 10.561 M+H 491.2 pyridyl))carbonylamino]methyl}ethyl)-2-hydroxyacetamide
N-((3R)-2-oxo(3-piperidyl))(6-(2-cyanophenyl)-2-{[2-(3- 0.352 M+H 458.3 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
{2-[((2R)-2-phenylpropyl)amino]-6-phenyl(3-pyridyl)}-N-(3- 17.307 M+H 423.1 pyridylmethyl)carboxamide
N-(carbamoylethyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.564 M+H 432.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamϊde
0.532 M+H 432.1 N-((1 R)-1-carbamoylethyl)(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide methyl (2S)-2-[(6-(2-cyanophenyl)-2-{[2-(3-
6.98 M+H 447.1 fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]propanoate methyl (2R)-2-[(6-(2-cyanophenyl)-2-{[2-(3-
0.743 M+H 447.1 fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]propanoate methyl 2-[(6-(2-cyanophenyl)-2-{[2-(3-
0.101 M+H 433.1 fluorophenyl)ethyl]amino}-3-pyridyl)carbonylamino]acetate
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
1.083 M+H 405.1 pyridyl))-N-(2-hydroxyethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.238 M+H 419.1 pyridyl))-N-(2-methoxyethyl)carboxamide
N-[2-(dimethylamino)ethyl](6-(2-cyaπophenyl)-2-{[2-(3-
4.222 M+H 432.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{2-[(tert-butoxy)-N-methylcarbonylamino]ethyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
42.246 M+H 518.1 pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
4.455 M+H 418.1 pyridyl))-N-[2-(methylamino)ethyl]carboxamide
N-(3-aminopropyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.994 M+H 418.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fiuorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
0.985 M+H 446.1 methylpropanamide
(2R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amiπo}(3-pyridyl))carboπylamiπo]-N-
1.273 M+H 446.1 methylpropanamide
N-{2-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-3-
0.958 M+H 446.1 pyridyl)carbonylamino]ethyl}acetamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
1.118 M+H 462.1 pyridyl))-N-[2-(methoxycarbonylamino)ethyl]carboxamide
(6-(2-cyanophenyl)-2-{J2-(3-fluorophenyl)ethyl]amino}(3-
0.326 M+H 482.1 pyridyl))-N-{2-[(methylsulfonyl)amino]ethyl}carboxamide ethyl 3-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-
4.792 M+H 461.1 3-pyridyl)carbonylamino]propanoate methyl 4-[(6-(2-cyanophenyl)-2-{[2-(3-
0.713 M+H 461.1 fluorophenyl)ethyl]amiπo}-3-pyrϊdyl)carbonylamino]butanoate
3-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.34 M+H 446.1 pyridyl))carbonylamino]-N-methylpropanamide
4-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
2.956 M+H 460.1 pyridyl))carbonylamino]-N-rnethylbutanamide
N-(3-carbamoylpropyl)(6-(2-cyaπophenyl)-2-{[2-(3-
0.185 M+H 446.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
4-l(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-3-
0.627 M+H 447.1 pyridyl)carbonylamino]butanoic acid
N-(2-aminoethyl)(6-(2-cyanophenyl)-2-{[2-(3-
2.637 M+H 404.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
2.108 M+H 469.1 pyridyl))-N-[(4-fluorophenyl)methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.968 M+H 476.1 pyridyl))-N-[(4-cyanophenyl)methyl]carboxamide
N-[(3,4-difluorophenyl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
1.981 M+H 487.1 flαorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((1 S)-1 -carbamoyl-2-hydroxyethyl)(6-(2-cyanophenyl)-2-{[2-
1.02 M+H 448.1 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide (6-(2-cyanopheπyl)-2-{[2-(3-fluoropheπyl)ethyl]amino}(3-
0.318 M+H 419.1 pyridyl))-N-(3-hydroxypropyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.396 M+H 433.1 pyridyl))-N-(3-methoxypropyl)carboxamide methyl (2S)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-3-
4.177 M+H 463.1 hydroxypropanoate methyl (2R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-3-
0.513 M+H 463.1 hydroxypropanoate
(2S)-2-[<6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl)amino}(3-pyridyl))carbonylamino]-3-hydroxy-
1.121 M+H 462.1 N-methylpropanamide
(2R)-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-3-hydroxy-
0.544 M+H 462.1 N-methylpropanamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.029 M+H 452.1 pyridyl))-N-(2-pyridylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
24.295 M+H 465.1 pyridyl))-N-[(4-methylphenyl)methyl]carboxamide
(6-(2-cyanopheπyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.426 M+H 466.1 pyridyl))-N-[(6-methyl(3-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.054 M+H 466.1 pyridyl))-N-[(6-methyl(2-pyridyl))methyl]carboxamide
{6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.291 M+H 466.1 pyridyl))-N-(2-(2-pyridyl)ethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.15 M+H 466.1 pyridyl))-N-(2-(3-pyridyl)ethyl)carboxamide
N-[(6-amino(3-pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
0.026 M+H 467.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amiπo}(3-
8.099 M+H 482.1 pyridyl))-N-[(6-methoxy(3-pyridyl))methyl]carboxamide
(6-(2-cyaπophenyl)-2-{[2-(3-fluoropheπyl)ethyl]aιniπo}(3-
0.022 M+H 466.1 pyridyl))-N-[(2-methyl(3-pyridyl))methyl]carboxamide
N-[(2-amino(3-pyridyl))methyl](6-(2-cyanophenyl)-2-{[2-(3-
0.022 M+H 467.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.087 M+H 482.1 pyridyl))-N-[(2-methoxy(3-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.021 M+H 470.1 pyridyl))-N-[(1-hydroxy(2-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-([2-(3-fluorophenyl)ethyl]amino}(3-
0.019 M+H 470.1 pyridyl))-N-t(1-hydroxy(3-pyridyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
3.064 M+H 501.1 pyridyl))-N-[3-(4-methylpiperazinyl)propyi]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.136 M+H 415.1 pyridyl))-N-(cyclopropylmethyl)carboxamide
N-[2-(dimethylamino)ethyl]-2-[(6-(2-cyanophenyl)-2-{[2-(3-
9.309 M+H 489.1 fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]acetamide
2-[(6-(2-cyanopheπyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
2.07 M+H 462.1 pyridyl))carbonylamino]-N-(2-hydroxyethyl)acetamide
N-(2-carbamoylethyl)-2-[(6-(2-cyanophenyl)-2-{[2-(3-
12.17 M+H 489.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboπylamino]acetamide
3-{2-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-3-
9.666 M+H 490.1 pyridyl)carbonylamino]acetylamino}propanoic acid N-{3-[(tert-butoxy)carbonylamino]propyl}-2-[(6-(2- cyanophenyl)-2-{[2-(3-fluoropheny1)ethyl]amino}(3-
9.876 M+H 575.1 pyridyi))carbonylamino]acetamide
N-[3-(dimethylamino)propyl]-2-[(6-{2-cyanophenyl)-2-{[2-(3-
12.22 M+H 503.1 fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]acetamide
2-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
5.836 M+H 476.1 pyridyl))carbonylamino]-N-(3-hydroxypropyl)acetamide
N-{2-[(tert-butoxy)-N-methylcarbonylamino]ethyl}-2-[{6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
65.469 M+H 575.1 pyridyl))carbony!amino]acetamide
2-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]annino}{3-
11.096 M+H 475.1 pyridyl))carbonylamino]-N-[2-(methylamino)ethyl]acetamide methyl (2S)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-(3-
2.318 M+H 462.1 fluorophenyl)ethyl]amino}(3-pyridyl))carbonylaminojpropanoate
N-((1 S)-2-amino-1 -carbamoylethyl)(6-(2-cyanopheπyl)-2-{[2-(3-
0.816 M+H 447.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2S)-3-[(tert-butoxy)carbonylamino]-2-[(6-(2-cyanophenyl)-2-
{[2-(3-fluorophenyl)ethyl]amino}(3-
30.417 M+H 548.1 pyridyl))carbonylamiπo]propaπoic acid
(2S)-3-[(tert-butoxy)carbonylamino]-2-[(6-(2-cyanophenyl)-2-
{[2-(3-fluorophenyl)ethyl]amiπo}(3-pyridyl))carbonylamino]-N-
43.598 M+H 561.1 methylpropanamide
(2S)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamiπo]-N-
3.454 M+H 461.1 methylpropanamide
(2S)-3-amiπo-2-[(6-(2-cyaπopheπyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N,N-
23.721 M+H 475.1 dimethylpropanamide
(2S)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]propanoic
11.072 M+H 448.1 acid methyl (2S)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-(3-
0.619 M+H 462.1 fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]propanoate methyl (2S)-2-(acetylamino)-3-[(6-(2-cyanophenyl)-2-{[2-(3-
1.639 M+H 504.1 fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]propanoate
N-((2S)-2-amino-2-carbamoylethyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.669 M+H 447.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{(1S)-1-carbamoyl-2-[(6-(2-cyanophenyl)-2^[2-(3- fluorophenyl)ethyl]amino}(3-
2.629 M+H 489.1 pyridyl))carbonylamino]ethyl}acetamide
(2S)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
2.318 M+H 461.1 methylpropanamide
(2S)-2-amino-3-[(6-(2-cyanopheπyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N,N-
8.179 M+H 475.1 dimethylpropanamide
(2S)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]propanoic
9.758 M+H 448.1 acid
(2S)-2-(acetylamino)-3-[(6-(2-cyanophenyl)-2-{t2-{3- fluorophenyl)ethyl]amino}(3-pyridyl))carboπylamino]-N-
5.554 M+H 503.1 methylpropanamide methyl (2R)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-(3-
2.384 M+H 462.1 fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]propanoate N-((1 R)-2-amino-1-carbamoylethyl)(6-(2-cyanophenyl)-2-{[2-
0.538 M+H 447.1 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(2R)-3-amino-2-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
0.274 M+H 461.1 methylpropanarnide methyl (2R)-2-amino-3-[(6-(2-cyanophenyl)-2-{[2-(3-
2.29 M+H 462.1 fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]propanoate
N-((2R)-2-amino-2-carbamoylethyl)(6-(2-cyanophenyt)-2-{[2-
0.321 M+H 447.1 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amiπo}(3-
0.04 M+H 442.1 pyridyl))-N-(1,3-oxazol-2-ylmethyl)carboxamide
N-[(6-cyano(3-pyridyl))methyl](2-{[2-(3-
1.245 M+H 452.1 fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))carboxamide
N-{[6-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3-
0.42 M+H 456.1 fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))carboxamide
2-amiπo-1-(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3-
52.451 M+H 352.1 pyridyl))ethan-1-ol
N-{[4-(aminomethyl)(2-pyridyl)]methyl}(6-(2-cyanophenyl)-2-
0.598 M+H 481.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(5-{[(tert-butoxy)carbonylamino]methyl}(2-pyridyl))methyl](6-
(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
68.638 M+H 581.1 pyridyl))carboxamide
N-{[5-(aminomethyl)(2-pyridyl)]methyl}(6-<2-cyanophenyl)-2-
0.515 M+H 481.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[4-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
1.215 M+H 456.1 fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))carboxamide
N-{[5-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
1.061 M+H 456.1 fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))carboxamide
(6-(2-cyanopheπyl)-2-{[2-(3-fluoropheπy!)ethyl]amino}(3-
0.021 M+H 442.1 pyridyl))-N-(isoxazol-5-ylmethyI)carboxamide
2-{[2-(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3-pyridy!))-2-
51.566 M+H 409.1 hydroxyethyl]amino}acetamide ethyl 2-{[2-(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3-
15.082 M+H 438.1 pyridyl))-2-hydroxyethyl]amino}acetate
1-(2-{[2-(3-fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))-2-[(2-
19.362 M+H 443.1 pyridylmethyl)amino]ethan-1 -ol
N-(4-aminobutyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.416 M+H 432.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(5-aminopentyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.154 M+H 446.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(6-aminohexyl)(6-(2-cyanophenyl)-2-{[2-(3-
1.244 M+H 460.1 fluorophenyl)ethyl]amiπo}(3-pyridyl))carboxamide
N-{2-[6-(aminomethyl)(2-pyridyl)]ethyl}(6-(2-cyanophenyl)-2-
0.032 M+H 495.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{2-[6-(aminomethyl)(2-pyridyl)]ethyl}(2^{[2-(3-
0.252 M+H 470.1 fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))carboxamide
N-{[6-(2-amiπoethyl)(2-pyridyl)]methyl}(6-(2-cyanophenyl)-2-
0.011 M+H 495.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[6-(2-aminoethyl)(2-pyridyl)]methyl}(2-{[2-(3-
0.024 M+H 470.1 fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))carboxamide
N-[2-(2-aminoethoxy)ethyl](6-(2-cyaπophenyl)-2-{[2-(3-
1.62 M+H 448.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(β^-cyanophenylJ-Σ^p-CS-fluorophenylJethyllaminoXS-
0.037 M+H 482.1 pyridyl))-N-{[6-(hydroxymethyl)(2-pyridyl)]methyl}carboxamide N-{[3-(aminomethyl)phenyl]methyl}(6-(2-cyaπopheπyl)-2-{[2-(3-
0.012 M+H 480.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
2-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.532 M+H 446.1 pyridyl))carbonylamino]-N,N-dimethylacetamide
N-{2-[(2-aminoethyl)amino]ethyl}(6-(2-cyaπophenyl)-2-{[2-(3-
0.444 M+H 447.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyaπopheπyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.014 M+H 472.1 pyridyl))-N-[(2-oxo(3-piperidyl))methyl]carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.015 M+H 441.1 pyridyl))-N-(pyrazol-3-ylmethyl)carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.032 M+H 455.1 pyridyl))-N-[( 1 -methylpyrazol-3-yl)methyl]carboxa mide
N-{[4-(aminomethyl)phenyl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
0.277 M+H 480.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxarnide
N-[(6-{[(2-aminoethyl)amino]methyl}(2-pyridyl))methyl](6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.019 M+H 524.1 pyridyi))carboxamide methyl 6-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-3-
0.064 M+H 510.1 pyridyl)carbonylamino]methyl}pyridine-2-carboxylate
6-{[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-3-
0.047 M+H 496.1 pyridyl)carbonylamino]methyl}pyridine-2-carboxylic acid
6-{[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyI]amino}-3-
0.06 M+H 495.1 pyridyl)carbonylamino]methyl}pyridine-2-carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.031 M+H 455.1 pyridyl))-N-[(1-methylpyrazol-5-yl)methyl]carboxamide
N-(1-π[2-[(tert-butoxy)carbonylamino]ethyl}-2-oxo(3- piperidyl))(6-(2-cyanophenyl)-2-{[2-(3-
15.254 M+H 601.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[1-(2-aminoethyl)-2-oxo(3-piperidyl)](6-(2-cyanophenyl)-2-
18.531 M+H 501.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))-N-(2-{2-oxo-3-
11.834 M+H 635.1 [(phenylmethoxy)carbonylamino]piperidyl}ethyl)carboxamide
N-[2-(3-amino-2-oxopiperidyl)ethyl](6-(2-cyanophenyl)-2-{[2-(3-
2.95 M+H 501.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[2-(aminomethyl)phenyl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
0.024 M+H 480.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.032 M+H 458.1 pyridyl))-N-[(2-oxopyrrolidin-3-yl)methyl]carboxamide
N-[(2-{2-[(tert-butoxy)carbonylamino]ethyl}(3-pyridyl))methyl](6-
(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.47 M+H 595.1 pyridyl))carboxamide
N-{[2-(2-aminoethyl)(3-pyridyl)]nnethyl}(6-(2-cyanophenyl)-2-
0.006 M+H 495.1 {[2-(3-fluorophenyl)ethyl]amiπo}(3-pyridyl))carboxamide
N-{2-[3-(aminomethyI)(2-pyridyl)]ethyl}(6-(2-cyanophenyl)-2-
0.31 M+H 495.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-((3S)-2-oxopyrrolidin-3-yl)(6-(2-cyanophenyl)-2-{[2-(3-
3.246 M+H 444.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))-N-{[1-(2-hydroxyethyl)-2-oxo(3-
0.059 M+H 516.1 piperidyl)]methyl}carboxamide
N-{[1-(2-aminoethyl)-2-oxo(3-piperidyl)]methyl}(6-(2-
0.031 M+H 515.1 cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))-N-{[1-(3-diazo-3-azaprop-3-enyl)-2-oxo(3- 0.412 M+H 541.1 piperidyl)]methyl}carboxamide
(6-(2-cyaπopheπyl)-2-{[2-(3-fluorophenyl)ethyl]amino}{3- pyridyl))-N-{[3-(3-diazo-3-azaprop-3-enyl)-2-oxo(3- 15.844 M+H 541.1 piperidyl)]methyl}carboxamide
N-[((2R)piperazin-2-yl)methyl](6-(2-cyanophenyl)-2-{[2-(3- 12.204 M+H 459.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-methylpiperazin-2-yl)methyl](6-(2-cyanophenyl)-2- 15.724 M+H 473.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)-1-acetylpiperazin-2-yl)methyl](6-(2-cyanophenyl)-2- 7.437 M+H 501.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(ethylsulfonyl)piperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 16.793 M+H 551.1 pyridyl))carboxamide methyl (2 R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- 11.602 M+H 517.1 pyridyl))carbonylamino]methyl}piperazinecarboxylate
N-[((2S)-1-acetyl-4-methylpiperazin-2-yl)methyl](6-(2- cyanophenyl)~2-{[2-(3-fluorophenyl)ethyl]amino}(3- 6.789 M+H 515.1 pyridyl))carboxamide methyl (2S)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]methylH- 10.062 M+H 531.1 methylpiperazinecarboxylate
N-{[(2R)-1-(2-aminoacetyl)piperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
2.775 M+H 516.1 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)piperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
4.893 M+H 530.1 pyridyl))carboxamide
N-{[(2R)-1-(4-amiπobutaπoyl)piperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
5.475 M+H 544.1 pyridyl))carboxamide
N-{[(2S)-1-(2-aminoacetyl)-4-methylpiperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
1.283 M+H 530.1 pyridyl))carboxamide
N-{[(2S)-1-(3-aminopropanoyl)-4-methylpiperazin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
