WO2008016666A2 - Entités chimiques, compositions et méthodes - Google Patents

Entités chimiques, compositions et méthodes Download PDF

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Publication number
WO2008016666A2
WO2008016666A2 PCT/US2007/017231 US2007017231W WO2008016666A2 WO 2008016666 A2 WO2008016666 A2 WO 2008016666A2 US 2007017231 W US2007017231 W US 2007017231W WO 2008016666 A2 WO2008016666 A2 WO 2008016666A2
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Prior art keywords
optionally substituted
chemical entity
hydrogen
alkyl
methyl
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PCT/US2007/017231
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English (en)
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WO2008016666A3 (fr
Inventor
Xiangping Qian
Jeffrey T. Finer
Pu-Ping Lu
Chihyuan Chuang (Grace)
Bradley P. Morgan
David J. Morgans, Jr.
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Cytokinetics, Incorporated
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Publication of WO2008016666A2 publication Critical patent/WO2008016666A2/fr
Publication of WO2008016666A3 publication Critical patent/WO2008016666A3/fr

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    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms

Definitions

  • Myosin is present in all muscle and non-muscle cells. Of the ten distinct classes of myosin in human cells, myosin-ll is thought to be the form responsible for contraction of skeletal, cardiac, and smooth muscle. Myosin -Il is also the isoform present in non-muscle myosins, also known as cytoplasmic myosins. The non-muscle myosins are ubiquitously present in eukaryotic cells, where the smooth muscle myosins are generally present in smooth muscle cells.
  • Myosin-ll is significantly different in amino acid composition and in overall structure from myosins in the other nine distinct classes.
  • Myosin-ll consists of two globular head domains, called Subfragment-1 or S1 , linked together by a long alpha-helical coiled-coiled tail.
  • S1 contains the ATPase and actin-binding properties of the molecule. S1 has been shown to be sufficient to move actin filaments in vitro, and is therefore likely to be the motor domain of the molecule.
  • myosin-il isoforms from various tissues differ in a number of biological properties, they share the same basic molecular structure as a dimer of two heavy chains (approximately 200 kDa) which are noncovalently associated with two pairs of light chains (approximately 20 and 17 kDa).
  • the two globular amino-terminal heads are tethered together by the carboxy-terminal alpha-helical coiled-coil that forms a tail.
  • the tails are believed to be involved in the assembly of myosin molecules into filaments, whereas the heads are thought to have an actin-activated Mg 2+ -ATPaSe activity.
  • Each myosin head can be divided by three protease-sensitive regions into peptides of approximately 25, 50, and 20 kDa. The more amino-terminal 25 kDa - 50 kDa junction is close to the ATP binding region, whereas the actin-binding domain is near the 50 kDa - 20 kDa junction.
  • S1 consists of a globular actin binding and nucleotide binding region known as the catalytic domain. This domain is attached at its carboxy-terminus to an alpha-helix that has two light chains of about 20 kDa each wrapped around it. This light- chain binding domain of S1 is known as the lever arm. Upon transitioning from the pre- stroke to the post-stroke state, the lever arm is believed to swing through an angle of about 90 degrees about a fulcrum point in the catalytic domain near the nucleotide- binding site. The "power stroke” is driven by the hydrolysis of ATP.
  • the other end of the myosin molecule is an alpha-helical coiled-coiled tail involved in self assembly of myosin molecules into bipolar thick filaments. These thick filaments interdigitate between thinner actin filaments, and the two filament systems slide past one another during contraction of the muscle. This filament sliding mechanism is thought to involve conformational changes in the myosin heads causing them to walk along the thin actin filaments at the expense of ATP hydrolysis. While non- muscle myosins act in a similar manner, they are understood to slide at a slower velocity than the smooth muscle myosins.
  • W 1 is selected from NR 11 , O, and S;
  • W 2 is selected from CH and N;
  • W 3 is selected from CR 1 R 2 and NR 13 ;
  • W 4 is selected from * -C(O)-NH- and * -NH-C(O)-, where the " * " indicates the point of attachment to W 3 ;
  • X and Y are independently selected from CH 2 , NR 12 , and C(O), provided that X and Y are different;
  • R 1 and R 2 are independently selected from hydrogen, hydroxy, optionally substituted alky], optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroar ⁇ l, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 1 and R 2 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; for each occurrence, R 3 , R 4 .
