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  • 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
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  • 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
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  • 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
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  • 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
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  • 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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