2.393 M+H 544.1 fluoropheπyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-1-(4-aminobutaπoyl)-4-methylpiperaziπ-2-yl]methyl}(6- (2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
2.322 M+H 558.1 pyridyl))carboxamide
N-{[(2S)-4-(2-aminoacetyl)piperazin-2-yl]methyl}(6-(2- cyaπophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
8.885 M+H 516.1 pyridyl))carboxamide
N-{[(2S)-4-(3-aminopropanoyl)piperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 11.197 M+H 530.1 pyridyl))carboxamide
N-{[(2S)-4-(4-aminobutanoyl)piperazin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyI]amino}(3- 12.397 M+H 544.1 pyridyl))carboxamide
N-{[(2S)-4-(2-aminoacetyl)-1-methylpiperazin-2-yl]methyl}(6-(2- 6.97 M+H 530.1 cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxamide
N-{[(2S)-4-(3-aminopropanoyl)-1-methylpiperazin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3- 16.962 M+H 544.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2S)-4-(4-aminobutanoyl)-1-methylpiperazin-2-yl]methyl}(6-
(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 6.717 M+H 558.1 pyridyl))carboxamide
2-(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 13.156 M+H 466.1 pyridyl))-N-(3-pyridylmethyl)acetamide
N-[((2S)-1,4-diacetylpiperazin-2-yl)methyl](6-(2-cyanophenyl)- 17.175 M+H 543.1 2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2S)-4-methylpiperazin-2-yl)methyl](6-(2-cyanophenyl)-2- 2.92 M+H 473.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[((2R)azetidin-2-yl)methyl](6-(2-cyanophenyl)-2-{[2-(3- 0.413 M+H 430.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide methyl (2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- 0.073 M+H 488.1 pyridyl))carbonylamino]methyl}azetidinecarboxylate
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 0.248 M+H 437.1 pyridyl))-N-[(2-oxopyrrolidiπ-3-yl)methyl]carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-pyridyl))-N- 0.18 M+H 423.1 [(2-oxopyrrolidin-3-yl)methyljcarboxamide
N-{[(2R)-1-(2-hydroxyacetyl)pyrrolidin-2-yl]rnethyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.116 M+H 502.1 pyridyl))carboxamide methyl 4-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- 0.657 M+H 558.1 pyridyl))carbonylamino]methyl}pyrrolidinyl)-4-oxobutanoate
N-{[(2R)-1-(4-hydroxybutanoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.085 M+H 530.1 pyridyl))carboxamide
N-{[(2R)-1-(2-hydroxyacetyl)pyrrolidiπ-2-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 1.784 M+H 481.1 pyridyl))carboxamide methyl 4-((2R)-2-{[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3- 3.935 M+H 537.1 pyridyl))carbonylamino]methyl}pyrrolidinyl)-4-oxobutanoate
N-{[(2R)-1-(4-hydroxybutanoyl)pyrrolidin-2-yl]methy!}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 1.456 M+H 509.1 pyridyl))carboxamide
N-[((2R)-1-acetylazetidin-2-yl)methyl](6-(2-cyanophenyl)-2-{[2- 0.043 M+H 472.1 (3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(methyisulfoπyl)azetidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 1.524 M+H 508.1 pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)azetidin-2-yl]methyl}(6-(2- cyaπophenyl)-2-{[2-(3-fluoropheπyl)ethyl]amiπo}(3- 0.044 M+H 487.1 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)azetidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fIuorophenyl)ethyl]amino}(3- 0.045 M+H 501.1 pyridyl))carboxamide
N-{[(2R)-1-(4-amiπobutanoyl)azetidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.025 M+H 515.1 pyridyl))carboxamide N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.04 M+H 488.1 pyridyl))carboxamide methyl 4-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
0.519 M+H 544.1 pyridyl))carbonylamino]methyl}azetidinyl)-4-oxobutanoate
N-{[(2R)-1-(4-hydroxybutanoyl)azetidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.06 M+H 516.1 pyridyl))carboxamide
N-(azaperhydroepin-2-ylmethyl)(6-(2-cyanophenyl)-2-{[2-(3-
2.501 M+H 472.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(2-aminoacetyl)azaperhydroepin-2-yl]rnethyl}(6-(2- cyanophenyl)-2-{[2-(3-fluoropnenyl)ethyl]amino}(3-
0.248 M+H 529.1 pyridyl))carb.oxamide
N-{t1-(3-aminopropanoyl)azaperhydroepin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.256 M+H 543.1 pyridyl))carboxamide
N-{[1-(4-amiπobutanoyl)azaperhydroepin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.383 M+H 557.1 pyridyl))carboxamide
N-[(H3-[(tert-butoxy)carbonylamino]propyl}-2-oxopyrrolidin-3- yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
0.104 M+H 615.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxarriide
N-{[1-(3-aminopropyl)-2-oxopyrrolidin-3-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.382 M+H 515.1 pyridyl))carboxamide
N-[(1-{3-[(tert-butoxy)carbonylamino]propyl}-2-oxopyrrolidin-3- yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.589 M+H 580.1 pyridyl))carboxamide
N-{[1-(3-aminopropyl)-2-oxopyrrolidin-3-yl]methyl}(2-{[2-(3- fIuorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
3.125 M+H 480.1 pyridyl))carboxamide
N-[(1-{3-[(tert-butoxy)carbonylamino]propyl}-2-oxopyrrolidin-3- yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(1-
0.699 M+H 594.1 methy!pyrazol-4-yl)(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)-2-oxopyrrolidin-3-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
5.504 M+H 494.1 pyridyl))carboxamide tert-butyl (2R)-2-{[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-
3.167 M+H 509.1 4-yl(3-pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate
N-{[(2R)-1-(2-hydroxyacetyl)pyrrolidin-2-yl]methyl}(2-{[2-(3- fluorophenyOethyllamino^'pyrazoM-yKS-
1.185 M+H 467.1 pyridyl))carboxamide
(6-(2-cyanopheπyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.095 M+H 486.1 pyridyl))-N-[(7-oxoazaperhydroepin-2-yl)methyl]carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-pyridyl))-N-
0.687 M+H 451.1 [(7-oxoazaperhydroepiπ-2-yl)methyl]carboxamide
^-{^-(S-fluorophenyOethyljamino^-CI-methylpyrazoM-yOCS-
0.603 M+H 465.1 pyridyl))-N-[{7-oxoazaperhydroepin-2-yl)methyl]carboxannide
N-[(1-{3-[(tert-butoxy)carboπylamino]propyl}-7- oxoazaperhydroepin-2-yl)methyl](6-(2-cyanophenyl)-2-{[2-(3-
17.15 M+H 643.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[1-(3-aminopropyl)-7-oxoazaperhydroepin-2-yl]methyl}(6-(2-
0.273 M+H 543.1 cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))carboxamide
N-{[(2R)-1-(4-hydroxybutanoyl)pyrrolidin-2-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.963 M+H 495.1 pyridyl))carboxamide
N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-[5-(hydroxymethyl)(2-thienyl)](3-
2.541 M+H 499.1 pyridyl))carboxamide
N-{[(2R)-1-(2,3-dihydroxypropanoyl)azetidin-2-yl]methyl}(6-(2- cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.051 M+H 518.1 pyridyl))carboxamide tert-butyl (2R)-2-{[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-
0.525 M+H 495.1 4-yl(3-pyridyl))carbonylamino]methyl}azetidiπecarboxylate
N-[((2R)azetidin-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
5.442 M+H 395.1 pyridyl))carboxamide
N-[2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]methyl}azetidinyl)(1S)-1-
2.482 M+H 617.1 (hydroxymethyl)-2-oxoethyl](tert-butoxy)carboxamide
N-{[(2R)-1-((2S)-2-annino-3-hydroxypropanoyl)azetidin-2- yl)methyl}(6-(2-cyanophenyl)-2-{[2-(3-
0.088 M+H 517.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(1R)-2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamiπo]methyl}azetidinyl)-1-(hydroxymethyl)-2-
0.439 M+H 617.1 oxoethyl](tert-butoxy)carboxamide
N-{[(2R)-1-((2R)-2-amino-3-hydroxypropanoyl)azetidin-2- yl]methyl}(6-(2-cyanophenyl)-2-{[2-(3-
0.083 M+H 517.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[2-((2R)-2-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]methyl}azetidinyl)(1 S)-1 -(3-
1.349 M+H 644.1 aminopropyl)-2-oxoethyl](tert-butoxy)carboxamide
N-{[(2R)-1-((2S)-2,5-diaminopentanoyl)azetidin-2-yl]methyl}(6-
(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.274 M+H 544.1 pyridyl))carboxamide
N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.559 M+H 453.1 pyridyl))carboxamide
N-[((2R)-1-{2-[(tert-butoxy)carbonylamino]acetyl}azetidin-2- yl)methyl](2-{[2-(3-fluorophenyl)ethyl]annino}-6-pyrazol-4-yl(3-
2.989 M+H 552.1 pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)azetidin-2-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.562 M+H 452.1 pyridyl))carboxamide
N-[(6-bromo(2-pyridyl))methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.117 M+H 494.0 pyridyl))carboxamide
N-({6-[(3-aminopropyl)amino](2-pyridyl)}methyl)(2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.018 M+H 489.1 pyridyl))carboxamide
N-({6-[(2-aminoethyl)amino](2-pyridyl)}methyl)(2-{[2-(3- fluorophenyl)ethyl]amiπo}-6-pyrazol-4-yl(3-
0.02 M+H 475.1 pyridyl))carboxamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-pyridyl))-N-
0.039 M+H 476.1 ({6-[(2-hydroxyethyl)amino](2-pyridyl)}methyl)carboxamide methyl (2R)-2-{[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-
0.245 M+H 453.1 yl(3-pyridyl))carbonylamino]methyl}azetidinecarboxylate
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propanoyl}pyrrolidin- 2-yt)methyl](5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
0.505 M+H 612.1 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)pyrrolidin-2-yl]methyl}(5-fluoro- 2-{[2-(3-fluoropheπyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 0.07 M+H 512.1 pyridyl))carboxamide
N-[((2R)-1-{4-[(tert-butoxy)carbonylamino]butanoyl}pyrrolidJn-2- yl)methyl](5-ftuoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
0.483 M+H 626.1 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(5-fluoro-2- {[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.087 M+H 526.1 pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3-pyridyl))methyl](5- fluoro-2-{[2-(3-fluorophenyl>ethyl]amino}-6-(1-methylpyrazol-4-
0.388 M+H 578.1 yl)(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-rnethylpyrazol-4-yl)(3-
0.012 M+H 478.1 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}-5- oxopyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-( 1 -methylpy razol-4-yl)(3-
0.322 M+H 612.1 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(5- f)uoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
0.079 M+H 512.1 yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(2,3-dihydroxypropanoyl)pyrrolidin-2-yl]methyl}(5- fIuoro-2-{[2-(3-fIuorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
0.143 M+H 529.1 yl)(3-pyridyl))carboxamide
(2-[[2-{3-fluorophenyl)ethyl]amino}-6-[1-(2- hydroxyethyl)pyrazol-4-yl](3-pyridyl))-N-(3-
0.972 M+H 461.1 pyridylmethyl)carboxamide tert-butyl (2R)-2-{[(6-(2-cyanophenyl)-5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}(3-
9.038 M+H 562.1 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate
N-[((2R)pyrrolidin-2-yl)methyl](6-(2-cyanophenyl)-5-fluoro-2-
0.103 M+H 462.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonyIamino]methyl}(3-pyridyl))methyl](2- {[2-(3-fluorophenyl)ethyl]amino}-6-[1-(2-hydroxyethyl)pyrazol-4- 14.993 M+H 590.1 yl](3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{t2-(3- fluorophenyl)ethyl]amino}-6-[1-(2-hydroxyethyl)pyrazol-4-yl](3-
0.707 M+H 490.1 pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3-pyridyl))methyl](6- (2-cyanophenyl)-5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
5.358 M+H 599.1 pyridyl))carboxamide
N^p-CaminomethyOCS-pyridylJJmethylKe^-cyanophenylJ-S- fluoro-2-{[2-(3-fluorophenyl)ethyl]aπfiino}(3-
0.006 M+H 499.1 pyridyl))carboxamide
N-[((2R)-1-{2-[(tert-butoxy)carbonylamino]acetyl}pyrrolidin-2-
2.786 M+H 619.1 yl)methyl](6-(2-cyanophenyl)-5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-5-fluoro~2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.04 M+H 519.1 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propanoyl}pyrrolidin- 2-yl)methyl](6-(2-cyanophenyl)-5-fiuoro-2-{[2-(3-
2.771 M+H 633.1 fluorophenyl)ethyl]amino}(3-pyridy!))carboxamide
N-{[(2R)-1-(3-aminopropanoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.042 M+H 533.1 pyridyl))carboxamide
N-[((2R)-1-{4-[(tert-butoxy)carbonylamiπo]butaπoyl}pyrrolidin-2- yl)methyl](6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
1.059 M+H 647.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.038 M+H 547.1 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}-5- oxopyrrolidiπ-2-yl)methyl](6-(2-cyanophenyl)-5-fluoro-2-{[2-(3-
0.845 M+H 633.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-5-fluoro-24[2-(3-fluorophenyl)ethyl]amino}(3-
0.042 M+H 533.1 pyridyl))carboxamide
N-{[{2R)-1-(2,3-dihydroxypropanoyl)pyrrolidin-2-yl]methyl}(6-(2- cyanophenyl)-5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}(3- 0.11 M+H 550.1 pyridyl))carboxamide
N-[2-((2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3- pyridyl))carbonylamino]methyl}pyrrolidinyl)(1S)-1-methyl-2-
1.953 M+H 612.1 oxoethyl](tert-butoxy)carboxamide
N-{[(2R)-1-((2S)-2-aminopropanoyl)pyrrolidin-2-yl]methyl}(5- fluoro-2-{[2-(3-fluorophenyl)ethyl]annino}-6-(1-methylpyrazol-4-
0.099 M+H 512.1 yl)(3-pyridyl))carboxamide
N-[((2R)-1 -{(2S)-2,5-bis[(tert- butoxy)carbonylamino]pentanoyl}pyrrolidin-2-yl)methyl](5- fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4- 19.6 M+H 755.4 yl)(3-pyridyl))carboxamide
N-{[(2R)-1-((2S)-2,5-diaminopentandyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-fIuorophenyl)ethyl]amiπo}-6-(1-
0.078 M+H 555.1 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-[2-((2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3- pyridyl))carbonylamino]methyl}pyrrolidinyl)(1S)-1-
1.195 M+H 628.1 (hydroxymethyl)-2-oxoethyl](tert-butoxy)carboxamide
N-{[(2R)-1-((2S)-2-amino-3-hydroxypropanoyl)pyrrolidin-2- yl]methyl}(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]annino}-6-(1-
0.072 M+H 528.1 methylpyrazol-4-yl)(3-pyridyl))carboxamide methyl 4-((2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}- 6-(1 -methylpyrazol-4-yl)(3-
0.534 M+H 555.1 pyridyl))carbonylamino]methyl}pyrrolidinyl)-4-oxobutanoate
N-{[(2R)-1-(4-hydroxybutanoyl)pyrrolidin-2-yl]methyl}(5-fIuoro- 2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.245 M+H 527.1 pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3-pyridyl))methyl](5- 0.75 M+H 585.1 cyaπo-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4- yl)(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methy]}(5-cyano-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 0.05 M+H 485.1 pyridyl))carboxamide
N-[3-((5R)-5-{[(5-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}-6-{1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]rnethyl}-2- 1.15 M+H 619.1 oxopyrrolidinyl)propyl](tert-butoxy)carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-y!]methyl}(5- cyano-2-{[2-(3-fluorophenyl)ethyl]amino}-6-( 1 -methylpyrazol-4- 0.31 M+H 519.1 yl)(3-pyridyl))carboxamide tert-butyl (2R)-2-{[(5-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}- 6-(1-methylpyrazol-4-yl)(3-
2.518 M+H 548.1 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate
N-[((2R)pyrrolidin-2-yl)methyl](5-cyano-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-rnethylpyrazol-4-yl)(3-
0.281 M+H 448.1 pyridyl))carboxamide
N-[((2R)-1-{4-[(tert-butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](5-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
1.613 M+H 633.2 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(5-cyano-2- {[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.211 M+H 533.2 pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}{3-pyridyl))methyl](2- {[2-(3-fluoropheπyl)ethyl]amino}-5-methyl-6-(1-methylpyrazol-
1.122 M+H 574.1 4-yl)(3-pyridyl))carboxamide
N-{t2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-5-methyl-6-(1-methy]pyrazol-4-yl){3-
0.129 M+H 474.1 pyridyl))carboxamide
N-[((2R)-1-{3-((tert-butoxy)carbonylamino]propyl}-5- oxopyrrolidin-2-yl)methyI](2-{[2-(3-fluorophenyl)ethyl]amino}-5-
1.461 M+H 608.2 methyl-6-(1-methylpyrazol~4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(2-{[2- (3-fiuorophenyl)ethyl]amino}-5-methyl-6-(1-methylpyrazol-4-
0.577 M+H 508.2 yl)(3-pyridyl))carboxamide tert-butyl (2R)-2-{[(2-{[2-(3-fluorophenyl)ethyl]amino}-5-methyl- 6-(1 -methylpy razol-4-yl)(3-
3.702 M+H 537.1 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate
N-[((2R)pyrrolidiπ-2-yl)methyl](2-{[2-(3- fluorophenyl)ethyl]amino}-5-methyl-6-{1-methylpyrazol-4-yl)(3-
0.901 M+H 437.1 pyridyt))carboxamide
N-[((2R)-1-{4-[(tert-butoxy)carbonylamino]butaπoyl}pyrrolidin-2- yl)methyl](2-{[2-(3-fluorophenyl)ethyl]amino}-5-methyl-6-(1-
2.265 M+H 622.3 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrotidin-2-yl]methyl}(2-{[2-(3- fluorophenyl)ethyl]amino}-5-methyl-6-(1-methylpyrazo!-4-yl)(3-
0.381 M+H 522.2 pyridyl))carboxamide tert-butyl (2R)-2-{[(5-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}- 6-pyrazol-4-yl(3-
6.407 M+H 534.1 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate
N-[((2R)pyrrolidin-2-yl)methyl](5-cyano-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.624 M+H 434.1 pyridyl))carboxamide
N-[{(2R)-1-{4-[(tert-butoxy)carbonylamino]butanoyl}pyrro!idiπ-2-