  • R 5 and R 6 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 5 and R 6 , taken together with any intervening atoms, form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl ring; each R 7 and R 10 are independently selected from hydrogen, cyano, halo, hydroxy, azido, nitro, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted heteroaryloxy, optionally substituted heterocycl
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2 and 3; p is selected from 1 , 2, and 3; and q is selected from 0 and 1.
  • composition comprising a pharmaceutically acceptable carrier and at least one chemical entity described herein.
  • a packaged pharmaceutical composition comprising a pharmaceutical composition described herein, and instructions for using the composition to treat a patient suffering from a disease associated with smooth muscle myosin or non-muscle myosin.
  • Also provided is 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 described herein.
  • Also provided is a method of treating or ameliorating a disease associated with airway wall remodeling in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity described herein.
  • ATP adenosine 5'-triphosphate
  • BSA bovine serum albumin
  • NAOH nicotinamide adenine dinucleotide
  • EGTA ethylene glycol-bis(2-aminoethylether)-N,N,N',N 1 -tetraacetic acid
  • CDI carbonyldiimidazole
  • DIAD diisopropyl azodicarboxylate
  • DIPEA N,N-diisopropy!ethylamine
  • HBTU 0-(benzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /',/V'-tetramethyluronium hexafluorophosphate
  • NMP N-Methyl-2-pyrrolidone
  • Ph phenyl
  • TBAF tetrabutylammonium fluoride
  • TES triethylsilyl or triethylsilane
  • TMS trimethylsilyl or trimethylsilane
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • ATPase refers to an enzyme that is capable of hydrolyzing ATP.
  • ATPases include proteins comprising molecular motors such as myosins.
  • Alkyl encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms.
  • Ci-C 6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl residue having a specific number of carbons is named, all branched and straight chain versions 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 six carbons. 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 a subset of alky I, 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.
  • 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 molecule of hydrogen from adjacent carbon atoms of the parent alkyl.
  • 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; 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-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3- dien-2-yl; and the like.
  • an alkenyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms.
  • “Lower alkenyl” refers to alkenyl groups having two to six carbons.
  • Alkynyl refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the parent alkyl.
  • 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 -yn-1-yl, but-1 -yn-3-yl, but-3-yn-1-yl; and the like.
  • an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms.
  • “Lower alkynyl” refers to alkynyl groups having two to six carbons.
  • 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 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 six 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.
  • Forml refers to the group -C(O)H.
  • Carboxy and/or “carboxyl” refer to the group -C(O)OH.
  • a C 1 -C 6 alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • amino is meant the group -NH 2 .
  • “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 selected from H, optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, optionally substituted alkoxy; and R c is independently selected 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 Ci-C 4 alkyl, aryl, heteroaryl, aryl-d-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, Ci-C 4 haloalkyl, -OCi-C 4 alkyl, -OC 1 -C 4 alkylphenyl, -Ci-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
  • 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 selected 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 e is selected from hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • R f and R 9 are independently selected from hydrogen optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, provided that at least one of R ⁇ , R f , and R 9 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 selected from
  • -R a , -OR b optionally substituted amino (including -NR c COR b , -NR 0 CO 2 R 3 .
  • R c is independently selected from hydrogen and optionally substituted C1-C4 alkyl
  • 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-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, Ci-C 4 haloalkyl, -OCi-C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -OC 1 -C 4 haloalkyl, halo, -OH, -NH 2 , -C 1 -C 4 alkyl-NH 2 , -N(C 1 -C 4 alkyl)(C r C 4 alkyl), -NH(C 1 -C 4 alkyl), -N(
  • halo includes fluoro, chloro, bromo, and iodo
  • halogen includes fluorine, chlorine, bromine, and iodine
  • Haloalkyl indicates alkyl as defined above having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • Heteroaryl encompasses:
  • 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, be ⁇ zoimidazolinyl, 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
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O ' ) substituents, such as pyridinyl N-oxides.
  • heterocycloalkyl is meant a single, non-aromatic ring, usually with 3 to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms.
  • the ring may be saturated or have one or more carbon-carbon double bonds.
  • Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2- pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, and 2,5-piperizinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-mo ⁇ holinyl (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 6 )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(0)-(optionally substituted (Ci- C 6 )alkyl), -S(O)-optionally substituted aryl), -S(O)-optionally substituted heteroaryl), - S(O)-(optionally substituted heterocycloalkyl); and -S(O)-(optionally substituted amino).