3.421 M+H 619.2 yl)methyl](5-cyano-2-{[2-(3-fluoropheπyl)ethyl]amino}-6- pyrazol-4-yl(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(5-cyano-2-
{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.359 M+H 519.2 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}-5- oxopyrrolidin-2-yl)methyl](5-cyano-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
3.506 M+H 605.1 pyridyl ))carboxa mide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(5- cyano-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.735 M+H 505.1 pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3-pyridyl))methyl](5- cyano-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
1.003 M+H 571.1 pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-cyano-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.058 M+H 471.1 pyridyl))carboxamide
N-[(2-{[(tert-butoxy)carbonylamino]methyl}(3-pyridyl))methyl](6-
(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}-5-methyl(3-
4.252 M+H 595.2 pyridyl))carboxamide
N-{[2-(amiπomethyl)(3-pyridyl)]methyl}(6-(2-cyanophenyl)-2-
{[2-(3-fluorophenyl)ethyl]amino}-5-methyl(3-
0.158 M+H 495.2 pyridyl))carboxamide
N-[3-((5R)-5-{[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}-5-methyl(3- pyridyl))carbonylamino]methyl}-2-oxopyrrolidinyl)propyl](tert-
5.372 M+H 629.2 butoxy)carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(6-(2- cyanophenyO^-fP-CS-fluorophenyόethyllamino^δ-methyKS-
1.226 M+H 529.1 pyridyl))carboxamide methyl 5-chloro-2-{t2-(3-fluorophenyl)ethyl]amino}-6-(1-
15.521 M+H 389.0 methylpyrazol-4-yl)pyridine-3-carboxylate
N-[(2-{[(tert-butoxy)carbonylamiπo]methyl}(3-pyridyl))methyl](5- chloro-2-{[2-(3-fIuorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
0.414 M+H 594.1 yl)(3-pyridyl))carboxamide
N-IP-CaminomethylXS-pyridyOlmethylKS-chloro^-IP-CS- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.03 M+H 494.0 pyridyl))carboxamide
N-[((2R)-1-{3-[(tert-butoxy)carbonylamino]propyl}-5- oxopyrrolidin-2-yl)methyl](5-ch!oro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.443 M+H 628.2 pyridyl))carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidiπ-2-yl]methyl}(5- chloro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-
0.16 M+H 528.1 yl)(3-pyridyl))carboxamide tert-butyl (2R)-2-{[(5-chloro-2-{[2-(3-fluorophenyl)ethyl]amino}-
6-( 1 -methylpy razol-4-yl)(3-
1.601 M+H 557.1 pyridyl))carbonylamiπo]methyl}pyrrolidinecarboxylate
N-[((2R)pyrrolidin-2-yl)methyl](5-chloro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.167 M+H 457.1 pyridyl))carboxamide
N-[((2R)-i-{4-[(tert-butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](5-chloro-2-{[2-(3-fluoropheπyl)ethyl]amino}-6-(1-
0.683 M+H 642.2 methylpyrazol-4-yl)(3-pyridyl))carboxamide N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(5-chloro-2- {[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.047 M+H 542.1 pyridyl))carboxamide
N-{3-[(tert-butoxy)carbonylamino]propyl}(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
4.501 M+H 515.2 pyridyl))carboxamide
N-(3-aminopropyl)(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-
3.957 M+H 415.1 6-(1-methylpyrazol-4-yl)(3-pyridyl))carboxamide methyl (2R)-3-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- (1-methylpyrazo1-4-yl)(3-pyridyl))carbonylamino]-2- 0.1 M+H 458.1 methylpropanoate
(2R)-3-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-2-
3.841 M+H 444.1 methylpropanoic acid
2-[(tert-butoxy)carbonylamino]-N-{3-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-rnethylpyrazol-4-yl)(3-
0.768 M+H 572.2 pyridyl))carbonylamino]propyl}acetamide
2-amino-N-{3-[(5-fluoro-2-{[2-(3-fluoropheny])ethyl]amino}-6- (1-methylpyrazol-4-yl)(3-
2.494 M+H 472.1 pyridyl))carbonylamino]propyl}acetamide
N-{3-[(5-fluoro-2-{[2-{3-fluorophenyl)ethyl]amino}-6-(1-
2.617 M+H 457.1 methylpyrazol-4-yl)-3-pyridyl)carbonylamino]propyl}acetamide
N-((2R)-3-hydroxy-2-methylpropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 0.05 M+H 430.1 pyridyl))carboxamide
N-((2R)-2-carbamoylpropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.089 M+H 443.1 pyridyl))carboxamide
(2R)-3-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-2-methyl-N- 0.13 M+H 457.1 methylpropanamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazo!-4-yl(3-
0.024 M+H 424.1 pyridyl))-N-(pyrazol-3-ylmethyl)carboxamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol- 0.02 M+H 438.1 4-yl)(3-pyridyl))-N-(pyrazol-3-ylmethyl)carboxamide
N-((2R)-4-diazo-2-methyl-4-azabut-4-enyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amiπo}-6-(1-methylpyrazol-4-yl)(3-
0.118 M+H 455.2 pyridyl))carboxamide
5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-nriethylpyrazol- 10.538 M+H 412.1 4-yl)(3-pyridyl) 3-methylazetidinyl ketone
N-((2S)-3-amino-2-methylpropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 1.05 M+H 429.2 pyridyl))carboxamide
N-{(2R)-3-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-2-methylpropyl}-
0.373 M+H 586.5 2-[(tert-butoxy)carbonylamino]acetamide
N^RJ-S-Kδ-fluoro^-CP-CS-fluorophenyOethyllamino^-CI- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-2-methylpropyl}-
0.152 M+H 486.2 2-aminoacetamide
N-{(2R)-3-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-2-methylpropyl}-
0.105 M+H 487.1 2-hydroxyacetamide tert-butyl (2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-
0.525 M+H 527.1 6-(1-methylpyrazol-4-yl)(3- pyridyl))carbonylamino]methyl}azetidinecarboxylate
N-[((2R)azetidin-2-yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
1.582 M+H 427.1 pyridyl))carboxamide
N-[((2R)-1 -{2-[(tert-butoxy)carbonylamino]acetyl}azetid in-2- yl)methyl](5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
0.436 M+H 584.3 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)azetidin-2-yl]methyl}(5-fluoro-2-{[2- (3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 0.05 M+H 484.1 pyridyl))carboxamide
N-[((2R)-1-{4-[(tert-butoxy)carbonylamino]butaπoyl}azetidin-2- yl)methyl](5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-
0.122 M+H 612.3 methylpyrazol-4-yl)(3-pyridyl))carboxamide
N-{[(2R)-1-(4-aminobutanoyl)azetidin-2-yl]methyl}(5-fluoro-2- {[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 0.04 M+H 512.1 pyridyl))carboxamide
N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2-yl]methyl}(5-flυoro-2-{[2- (3-fiuorophenyl)ethyljamino}-6-(1-methylpyrazol-4-yl)(3-
0.047 M+H 485.2 pyridyl))carboxamide methyl (2S)-3-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- (1-methylpyrazol-4-yl)(3-pyridyl))carbonylamino]-2-
0.141 M+H 458.1 methylpropanoate
N-((2S)-3-hydroxy-2-methylpropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- 0.09 M+H 430.1 pyridyl))carboxamide
N-((2R)-3-hydroxy-2-methylpropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.059 M+H 416.1 pyridyl))carboxamide methyl (2R)-3-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
0.073 M+H 444.1 pyrazol-4-yl(3-pyridyl))carbonylamino]-2-methylpropanoate methyl (2R)-3-[(6-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-2-
0.186 M+H 461.1 methylpropanoate
N-((2R)-3-hydroxy-2-methylpropyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.061 M+H 433.2 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-[(2,2-dimethyl(1,3-dioxan-5-yl))methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
2.226 M+H 486.2 pyridyl))carboxamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol- 4-yl)(3-pyridyl))-N-[3-hydroxy-2-
0.134 M+H 446.2 (hydroxymethyl)propyl]carboxamide
N-[(2,2-dimethyl(1,3-dioxan-5-yl))methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.927 M+H 472.2 pyridyl))carboxamide
(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.215 M+H ' 432.2 pyridyl))-N-[3-hydroxy-2-(hydroxymethyl)propyl]carboxamide
N-[(2,2-dimethyl(1,3-dioxaπ-5-yl))methyl)(6-(2-cyanophenyl)-2-
1.023 M+H 489.2 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
(6-(2-cyanophenyl)-2-{[2-(3-fIuorophenyl)ethyl]amino}(3-
0.209 M+H 449.2 pyridyl))-N-[3-hydroxy-2-(hydroxymethyl)propyl]carboxamide methyl (2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- (1 -methylpyrazol-4-yl){3-
0.117 M+H 472.1 pyridyl))carbonylamino]methyl}butanoate
0.039 M+H 444.1 N-((2R)-2-ethyl-3-hydroxypropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3- pyridy I) )carboxam ide methyl (2R)-2-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
0.117 M+H 458.1 pyrazol-4-yl(3-pyridyl))carboπylamino]methyl}butaπoate
N-((2R)-2-ethy]-3-hydroxypropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.052 M+H 430.1 pyridyl))carboxamide methyl (2R)-2-[(tert-butoxy)carbonylamiπo]-3-[(5-fluoro-2-{[2-
(3-fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
90.761 M+H 559.2 pyridyl))carbonylamino]propanoate methyl (2R)-2-amino-3-[(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.568 M+H 459.2 pyridyl))carbonylamino]propanoate
N-tCIR^I-IKδ-fluoro^p-CS-fluorophenylJethylJaminoJ-e-CI- methylpyrazol-4-yl)(3-pyridyl))carbonylamino]rnethyl}-2-
25.925 M+H 531.2 hydroxyethyl)(tert-butoxy)carboxamide
N-((2R)-2-amino-3-hydroxypropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
1.258 M+H 431.2 pyridyl))carboxamide
N-((1R)-1-{[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrazol-4-yl(3-pyridyl))carbonylamino]methyl}~2-
57.166 M+H 517.2 hydroxyethyl)(tert-butoxy)carboxamide
N-{(2R)-2-amino-3-hydroxypropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
1.825 M+H 417.2 pyridy!))carboxamide
N-(2,3-dihydroxypropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-(1-methylpyrazol-4-yl)(3-
0.307 M+H 432.1 pyridyl))carboxamide
N-{2,3-dihydroxypropyl)(5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.448 M+H 418.1 pyridyl))carboxamide methyl (2R)-3-{[2-amino-5-fluoro-6-(1 -methylpyrazol-4-yl)(3-
86.027 M+H 336.1 pyridyl)]carbonylamino}-2-methylpropanoate
N-{[(2R)-1-(2-hydroxy-2-methylpropanoyl)azetidin-2- yl]methyl}(5-fluoro-2H[[2-(3-fluorophenyl)ethyl]amino}-6-(1-
0.141 M+H 513.1 methylpyrazol-4-yl)(3-pyridyl))carboxamide tert-butyl (2R)-2-{[(5-fluoro-2-{[2-{3-fluoropheπyl)ethyl]amiπo}-
6-pyrazol-4-yl(3-
0.289 M+H 513.1 pyridyl))carbonylamino]methyl}azetidinecarboxylate
N-{[(2R)-1-(2-hydroxyacetyl)azetidin-2-yl]methyl}(5-fluoro-2-{[2-
(3-fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.046 M+H 471.1 pyridyl))carboxamide
N-[((2R)azetidin-2-yl)methyl](5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}-6-pyrazol-4-yl(3-
0.466 M+H 413.1 pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
0.019 M+H 456.1 fluorophenyl)ethyl]amino}-6-phenyl(3-pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(6-(2-cyanophenyl)-2-
0.009 M+H 481.1 {[2-(3-fluorophenyl)ethyl]amiπo}(3-pyridyl))carboxamide
N-(carbamoylmethyl)(6-(2-cyanophenyl)-2-{E2-(3-
0.104 M+H 418.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-(2-carbamoylethyl)(6-(2-cyanophenyl)-2-{[2-(3-
0.099 M+H 432.1 fluorophenyl)ethy]]amino}(3-pyridyl))carboxamide
0.102 M+H 432.1 2-[(6-(2-cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]-N-methylacetamide N-((3S)-2-oxo(3-piperidyl))(6-(2-cyanophenyl)-2-{[2-(3-
5.614 M+H 458.1 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
Example 14:
Figure imgf000307_0001
I
2-(3-fluorophenethylamino)-iV-(pyridin-3-ylmethyl)-6-(pyrrolidin-l-yl)nicotinamide
Figure imgf000307_0002
[0269] A mixture of 2,6-dichloronicotinic acid (19.2 g, 0.1 mol), N1N'- carbonyldiimidazole (CDI, 17.8 g, 0.11 mmol) and THF (1 L) was stirred at 6O0C for 30 min and cooled to room temperature. To the mixture was added 3-aminomethyl pyridine (10.2 ml_, 0.1 mol) and DIEA (21 ml_, ,0.12 mol). The reaction mixture was stirred at room temperature for 4 hrs, and diluted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4. Concentration of the organic solution gave 2,6-dichloro-N-(pyridin-3-ylmethyl)picotinamide (20.5 g, 73%). LRMS (M+H+) m/z 282.0; (M+2+H+) m/z 283.9.
Figure imgf000308_0001
[0270] A mixture of 2,6-dichloro-N-(pyridin-3-ylmethyl)nicotinamide (20.4 g, 72.3 mmol), 3-fluorophenethyl amine (11.1 g, 79.5 mmol), K2CO3 (20 g 145 mmol) and DMF (200 mL) was stirred at 1000C for 10 hours. The mixture was diluted with ethyl acetate (2 X 300 mL) and washed with saturated ammonium chloride, sodium bicarbonate and brine. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography to 6-chloro-2-(3- fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (12.6 g, 46%). LRMS (M+H+) m/z 385.1.
Figure imgf000308_0002
[0271] A mixture of 6-chloro-2-(3-fluorophenethylamino)-N-(pyridin-3- ylmethyl)nicotinamide (50 mg, 0.13 mmol) and pyrrolidine (94 mg, 1.3 mmol) in a sealed tube was heated to 150 0C for 10 min. LC/MS indicated the reaction was complete. The crude was diluted with MeOH1 filtered, and purified on RP-HPLC using a mixture of acetonitrile and H2O to a give 2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)-6-(pyrrolidiπ-1-yl)nicotinamide (20.2 mg, 37%). LRMS (M +H+) m/z 420.2.
Example 15:
Figure imgf000309_0001
2-(3-fluorophenethylamino)-6-(cyclopentene)-Λ/-(2-methylamino-3-ylmethyl)nicotinamide
Figure imgf000309_0002
[0272] A mixture of the acid 6-chloro-2-(3-fluorophenethylamino)nicotinic acid (1.2 g, 4.2 mmol), DIPEA (0.69 ml_, 4.2 mmol), HBTU (1.6 g, 4.2 mmol) and DMF (7 ml_) was stirred at room temperature. An amine tert-butyl (3-(aminomethyl)pyridin-2-yl)methylcarbamate (0.9 g, 3.8 mmol) dissolved in DMF (3.5 mL) was added to the reaction mixture and allowed to stir at room temperature until complete. The mixture was diluted with EtOAc and washed with H2O1 1 M NaOH, brine and dried (Na2SOi). The organics were concentrated and purified by a silica gel chromatography with a mixture of EtOAc and hexane to give tert-butyl (3-((6-chloro-2-(3- fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate (0.9 g, 46%). LC/MS (M+H+) m/z 514.1.
Figure imgf000309_0003
[0273] A mixture of (3-((6-chloro-2-(3- fluorophenethylamino)nicotinarnido)methyl)pyridin-2-yl)rnethylcarbamate (0.10 g, 0.19 mnnol), tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mmol), K2CO3 (0.081 g, 0.59 mmol), cyclopenten-1 -yl boronic acid (0.026 g, 0.23 mmol) and NMP (0.2 ml_) was sealed in a tube and microwaved at 1500C for 30 min. The reaction mixture was filtered through a silica plug with EtOAc1 washed with H2O, brine, dried (Na2SO4) and concentrated to give tert-butyl (3-((6- cyclopentenyl-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate. LC/MS (M+H+) m/z 546.2.
Figure imgf000310_0001
[0274] tert-butyl (3-((6-cyclopentenyl-2-(3- fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate was dissolved in MeOH (1 ml_) and allowed to stir at room temperature. HCI/dioxane (4M, 2 mL) was added dropwise and stirred until complete. The reaction mixture was concentrated, diluted with EtOAc, washed with saturated sodium bicarbonate, brine and dried (Na2SO4). The organics were concentrated and purified by RP-HPLC with a mixture of acetonitrile and H2O to give N-((2- (aminomethyl)pyridin-3-yl)methyl)-6-cyclopentenyl-2-(3-fluorophenethylamino)nicotinamide as a solid (0.026 g, 25%). LC/MS (M+H+) m/z 446.2.
Example 16:
Figure imgf000311_0001
methyl 4-(6-(3-fIuorophenethylamino)-5-(pyridin-3-ylmethylcarbamoyl)pyridin-2-yl)-5,6-dihydropyridine-1(2W)- carboxylate
Figure imgf000311_0002
[0275] A mixture of 2,6-dichloro-N-(pyridin-3-ylmethyl)nicotinamide (234 mg, 0.6 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)- carboxylate (234 mg, 0.75 mmol), Pd(PPh3)4 (69 mg. 0.06 mmol), K2CO3 (249 mg, 1.8 mmol) and DMF (6 mL) was stirred at 150 0C in microwave for 1 h, then concentrated to dryness. The residue was dissolved in EtOAc-MeOH (9:1 , 10 mL), filtered through a silica gel pak. Concentration of the mixture followed by the purification on RP-HPLC using a mixture of acetonitrile and H2O gave tert-butyl 4-(6-(3-fluorophenethylamino)-5-(pyridin-3- ylmethylcarbamoyl)pyridin-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate as a pale yellow solid (240 mg, 75%). LRMS (M+H+) m/z 532.2
Figure imgf000312_0001
[0276] To a solution of tert-butyl 4-(6-(3-fluorophenethylamino)-5-(pyridin-3- ylmethylcarbamoyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.377 mmol) in MeOH (8 ml_) at 0 0C was added HCI (2.0 rriL, 8 mmol, 4 M in dioxane) under nitrogen. The reaction mixture was warmed to room temperatures stirred at r.t. for 4 h. LC/MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)-6-(1 ,2,3,6-tetrahydropyridin-4- yl)nicotinamide which was used for next step without further purification. LRMS (M +H+) m/z 444.2.
Figure imgf000312_0002
[0277] To a mixture of 4 (69 mg, 0.128 mmol), DIEA (111 μL, 0.640 mmol) and DCM (2 ml_) at 0 0C was added methyl chloroformate (12 μL, 0.154 mmol) dropwise. The mixture was stirred at r.t. for 0.5h. Concentration of the mixture followed by the purification on RP-HPLC using a mixture of acetonitrile and H2O gave methyl 4-(6-(3-fluorophenethylamino)-5-(pyridin-3- ylmethylcarbamoyl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (33 mg, 53%). LRMS (M+H+) m/z 490.2.
Example 17 [0278] Using procedures similar to those described herein, the compounds in the following table were synthesized and tested.
IC50
Arithmetic
Mean ion m/z ChemicalName
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-piperidyl(3-pyridyl))-N-(3-
0.3713 M+H 434.2 pyridylmethyl)carboxamide
N-{[(3S)-1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidiπ-3-
3.7733 M+H 491.2 yl]methyl}acetamide
(6-((3R)-3-hydroxypyrrolidiny!)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-
11.4467 M+H 402.2 (carbamoylmethyl)carboxamide
2-[(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carboπylamino]-N-
3.4375 M+H 416.2 methylacetamide
(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3-
71.3315 M+H 373.2 fluorophenyl)ethyl]amiπo}(3-pyridyl))-N,N-dimethylcarboxamide
N-(carbamoylmethyl)(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
1.4612 M+H 386.2 pyrrolidinyl(3-pyridyl))carboxamide
(6-[{3R)-3-(hydroxymethyl)pyrrolidinyl]-2-{[2-(3- fiuorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.3107 M+H 450.2 pyridy!methyl)carboxamide
(6-{(3S)-3-[(methylamino)methyl]pyrrolidinyl}-2-{[2-(3- fluorophenyl)ethylJamino}(3-pyridyl))-N-{3-
64.7725 M+H 463.2 pyridylmethyl)carboxamide
N-{t(3R)-1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-yl]methyl}-N-
47.5598 M+H 505.2 methylacetamide
(6~{(3S)-3-[(dimethylamino)methyl]pyrrolidinyl}-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
75.0803 M+H 477.3 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2-oxopiperidyl)(3-pyridyl))-
5.4042 M+H 448.1 N-(3-pyridylmethyl)carboxamide
(6-[(3S)-3-(aminomethyl)pyrrolidinyl]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
16.8833 M+H 449.2 pyridylmethyl)carboxamide
N-[(6-amino(3-pyridyl))methyl](2-{[2-(3-
0.243 M+H 435.2 fluorophenyl)ethyl]amiπo}-6-pyrrolidinyl(3-pyridyl))carboxamide
N-(2-carbamoylethyl)(2-{[2-(3-fluorophenyl)ethyl]amino}-6-
1.5893 M+H 400.2 pyrrolidinyl(3-pyridyl))carboxamide
(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.5329 M+H 436.2 pyridylmethyl)carboxamide b-KP-CS-fluoropheπyOethylJamino^θ^-oxopyrrolidinyOCS-
4.5555 M+H 434.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyf)ethyl]amino}-6-pyrrolidinyl(3-pyridyl))-N-
0.1306 M+H 420.2 (3-pyridylmethyl)carboxamide
(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3-
15.9209 M+H 416.2 fIuorophenyl)ethyl]amino}(3-pyridyl))-N-(2- IC50
Arithmetic
Mean Ion m/z ChemicalName carbamoylethyl)carboxamide
(6-((3S)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluoropheπyl)ethyl]amino}(3-pyridyl))-N-(3-
1.0159 M+H 436.2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[4-
(hydroxymethyl)piperidyl](3-pyridyl))-N-(3-
0.3825 M+H 464.2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(5-hydroxy-2-
29.6559 M+H 464.2 oxopiperidyl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-oxopiperazinyl)(3-
6.9699 M+H 449.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-methylpiperazinyl)(3-
59.8594 M+H 449.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluoropheπyl)ethyl]amino}-6-[4-(2- hydroxyethyl)piperidyl](3-pyridyl))-N-(3-
0.4705 M+H 478.2 pyridylmethyljcarboxamide tert-butyl 4-(6-{[2-{3-fluorophenyl)ethyl]amino}-5-[N-(3-
59.7576 M+H 549.2 pyridylmethyl)carbamoyl](2-pyridyl))-3-oxopiperazinecarboxylate
(2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(2-oxopiperazinyl)(3-
70.7815 M+H 449.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2oxopiperidyl)(3-pyridyl))-
53.3561 M+H 385.1 N , N-dimethylcarboxamide
(6-[(3S)-3-(hydroxymethyl)pyrrolidinyl]-2-{[2-(3- fluoropheπyl)ethyl]amiπo}(3-pyridyl))-N-(3-
0.4654 M+H 450.2 pyridylmethyl)carboxamide
2-[(2-{[2-(3-fluorophenyl)ethyl]annino}-6-pyrrolidinyl(3-
0.3292 M+H 400.2 pyridyl))carboπylamiπo]-N-methylacetamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-pyrrolinyl)(3-pyridyl))-N-
0.1539 M+H 418.1 (3-pyridylmethyl)carboxam ide
(6-((3S)-3-aminopyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
28.4133 M+H 435.2 pyridylmethyl)carboxamide
N-[(3R)-1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-
67.7779 M+H 506.2 yl](dimethylamino)carboxamide
(6-azetidinyl-2-{[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
1.1721 M+H 406.2 pyridylmethyl)carboxamide
{2-[(2-(2-pyridyl)ethyl)amino]-6-pyrrolidinyl(3-pyridyl)}-N-(3-
32.8026 M+H 403.2 pyridylmethyl)carboxamide
{6-(4-methylpiperidyl)-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-
14.3105 M+H 431.2 (3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1,3-oxazolin-2-yl)(3-
1.5042 M+H 420.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[2-(aminomethyl)(3-
0.3268 M+H 465.2 pyridyl)]methyl}carboxamide
N-{[2-(amiπomethyl)(3-pyridyl)]methyl}(6-cyclopent-1-enyl-2-{[2-
0.0146 M+H 446.2 (3-fiuorophenyl)ethyl]amino}(3-pyridyf))carboxamide
(6-((3S)-3-fIuoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[2-(aminomethyl)(3-
0.0882 M+H 467.1 pyridyl)]methyl}carboxamide IC50
Arithmetic Mean Ion m/z ChemicalName
(6-<(3R)-3-fluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[2-(aminomethyl)(3-
0.0313 M+H 467.1 pyridyl)]methyl}carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- 0.0656 M+H 463.2 fluorophenyl)ethyl]amino}-6-piperidyl(3-pyridyl))carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(2-{[2-(3- 0.0297 M+H 449.1 fIuorophenyl)ethyl]amino}-6-pyrrolidinyl(3-pyridyl))carboxamide
N-[(3S)-1-(6-{[2-(3-fIuorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-
12.277 M+H 493.2 yl]methoxycarboxamide methyl 4-(6-{[2-(3-f luorophenyl)ethyl]amino}-5-{N-[( N- methylcarbamoyl)methyl]carbamoyl}-2-pyridyl)-1 ,2,5,6- 0.6271 M+H 470.2 tetrahydropyridinecarboxylate
N-[(3R)-1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-
4.5022 M+H 493.2 yljmethoxycarboxamide
{6-piperidyl-2-[(2-(2-pyridyl)ethyl)amino](3-pyridyl)}-N-(3- 13.1958 M+H 417.1 pyridylmethyl)carboxamide
(6-((3R)-3-aminopyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
35.5447 M+H 435.2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(1,2,5,6- 0.6872 M+H 432.2 tetrahydropyridyl)(3-pyridyI))-N-(3-pyridylmethyl)carboxamide
(5-chloro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3- 0.2341 454.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(έ-cyano^-CP-CS-fluorophenyOethyllaminoJ-β-pyrrolidinyKS- 0.1649 445.1 pyridyl))-N-(3-pyridylmethyl)carboxamide methyl 2-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
21.1565 477.1 pyridylmethyl)carbamoyl]-2-pyridyl)-2-imidazolinecarboxylate
(6-(1-cyano(2-imidazolin-2-yl))-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.4347 444.1 pyridylmethyl)carboxamide
N-{[(2R)-1-(3-aminopropyl)-5-oxopyrrolidin-2-yl]methyl}(5-fliJoro-
2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3- 0.1186 501.2 pyιϊdyl))carboxamide
(6-((3R)-3-fluoropyrrolidinyl)-5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{i2-(aminomethyl)(3-
0.023 485.1 pyridyl)]methyl}carboxamide
^-((SRJ-S-hydroxypyrrolidinyO-S-fluoro^-fP-CS- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(2-{[(tert-
6.7754 M+H 583.1 butoxy)carbonylamino]methyl}(3-pyridyl))methyl]carboxamide
(6-((3R)-3-hydroxypyrrolidinyl)-5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{f2-(aminomethyl)(3-
0.1249 M+H 483.1 pyridyl)]methyl}carboxamide
(6-(1-acetyl(4-1 ,2,5,6-tetrahydropyridyl))-2-{[2-(3- fluorophenyl)ethyl]amiπo}(3-pyridyl))-N-(3-
0.4299 M+H 474.2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-1,2,5,6-
10.5122 M+H 432.2 tetrahydropyridyl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide tert-butyl 4-(6-{{2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
2.148 M+H 532.2 pyridylmethyl)carbamoyl]-2-pyridyl)-1 , 2,5,6- IC50
Arithmetic
Mean Ion m/z ChemicalName tetrahydrαpyridinecarboxylate
(e-cyclopentyl^-^-β-fluorophenyOethyllaminoKS-pyridyOJ-N-
4.4109 M+H 419.2 (3-pyridylmethyl)carboxamide
(6-(1 ,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
1.8243 M+H 489.2 pyιϊdylmethyl)carboxamide methyl 4-(6-{[2-(3-fluorophenyI)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl]-2-pyridyl)-1 , 2,5,6-
0.1001 M+H 490.2 tetrahydropyridinecarboxylate
(δ-cyclopent-i-enyl^^-fS-fluorophenylJethyπaminoXS-
0.637 M+H 417.2 pyridyl))-N-(3-pyιϊdylmethyl)carboxamide
N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrrolidinyl(3-pyridyl))carbonylamino]-isopropyl}-2-[(tert-
15.099 M+H 561.2 butoxy)carbonylamino]acetamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-oxocyclohex-1-enyl)(3-
0.6709 M+H 445.1 pyιϊdyl))-N-(3-pyridylmethyl)carboxamide
(6-((3R)-3-fluoropyrrolidinyl)-5-fluoro"-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(2-{[(tert-
8.243 M+H 585.2 butoxy)carbonylamino]methyl}(3-pyridyl))methyl]carboxamide
(e-cyclohexyl^p-tS-fluorophenylJethylJaminoKS-pyridylJJ-N^S-
4.1699 M+H 433.2 pyridylmethyl)carboxamide
(6-cyclohex-1-enyl-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.1169 M+H 431.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
N-[((2R)-1-{3-i(tert-butoxy)carbonylamino]propyl}-5- oxopyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3-
3.3223 M+H 601.2 fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-pyridyl))carboxamide
{6-[1-(N,N-dimethylcarbamoyl)(4-1,2,5,6-tetrahydropyridyl)]-2-
{[2-(3-fluorophenyl)ethyl]amiπo}(3-pyridyl))-N-(3-
0.4518 M+H 503.2 pyridylmethyl)carboxamide
(5-bromo-2-{[2-(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
0.2947 M+H 498.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl)amino}-6-(1-methyl(4-1,2,5,6-
4.3572 M+H 446.2 tetrahydropyridyl))(3-pyridyl))-N-(3-pyridylmethyl)carboxamide methyl 4-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl]-2-pyridyl)-1 , 4,5,6-
5.7696 M+H 490.2 tetrahyd ropyridiπ eca rboxylate
(2-{[2-(3-fluorophenyl)ethyI]amino}-6-(2-imidazoliπ-2-yl)(3-
56.4278 M+H 419.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
N-{[(2R)-1-(4-aminobutanoyl)pyrrolidin-2-yl]methyl}(5-fluoro-2-
{[2-(3-fluorophenyl)ethyl]amino}-6-ρyrrolidinyl(3-
0.3084 M+H 515.2 pyridyl))carboxamide
N-[((2R)-1-{4-[{tert-butoxy)carbonylamino]butanoyl}pyrrolidin-2- yl)methyl](5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6-
8.5545 M+H 615.3 pyrrolidinyl(3-pyridyl))carboxamide
N-{[(2R)-1-(2-aminoacetyl)pyrrolidin-2-yl]methyl}(5-fluoro-2-{[2-
(3-fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-
0.212 M+H 487.2 pyridyl))carboxamide
N-[((2R)-1-{2-[(tert-butoxy)carbonylamino]acetyl}pyrrolidin-2- yl)methyl](5-fluoro-2-{[2-(3-fIuorophenyl)ethyl]amino}-6-
13.6492 M+H 587.3 pyrrolidinyl(3-pyridyl))carboxamide 0.0259 M+H 467.1 N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2-{[2-(3- IC50 Arithmetic Mean Ion m/z ChemicalName fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-pyridyl))carboxamide
N-[((2R)pyrrolidin-2-yl)methyl](5-fluoro-2-{[2-(3-
1.7993 M+H 430 fluorophenyl)ethyl]amiπo}-6-pyrrolidiπyl(3-pyridyl))carboxamide tert-butyl (2R)-2-[[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrrolidinyl(3-
6.8551 M+H 530.2 pyridyl))carbonylamino]methyl}pyrrolidinecarboxylate
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(6-cyclopropyl-5-fluoro-2-
1.3219 M+H 438.1 {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide
N-{(1R)-2-[(5-fluoro-2-{[2-(3-fluorophenyl)ethyl]amino}-6- pyrrolidinyl(3-pyridyl))carbonylamino]-isopropyl}-2-
0.1973 M+H 461.2 amiπoacetamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[1-(methylsulfonyl)(4-
1,2,5,6-tetrahydropyridyl)](3-pyridyl))-N-(3-
6.3961 M+H 510.2 pyridylmethyl)carboxamide
[4-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))piperazinyl]-N,N-
48.4841 M+H 506.2 dimethylcarboxamide methyl 4-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
1.5317 M+H 493.2 pyridylmethyl)carbamoyl]-2-pyridyl)piperazinecarboxylate
(6-{3-aminopyrrolidinyl)-2-{[2-(3-fiuorophenyl)ethyl]amino}(3-
23.1246 M+H 435.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-morpholiπ-4-yl(3-pyridyl))-
2.6652 M+H 436.2 N-(3-pyridylmethyl)carboxamide
(6-[(2R)-2-(hydroxymethyl)pyrrolidinyl]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
10.5355 M+H 450.2 pyridylmethyl)carboxamide
2-[(6-((3S)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
8.2504 M+H 416.1 methylacetamide
2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-hydroxypiperidyl)(3-
9.4962 M+H 430.1 ρyridyl))carbonylamino]-N-methylacetamide
(tert-butoxy)-N-[1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
18.4756 M+H 535.2 pyridylmethyl)carbamoyl](2-pyridyl))pyrrolidin-3-yl]carboxamide
(6-[(3R)-3-(dimethylamino)pyrrolidinyl]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
75.9885 M+H 463.2 pyridylmethyl)carboxamide
2-[(6-((3S)-3-fluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
1.062 M+H 418.1 methylacetamide
2-[(6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
3.6861 M+H 416.1 methylacetamide
2-t1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
5.6018 M+H 478.2 pyridylmethyl)carbamoyl]-2-pyridyl)pyrrolidin-3-yl]acetic acid
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-(4-pyridyl)pyrrolidinyl)(3-
2.968 M+H 497.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
2-[(6-(3,3-difluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))carbonylamino]-N-
0.9312 M+H 436.1 methylacetamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
0.2133 M+H 449.2 fluorophenyl)ethyl]amino}-6-pyrrolidinyl(3-pyridyl))carboxamide IC50
Arithmetic Mean Ion m/z ChemicalName
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[3- (trifluoromethyl)pyrrolidinyl](3-pyridyl))-N-(3-
2.4916 M+H 488.2 pyridylmethyl)carboxamide
(6-(3,3-difluoropyrrolidinyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
0.274 456.1 pyridyl))-N-(3-pyridylmethyl)carboxamide N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
0.3336 M+H 463.2 fluoropheπyl)ethyl]amiπo}-6-piperidyl(3-pyridyl))carboxamide (6-((3S)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[6-(aminomethyl)(2-
3.0712 M+H 465.1 pyridyl)]methyl}carboxamide (6-((3R)-3-hydroxypyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyljamino}(3-pyridyl))-N-{[6-(aminomethyl)(2-
2.2162 M+H 465.2 pyridyl)]methyl}carboxamide (6-((3R)-3-fluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]arnino}(3-pyridyl))-N-(3-
0.1066 M+H 438.2 pyridylmethyl)carboxamide
(6-[4-(aminomethyl)piperidyl]-2-{[2-(3- fluoropheπyl)ethyl]amino}(3-pyridyl))-N-(3-
39.1112 M+H 463.2 pyridylmethyl)carboxamide
2-[(2-{[2-(3-fIuorophenyOethyl]amino}-6-piperidyl(3-
1.1175 M+H 414.2 pyridyl))carbonylamino]-N-methylacetamide
(2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-[3-
(methylsulfonyl)pyrrolidinyl](3-pyridyl))-N-(3-
11.54 M+H 498.2 pyridylmethyl)carboxamide
(6-[(2S)-2-(methoxymethyl)pyrrolidinyl]-2-{[2-(3- fluoropheπyl)ethyl]amino}(3-pyridyl))-N-(3-
67.3028 M+H 464.2 pyridylmethyl)carboxamide
(tert-butoxy)-N-{[1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- pyridylmethyl)carbamoyl](2-pyridyl))(4-
4.5603 M+H 563.3 piperidyl)]methyl}carboxamide (tert-butoxy)-N-[1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
16.3821 M+H 549.2 pyridylmetnyl)carbamoyl](2-pyridyl))(4-piperidyl)]carboxamide
(2-{[2-(3-fliJorophenyl)ethyl]amiπo}-6-(4-hydroxy-4-
16.6585 M+H 526.2 pheny]piperidyl)(3-pyridyl))-N-(3-pyridylmethyl)carboxamide ethyl 1 -(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
1.5586 M+H 506.2 pyridylmethyl)carbamoyl]-2-pyridyl)piperidine-4-carboxylate
(6-((3S)-3-fluoropyrrolidinyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.4307 M+H 438.2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[4-(N- methylcarbamoyl)piperidyl](3-pyridyl))-N-(3-
11.0012 M+H 491.2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(4-hydroxypiperidyl)(3-
0.7562 M+H 450.2 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-piperazinyl(3-pyridyl))-N-
31.7978 M+H 435.2 (3-pyridylmethyl)carboxamide
(6-((3S)-3-hydroxypiperidyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.5153 M+H 450.2 pyridylmethyl)carboxamide
N-[1-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
20.7136 M+H 477.2 pyridylmethyl)carbamoyl]-2-pyridyl)pyrrolidiπ-3-yl]acetamide IC50
Arithmetic
Mean Ion m/z ChemicalName
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[2-
(hydroxymethyl)morpholin-4-yl](3-pyridyl))-N-(3-
7.2059 M+H 466.2 pyridylmethyl)carboxamide
(6-[(3S)-3-(methylamino)pyrrolidinyl]-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
59.5321 M+H 449.2 pyridylmethyl)carboxamide
(2-{[2-(3-fIuorophenyl)ethyl]amino}-6-(1 ,4-thiazaperhydroin-4-
1.5743 M+H 452.1 yl)(3-pyridy!))-N-(3-pyridylmethyl)carboxamide (6-(1 , 1 -dioxo(1 ,4-thiazaperhydroin-4-yl))-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
29.8736 M+H 484.2 pyridylmethyl)carboxamide (β^-acetylpiperazinylJ^-d∑-CS-fluorophenyOethyllaminoKS-
8.5678 M+H 477.2 pyridyl))-N-(3-pyridylmethyl)carboxamide (2-{[2-(3-fluorophenyl)ethyl]amiπo}-6-(4-piperidylpiperidyl)(3-
29.7341 M+H 517.3 pyridyl))-N-(3-pyridylmethyl)carboxamide ethyl 4-(6-{[2-(3-fluorophenyl)ethyl]annino}-5-[N-(3-
3.1634 M+H 507.2 pyridylmethyl)carbamoylJ-2-pyridyl)piperazinecarboxylate
Example 18:
Figure imgf000319_0001
(£)-2-(3-fluorophenethylamino)-6-(prop-l-enyl)-Λ^-(pyridin-3-ylmethyl)nicotinamide
Figure imgf000319_0002
[0279] A mixture of acid 2,6-dichloronicotinic acid (19.2 g, 0.1 mol), N1N'- carbonyldiimidazole (CDI, 17.8 g, 0.11 mmol) and THF (1 L) was stirred at 60°C for 30 min and cooled to room temperature. To the mixture was added 3-aminomethyl pyridine (10.2 mL, 0.1 mol) and DIEA (21 mL, 0.12 mol). The reaction mixture was stirred at room temperature for 4 hrs, and diluted with EtOAc. The organic layer was washed with H2θ, brine, dried over Na2SO4. Concentration of the organic solution gave the 2,6- dichloro-N-(pyridin-3-ylmethyl)nicotinamide (20.5 g, 73%). LRMS (M+H+) m/z 282.0; (M+2+H+) m/z 283.9.
Figure imgf000320_0001
[0280] A mixture of chloride 2,6-dichloro-N-(pyridin-3-ylmethyl)nicotinamide (20.4 g, 72.3 mmol), 3-fluorophenethyl amine (11.1 g, 79.5 mmol), K2CO3 (20 g 145 mmol) and DMF (200 mL) was stirred at 1000C for 10 hours. The mixture was diluted with ethyl acetate (2 X 300 mL) and washed with saturated ammonium chloride, sodium bicarbonate and brine. The organic layers were combined, dried (MgSO4) and ∞110611^1^. The residue was purified by silica gel chromatography to give the desired product 6- chloro-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (12.6 g, 46%). LRMS (M+H+) m/z 385.1.
Figure imgf000321_0001
[0281] A mixture of chloride 6-chloro-2-(3-fluorophenethylamino)-N-(pyridin-3- ylmethyl)nicotinamide (100 mg, 0.260 mmol), trans-1-propen-1-yl boronic acid (27 mg, 0.312 mmol), PdCI2(dppf)2 (14 mg, 0.026 mmol), 2N K2CO3 (0.39 mL, 0.78 mmol) and THF (1.5 mL) was stirred at 1250C for 30 min. The mixture was filtered through the silica gel pad and washed with EtOAc. The filtrate was concentrated to dryness and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (E)-2-(3- fluorophenethylamiπo)-6-(prop-1-enyl)-N-(pyridin-3-ylmethyl)nicotinamide as a pale yellow solid (59 mg, 86%). LRMS (M+H+) m/z 391.2.
Example 19:
Figure imgf000321_0002
2-(3-fluorophenethylamino)-6-(cyanoimidamide)-Λ/-(pyridine-3-ylmethyl)nicotinamide
Figure imgf000322_0001
[0282] A mixture of 6-chloro-2-(3-fluorophenethylamino)-N-(pyridin-3- ylmethy])nicotinamide (1.3 g, 3.3 mmol), NiBr2 (1.1 g, 4.9 mmol), NaCN (0.48 g, 9.8 mmol) and NMP (6 mL) was stirred at 2200C for 1 hour. The reaction mixture was filtered through Celite with EtOAc. The organics were washed with water, brine, dried (Na2SO4) and concentrated to give the nitrile 6-cyano-2-(3-fluorophenethylamino)-N- (pyridin-3-ylmethyl)nicotinamide (0.85 g, 69%). LC/MS (M+H+) m/z 376.1.
Figure imgf000322_0002
[0283] A three neck round bottom flask fixed with a dry ice acetone condenser was charged with the nitrile nitrile 6-cyano-2-(3-fluorophenethylamino)-N-(pyridin-3- ylmethyl)nicotinamide (0.10 g, 0.27 mmol), EtOH (2 mL) and stirred with HCICg)for 20 minutes. The reaction mixture was then concentrated to dryness to give the ethyl 6-(3- fluorophenethylamino)-5-(pyridin-3-ylmethylcarbamoyl)picolinimidate. LC/MS (M+H+) m/z 422.1.
Figure imgf000323_0001
[0284] A mixture of the ethyl 6-(3-fluorophenethylamino)-5-(pyridin-3- ylmethylcarbamoyl)picolinimidate and NH3ZMeOH (7N1 0.76 mL) was stirred at 500C for 1 hour. The reaction mixture was concentrated to dryness to give 6-carbamirnidoyl-2-(3- fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide. LC/MS (M+H+) m/z 394.1.
Figure imgf000323_0002
II
[0285] A mixture of 6-carbamimidoyl-2-(3-fluorophenethylamino)-N-(pyridin-3- ylmethyl)nicotinamide (0.013 g, 0.034 mmol), CNBr (3N, 0.017 mL, 0.051 mmol), DIPEA (0.0085 mL, 0.051 mmol), in DCM (0.10 mL) was stirred at room temperature until the reaction was complete. The reaction mixture was concentrated to dryness and purified by RP-HPLC using a mixture of acetonitrile and H2O to give 6-(N- cyanocarbamimidoyl)-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide as a solid (0.0058 g, 41%). LC/MS (M+H+) m/z 418.1.
Example 20
[0286] Using procedures similar to those described herein, the compounds in the following table were synthesized and tested.