  • sulfonyl includes the groups: -S( ⁇ 2 )-(optionally substituted (CrC 6 )alkyl), -S(O 2 )-optionally substituted aryl), -S(0 2 )-optionally substituted heteroaryl), -S( ⁇ 2)-(optionally substituted heterocycloalkyl), and -S( ⁇ 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, 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 selected from
  • -R a , -OR b optionally substituted amino (including -NR c COR b , -NR c CO 2 R a , -NR c CONR b R c , -NR b C(NR c )NR b R c , -NR b C(NCN)NR b R c , and -NR 0 SO 2 R 3 ), halo, cyano, azido, nitro, oxo (as a substitutent for cycloalkyl or heterocycloalkyl), 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 c , -OCONR b R c , -OP(O)
  • R b is selected from hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently selected from hydrogen and optionally substituted CrC 4 alkyl
  • 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-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, C 1 -C 4 haloalkyl, -OCi-C 4 alkyl, -OCi-C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -OCi-C 4 haloalkyl, halo, -OH, -NH 2 , -Ci-C 4 alkyl-NH 2 , -N(Ci-C 4 alkyl)(d-C 4 alkyl), -NH(Ci-C 4 alkyl), -N(Ci-C 4 al
  • -CO 2 H -C(O)OCi-C 4 alkyl, -CON(Ci-C 4 alkyl)(Ci-C 4 alkyl), -CONH(C 1 -C 4 alkyl), -CONH 2 , -NHC(O)(Ci-C 4 alkyl), -NHC(O)(phenyl), -N(Ci-C 4 alkyl)C(O)(d-C 4 alkyl), -N(Ci-C 4 alkyl)C(O)(phenyl), -C(O)Ci-C 4 alkyl, -C(O)Ci-C 4 alkylphenyl, -C(O)Ci-C 4 haloalkyl, -OC(O)Ci-C 4 alkyl, - SO 2 (Ci-C 4 alkyl), -SO 2 (phenyl), -SO 2 (C 1 -C 4 haloalkyl), -SO 2
  • 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 selected 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 c , and -NR c SO 2 R a ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl or heterocycloalkyl), 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 8 , -OCONR b R c , -OCONR b R c , -OP(O)(OR b )
  • R b is selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently selected 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.
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e. -O-(substituted alkyl)) wherein “substituted alkyl” refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected 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 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 or heterocycloalkyl), optionally substituted acyl (
  • R b is selected from H, optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently selected 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 C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, C 1 -C 4 haloalkyl, -OC 1 -C 4 alkyl, -OCi-C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -OCi-C 4 haloalkyl, halo, -OH, -NH 2 , -C 1 -C 4 alkyl-NH 2 , -N(Ci-C 4 alkyl)(d-C 4 alkyl), -NH(Ci-C 4 alkyl), -N(Ci-C 4
  • a substituted alkoxy group is "polyalkoxy" or -O- (optionally substituted alkylene)-(optionally substituted alkoxy), and includes groups such as -OCH2CH2OCH3, and residues of glycol ethers such as polyethyleneglycol, and -O(CH2CH2O)xCH3, where x is an integer of 2-20, such as 2-10, and for example, 2-5.
  • Another substituted alkoxy group is hydroxyalkoxy or -OCH2(CH2)yOH, where y is an integer of 1-10, such as 1-4.
  • 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 selected 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 c )NR b R°, -NR b C(NCN)NR b R c , and -NR c SO 2 R a ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl or heterocycloalkyl), 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 c , -OCONR b R c , -OP(O)(OR b )
  • R b is selected from H, optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R° is independently selected from hydrogen and optionally substituted Ci-C 4 alkyl
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from Ci-C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, Ci-C 4 haloalkyl, -OCi-C 4 alkyl, -OCi-C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -OCi-C 4 haloalkyl, halo, -OH, -NH 2 , -Ci-C 4 alkyl-NH 2l -N(C r C 4 alkyl)(Ci-C 4 alkyl), -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl)
  • substituted amino refers to the group -NHR d or -NR d R ⁇ wherein R d is selected from hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein R e is selected 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, heteroaryl, and heteroaryl refer respectively
  • -R a , -OR b optionally substituted amino (including -NR c COR b , -NR c CO 2 R a , -NR c CONR b R c , -NR b C(NR c )NR b R c , -NR b C(NCN)NR b R c , and -NR 0 SO 2 R 3 ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO 2 R 6 ), aminocarbonyl (such as -CONR b R c ), -OCOR b , -OCO 2 R 3 , -OCONR b R c , -OCONR b R c , -OP(O)(OR b ,
  • R c is independently selected 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 C1-C4 alkyl, aryl, heteroaryl, aryl-Ci-C4 alkyl-, heteroaryl-Ci-C 4 alkyl-, C1-C4 haloalkyl, -OC 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C4 alkyl-OH, -OC1-C 4 haloalkyl, halo, -OH, -NH 2 , -C1-C4 alkyl-NH 2 , -N(C 1 -C 4 alkyl)(Ci-C 4 alkyl), -NH(C 1 -C 4 alkyl), -N(C 1
  • 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 I include, but are not limited to, optical isomers of compounds of Formula I, 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.