IC50 Ion m/z CHEMICAL NAME Arithmetic
Mean
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
457. fluorophenyl)ethyl]amino}-5-(3-pyridyl)(3-
7.3929 M+H 1 pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
457. fluorophenyl)ethyl]amino}-5-(4-pyridyl)(3-
9.8364 M+H 1 pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3-
460. fluorophenyl)ethyl]amino}-5-(1-methylpyrazol-4-
17.7374 M+H 1 yl)(3-pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(5-(2-
481. cyanophenyl)-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
6.0282 M+H 1 pyridyl))carboxamide
376. (5-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
12.683 M+H 1 pyridyl))-N-(2-pyridylrnethyl)carboxamide
(5-bromo-2-{[2-(3-fluorophenyl)ethyl]amiπo}(3- pyridyl))-N-[(6-methyI(2-
17.7243 M+H 445 pyridyl))methyl]carboxamide
(5-bromo-6-chloro-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(2-
17.258 M+H 446655 pyridylmethyl)carboxamide 5-bromo-2-{[2-(3-
11.19 M+H 341 fluorophenyl)ethyl]amino}pyridine-3-carboxylic acid
300. methyl 5-cyaπo-2-{[2-(3-
14.887 M+H 1 fluorophenyl)ethyl]amino}pyridiπe-3-carboxylate N-({6-[(1,3-dioxobenzo[c]azolin-2-yl)methyl](2- pyridyl)}methyl)(5-bromo-2-{[2-(3- /
9.7159 M+H 559900 fluorophenyl)ethyl]amino}(3-pyridyl))carboxamide (5-bromo-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
11.8154 M+H 431 pyridyl))-N-(2-pyridylmethyl)carboxamide N-{[6-(aminomethyl)(2-pyridyl)]methyl}(5-bromo-2-
{[2-(3-flυorophenyl)ethyl]amino}(3-
15.0424 M+H 460 pyridyl))carboxamide
N-{[6-(aminomethyl)(2-pyridyl)]methyl}(2-{[2-(3- 457. fluorophenyl)ethyl]amino}-5-(2-pyridyl)(3-
16.0219 M+H 1 pyridyl))carboxamide
389. methyl 6-[(4-carbamoylbutyl)amino]-2-{[2-(3-
44.3072 M+H 2 fluorophenyl)ethyl]amino}pyridine-3-carboxylate 5-[(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
493. pyridylmethyl)carbamoyl](2-pyridyl))amino]-N,N-
55.0688 M+H 2 dimethylpentanamide
5-[(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- 479. pyridylmethyl)carbamoyl](2-pyridyl))amino]-N-
38.046 M+H 2 methylpentanamide
(6-[(4-carbamoylbutyl)amino]-2-{[2-(3- 465. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
6.7378 M+H 2 pyridylmethyl)carboxamide
4-[(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3- 479. pyridylmethyl)carbamoyl](2-pyridyl))amino]-N,N-
70.3134 M+H 2 dimethylbutanamide
(6-[(3-carbamoylpropyl)amino]-2-{[2-(3- 451. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
42.7772 M+H 2 pyridylmethyl)carboxamide (6-(dimethylamino)-2-{[2-(3- 394. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
4.919 M+H 1 pyridylmethyl)carboxamide 5-[(6-{[2-(3-fluorophenyl)ethyl]amino>-5-[N-(3-
556. pyridylmethyl)carbamoyl](2-pyridyl))amino]-N-(3-
49.2162 M+H 2 pyridylmethyl)pentanamide
380. (2-{[2-(3-fluorophenyl)ethyl]amino}-6-
10.883 M+H 2 (methylamino)(3-pyridyl))-N-(3- pyridylmethyl)carboxamide
N-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
422. pyridylmethyl)carbamoylJ(2-pyridyl))-N-
33.5035 M+H 2 methylacetamide
N-(6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
452. pyridylmethyl)carbamoyl](2-pyridyl))-N-(2-
53.412 M+H 2 hydroxyethyl)acetamide
394. 6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
13.9674 M+H 1 pyridylmethyl)carbamoyl]pyridine-2-carboxamide
376. (6-cyano-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
65.8061 M+H 1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(3-
457. pyridylmethyl)amino]{3-pyridyl))-N-(3-
5.6092 M+H 1 pyridylmethyl)carboxamide
(6-[(cyanoamino)iminomethyl]-2-{[2-(3-
418. fluorophenyl)ethyl3amino}(3-pyridyl))-N-(3-
0.2309 M+H 1 pyridylmethyl)carboxamide
(6-((1 Z)- 1 -methylprop-1 -enyl)-2-{[2-(3-
405. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
10.5082 M+H 1 py ridy lmethyl)carboxa m ide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(N-
408. methylcarbamoyl)(3-pyridyl))-N-(3-
44.1181 M+H 1 pyridylmethyl)carboxamide
409. methyl 6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
4.3507 M+H 1 pyridylmethyl)carbamoyl]pyridine-2-carboxylate
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2-
457. pyridylmethyl)amino](3-pyridyl))-N-(3-
10.7731 M+H 2 pyridylmethyl)carboxamide
(6-((1 E)prop-1 -enyl)-5-bromo-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.7796 M+H 469 pyridylmethyl)carboxamide methyl (2E)-3-(6-{[2-(3-fIuorophenyl)ethyl]amino}-
449. 5-[N-(3-pyridylmethyl)carbamoyl](2-pyridyl))but-2-
3.4457 M+H 1 enoate
(2-{[2-(3-fluoropheny!)ethyl]amino}-6-[(4-
457. pyridylmethyl)amino](3-pyridyl))-N-(3-
33.9795 M+H 1 pyridylmethyl)carboxamide
423. ethyl 6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
2.6522 M+H 1 pyridylmethyl)carbamoyl]pyridine-2-carboxylate (6-((1 E)prop-1-enyl)-2-{[2-(3-
391. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.3021 M+H 2 pyridylmethyl)carboxamide (6-((1 E)prop-1-enyl)-5-cyano-2-{[2-(3-
416. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.3608 M+H 1 pyridylmethyl)carboxamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-(2-
405. methylprop-1-enyl)(3-pyridyl))-N-(3-
0.3473 M+H 2 pyridylmethyl)carboxamide (6-[(dimethylamino)iminomethyl]-2-{[2-(3-
421. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
17.2629 M+H 2 pyridylmethyl)carboxamide
(6-[(1 E)-1 -(dimethylamino)-2-cyano-2-azavinyl]-2-
446. {[2-(3-fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
5.1875 M+H 1 pyridylmethyl)carboxamide
339933.. 6-{[2-(3-fluorophenyl)ethyl]amino}-5-[N-(3-
6.619 M+H 1 pyridylrnethyl)carbamoyl]pyridine-2-carboxamidine
407. 2-[(2-{[2-(3-fluorophenyl)ethyl]amino}-5-phenyl(3-
14.9996 M+H 1 pyridyl))carbonylamino]-N-methylaceta'mide
(6-((1 E)prop-1-enyl)-2-{[2-(3-
420. fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[2-
0.038 M+H 1 (aminomethyl)(3-pyridyl)]methyl}carboxamide
17.9719 M+H 432. 2-[(5-(2-cyanophenyl)-2-{[2-(3- fluorophenyl)ethyl]amino}(3- pyridyl))carbonylamino]-N-methylacetamide
(6-((1 E)-3-methoxyprop-1 -enyl)-2-{[2-(3-
421. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.9273 M+H 2 pyridylmethyl)carboxamide
(6-(ethoxyethyl)-2-{[2-(3-
423. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
73.03 M+H 2 pyridylmethyl)carboxamide
393. (6-acetyl-2-{[2-(3-fluorophenyl)ethyl]amino}(3-
24.7905 M+H 1 pyridyl))-N-(3-pyridylmethyl)carboxamide
(6-((1 E)prop-1-enyl)-5-fluoro-2-{[2-(3-
438. fluorophenyl)ethyl]amino}(3-pyridyl))-N-{[2-
0.0805 M+H 1 (aminomethyl)(3-pyridyl)]methyl}carboxamide
(6-((1 E)prop-1 -enyl)-5-fluoro-2-{[2-(3- fluorophenyl)ethyl]amino}(3-pyridyl))-N-[(2-{[(tert-
538. butoxy)carbonylamino]methyl}(3-
11.7073 M+H 2 pyridyl))methyl]carboxamide
N-{[2-(aminomethyl)(3-pyridyl)]methyl}(5-fluoro-2-
{[2-(3-fluorophenyl)ethyl]amino}(3-
2.6897 M+H 398 pyridyl))carboxamide
351. (2-{[2-(3-fluorophenyl)ethyl]amiπo}(3-pyridyl))-N-(3-
26.8336 M+H 1 pyridylmethyl)carboxamide
(6-(1 ,2-dimethylprop-1-enyl)-2-{[2-(3-
419. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
2.7696 M+H 2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-(3-
423. methoxypropyl)(3-pyridyl))-N-(3-
8.1803 M+H 1 pyridylmethyl)carboxamide
(6-(1 -ethoxyvinyl)-2-{[2-(3-
421. fluorophenyl)ethyl]amino}(3-pyridyl))-N-(3-
0.7025 M+H 2 pyridylmethyl)carboxamide (2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2-
410. hydroxyethyl)amino](3-pyridyl))-N-(3-
13.0601 M+H 2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2-
424. hydroxyethyl)methylamino](3-pyridyl))-N-(3-
45.4109 M+H 2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2-
424. methoxyethyl)amino](3-pyridyl))-N-(3-
7.6223 M+H 2 pyridy!methyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(2-
438. hydroxypropyl)methylamino](3-pyridyl))-N-(3-
10.4821 M+H 2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(3-
438. methoxypropyl)amino](3-pyridyl))-N-(3-
11.0022 M+H 2 pyridylmethyl)carboxamide
(2-{[2-(3-fluorophenyl)ethyl]amino}-6-[(3-
424. hydroxypropyl)amino](3-pyridyl))-N-(3-
8.4659 M+H 2 pyridylmethyl)carboxamide
EXAMPLE 21 : Synthesis of 6-(2-cyanophenyl)-4-(3- fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide
Figure imgf000330_0001
I
6-(2-cyanophenyl)-4-(3-fluorophenethylamino)-Λ/-(pyridin-3-ylmethyl)nicotinamide
Figure imgf000330_0002
[0287] To a solution of ethyl 4,6-dichloronicotinate (2.2 g, 10.0 mmol) and 3- fluoro-phenylethylamine(1.5g, 11.Ommol) in DMF (20 ml_) was added K2CO3 (4.1g, 30 mmol) at r.t.. The reaction mixture was stirred at r.t. overnight. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O tcgive ethyl 6-chloro-4-(3- fluorophenethylamino)nicotinate (1.1 mg, 34%). LRMS (M+H+) m/z 323.0.
Figure imgf000330_0003
[0288] To a mixture of ethyl 6-chloro-4-(3-fluorophenethylamino)nicotinate (1.2 g, 3.7 mmol), 2-cyano-phenylboronic acid (1.1 g, 7.4mmol) and K2CO3 (1.5 g, 11.1 mmol) in DMF (25 ml.) was added PdCtø dppf (0.2 g, 0.37 mmol). The reaction mixture was stirred at 100 0C for 4 h. LC/MS indicated the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give ethyl 6-(2-cyanophenyl)-4- (3-fluorophenethylamino)nicotinate (500 mg, 34%). LRMS (M+H+) m/z 389.0.
Figure imgf000331_0001
[0289] To a solution of ethyl 6-(2-cyanophenyl)-4-(3- fluorophenethylamino)nicotinate (100 mg, 0.26 mmol) and 3-aminomethylpyridine (39 mg, 0.36mmol) in toluene (1 mL) was added AIMe3 (0.2 mL, 2M in toluene, 0.39 mmol) at r.t.. The reaction mixture was stirred at 70 0C overnight. The reaction was cooled, quenched with sat. 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 6-(2-cyanophenyl)-4-(3~ fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (10 mg, 8.6%). LRMS (M+H+) m/z 452.0.
Example 22
[0290] Using procedures similar to those described herein, the compounds in the following table were synthesized and tested. IC50
Arithmetic
Mean Ion m/z Object_CH EMICALNAM E
(6-(2-cyanophenyl)-4-{[2-(3-fluorophenyl)ethyl]amino}(3- 2.02 M+H 452.1 pyridyl))-N-(3-pyridylmethyl)carboxamide
2-[(6-(2-cyanophenyl)-4-{[2-(3-fluorophenyl)ethyl]amino}(3- 48.426 M+H 432.1 pyridyl))carbonylamino]-N-methylacetamide
[4-{[2-{3-fluorophenyl)ethyl]amino}-6-(2-{imino[(3- pyridylmethyl)amino]methyl}phenyl)(3-pyridyl)]-N-(3- 61.236 M+H 560.2 pyridylmethyl)carboxamide
Example 23: In vitro Model of Dose Dependent Smooth Muscle Myosin ATPase Modulation
[0291] 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.
[0292] 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. [0293] 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, PEP1 crosslinked smooth muscle actomyosin (subfragment-1), antifoam, and water. The assay is started by adding an equal volume of solution containing potassium Pipes, MgCb, KCI, BSA, 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.
[0294] Certain chemical entities described herein have an IC50 less than 10 μM; for example, less than 1 μM.
[0295] 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 chosen from compounds of Formula X
Figure imgf000334_0001
Formula X and pharmaceutically acceptable salts thereof wherein
W1 is chosen from N and CR6 and W2 is chosen from N and CR4, provided that both W1 and W2 are not N;
R1 and R4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
Z1 is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , cyano, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted carbamimidoyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, sulfonyl, sulfinyl, and sulfanyl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is chosen from hydrogen, halogen, and optionally substituted alkyl;
R3 is chosen from hydrogen and optionally substituted alkyl; and
R6 is chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl.
2. At least one chemical entity of claim 1 wherein the compound of Formula X is chosen from compounds of Formula I
Figure imgf000335_0001
Formula I wherein
R1 and R4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted aikyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
Z1 is chosen from optionally substituted aryl and optionally substituted heteroaryl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alky I, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is chosen from hydrogen and optionally substituted alkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
3. At least one chemical entity of claim 2 wherein the compound of Formula I is chosen from compounds of Formula Il
Figure imgf000336_0001
Formula Il wherein
R1 and R4 are independently chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, suifinyl, and sulfanyl;
Z1 is optionally substituted aryl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, and optionally substituted aminocarbonyl;
Z3 is chosen from optionally substituted aralkyl and optionally substituted heteroaralkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
4. At least one chemical entity of Claim 3 wherein Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
5. At least one chemical entity of Claim 4 wherein Z2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
6. At least one chemical entity of Claim 5 wherein Z2 is chosen from (2-(N- acety laminomethyl)piperidin-1 -yl)carbonyl; (2-aminomethylpiperidin-1 -yl)carbonyl; 1 -hydroxy-2- amino-ethyl; 2-((methylsulfonamido)methyl)piperidin-1 -ylcarbonyl; 2-
(methylaminocarbonyl)ethenyl; 2-(pyridin-3-ylmethyl)-2H-tetrazol-5-yl; aminomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ylcarbonyl.
7. At least one chemical entity of any one of Claims 3 to 6 wherein R3 is chosen from hydrogen and optionally substituted lower alkyl.
8. At least one chemical entity of Claim 7 wherein R3 is chosen from hydrogen and lower alkyl.
9. At least one chemical entity of Claim 8 wherein R3 is chosen from hydrogen and methyl.
10. At least one chemical entity of Claim 9 wherein R3 is hydrogen.
11. At least one chemical entity of Claim 2 wherein Z2 is -C(O)NR2R5 wherein R2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
12. At least one chemical entity of any one of Claims 3 to 11 wherein R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl.
13. At least one chemical entity of Claim 12 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl.
14. At least one chemical entity of Claim 13 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-STylmethylaminocarbonyl, aminomethyl, and hydroxy methyl.
15. At least one chemical entity of Claim 14 wherein R4 is hydrogen.
16. At least one chemical entity of any one of Claims 11 to 15 wherein R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
17. At least one chemical entity of Claim 16 wherein R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
18. At least one chemical entity of Claim 17 wherein R2 is chosen from (1-(2-aminoethyl)-
1 H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin-3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyl; (1 H-imidazol-2-yl)methyl; (1 H-pyrazol-3-yl)methyl; (1-methyl-1 H- pyrazol-3-yl)methyl; (1-methyl-1 H-pyrazol-5-yl)methyl; (2-
(aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)carbonylmethyl; (2-(methylamino)ethylamino)carbonylmethyl; (2-(N- methyl-N-(t-butoxycarboπyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylmethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylamino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)rnethyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- aminoethylamino)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)methyl; (6-(hydroxymethyl)pyridiπ-2-yl)methyl; (6-bromopyridin-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1 -(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1 -(2-(tert-butoxycarbonylamino)ethyl)-1 H- pyrazol-5-ylmethyl; 1-(aminocarbonyl)-2-(amino)-eth-1-yl; 1-(aminocarbonyl)-3-{amino)-propyl; 1-(aminocarbonyl)-4-(amino)-butyl; 1-(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1- (aminocarbonyl)-5-(amino)-pentyl; 1-(aminocarbonyl)eth-1-yl; 1-(carboxy)-2-(amino)-eth-1-yl; 1- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 1-(hydroxy)-2-(aminocarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(ethoxycarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(pyridin-2-ylmethylamino)eth- 1-yl; 1-(methoxycarbonyl)-2-(amino)-eth-1-yl; 1-(methoxycarbonyl)-2-(t-butoxycarbonylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(amino)-eth-1-yl (2 occ); 1- (methylaminocarbonyl)eth-i-yl; i-aminocarbonyl-2-hydroxy-eth-i-yl; 1-methoxycarbonyl-2- hydroxy-eth-1-yl; 2-(2-aminoethoxy)ethyl; 2-(2-aminoethyl)-pyridin-6-ylmethyl; 2-(2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-(acetylamino)ethyl; 2-(amino)ethyl; 2-(aminocarbonyl)-2- (acetylamino)-eth-i -yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamino)ethyl; 2- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 2-(ethoxycarbonyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamino)-eth-i-yl; 2-(methoxycarbonyl)-2-(amino)-eth-1-yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1-yl; 2- (methylaminocarbonyl)-2-(amino)-eth-1 -yl; 2-(methylsulfonamido)ethyl; 2-{methyoxycarbonyl)-2- (amino)-eth-i-yl; 2-(N-(t-butoxycarbonyl)-N-(methyl)-amino)ethyl; 2-(piperazin-1-yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridin-3-ylmethyl; 2-(t-butoxycarbonylaminomethyl)pyridin-6- ylmethyl; 2-(trifluoromethyl)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridin-5- ylmethyl; 2-chloropyridin-5-y!methyl; 2-cyanopyridin-5-ylmethyl; 2-hydroxy-3-amino-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yI; 2-methoxypyridin-3-ylmethyl; 2-methoxypyridin-5-ylmethyl; 2- methylpyridin-3-yImethyl; 2-methylpyridin-5-ylmethyl; 2-methylpyridin-6-ylmethyl; 3-(2- aminoethyl)cyclohexyl)methyl; 3-(4-methylpiperazin-1-yl)propyl; 3-(amino)-3- (methylaminocarbonyl)prop-i-yl; 3-(aminocarbonyl)propyl; 3-(aminomethyl)beπzyl; 3- (amiπomethyl)pyridin-2-ylmethyl; 3-(methoxycarbonyl)propyl; 3-(methylaminocarbonyl)propyl; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; 3-carbamoylcyclopentyl; 3-carboxypropyl; 3-hydroxypropyl; 3-methoxypropyl; 4- (aminomethyl)-pyridin-2-ylmethyl; 4-(N,N-dimethylamino)pyridin-3-ylmethyl; 4-(t- butoxycarbonylamiπo)-morpholinomethyl; 4-aminobutyl; 4-amiπomethylpyridin-3-ylmethyl; 4- cyanobenzyl; 4-fluorobenzyl; 4-methylaminopyridin-3-ylmethyl; 4-methylbenzyl; 4- morpholinopyridin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5-
((bis(dimethylamino)methylamino)methyl)pyridin-3-ylmethyl; 5-(aminomethyl)pyridin-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethy!; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarboπylaminomethyl)-pyridin-2-ylmethyl; 5-(trifluoromethyl)-pyridin-2-ylmethyt; 5- aminopentyl; 5-aminopyridin-2-ylmethyl; 6-((bis(dimethylamino)methyleneamino)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1 -yl)pyridiπ-3-ylmethyl); 6-(aminomethyl)pyridin-2-yl)methyl; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylaminocarbonylmethyl; isopropyl; isoxazol-5-ylmethyl; methoxycarbonylmethyl; methyl; methylaminocarbonylmethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-ylmethyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
19. At least one chemical entity of any one of Claims 3 to 18 wherein Z3 is chosen from - (CH2)rR20 wherein r is chosen from 1 , 2, and 3 and R20 is chosen from optionally substituted aryl and optionally substituted heteroaryl.