  • compounds of Formula I include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds. Where compounds of Formula I exists in various tautomeric forms, chemical entities described herein include all tautomeric forms of the compound.
  • Chemical entities described herein include, but are not limited to compounds of Formula I 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 I.
  • prodrugs includes any chemical entities that become compounds of Formula I 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 I.
  • solvate refers to the chemical entity formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
  • chelate refers to the chemical entity formed by the coordination of a compound to a metal ion at two (or more) points.
  • non-covalent complex refers to the chemical entity formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule.
  • complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • an active agent is used to indicate a chemical entity which has biological activity.
  • an “active agent” is a compound having pharmaceutical utility.
  • an active agent may be an anti-cancer therapeutic.
  • 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.
  • terapéuticaally effective amount of a chemical entity described herein means an amount effective, when administered to a human or non- human patient, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.
  • Treatment means any treatment of a disease in a patient, including: a) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; b) inhibiting the disease; c) slowing or arresting the development of clinical symptoms; and/or d) relieving the disease, that is, causing the regression of clinical symptoms.
  • Patient refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful in both human therapy and veterinary applications.
  • the patient is a mammal; in some embodiments the patient is human; and in some embodiments the patient is selected from cats and dogs.
  • W 1 is selected from NR 11 , O, and S;
  • W 2 is selected from CH and N;
  • W 3 is selected from CR 1 R 2 and NR 13 ;
  • W 4 is selected from *-C(O)-NH- and *-NH-C(O)-, where the " * " indicates the point of attachment to W 3 ;
  • X and Y are independently selected from CH 2 , NR 12 , and C(O), provided that X and Y are different;
  • R 1 and R 2 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 1 and R 2 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl; for each occurrence, R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted acyl
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; m is selected from 0, 1 , 2 and 3; n is selected from 0, 1 , 2 and 3; p is selected from 1 , 2, and 3; and q is selected from 0 and 1.
  • W 1 is NR 11 .
  • R 11 is selected from hydrogen and optionally substituted alkyl.
  • R 11 is selected from hydrogen and optionally substituted lower alkyl.
  • R 11 is selected from hydrogen and lower alkyl.
  • R 11 is hydrogen
  • W 1 is O.
  • W 1 is S.
  • W 2 is CH.
  • W 2 is N.
  • W 3 is CR 1 R 2 .
  • R 1 is selected from hydrogen and optionally substituted lower alkyl.
  • R 1 is selected from hydrogen and lower alkyl.
  • R 1 is selected from methyl, ethyl, isopropyl, propyl, butyl, and t-butyl.
  • R 1 is methyl or ethyl.
  • R 2 is selected from hydrogen and optionally substituted lower alkyl.
  • R 2 is hydrogen
  • R 1 and R 2 together with any intervening atoms form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.
  • R 1 and R 2 together with any intervening atoms form a group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, and 2H-3,4,5,6-tetrahydropyranyl, each of which is optionally substituted.
  • R 1 and R 2 together with any intervening atoms form a group selected from cyclopentyl, cyclohexyl, piperidinyl, and 2H-3,4,5,6- tetrahydropyranyl, each of which is optionally substituted.
  • W 3 is NR 13 .
  • R 13 is selected from hydrogen and optionally substituted alkyl.
  • R 13 is selected from hydrogen and optionally substituted lower alkyl.
  • R 13 is selected from hydrogen and lower alkyl.
  • R 13 is hydrogen
  • X is CH 2 .
  • Y is C(O).
  • Y is NR 12 .
  • R 12 is selected from hydrogen and optionally substituted alkyl.
  • R 12 is selected from hydrogen and optionally substituted lower alkyl.
  • R 12 is selected from hydrogen and optionally substituted lower alkyl.
  • R 12 is hydrogen
  • X is C(O).
  • Y is CH 2 .
  • Y is NR 12 .
  • R 12 is selected from hydrogen and optionally substituted alkyl.