20. At least one chemical entity of Claim 19 wherein Z3 is chosen from 2-(3- methylphenyl)ethyl, 2-(1H-imidazol-4-yl)ethyl, 2-(1-methyl-1H-imidazol-4-yl)ethyl, 2-(2,3- difluorophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2- (2-methoxyphenyl)ethyI, 2-(2-methylphenyl)ethyl, 2-(3-(trifluoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethyl-1 H-pyrazol-1-yl)ethyl, 2-(3,5- dimethyl-1 H-pyrazol-4-yi)ethyl, 2-(3-carbamoylphenyl)ethyl, 2-(3-carboxyphenyl)ethyl, 2-(3- cyanophenyl)ethyl, 2-(3-fluorophenyl)-2-(hydroxy)-ethyl, 2-(3-fluorophenyl)ethyl, 2-(3- fluoropyridin-2-yl)ethyl, 2-(3-methoxycarbonylphenyl)ethyl, 2-(3-methoxyphenyl)ethyI, 2-(3- methylphenyl)ethyl, 2-(4-aminophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2- (4-hydroxyphenyl)ethyl, 2-(benzo[d][1 ,3]dioxol-5-yl)ethyl, 2-(furan-2-yl)ethyl, 2-(hydroxy)-2- (phenyl)ethyl, 2-(phenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-phenylprop-1-yl, 3-(1 H-imidazol-1-yl)prop-1-yl, 3-phenylpropyl, benzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, and thiophen-3-ylmethyl.
21. At least one chemical entity of Claim 20 wherein Z3 is 2-(pyridin-2-yl)ethyl.
22. At least one chemical entity of any one of Claims 3 to 21 wherein Z1 is chosen from aryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl.
23. At least one chemical entity of Claim 22 wherein Z1 is chosen from phenyl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, lower alkenyl, lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, lower acyl, dialkylamino, acetylamino, carbamimidoyl optionally substituted with cyano, aralkyl, and herteroaralkyl, and aminocarbonyl.
24. At least one chemical entity of Claim 23 wherein Z1 is chosen from phenyl, 2- aminocarbonylphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-hydroxyphenyl, 2-methylphenyl, 2- methoxyphenyl, 2-cyanophenyl, 2-cyanomethylphenyl, 2-vinylphenyl, 2-formylphenyl, 3,4- difluorophenyl, 3-methylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-cyanophenyl, 3- dimethylaminophenyl, 3-methoxyphenyl, 3-methoxymethylphenyl, 3-hydroxyphenyl, 3- trifluoromethylphenyl, 4-aminocarbonylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-hydroxymethylphenyl, 4- trifluoromethylphenyl, 4-methoxycarbonylphenyl, 4-dimethylaminophenyl, 4-acetylphenyl, 4- carboxyphenyl, 4-ethylphenyl, 4-acetylaminophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 2,3- dimethylphenyl, 2,5-dimethylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4- dimethylphenyl, 2-chloro-4-fluoro-phenyl, 2-cyano-4-fluoro-phenyl, 2-chloro-6-fluoro-phenyl, 2- chloro-4-methoxy-phenyl, 2-cyano-4-methoxy-phenyl, 2-cyano-6-fluoro-phenyl, 2-chloro-5- fluoro-phenyl, 2-cyano-5-fluoro-phenyl, 2-chloro-4-methylphenyl, 2-chloro-4-hydroxymethyl- phenyl, 2-(N-(pyridin-3-ylmethyl)carbamimidoyl)pheπyl, and 2-cyano-4-methylphenyl.
25. At least one chemical entity of any one of Claims 3 to 24 wherein R1 is chosen from hydrogen and optionally substituted lower alkyl.
26. At least one chemical entity of Claim 25 wherein R1 is chosen from hydrogen and lower alkyl.
27. At least one chemical entity of Claim 26 wherein R1 is chosen from hydrogen and methyl.
28. At least one chemical entity of claim 2 wherein the compound of Formula I is chosen from compounds of Formula III
Figure imgf000342_0001
Formula III wherein
R1 and R4 are independently chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
Z1 is optionally substituted heteroaryl; /
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, and optionally substituted aminocarbonyl;
Z3 is chosen from optionally substituted aralkyl and optionally substituted heteroaralkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
29. At least one chemical entity of Claim 28 wherein Z1 is chosen from 1 H-pyrazol-3-yl; 1 H- pyrazol-4-yl; 1 H-tetrazol-5-yl; 1-methyl-1H-pyrazol~4-yl; 1-methyl-1 H-pyrazol-5-yl; 2- aminomethylthiophen-5-yl; 2-cyanothiophen-3-yl; 2-formylthiophen-3-yl; 2-formylthiophen-4-yl; 2H-pyrrol-1 (5H)-yl; 2-hydroxymethylthiophen-3-yl; 2-hydroxymethylthiopheπ-4-yl; 2- hydroxymethylthiophen-5-yl; 3-aminomethylthiophen-2yl; 3-cyano-1 -methyl-1 H-pyrazol-4-yl; 3- cyanothiophen-4-yl; 3-formylthiophen-2-yl; 3-hydroxymethylthiophen-2-yl; 4-methylthiophen-2- yl; 4-methylthiophen-3-yl; 5-(1-hydroxyeth-1-yl)-thiophen-2-yl; 5-acetylthiophen-5-yl; 5-cyano- 1 H-pyrazol-4-yl; 5-cyano-1 -methyl-1 H-pyrazol-4-yl; 5-cyanothiophen-2-yl; 5-formylthiophen-2-yl; 5-hydroxymethylthiophen-2-yl; isoxazol-4-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; thiazol-2- yl;thiophen-2-yl; and thiophen-3-yl.
30. At least one chemical entity of Claim 29 wherein Z1 is chosen from 1 H-pyrazol-3-yl; 1H- pyrazol-4-yl; 1 H-tetrazol-5-yl; 1 -methyl-1 H-pyrazol-4-yl; 1 -methyl-1 H-pyrazol-5-yl; 2- (hydroxymethyl)thiophen-3-yl; 2,2'-bipyridine; 2,3'-bipyridine; 2,4 -bipyridine; 2-cyanothiophen-3- yl; 2-formylthiophen-3-yl; 3-(hydroxymethyl)thiophen-2-yl; 3-cyano-1 -methyl-1 H-pyrazol-4-yl; 3- formylthiophen-2-yl; 4-cyanothiophen-3-yl; 4-methylthiophen-2-yl; 4-methylthiophen-3-yl; 5-(1- hydroxyethyl)thiophen-2-yl; 5-(aminomethyl)thiophen-2-yl; 5-(hydroxymethyl)thiophen-2-yl; 5- (hydroxymethyl)thiophen-3-yl; 5-acetylthiophen-2-yl; 5-cyano-1 H-pyrazol-4-yl; 5-cyano-1- methyl-1 H-pyrazol-4-yl; 5-cyanothiophen-2-yl; 5-formylthiophen-2-yl; 5-formylthiophen-3-yl; 3- (aminomethyl)thiophen-2-yl; isoxazol-4-yl; thiazol-2-yl; thiophen-2-yl; and thiophen-3-yl.
31. At least one chemical entity of any one of Claims 28 to 30 wherein Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
32. At least one chemical entity of Claim 31 wherein Z2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
33. At least one chemical entity of Claim 32 wherein Z2 is chosen from 2-(methylamino)-2- oxoethyl, 2-amino-2-oxoethyl, 3-amiπo-3-oxopropyl, (2-(N-acetylaminomethyl)piperidin-1- yl)carbonyl; (2-aminomethylpiperidin-1-yl)carbonyl; 1-hydroxy-2-amino-ethyl; 2- ((methylsulfonamido)methyl)piperidin-1-ylcarbonyl; 2-(methylaminocarbonyl)ethenyl; 2-(pyridin- 3-ylmethyl)-2H-tetrazol-5-yl; aminomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ylcarbonyl.
34. At least one chemical entity of any one of Claims 28 to 33 wherein R3 is chosen from hydrogen and optionally substituted lower alkyl.
35. At least one chemical entity of Claim 34 wherein R3 is chosen from hydrogen and lower alkyl.
36. At least one chemical entity of Claim 35 wherein R3 is chosen from hydrogen and methyl.
37. At least one chemical entity of Claim 36 wherein R3 is hydrogen.
38. At least one chemical entity of Claim 28 wherein Z2 is -C(O)NR2R5 wherein R2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
39. At least one chemical entity of any one of Claims 28 to 38 wherein R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl.
40. At least one chemical entity of Claim 39 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl.
41. At least one chemical entity of Claim 40 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl.
42. At least one chemical entity of Claim 41 wherein R4 is hydrogen.
43. At least one chemical entity of any one of Claims 38 to 42 wherein R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
44. At least one chemical entity of Claim 43 wherein R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
45. At least one chemical entity of Claim 44 wherein R2 is chosen from (1-(2-aminoethyl)- 1H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin-3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyl; (1H-imidazol-2-yl)methyl; (1H-pyrazol-3-yl)methyl; (1-methyl-1 H- pyrazol-3-yl)methyl; (1 -methyl-1 H-pyrazol-5-yl)methyl; (2-
(aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)carbonylmethyl; (2-(methylamino)ethylamino)carbonylmethyl; (2-(N- methyl-N-(t-butoxycarbonyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylrnethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylamino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)methyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1 ,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- aminoethylamino)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)methyl; (6-(hydroxymethyl)pyridin-2-yl)methyl; (6-bromopyridin-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1-(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1-(2-(tert-butoxycarbonylamino)ethyl)-1 H- pyrazol-5-ylmethyl; 1-(aminocarbonyl)-2-(amino)-eth-1-yl; 1-(aminocarbonyl)-3-(amino)-propyl; 1-(aminocarbonyl)-4-(amino)-butyl; 1-(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1- (aminocarbonyl)-5-(amino)-pentyl; 1-(aminocarbonyl)eth-1-yl; 1-(carboxy)-2-(amino)-eth-1-yl; 1- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 1-(hydroxy)-2-(aminocarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(ethoxycarbonylrnethylamino)eth-1-yl; 1-(hydroxy)-2-(pyridin-2-ylmethylamiπo)eth- 1-yl; 1-(methoxycarbonyl)-2-(amino)-eth-1-yl; 1-(methoxycarbonyl)-2-(t-butoxycarbonylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(amino)-eth-1-yl (2 occ); 1- (methylaminocarbonyl)eth-i-yl; i-aminocarbonyl-2-hydroxy-eth-i-yl; 1-methoxycarbonyl-2- hydroxy-eth-1 -yl; 2-(2-aminoethoxy)ethyl; 2-(2-aminoethyl)-pyridin-6-ylmethyl; 2-(2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-(acetylamino)ethyl; 2-(amino)ethyl; 2-(aminocarbonyl)-2- (acetylamino)-eth-i-yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamino)ethyl; 2- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 2-(ethoxycarbσnyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamino)-eth-i-yl; 2-(methoxycarbonyl)-2-(amino)-eth-1-yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1 -yl; 2- (methylaminocarbonyl)-2-(amino)-eth-1 -yl; 2-(methylsulfonamido)ethyl; 2-(methyoxycarbonyl)-2- (amino)-eth-i-yl; 2-(N-(t-butoxycarbonyl)-N-(methyl)-amino)ethyl; 2-(piperazin-1-yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridiπ-3-ylmethyl; 2-(t-butoxycarbonylaminomethyl)pyridin-6- ylmethyl; 2-(trifluoromethyl)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridfn-5- ylmethyl; 2-chloropyridin-5-ylmethyl; 2-cyanopyridin-5-ylmethyl; 2-hydroxy-3-amino-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yl; 2-methoxypyridin-3-ylmethyl; 2-methoxypyridin-5-ylmethyl; 2- methylpyridin-3-ylmethyl; 2-methylpyridin-5-ylmethyl; 2-methylpyridin-6-ylmethyl; 3-(2- aminoethyl)cyclohexyl)methyl; 3-(4-methylpiperazin-1-yl)propyl; 3-(amino)-3- (methylaminocarbonyl)prop-i-yl; 3-(aminocarbonyl)propyl; 3-(aminomethyl)benzyl; 3- (aminomethyl)pyridin-2-ylmethyl; 3-(methoxycarbonyl)propyl; 3-(methylamiπocarboπyl)propyl; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; 3-carbamoylcyclopentyl; 3-carboxypropyl; 3-hydroxypropyl; 3-methoxypropyl; 4- (aminomethyl)-pyridin-2-ylmethyl; 4-(NlN-dimethylamino)pyridin-3-ylmethyl; 4-(t- butoxycarbonylamino)-morpholinomethyl; 4-aminobutyl; 4-aminomethylpyridin-3-ylmethyl; A- cyanobenzyl; 4-fluorobenzyl; 4-methylaminopyridin-3-ylmethyl; 4-methylbenzyl; 4- morpholinopyridin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5-
((bis(dimethylamino)methyIamino)methyl)pyridin-3-ylmethyl; 5-(aminomethyl)pyridin-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethyl; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarbonylaminomethyl)-pyridrn-2-ylmethyl; 5-(trifluoromethyl)-pyridin-2-ylmethyl; 5- aminopentyl; 5-aminopyridin-2-ylmethyl; 6-((bis(dimethylamino)methyleneamino)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1-yl)pyridin-3-ylmethyl); 6-(aminomethyl)pyridin-2-yl)methyl; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylaminocarbonylmethyl; isopropyl; isoxazol-5-yl methyl; methoxycarbonylmethyl; methyl; methylaminocarbonylmethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-ylmethyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
46. At least one chemical entity of any one of Claims 28 to 45 wherein Z3 is chosen from - (CH2)rR20 wherein r is chosen from 1 , 2, and 3 and R20 is chosen from optionally substituted aryl and optionally substituted heteroaryl.
47. At least one chemical entity of Claim 46 wherein Z3 is chosen from 2-{3- methylphenyl)ethyl, 2-(1H-imidazol-4-yl)ethyl, 2-(1-methyl-1H-imidazol-4-yl)ethyl, 2-(2,3- difluorophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2- (2-methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-(trifluoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethyl-1 H-pyrazol-1-yl)ethyl, 2-(3,5- dimethyl-1H-pyrazol-4-yl)ethyl, 2-(3-carbamoylphenyl)ethyl, 2-(3-carboxyphenyl)ethyl, 2-(3- cyanophenyl)ethyl, 2-(3-fluorophenyl)-2-(hydroxy)-ethyl, 2-(3-fluorophenyl)ethyl, 2-(3- fluoropyridin-2-yl)ethyl, 2-(3-methoxycarbonylphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(3- methylphenyl)ethyl, 2-(4-aminophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2- (4-hydroxyphenyl)ethyl, 2-(benzo[d][1,3]dioxol-5-yl)ethyl, 2-(furan-2-yl)ethyl, 2-(hydroxy)-2- (phenyl)ethyl, 2-(phenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-phenylprop-1-yl, 3-(1H-imidazol-1-yl)prop-1-yl, 3-phenylpropyl, benzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, and thiophen-3-ylmethyl.
48. At least one chemical entity of Claim 47 wherein Z3 is chosen from 3-fluorophenethyl, 3,5-difluorophenethyl, and 2-(pyridin-2-yl)ethyl.
49. At least one chemical entity of any one of Claims 28 to 48 wherein R1 is chosen from hydrogen and optionally substituted lower alkyl.
50. At least one chemical entity of Claim 49 wherein R1 is chosen from hydrogen and lower alkyl.
51. At least one chemical entity of Claim 50 wherein R1 is chosen from hydrogen and methyl.
52. At least one chemical entity of Claim 51 wherein R1 is hydrogen.
53. At least one chemical entity of Claim 2 wherein the compound of Formula I is chosen from compounds of Formula IV
Figure imgf000348_0001
Formula IV
wherein
R1 and R4 are independently chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
Z1 is chosen from optionally substituted aryl and optionally substituted heteroaryl;
Z2 is chosen from hydrogen, carboxyl, optionally substituted alkoxy carbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted amidino, and optionally substituted aminocarbonyl;
Z3 is optionally substituted alkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
54. At least one chemical entity of Claim 53 wherein Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
55. At least one chemical entity of Claim 54 wherein Z2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted pyridinylmethylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
56. At least one chemical entity of Claim 55 wherein Z2 is chosen from pyridin-3- ylmethylcarbonyl, (2-(N-acetylaminomethyl)piperidin-1 -yl)carbonyl; (2-aminomethylpiperidin-1 - yl)carbonyl; 1-hydroxy-2-amino-ethyl; 2-((methylsulfonamido)methyl)piperidin-1-ylcarbonyl; 2- (methylaminocarbonyl)ethenyl; 2-(pyridin-3-ylmethyl)-2H-tetrazol-5-ylmethyl; aminomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ylcarbonyl.
57. At least one chemical entity of any one of Claims 53 to 56 wherein R3 is chosen from hydrogen and optionally substituted lower alkyl.
58. At least one chemical entity of Claim 57 wherein R3 is chosen from hydrogen and lower alkyl.
59. At least one chemical entity of Claims 58 wherein R3 is chosen from hydrogen and methyl.
60. At least one chemical entity of Claim 59 wherein R3 is hydrogen.
61. At least one chemical entity of Claim 53 wherein Z2 is -C(O)NR2R5 wherein R2 is chosen from optionally substituted alkyl and optionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
62. At least one chemical entity of any one of Claims 53 to 61 wherein R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl.
63. At least one chemical entity of Claim 62 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl.
64. At least one chemical entity of Claim 63 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl.
65. At least one chemical entity of Claim 64 wherein R4 is hydrogen.
66. At least one chemical entity of any one of Claims 61 to 65 wherein R5 is chosen from hydrogen and lower alkyl.
67. At least one chemical entity of Claim 66 wherein R5 is chosen from hydrogen and methyl.
68. At least one chemical entity of Claim 67 wherein R5 is hydrogen.
69. At least one chemical entity of any one of Claims 61 to 68 wherein R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
70. At least one chemical entity of Claim 69 wherein R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
71. At least one chemical entity of Claim 70 wherein R2 is chosen from (1-(2-aminoethyl)- 1 H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; <1-acetylpiperidin-3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyl; (1H-imidazol-2-yl)methyl; (1 H-pyrazol-3-yl) methyl; (1-methyl-1 H- pyrazol-3-yl)methyl; (1-methyl-1 H-pyrazol-5-yl)methyl; (2-
(aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- <hydroxy)ethylamino)carbonylmethyl; (2-(methylamino)ethylamino)carbonyImethyl; (2-(N- methyl-N-(t-butoxycarbonyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylmethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylamino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)methyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1 ,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- aminoethylamino)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)rnethyl; (6-(hydroxymethyl)pyridin-2-yl)methyl; (6-bromopyridin-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1-(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1 -(2-(tert-butoxycarbonylamino)ethyl)-1 H- pyrazol-5-ylmethyl; 1-(aminocarbonyl)-2-(amino)-eth-1-yl; 1-(aminocarbonyl)-3-(amino)-propyl; 1-(aminocarbonyl)-4-(amino)-butyl; 1-(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1- (aminocarbonyl)-5-(amino)-pentyl; 1 -(aminocarbonyl)eth-i -yl; 1 -(carboxy)-2-(am ino)-eth-1 -yl; 1 - (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 1-(hydroxy)-2-(aminocarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(ethoxycarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(pyridin-2-ylmethylamino)eth- 1-yl; 1-(methoxycarbonyl)-2-(amino)-eth-1-yl; 1-(methoxycarbonyl)-2-(t-butoxycarbonylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(amino)-eth-1-yl (2 occ); 1- (methylaminocarbonyl)eth-i-yl; 1-aminocarbonyl-2-hydroxy-eth-1-yl; 1-methoxycarbonyl-2- hydroxy-eth-1 -yl; 2-(2-aminoethoxy)ethyl; 2-{2-aminoethyl)-pyridin-6-ylmethyl; 2-(2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-(acetylamino)ethyl; 2-(amino)ethyl; 2-(aminocarbonyl)-2- (acetylamino)-eth-i-yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamino)ethyl; 2- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 2-(ethoxycarbonyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamino)-eth-i-yl; 2-(methoxycarbonyl)-2-(amino)-eth-1-yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1 -yl; 2- (methylaminocarbonyl)-2-(amino)-eth-1 -yl; 2-(methylsulfonamido)ethyl; 2-(methyoxycarbonyl)-2- (amino)-eth-i-yl; 2-(N-(t-butoxycarbonyl)-N-(methyl)-amino)ethyl; 2-(piperazin-1-yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridin-3-ylmethyl; 2-(t-butoxycarbonylaminomethyl)pyridin-6- ylmethyl; 2-(trifluoromethyI)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridin-5- ylmethyl; 2-chloropyridin-5-ylmethyl; 2-cyanopyridin-5-ylmethyl; 2-hydroxy-3-amino-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yl; 2-methoxypyridin-3-yImethyl; 2-methoxypyridin-5-ylmethyl; 2- methylpyridin-3-ylmethyl; 2-methylpyridin-5-ylmethyl; 2-methylpyridin-6-ylmethyl; 3-(2- aminoethyl)cyclohexyl)methyl; 3-(4-methylpiperazin-1 -yl)propyl; 3-(amino)-3- (methylaminocarbonyl)prop-i-yl; 3-(aminocarbonyl)propyl; 3-(aminomethyl)benzyl; 3- (aminomethyl)pyridin-2-ylmethyl; 3-(methoxycarbonyl)propyl; 3-(methylaminocarbonyl)propyI; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; 3-carbamoylcyclopentyl; 3-carboxypropyl; 3-hydroxypropyl; 3-methoxy propyl; 4- (aminomethyl)-pyridin-2-ylmethyl; 4-(N,N-dimethylamino)pyridin-3-ylmethyl; 4-(t- butoxycarbonylamino)-morpholinomethyl; 4-aminobutyl; 4-aminomethylpyridin-3-ylmethyl; 4- cyanobenzyl; 4-fluorobenzyl; 4-methylaminopyridin-3-ylmethyl; 4-methylbenzyl; A- morpholinopyridin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5-
((bis(dimethylamino)methylamino)methyl)pyridin-3-ylmethyr, 5-(aminomethyl)pyridin-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethyl; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarbonylaminomethyl)-pyridin-2-ylmethyl; 5-(trifluoromethy!)-pyridin-2-ylmethyl; 5- aminopentyl; 5-amiπopyridiπ-2-ylmethyl; 6-((bis(dimethylamino)methyleneamino)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1 -yl)pyridin-3-ylmethyl); 6-(amiπomethyl)pyridin-2-yl)methyl; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylamiπocarbonylmethyl; isopropyl; isoxazol-5-ylmethyl; methoxycarbonylmethyl; methyl; methylaminocarbonylmethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-ylmethyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
72. At least one chemical entity of Claim 71 wherein R2 is pyridin-3-ylmethyl.
73. At least one chemical entity of any one of Claims 53 to 72 wherein Z3 is chosen from - (CH2)rR20 wherein r is chosen from 1 , 2, and 3 and R20 is chosen from optionally substituted heterocycloalkyl and optionally substituted cycloalkyl.