  • R 12 is selected from hydrogen and optionally substituted lower alkyl.
  • R 12 is selected from hydrogen and lower alkyl.
  • R 12 is hydrogen
  • X is NR 12 .
  • R 12 is selected from hydrogen and optionally substituted alkyl.
  • R 12 is selected from hydrogen and optionally substituted lower alkyl.
  • R 12 is selected from hydrogen and lower alkyl. [0117] In some embodiments, R 12 is hydrogen.
  • Y is CH 2 .
  • Y is C(O).
  • q is 1.
  • R 5 and R 6 is independently selected from hydrogen, optionally substituted lower alkyl and lower alkoxycarbonyl.
  • R 5 and R 6 is independently selected from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, and methoxycarbonyl.
  • each R 5 and R 6 is hydrogen.
  • R 5 and R 6 taken together with any intervening atoms, form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl ring. In some embodiments, R 5 and R 6 , taken together with any intervening atoms, form an optionally substituted heterocycloalkyl ring. In some embodiments, R 5 and R 6 , taken together with any intervening atoms, form an optionally substituted piperidine ring.
  • R 5 and R 6 taken together with any intervening atoms, form a piperidine ring optionally substituted with a group chosen from optionally substituted alkyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, and optionally substituted acyl.
  • q is two and for one occurrence, R 5 and R 6 , taken together with any intervening atoms, form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl ring. In some embodiments, R 5 and R 6 , taken together with any intervening atoms, form an optionally substituted heterocycloalkyl ring. In some embodiments, R 5 and R 6 , taken together with any intervening atoms, form an optionally substituted piperidine ring.
  • R 5 and R 6 taken together with any intervening atoms, form a piperidine ring optionally substituted with a group chosen from optionally substituted alkyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, and optionally substituted acyl.
  • q is 0.
  • W 4 is -C(O)-NH-.
  • W 4 is -NH-C(O)-.
  • m is 1 or 2.
  • R 7 is selected from chloro, fluoro, methyl, and trifluoromethyl.
  • m is 1 and R 7 is chloro.
  • m is 2 and each R 7 is chloro.
  • a chloro is at position 2 and position 3 relative to the attachment of the phenyl ring.
  • m is 2 and a first occurrence of R 7 is chloro and a second occurrence of R 7 is fluoro.
  • n is selected from 1 and 2.
  • n 1
  • each R 3 and R 4 is independently selected from hydrogen, optionally substituted lower alkyl, and optionally substituted lower alkoxycarbonyl.
  • each R 3 and R 4 is independently selected from hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, and methoxycarbonyl.
  • each R 3 and R 4 is hydrogen.
  • p is selected from 1 and 2.
  • p is 1.
  • each R 10 is independently selected from cyano, chloro, bromo, methyl, ethyl, isopropyl, t-butyl, hydroxymethyl, trifluoromethyl, methoxycarbonyl, phenoxy, trifluoromethoxy, methoxy, N.N-dimethyamino, and 1H- imidazolyl.
  • each R 10 is selected from methyl, ethyl, and isopropyl.
  • p is 1 and R 10 is isopropyl.
  • a compound of Formula I selected from (te(tert-butoxy)-n-[2-(4- ⁇ n-[(2-chlorophenyl)methyl]carbamoyl ⁇ -4- ⁇ [(5-ethylindol-2- yl)carbonylamino]methyl ⁇ piperidyl)-2-oxoethyl]carboxamide; tert-butyl 4- ⁇ n-[(2-chlorophenyl)methyl]carbamoyl ⁇ -4- ⁇ [(5-ethylindol-2- yl)carbonylamino]methyl ⁇ piperidinecarboxylate; (1-(2-aminoacetyl)-4- ⁇ [(5-ethylindol-2-yl)carbonylamino]methyl ⁇ (4-piperidyl))-N-[(2- chlorophenyl)methyl]carboxamide; (1-(2-aminoacetyl)-4- ⁇ [(5-methylbenzimida
  • a chemical name generated for a given structure by one program may be given a different or alternate name by a second program.
  • a chemical name generated for a given structure drawn in one program may or may not give the same structure when that name is converted into a structure in a different program.
  • Step 1 to a solution of a base such as diisopropylamine in a polar, aprotic solvent such as tetrahydrofuran at about -78 0 C is added an excess (such as about 1.2 equivalents) of an organometallic reagent such as n-butyllithium (for example, 2M n-butyllithium in hexane). The reaction mixture is stirred for about 1 hour. A solution of a compound of Formula 101 in a polar, aprotic solvent such as tetrahydrofuran is then added dropwise at about -78 0 C. The reaction mixture is stirred for about 1 hour and then an excess (such as about 1.1 equivalents) of methyl chloroformate is added. The product, a compound of Formula of 102, is isolated and optionally purified.
  • a base such as diisopropylamine in a polar, aprotic solvent such as tetrahydrofuran at about -78 0 C is added
  • Step 2 to a solution of a compound of Formula 102 in a polar solvent system such as a 1:1 mixture of tetrahydrofuran and methanol is added an excess (such as about 1.1 equivalents) of an aqueous base solution such as lithium hydroxide (for example, 2N lithium hydroxide in water). The reaction mixture is stirred at about 80 0 C for about 1 hour. The product, a compound of Formula 103, is isolated and optionally purified.
  • a polar solvent system such as a 1:1 mixture of tetrahydrofuran and methanol
  • an aqueous base solution such as lithium hydroxide (for example, 2N lithium hydroxide in water).
  • the reaction mixture is stirred at about 80 0 C for about 1 hour.
  • the product, a compound of Formula 103 is isolated and optionally purified.
  • Step 3 to a solution of a compound of Formula 103 in a polar, aprotic solvent such as dimethylformamide is added an excess (such as about 1.2 equivalents) of a peptide coupling reagent such as N.N.N'.N 1 - tetramethyl-0-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, an excess (such as about 1.2 equivalents) of a compound of Formula 104, and an excess (such as about 0.1 equivalents) of a base such as diisopropylethylamine.
  • a peptide coupling reagent such as N.N.N'.N 1 - tetramethyl-0-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate
  • an excess such as about 1.2 equivalents
  • a compound of Formula 104 an excess (such as about 0.1 equivalents) of a base such as diisopropylethy
  • Step 4 to a solution of a compound of Formula 105 in a polar, protic solvent system such as 2:1 methanohwater is added an excess (such as about 1.2 equivalents of a base such as sodium hydroxide. The reaction mixture is stirred for about 1 hour. The product, a compound of Formula 106, is isolated and optionally purified.
  • a polar, protic solvent system such as 2:1 methanohwater
  • Step 5 to a solution of a compound of Formula 106 in a polar, aprotic solvent such as dimethylformamide is added an excess (such as about 1.2 equivalents) of a peptide coupling reagent such as N, N 1 N', N'- tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate and an excess (such as about 1.2 equivalents) of 1-hydroxybenzothazole, and an excess (such as about 1.0 equivalent) of a compound of Formula 107.
  • the resulting mixture is stirred for about 0.5 hours.
  • the product, a compound of Formula 108 is isolated and optionally purified.
  • Step 1 to a solution of a compound of Formula 201 in a polar, protic solvent such as methanol is added an excess of an acid such as hydrogen chloride (for example, 4M hydrogen chloride in dioxane). The resulting reaction mixture is stirred for about 0.5 hours. The product, a compound of Formula 202, is isolated and optionally purified.
  • a polar, protic solvent such as methanol
  • Step 2 to a compound of Formula 203, wherein Z is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, in a polar, aprotic solvent such as dimethylformamide is added an excess (such as about 1.2 equivalents) of N 1 N 1 N' ,N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, a compound of Formula 202, and an excess (such as about 2.0 equivalents) of a base such as diisopropylethylamine.
  • the reaction mixture is stirred for about 0.5 hours.
  • the product, a compound of Formula 204 is isolated and optionally purified.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin- layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures are provided in the Example. However, other equivalent separation or isolation procedures can, of course, also be used.
  • the (R) and (S) isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step may be required to liberate the desired enantiomeric form.
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts and/or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the chemical entities described herein may be useful in a variety of applications involving smooth muscle cells and/or non-muscle cells.
  • the chemical entities may be used to inhibit smooth muscle myosin.
  • the chemical entities may be useful to bind to, and/or inhibit the activity of, smooth muscle myosin.
  • the smooth muscle myosin is human, although the chemical entities may be used to bind to or inhibit the activity of smooth muscle myosin from other organisms, such as other mammals.
  • the chemical entities may be used to inhibit non-muscle myosin.
  • the chemical entities may be useful to bind to, and/or inhibit the activity of, non-muscle myosin.
  • the non-muscle myosin is human, although the chemical entities may be used to bind to or inhibit the activity of non-muscle myosin from other organisms, such as other mammals.
  • the chemical entities described herein may be used to treat disease states associated with smooth muscle and/or non-muscle myosin.