74. At least one chemical entity of Claim 73 wherein Z3 is chosen from (tetrahydrofuran-2- yl)methyl, 1-hydroxycyclohexylmethyl, 2-(1 ,3-dioxoIan-2-yl)ethyl, 2-(1 -methylpiperidin-4-yl)ethyl, 2-(2-oxoimidazolidin-1-yl)ethyl, 2-(2-oxopiperidin-1-yl)ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 2- cyclohex-1-enylethyl, 2-cyclohexylethyl, and 2-morpholinoethyl.
75. At least one chemical entity of any one of Claims 53 to 74 wherein Z1 is chosen from aryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted amino optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl, and heteroaryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl.
76. At least one chemical entity of Claim 75 wherein Z1 is chosen from aryl optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, optionally substituted lower acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and amino optionally substituted with alkyl, and heteroaryl optionally substituted by one or two groups selected from optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, optionally substituted lower acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and amino optionally substituted with alkyl.
77. At least one chemical entity of Claim 76 wherein Z1 is chosen from phenyl, 1H-pyrazol-3- yl; 1 H-pyrazol-4-yl; 1 H-tetrazol-5-yl; 1-methyl-1 H-pyrazol-4-yl; 1-methyl-1H-pyrazol-5-yl; 2- aminomethylthiophen-5-yl; 2-cyanothiophen-3-yl; 2-formylthiophen-3-yl; 2-formylthiophen-4-yl; 2H-pyrrol-1 (5H)-yl; 2-hydroxymethylthiophen-3-yl; 2-hydroxymethylthiophen-4-yl; 2- hydroxymethylthiophen-5-yl; 3-aminomethylthiophen-2yl; 3-cyano-1-methyl-1H-pyrazol-4-yl; 3- cyanothiophen-4-yl; 3-formylthiophen-2-yl; 3-hydroxymethylthiophen-2-yl; 4-methylthiophen-2- yl; 4-methylthiopheπ-3-yl; 5-(1-hydroxyeth-1-yl)-thiophen-2-yl; 5-acetylthiophen-5-yl; 5-cyano- 1 H-pyrazol-4-yl; 5-cyano-1-methyl-1H-pyrazol-4-yl; 5-cyanothiophen-2-yl; 5-formylthiophen-2-yl; 5-hydroxymethylthiophen-2-yl; isoxazol-4-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; thiazol-2- yl;thiophen-2-yl; and thiophen-3-yl.
78. At least one chemical entity of any one of Claims 53 to 77 wherein R1 is chosen from hydrogen and optionally substituted lower alkyl.
79. At least one chemical entity of Claim 78 wherein R1 is chosen from hydrogen and methyl.
80. At least one chemical entity of Claim 79 wherein R1 is hydrogen.
81. At least one chemical entity of claim 1 wherein the compound of Formula X is chosen from compounds of Formula V
Figure imgf000354_0001
Formula V wherein R1 is selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl;
Z1 is selected from hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocydoalkyl , cyano, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aminocarbonyl; optionally substituted carbamimidoyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, sulfonyl, sulfinyl, and sulfanyl,
Z2 is selected from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocydoalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is selected from optionally substituted alkyl and optionally substituted heteroaralkyl;
R3 is chosen from hydrogen and optionally substituted alkyl; and
R6 is chosen from hydrogen, optionally substituted acyl, optionally substituted alkyl, cyano, halo, azido, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, sulfonyl, sulfinyl, and sulfanyl.
82. At least one chemical entity of Claim 81 wherein Z1 is chosen from phenyl substituted with one, two or three groups chosen from halo, alkyl, alkoxy, cyano, and optionally substituted acyl.
83. At least one chemical entity of Claim 82 wherein Z1 is chosen from 3,4-difluorophenyl and 2-cyanophenyl.
84. At least one chemical entity of any one of Claims 81 to 83 wherein Z2 is chosen from methylaminocarbonyl, methylaminocarbonylmethylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and isopropylaminocarbonyl, wherein the methyl, ethyl, propyl, and isopropyl group is optionally substituted with one, two or three groups independently selected from optionally substituted methoxy, optionally substituted ethoxy, optionally substituted phenyl, and optionally substituted pyridinyl.
85. At least one chemical entity of Claim 84 wherein Z2 is chosen from 2-methoxyeth-1- ylaminocarbonyl, benzylaminocarbonyl, isopropylaminocarbonyl, pyridin-3- ylmethylaminocarbonyl, and pyridin-4-ylmethylaminocarbonyl.
86. At least one chemical entity of any one of Claims 81 to 85 wherein Z3 is chosen from ethyl, methyl and propyl substituted with one, two or three groups independently selected from optionally substituted aryl and optionally substituted heteroaryl.
87. At least one chemical entity of Claim 86 wherein Z3 is chosen from ethyl and methyl substituted with a group selected from optionally substituted phenyl and optionally substituted pyridinyl.
88. At least one chemical entity of Claim 87 wherein Z3 is chosen from 2-(3- fluorophenyl)ethyl, 2-(3-methylphenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(3-methylphenyl)ethyl and pyridin-2-ylmethyl.
89. At least one chemical entity of any one of Claims 81 to 88 wherein R1 is chosen from hydrogen and optionally substituted lower alkyl.
90. At least one chemical entity of Claim 89 wherein R1 is chosen from hydrogen and lower alkyl.
91. At least one chemical entity of Claim 90 wherein R1 is chosen from hydrogen and methyl.
92. At least one chemical entity of Claim 91 wherein R1 is hydrogen.
93. At least one chemical entity of any one of Claims 81 to 92 wherein R3 is chosen from hydrogen and optionally substituted lower alkyl.
94. At least one chemical entity of Claim 93 wherein R3 is chosen from hydrogen and lower alkyl.
95. At least one chemical entity of Claims 94 wherein R3 is chosen from hydrogen and methyl.
96. At least one chemical entity of Claim 95 wherein R3 is hydrogen.
97. At least one chemical entity of any one of claims 81 to 96 wherein Rβ is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alky I.
98. At least one chemical entity of Claim 97 wherein Rδ is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl.
99. At least one chemical entity of Claim 98 wherein R6 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl.
100. At least one chemical entity of Claim 99 wherein R6 is hydrogen.
101. At least one chemical entity of claim 1 wherein the compound of Formula X is chosen from compounds of Formula Vl
Figure imgf000357_0001
Formula Vl
wherein R1 and R4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted carbaminodoyl;
Z1 is chosen from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is chosen from halo and optionally substituted alkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
102. At least one chemical entity of Claim 101 wherein Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
103. At least one chemical entity of Claim 102 wherein Z2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
104. At least one chemical entity of Claim 103 wherein Z2 is chosen from (2-(N- acetylaminomethyl)piperidin-1-yl)carbonyl; (2-aminomethylpiperidin-1-yl)carbonyl; 1-hydroxy-2- amino-ethyl; 2-((methylsulfonamido)methyl)piperidin-1-ylcarbonyl; 2-
(methylaminocarbonyl)ethenyl; 2-(pyridin-3-ylmethyl)-2H-tetrazol-5-yl; aminomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ylcarbonyl.
105. At least one chemical entity of any one of Claims 101 to 104 wherein R3 is chosen from hydrogen and optionally substituted lower alkyl.
106. At least one chemical entity of Claim 105 wherein R3 is chosen from hydrogen and lower alkyl.
107. At least one chemical entity of Claims 106 wherein R3 is chosen from hydrogen and methyl.
108. At least one chemical entity of Claim 107 wherein R3 is hydrogen.
109. At least one chemical entity of Claim 101 wherein Z2 is -C(O)NR2R5 wherein R2 is cchhoosseenn ffrroomm ooppttiioonnaallllyy ssuubbssttiittuutteedd aallkkyyll aanndd oopp'tionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
110. At least one chemical entity of any one of Claims 101 to 109 wherein R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl.
111. At least one chemical entity of Claim 110 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl.
112. At least one chemical entity of Claim 1 11 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl.
113. At least one chemical entity of Claim 12 wherein R4 is hydrogen.
114. At least one chemical entity of any one of Claims 109 to 113 wherein R5 is chosen from hydrogen and lower alkyl.
115. At least one chemical entity of Claim 114 wherein R5 is chosen from hydrogen and methyl.
116. At least one chemical entity of Claim 115 wherein R5 is hydrogen.
117. At least one chemical entity of any one of Claims 109 to 116 wherein R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
118. At least one chemical entity of Claim 117 wherein R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
119. At least one chemical entity of Claim 118 wherein R2 is chosen from (1-(2-aminoethyl)- 1 H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1 -acetylpiperidin-3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyl; (1 H-imidazol-2-yl)methyl; (1H-pyrazol-3-yl)methyl; (1-methyl-1H- pyrazol-3-yl)methyl; (1-methyl-1 H-pyrazol-5-yl)methyl; (2-
(arninocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)carbonylmethyl; (2-(methylamino)ethylamino)carbonylrnethyl; (2-(N- methyl-N-(t-butoxycarbonyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylmethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylarnino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)methyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- aminoethylamino)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)methyl; (6-(hydroxymethyl)pyridin-2-yl)methyl; (6-bromopyridin-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1-(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1-(2-(tert-butoxycarbonylamino)ethyl)-1 H- pyrazol-5-ylmethyl; 1-(aminocarbonyl)-2-(amino)-eth-1-yl; 1-(aminocarbonyl)-3-(amino)-propyl; 1-(aminocarbonyl)-4-(amino)-butyl; 1-(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1- (aminocarbonyl)-5-(amiπo)-pentyl; 1 -(aminocarbonyl)eth-i -yl; 1 -(carboxy)-2-(amino)-eth-1 -yl; 1 - (dimethylaminocarbonyl)-2-(amino)-eth-1 -yl; 1 -(hydroxy)-2-(aminocarbonylmethylamino)eth-1 -yl; 1-(hydroxy)-2-(ethoxycarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(pyridin-2-ylmethylamino)eth- 1-yl; 1-(methoxycarbonyl)-2-(amiπo)-eth-1 -yl; 1-(methoxycarbonyl)-2-(t-butoxycarboπylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(amino)-eth-1-yl (2 occ); 1- (methylaminocarbonyl)eth-i-yl; 1-aminocarbonyl-2-hydroxy-eth-1 -yl; 1-methoxycarbonyl-2- hydroxy-eth-1-yl; 2-(2-aminoethoxy)ethyl; 2-(2-aminoethyl)-pyridin-6-ylmethyl; 2-{2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-(acetylamino)ethyl; 2-(amino)ethyl; 2-(aminocarbonyl)-2- (acetylamino)-eth-i-yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamino)ethyl; 2- (dimethylaminocarbonyl)-2-(amino)-eth-1 -yl; 2-(ethoxycarbonyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamino)-eth-i -y I; 2-(methoxycarbonyl)-2-(amino)-eth-1 -yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1 -yl; 2- (methylaminocarbonyl)-2-(amino)-eth-1-yl; 2-(methylsulfonamido)ethyl; 2-(methyoxycarbonyl)-2- (amiπo)-eth-i-yl; 2-(N-(t-butoxycarbonyl)-N-(methyl)-amino)ethyl; 2-(piperazin-1-yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridin-3-ylmethyl; 2-(t-butoxycarbonylaminomethyl)pyridin-6- ylmethyl; 2-(trifluoromethyl)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridin-5- ylmethyl; 2-chloropyridin-5-ylmethyl; 2-cyanopyridiπ-5-ylmethyl; 2-hydroxy-3-amino-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yl; 2-methoxypyridin-3-ylmethyl; 2-methoxypyridin-5-ylmethyl; 2- methylpyridin-3-ylmethyl; 2-methylpyridin-5-ylmethyl; 2-methylpyridin-6-ylmethyl; 3-(2- aminoethyl)cyclohexyl)methyl; 3-(4-methylpiperazin-1-yl)propyl; 3-(amino)-3- (methylaminocarbonyl)prop-i-yl; 3-(aminocarbonyl)propyl; 3-(aminomethyl)benzyl; 3- (aminomethyl)pyridin-2-ylmethyl; 3-(methoxycarbonyl)propyl; 3-(methylaminocarbonyl)propyl; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; S-carbamoylcyclopentyl; 3-carboxypropyl; 3-hydroxy propyl; 3-methoxypropyl; 4- (aminomethyl)-pyridin-2-ylmethyl; 4-(N,N-dimethylannino)pyridin-3-ylmethyl; 4-(t- butoxycarbonylamino)-morpholinomethyl; 4-aminobutyl; 4-aminomethylpyridin-3-ylmethyl; 4- cyanobenzyl; 4-fluorobeπzyl; 4-methylaminopyridin-3-ylmethyl; 4-methylbenzyl; 4- morphoIinopyπdin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5- ((bis(dimethylamino)methylamino)methyl)pyridin-3-ylmethyl; 5-(aminomethyl)pyridiπ-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethyl; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarbonylaminomethyl)-pyridin-2-ylmethyl; 5-(trifluoromethyl)-pyridin-2-ylmethyl; 5- aminopentyl; 5-aminopyridin-2-ylmethyl; 6-((bis{dimethylamino)methyleneamino)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1-yl)pyridin-3-ylmethyl); 6-(aminomethyl)pyridiπ-2-yl)methyl; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylaminocarbonylmethyl; isopropyl; isoxazol-5-ylmethyl; methoxycarbonylmethyl; methyl; methylaminocarbonylmethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-ylmethyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
120. At least one chemical entity of any one of Claims 101 to 119 wherein Z3 is chosen from halo and optionally substituted lower alkyl.
121. At least one chemical entity of Claim 120 wherein Z3 is chosen from halo, optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl wherein the methyl, ethyl and propyl groups are optionally substituted with one or two groups selected from hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, and optionally substituted aryloxy.
122. At least one chemical entity of Claim 121 wherein Z3 is chosen from 2-{3- methylphenyl)ethyl, (tetrahydrofuran-2-yl)methyl, 1-hydroxycyclohexylmethyl, 2-(1 ,3-dioxolan-2- yl)ethyl, 2-(1 H-imidazol-4-yl)ethyl, 2-(1-methyl-1 H-imidazol-4-yl)ethyl, 2-(1-methylpiperidin-4- yl)ethyl, 2-(2,3-difluorophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyi, 2- (2-methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(2-oxoimidazolidin-1-yl)ethyl, 2-(2- oxopiperidin-1 -yl)ethyl, 2-(2-oxopyrrolidin-1 -yl)ethyl, 2-(3-(trifluoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethyl-1H-pyrazσl-1-yl)ethyl, 2-(3,5- dimethyl-1H-pyrazol-4-yl)ethyl, 2-(3-carbamoylphenyl)ethyl, 2-(3-carboxyphenyl)ethyl, 2-(3- cyanophenyl)ethyl, 2-(3-fluorophenyl)-2-(hydroxy)-ethyl, 2-(3-fluorophenyl)ethyl, 2-(3- fluoropyridin-2-yl)ethyl, 2-(3-methoxycarbonylphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(3- methylphenyl)ethyl, 2-(4-aminophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2- (4-hydroxyphenyl)ethyl, 2-(benzo[d][1,3]dioxol-5-yl)ethyl, 2-{furan-2-yl)ethyl, 2-(hydroxy)-2- (phenyl)ethyl, 2-(phenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-cyclohex-1-enylethyl, 2-cyclohexylethyl, 2-morpholinoethyl, 2-phenoxyethyl, 2-phenylprop-1- yl, 3-{1H-imidazol-1-yl)prop-1-yl, 3-phenylpropyl, benzyl, chloro, isopentyl, propyl, pyridin-2- ylmethyl, pyridin-3-ylmethyl, and thiophen-3-ylmethyl.
123. At least one chemical entity of Claim 122 wherein Z3 is chosen from 2-(3- fluorophenyl)ethyl and 2-(pyridin-2-yl)ethyl.
124. At least one chemical entity of any one of Claims 101 to 123 wherein Z1 is chosen from cycloalkyl and heterocycloalkyl, where each group is optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl.
125. At least one chemical entity of Claim 124 wherein Z1 is chosen from cycloalkyl and heterocycloalkyl, where each group is optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, carboxyl, optionally substituted lower alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl.
126. least one chemical entity of Claim 125 wherein Z1 is chosen from 1-(2H)- (methoxycarbonyl)-3,4-dihydropyridin-4-yl; 1 -(2H)-(methoxycarbonyl)-5,6-dihydropyridin-4-yl; 1 - (2H)-(methoxymethyl)-5,6-dihydropyridin4-yl; 1-(2H)-(t-butoxycarbonyl)-5,6-dihydropyridin-4-yl; 1-(2H)-5,6-dihydropyridin-4-yl; 1-(acetyl)-4,5-dihydroimidazo-2-yl; i-(dimethylcarbamoyl)-
1 ^.S.θ-tetrahydropyridin^-yl; 1-(methoxymethyl)-4,5-dihydroimidazo-2-yl; 1-cyano-4,5-dihydro- 1 H-imidazol-2-yl; 1-methyl-1 ^^.δ-tetrahydropyridin^-yl; 2-{acetylaminomethyl)pyrrolidin-1-yl; 2-(hydroxymethyl)morpholino; 2-(hydroxymethyl)pyrrolidin-1 -yl; 2-(methoxymethyl)pyrrolidin-1 - yl; 2H-pyrrol-1 (5H)-yl; 2-hydroxymorpholino; 2-methyl-4-(t-butoxycarbonyl)-piperaziπ-1-yl; 2- oxo-5-hydroxy-piperidinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 3-(3,3- dimethylureido)pyrrolidin-1-yl; 3-(aminomethyl)-pyrrolidin-1-yl; 3-(carboxymethyl)-pyrrolidinyl; 3- (dimethylamino)pyrrolidin-i -yl; 3-(dimethylaminomethyl)-pyrrolidin-1-yl; 3- (hydroxymethyl)pyrrolidin-i -yl; 3-(methoxycarbonylamino)-pyrrolidinyl; 3- (methylsulfonyl)pyrrolidin-i-yl; 3-(N-acetyl-N-methyl)-aminomethyl)-pyrrolidin-1-yl; 3-(pyridin-4- yl)pyrrolidin-1 -yl; 3-(t-butoxycarboπylamino)-pyrrolidinyl; 3-(trifluoromethyl)pyrrolidin-1 -yl; 3,3- difluoropyrrolidinyl; 3-acetylaminopyrrolidinyl; 3-aminopyrrolidin-1-yl; 3-fluoropyrrolidin-1-yl; 3- hydroxymethylpyrrolidin-1-yl; 3-hydroxypyrrolidin-1-yl;3-methoxymethylpyrrolidin-1-yl; 3- methylamino-pyrrolidinyl; 3-oxopiperazin-1-yl; 4-(acetyl)-piperazin-1-yl; 4- (aminomethyl)piperidin-i-yl; 4-(ethoxycarbonyl)-piperazin-1-yl; 4-(ethoxycarbonyl)-piperidinyl; 4- (methoxycarbonyl)-piperazin-i-yl; 4-(methylsulfonyl)cyclohex-1-enyl; 4-(N1N- dimethylaminocarbonyl)-piperazin-1 -yl; 4-(t-butoxycarbonylamino)-piperidin-1 -yl; 4-(t- butoxycarbonylaminomethyl)-piperidin-1 -yl; 4,5-dihydro-1 H-imidazol-2-yl; 4,5-dihydrooxazol-2- yl;4-hydroxy-4-phenylpiperidin-1-yl;4-hydroxyethyl-piperidin-yl;4-hydroxyrnethyl-piperidin-yl;4- hydroxypiperidinyl; 4-methylaminocarbonyl-piperidinyl; 4-methylpiperazin-1-yl; 4- methylpiperidinyl; 4-oxocyclohex-1-enyl; 5,6-dihydropyridin-1(2H)-yl; azetidinyl; cyclohex-1-enyl; cyclohexyl; cyclopent-1 -enyl; cyclopentyl; morpholino; piperazinyl; piperidinyl.pyrrolidinyl; and thiomorpholino.