  • 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.
  • the chemical entities described herein are applied to cells or administered to individuals afflicted or subject to impending affliction with any one of these disorders or states.
  • the chemical entities described herein may be useful for the treatment of diseases or symptoms related to abnormal increased muscle tone or excessive contraction, or spasm of vascular smooth muscle in systemic, coronary, pulmonary circulation, and micro-circulatory smooth muscle as well, such as systemic hypertension, malignant hypertension, hypertension crisis, symptomatic hypertension, pulmonary hypertension, pulmonary infarction, angina pectoris, cardiac infarction, micro-circulation malfunction under shock condition, and infarction occurred in other location or organs of the human or animal body.
  • diseases or symptoms related to abnormal increased muscle tone or excessive contraction, or spasm of vascular smooth muscle in systemic, coronary, pulmonary circulation, and micro-circulatory smooth muscle as well such as systemic hypertension, malignant hypertension, hypertension crisis, symptomatic hypertension, pulmonary hypertension, pulmonary infarction, angina pectoris, cardiac infarction, micro-circulation malfunction under shock condition, and infarction occurred in other location or organs of the human or animal body.
  • spasm of gastro-intestine smooth muscle including sphincters, such as gastric spasm, pylorospasm, and spasms of biliary tract, pancreatic tract, urinary tract, caused by inflammation, stimulation of stones or parasites; spasm of other visceral organs such as uterus, Fallopian tube, and so on; spasm of trachea-bronchial tree smooth muscle, diaphragm muscle, such as various asthma, breathlessness, dyspnea, diaphragmatic convulsion, and so on; spasm of alimentary canal smooth muscle, including stomach, intestine and colons, biliary and pancreatic duct etc.; and spasm of urinary tract smooth muscle.
  • sphincters such as gastric spasm, pylorospasm, and spasms of biliary tract, pancreatic tract, urinary tract, caused by inflammation, stimulation of stones or parasites
  • spasm of other visceral organs
  • the chemical entities described herein can be used for control, management and manipulation of labor during pregnancy.
  • the method is particularly useful for inhibition of spontaneous preterm labor which would, if untreated, result in premature delivery or abortion and for inhibition of surgically induced labor during transuterine fetal surgery.
  • the method is also useful for inducing the labor in overterm pregnancies where the labor does not occur on term and when it is necessary to induce labor in order to assure the normal delivery.
  • airway wall remodeling is a condition associated with diseases or conditions characterized by airway wall thickening and air obstruction, which may, for example occur in the small airways of patients with certain respiratory disease conditions, such as, chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Such disease states which can be treated by the chemical entities, compositions and methods provided herein also include, but are not limited to glaucoma and other ocular indications. More specifically, chemical entities described herein may be useful for the treatment of diseases or symptoms related to glaucoma, including increased intraocular pressure, reduced flow of intraocular aqueous humor, and optical nerve damage. Other diseases or symptoms that can be treated with the chemical entities, compositions, and methods described herein including intraocular hypertenstion.
  • ATP hydrolysis is employed by myosin to produce force.
  • An increase in ATP hydrolysis would correspond to an increase in the force or velocity of muscle contraction.
  • myosin ATPase activity is stimulated more than 100-fold.
  • Assays for such activity may employ smooth muscle myosin from a human source, although myosin from other organisms can also be used. Systems that model the regulatory role of calcium in myosin binding may also be used.
  • the in vitro rate of ATP hydrolysis correlates to smooth muscle myosin potentiating activity, which can be determined by monitoring the production of either ADP or phosphate, for example as described in U.S. Patent No. 6,410,254.
  • ADP production can also be monitored by coupling the ADP production to NADH oxidation (using, for example, the enzymes pyruvate kinase and lactate dehydrogenase) and monitoring the NADH level, by example, either by absorbance or fluorescence (Greengard, P., Nature 178 (Part 4534): 632-634 (1956); MoI 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 (JProc Natl Acad Sci U S A ⁇ 992 Jun 1 ;89(11):4884-7) or fluorescence (Biochem J 1990 Mar 1 ;266(2):611-4). While a single measurement is employed, multiple measurements of the same sample at different times in order may be used to determine the absolute rate of the protein activity; such measurements have higher specificity particularly in the presence of test compounds that have similar absorbance or fluorescence properties with those of the enzymatic readout.
  • Test compounds may be assayed in a highly parallel fashion using multiwell plates by placing the compounds either individually in wells or testing them in mixtures. Assay components including the target protein complex, coupling enzymes and substrates, and ATP may then be added to the wells and the absorbance or fluorescence of each well of the plate can be measured with a plate reader.