127. At least one chemical entity of any one of Claims 101 to 126 wherein R1 is chosen from hydrogen and optionally substituted lower alkyl.
128. At least one chemical entity of Claim 127 wherein R1 is chosen from hydrogen and lower alkyl.
129. At least one chemical entity of Claim 128 wherein R1 is chosen from hydrogen and methyl
130. At least one chemical entity of Claim 129 wherein R1 is hydrogen.
131. At least one chemical entity of claim 1 wherein the compound of Formula X is chosen from compounds of Formula VII
Figure imgf000365_0001
Formula VII
wherein
R1 and R4 are independently chosen from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, su If any I, optionally substituted alkoxy, optionally substituted acyloxy, optionally substituted aminocarbonyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted aminocarbonyl, and optionally substituted carbaminodoyl;
Z1 is chosen from hydrogen, cyano, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aminocarbonyl, optionally substituted carbamimidoyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkenyl, optionally substituted alkynyl, sulfonyl, sulfinyl, and sulfanyl;
Z2 is chosen from hydrogen, optionally substituted amidino, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted aminocarbonyl;
Z3 is chosen from optionally substituted alkyl; and
R3 is chosen from hydrogen and optionally substituted alkyl.
132. At least one chemical entity of Claim 131 wherein Z2 is chosen from carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted alkenyl, and optionally substituted alkyl.
133. At least one chemical entity of Claim 132 wherein Z2 is chosen from carboxyl, optionally substituted piperidinylcarbonyl, optionally substituted pyridinylcarbonyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, and lower alkoxycarbonyl.
134. At least one chemical entity of Claim 133 wherein Z2 is chosen from (2-(N- acetylaminomethyl)piperidin-1-yl)carbonyl; (2-aminomethylpiperidin-1-yl)carbonyl; 1-hydroxy-2- amino-ethyl; 2-((methylsulfonamido)methyl)piperidin-1 -ylcarbonyl; 2- (methylaminocarbonyl)ethenyl; 2-(pyridin-3-ylmethyl)-2H-tetrazol-5-ylmethyl; aminomethyl; carboxyl; methoxycarbonyl; pyridin-2-ylcarbonyl; pyridin-3-ylcarbonyl; and pyridin-4-ylcarbonyl.
135. At least one chemical entity of any one of Claims 131 to 134 wherein R3 is chosen from hydrogen and optionally substituted lower alkyl.
136. At least one chemical entity of Claim 135 wherein R3 is chosen from hydrogen and lower alkyl.
137. At least one chemical entity of Claims 136 wherein R3 is chosen from hydrogen and methyl.
138. At least one chemical entity of Claim 137 wherein R3 is hydrogen.
139. At least one chemical entity of Claim 131 wherein Z2 is -C(O)NR2R5 wherein R2 is cchhoosseenn ffrroomm ooppttiioonnaallllyy ssuubbssttiittuutteedd aallkkyyll aanndd oopptionally substituted cycloalkyl; and R5 is chosen from hydrogen and optionally substituted alkyl.
140. At least one chemical entity of any one of Claims 131 to 139 wherein R4 is chosen from hydrogen, cyano, halo, azido, optionally substituted aminocarbonyl, and optionally substituted alkyl.
141. At least one chemical entity of Claim 140 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, fluoro, azido, optionally substituted alkylaminocarbonyl, and optionally substituted methyl.
142. At least one chemical entity of Claim 141 wherein R4 is chosen from hydrogen, cyano, chloro, bromo, azido, pyridin-3-ylmethylaminocarbonyl, aminomethyl, and hydroxymethyl.
143. At least one chemical entity of Claim 142 wherein R4 is hydrogen.
144. At least one chemical entity of any one of Claims 139 to 143 wherein R5 is chosen from hydrogen and lower alkyl.
145. At least one chemical entity of Claim 144 wherein R5 is chosen from hydrogen and methyl.
146. At least one chemical entity of Claim 145 wherein R5 is hydrogen.
147. At least one chemical entity of any one of Claims 139 to 146 wherein R2 is chosen from optionally substituted methyl, optionally substituted ethyl, optionally substituted propyl, optionally substituted butyl, optionally substituted pentyl, optionally substituted hexyl, optionally substituted cyclopropyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl where each optionally substituted group is optionally substituted with one, two or three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
148. At least one chemical entity of Claim 147 wherein R2 is chosen from methyl and ethyl, where the methyl and ethyl groups are optionally substituted with one or two groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted aminocarbonyl, optionally substituted amino, hydroxy, carboxyl, optionally substituted alkoxycarbonyl, and optionally substituted alkoxy.
149. At least one chemical entity of Claim 148 wherein R2 is chosen from (1-(2-aminoethyl)- 1 H-pyrazol-3-yl)methyl; (1-(methylsulfonyl)piperidin-3-yl)methyl; (1-acetylpiperidin-3-yl)methyl; (1-acetylpyrrolidin-2-yl)methyl; (1 H-imidazol-2-yl)methyl; (1 H-pyrazol-3-yl)methyl; (1 -methyl-1 H- pyrazol-3-yl)methyl; (1 -methyl-1 H-pyrazol-5-yl)methyl; (2-
(aminocarbonyl)ethylamino)carbonylmethyl; (2-(aminomethyl)pyridin-3-yl)methyl; (2- (carboxy)ethylamino)carbonylmethyl; (2-(dimethylamino)ethylamino)carbonylmethyl; (2- (hydroxy)ethylamino)carbonylmethyl; (2-(methylamino)ethylamino)carbonylmethyl; (2-(N- methyl-N-(t-butoxycarbonyl)-amino)ethylamino)carbonylmethyl; (2-oxopiperidin-3-yl)methyl; (3- (dimethylamino)propylamino)carbonylmethyl; (3-(hydroxy)ethylamino)carbonylmethyl; (3-(t- butoxycarbonylamino)propylamino)carbonylmethyl; (4-(aminomethyl)pyridin-2-yl)methyl; (5- (aminomethyl)pyridin-2-yl)methyl; (6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)methyl; (6-(2- aminoethylamino)pyridin-2-yl)methyl; (6-(3-aminopropylamino)pyridin-2-yl)methyl; (6- (aminomethyl)pyridin-2-yl)methyl; (6-(hydroxymethyl)pyridin-2-yl)methyl; (6-bromopyridin-2- yl)methyl; (methylsulfonamido)carbonylmethyl; (pyridin-2-yl)ethylamino; 1-(2-(tert- butoxycarbonylamino)ethyl)-1 H-pyrazol-3-ylmethyl; 1-(2-(tert-butoxycarbonylamino)ethyl)-1 H- pyrazol-5-ylmethyl; 1-(aminocarbonyl)-2-(amino)-eth-1-yl; 1-(aminocarbonyl)-3-(amino)-propyl; 1 -(aminocarbonyl)-4-(amino)-butyl; 1-(aminocarbonyl)-4-(benzyloxycarbonylamino)-pentyl; 1- (aminocarbonyl)-5-(amino)-pentyl; 1-(aminocarbonyl)eth-1-yl; 1-(carboxy)-2-(amino)-eth-1-yl; 1- (dimethylaminocarbonyl)-2-(amino)-eth-1-yl; 1-(hydroxy)-2-(aminocarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(ethoxycarbonylmethylamino)eth-1-yl; 1-(hydroxy)-2-(pyridin-2-ylmethylamino)eth- 1 -yl; 1 -(methoxycarbonyl)-2-(amino)-eth-1 -yl; 1 -(methoxycarbonyl)-2-(t-butoxycarbonylamino)- eth-1-yl; 1-(methoxycarbonyl)eth-1-yl; 1-(methylaminocarbonyl)-2-(amino)-eth-1-yl (2 occ); 1- (methylaminocarbonyl)eth-i-yl; 1-aminocarbonyl-2-hydroxy-eth-1-yl; 1-methoxycarbonyl-2- hydroxy-eth-1-yl; 2-(2-aminoethoxy)ethyl; 2-(2-aminoethyl)-pyridin-6-ylmethyl; 2-(2- aminoethylamino)ethyl; 2-(3-fluorophenyl)ethyl; 2-(3-methoxycarbonyl)ethyl; 2-(6- (aminomethyl)pyridin-2-yl)ethyl; 2-(acetylamino)ethyl; 2-(amino)ethyl; 2-(aminocarbonyl)-2- (acetylamino)-eth-i-yl; 2-(aminocarbonyl)-2-(amino)-eth-1-yl; 2-(aminocarbonyl)ethyl; 2- (aminomethyl)pyridin-5-ylmethyl; 2-(carboxy)-2-(amino)-eth-1-yl; 2-(dimethylamino)ethyl; 2- (dimethylaminocarbonyl)-2-(amino)-eth-1 -yl; 2-(ethoxycarbonyl)ethyl; 2-(methoxycarbonyl)-2- (acetylamino)-eth-i-yl; 2-(methoxycarbonyl)-2-(amino)-eth-1-yl; 2-(methoxycarbonylamino)ethyl; 2-(methylamino)ethyl; 2-(methylaminocarbonyl)-2-(acetylamino)-eth-1-yl; 2- (methylaminocarbonyl)-2-(amino)-eth-1 -yl; 2-(methylsulfonamido)ethyl; 2-(methyoxycarbonyl)-2- (amino)-eth-i-yl; 2-(N-(t-butoxycarboπyl)-N-(methyl)-amino)ethyl; 2-(piperazin-1 -yl)ethyl; 2- (pyrazin-2-yl)ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-(t- butoxycarbonylaminomethyl)pyridin-3-ylmethyl; 2-(t-butoxycarbonylaminomethyl)pyridin-6- ylmethy!; 2-(trifluoromethyl)-pyridin-6-ylmethyl; 2-aminopyridin-3-ylmethyl; 2-aminopyridin-5- ylmethyt; 2-chloropyridin-5-ylmethyl; 2-cyanopyridin-5-ylmethyl; 2-hydroxy-3-amino-prop-1-yl; 2- hydroxyethyl; 2-methoxyeth-1-yl; 2-methoxypyridin-3-ylmethyl; 2-methoxypyridin-5-ylmethyl; 2- methylpyridin-3-ylmethyl; 2-methylpyridin-5-yl methyl; 2-methylpyridin-6-yImethyl; 3-(2- aminoethyl)cyclohexyl)methyl; 3-(4-methylpiperazin-1 -yl)propyl; 3-(amino)-3- (methylaminocarbonyl)prop-i-yl; 3-(aminocarbonyl)propyl; 3-(aminomethyl)benzyl; 3- (aminomethyl)pyridin-2-ylmethyI; 3-(methoxycarbonyl)propyl; 3-(methylaminocarbonyl)propyl; 3- (trifluoromethyl)-pyridin-2-ylmethyl; 3,4-difluorobenzyl; 3-aminomethylpyridin-4-ylmethyl; 3- aminopropyl; S-carbamoylcyclopentyl; 3-carboxypropyl; 3-hydroxypropyl; 3-methoxy propyl; 4- (aminomethyl)-pyridin-2-ylmethyl; 4-(N,N-dimethylamino)pyridin-3-ylmethyl; 4-(t- butoxycarbonylamino)-morpholinomethyl; 4-aminobutyl; 4-aminomethylpyridin-3-ylmethyl; 4- cyanobenzyl; 4-fluorobenzyl; 4-methylaminopyridin-3-ylmethyl; 4-methylbenzyl; 4- morpholinopyridin-3-ylmethyl; 4-piperazinylpyridin-3-ylmethyl; 5-
((bis(dimethylamino)methylamino)methyl)pyridin-3-ylmethyl; 5-(aminomethyl)pyridin-2-ylmethyl; 5-(aminomethyl)pyridin-3-ylmethyl; 5-(hydroxymethyl)pyridin-3-ylmethyl; 5-(t- butoxycarbonylaminomethyl)-pyridin-2-ylmethyl; 5-(trifluoromethyl)-pyridin-2-ylmethyl; 5- aminopentyl; 5-aminopyridin-2-ylmethyl; 6-((bis(dimethylamino)methyleneamino)methyl)pyridin- 2-yl)methyl; 6-(4-acetylpiperazin-1 -yl)pyridin-3-ylmethyl); 6-(aminomethyl)pyridin-2-yl)methyl; 6- aminohexyl; aminocarbonylmethyl; benzyl; cyclopropylmethyl; dimethylaminocarbonylmethyl; isopropyl; isoxazol-5-ylmethyl; methoxycarbonylmethyl; methyl; methylaminocarbonylmethyl; oxazol-2-ylmethyl; piperidin-4-ylmethyl; prop-2-en-1-yl; pyrazin-2-ylmethyl; pyridin-2-ylmethyl; pyridin-2-ylmethyl -N-oxide; pyridin-3-ylmethyl; pyridin-3-ylmethyl -N-oxide; pyridin-4-ylmethyl; thiophen-2-ylmethyl; and thiophen-3-ylmethyl.
150. At least one chemical entity of any one of Claims 131 to 149 wherein Z3 is chosen from optionally substituted lower alkyl.
151. At least one chemical entity of Claim 150 wherein Z3 is chosen from optionally substituted methyl, optionally substituted ethyl, and optionally substituted propyl wherein the methyl, ethyl and propyl groups are optionally substituted with one or two groups selected from hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, and optionally substituted aryloxy.
152. At least one chemical entity of Claim 151 wherein Z3 is chosen from 2-(3- methylphenyl)ethyl, (tetrahydrofuran-2-yl)methyl, 1-hydroxycyclohexylmethyl, 2-(1 ,3-dioxolan-2- yl)ethyl, 2-(1 H-imidazol-4-yl)ethyl, 2-(1-methyl-1H-imida2ol-4-yl)ethyl, 2-(1-methylpiperidin-4- yl)ethyl, 2-(2,3-difluorophenyl)ethyl, 2-(2,5-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(2- chlorophenyl)ethyl, 2-(2-cyanophenyl)ethyl, 2-(2-fluorophenyl)ethyl, 2-(2-hydroxyphenyl)ethyl, 2- (2-methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(2-oxoimidazolidin-1-yl)ethyl, 2-(2- oxopiperidin-1-yl)ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 2-(3-(trifluoromethyl)phenyl)ethyl, 2-(3,4- difluorophenyl)ethyl, 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dim ethyl- 1 H-pyrazol-1-yl)ethyl, 2-(3,5- dimethyl-1H-pyrazol-4-yl)ethyl, 2-(3-carbamoylphenyl)ethyl, 2-(3-carboxyphenyl)ethyl, 2-(3- cyanophenyl)ethyl, 2-(3-fluorophenyl)-2-(hydroxy)-ethyl, 2-(3-fluorophenyl)ethyl, 2-{3- fluoropyridin-2-yl)ethyl, 2-(3-methoxycarbonylphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(3- methylphenyl)ethyl, 2-(4-aminophenyi)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2- (4-hydroxyphenyl)ethyl, 2-(benzo[d][1 ,3]dioxol-5-yl)ethyl, 2-(furan-2-yl)ethyl, 2-(hydroxy)-2- (phenyl)ethyl, 2-(phenyl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(thiophen-2-yl)ethyl, 2-cyclohex-1-enylethyl, 2-cyclohexylethyl, 2-morpholinoethyl, 2-phenoxyethyl, 2-phenylprop-1- yl, 3-(1 H-imidazol-1-yl)prop-1-yl, 3-phenylpropyl, benzyl, chloro, isopentyl, propyl, pyridin-2- ylmethyl, pyridin-3-yl methyl, and thiophen-3-ylmethyl.
153. At least one chemical entity of Claim 152 wherein Z3 is chosen from 2-(3- fluorophenyl)ethyl and 2-(pyridin-2-yl)ethyl.
154. At least one chemical entity of any one of Claims 131 to 153 wherein Z1 is chosen from cyano, halo, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted amino, optionally substituted aminocarbonyl, and optionally substituted carbamimidoyl.
155. At least one chemical entity of Claim 154 wherein Z1 is chosen from acyl, alkenyl, alkoxycarbonyl, alkyl, amino, aminocarbonyl, and carbamimidoyl, where each group is optionally substituted by one or two groups selected from cyano, halo, hydroxy, formyl, optionally substituted alkyl, optionally substituted alkenyi, optionally substituted alkoxy, carboxyl, optionally substituted alkoxycarbonyl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted carbamimidoyl, and optionally substituted sulfonyl.
156. At least one chemical entity of Claim 155 wherein Z1 is chosen from (5-oxo- tetrahydrofuran-2-yl)methylamino; (E)-N'-cyano-N,N-dimethylcarbamimidoyl; (Z)-4-(N-(2- hydroxyethyl)-N,N'-bis(methoxycarbonyl)carbamimidoyl); (Z)-but-2-en-2-yl; 1-ethoxyeth-1-yl; 1- ethoxyvinyl;2-hydroxyeth-1-ylamino 2-methoxyeth-1ylamino;2-methylprop-1-enyl; 3- (methoxycarbonyl)-prop-2-en-2-yl; 3-(N,N-dimethylamino)carbonyl-prop-1-ylamino; 3- aminocarbonyl-prop-1-ylamino; 3-hydroxyprop-1-ylamino; 3-methoxy-prop-1-enyl; 3- methoxyprop-1-ylamino; 3-methoxypropyl; 3-methylbut-2-en-2-yl; 4-((pyridin-3- ylmethyl)aminocarbonyl)butylamino; 4-(N,N-dimethylamino)carbonyl-but-1-ylamino; 4-(N- methylamino)carbonyl-but-1-ylamino; 4-aminocarbonyl-but-1-ylamino; acetyl; aminocarbonyl; carbamimidoyl; chloro; cyano; dimethylamino; ethoxycarbonyl; hydrogen; methoxycarbonyl; methylamino; N-(2-hydroxyethyl)-N-(acetyl)-amino; N-(2-hydroxyethyl)-N-(methyl)-amino; N-(2- hydroxyprop-1-yl)-N-(methyl)-amino; N-(methyl)-aminocarbonyI; N-(pyridin-2-ylmethyl)amino; N- (pyridin-3-ylmethyl)amino; N-(pyridin-4-ylmethyl)amino; N,N-dimethylcarbamimidoyl; N- cyanocarbamimidoyl; N-methyl-N-acetylamino; and prop-1-enyl.
157. At least one chemical entity of any one of Claims 131 to 156 wherein R1 is chosen from hydrogen and optionally substituted lower alkyl.
158. At least one chemical entity of Claim 157 wherein R1 is chosen from hydrogen and lower alkyl.
159. At least one chemical entity of Claim 158 wherein R1 is chosen from hydrogen and methyl.
160. At least one chemical entity of Claim 159 wherein R1 is hydrogen.
161. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier and at least one chemical entity of any one of Claims 1 to 160.
162. A pharmaceutical composition of Claim 161 wherein the composition is formulated in a form chosen from tablets, capsules, powders, liquids, suspensions, suppositories and aerosols.
163. A packaged pharmaceutical composition comprising a pharmaceutical composition of Claim 161 or 162 and instructions for using the composition to treat a patient suffering from a disease associated with smooth muscle myosin or non-muscle myosin.
164. The packaged pharmaceutical composition of Claim 163 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.
165. 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 160.
166. A method of Claim 165 wherein said diseases 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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