  • One method uses a 384 well plate format and a 25 ⁇ L reaction volume.
  • a pyruvate kinase/lactate dehydrogenase coupled enzyme system (Huang TG and hackney DD. (1994) J Biol Chem 269(23): 16493-16501) is used to measure the rate of ATP hydrolysis in each well.
  • the assay components are added in buffers and reagents. Since the methods outlined herein allow kinetic measurements, incubation periods may be optimized to give adequate detection signals over the background. The assay is performed in real time to give the kinetics of ATP hydrolysis to increase the signal-to-noise ratio of the assay.
  • Selectivity for smooth muscle myosin may be determined by substituting other myosins in one or more of the above-described assays and comparing the results obtained against those obtained using the cardiac equivalents.
  • Chemical entities identified by the methods described herein as smooth muscle myosin modulators may be further tested in an efficacy screen, such as a screen using strips of permeabilized smooth muscle from, e.g., chicken gizzard.
  • Calcium-sensitive smooth muscle strips are prepared by dissecting chicken gizzard tissue, followed by treatment with 1% Triton X-100 to make the strips permeable to exogenous compounds (Barsotti, RJ, et al., Am J Physiol. 1987 May;252(5 Pt 1):C543- 54). These strips can be stored in 50% glycerol for several weeks at -20 0 C, allowing multiple experiments to be performed with each batch of muscle strips.
  • the chemically skinned gizzard fibers are relaxed when bathed in low calcium solutions (pCa 8), but develop isometric tension when the free calcium of the bathing solution is increased to pCa 5. These fibers can be repeatedly contracted and relaxed by switching between high and low calcium bathing solutions.
  • the chemical entities are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment of the disease states previously described.
  • a daily dose is from about 0.05 to about 100 mg/kg of body weight, such as from about 0.10 to about 10 mg/kg of body weight or from about 0.15 to about 1 mg/kg of body weight.
  • the dosage range is from about 3.5 to about 7000 mg per day, such as from about 7 to about 700 mg per day or from about 10 to about 100 mg per day.
  • the amount of active chemical entity administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician; for example, a dose range for oral administration may be from about 70 to about 700 mg per day, whereas for intravenous administration the dose range may be from about 700 to about 7000 mg per day.
  • the active agents may be selected for longer or shorter plasma half-lives, respectively.
  • Administration of the chemical entities described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, 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.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, and the like.
  • the chemical entities can also be administered in sustained- or control led-release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, drops and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compositions may be provided in unit dosage forms suitable for single administration of a precise dose.
  • the chemical entities may be administered either alone or in combination with a conventional pharmaceutical carrier or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmeliose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
  • a conventional pharmaceutical carrier or the like e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmeliose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical composition may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate.
  • the pharmaceutical composition may contain from about 0.005% to about 95%, for example, from about 0.5% to about 50%, by weight of at least one chemical entity described herein.
  • Actual methods of preparing such dosage forms are known or will be apparent, to those skilled in this art; for example, see Remington's Pha ⁇ vace ⁇ tical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • Pharmaceutical compositions are also referred to as pharmaceutical formulations.
  • the chemical entities may be co-administered with, and the pharmaceutical compositions can include, other medicinal agents, pharmaceutical agents, adjuvants, and the like.
  • the compositions are in the form of a pill or tablet and contain, along with the active ingredient, one or more of a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives and the like.
  • a powder, marume, solution or suspension e.g., in propylene carbonate, vegetable oils or triglycerides
  • Liquid pharmaceutical compositions may, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and one or more optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like) to form a solution or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like
  • injectables may be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject.
  • percentages of active ingredient ranging from about 0.01% to about 10% in solution may be used, and may be higher if the composition is a solid which will be subsequently diluted to the above percentages.
  • the composition has from about 0.2% to about 2% of the active agent in solution.
  • compositions comprising at least one chemical entity may be administered intraocularly (including intraocular, periocular, and retrobulbar injection and perfusion).
  • intraocularly including intraocular, periocular, and retrobulbar injection and perfusion.
  • the sterile composition is typically aqueous.
  • An appropriate buffer system may be added to prevent pH drift under storage conditions.
  • the use of balanced salt irrigating solutions may be necessary.
  • preservatives may be required to prevent microbial contamination during use.
  • compositions comprising at least one chemical entity may also be administered topically as eye drops, eye wash, creams, ointments, gels, and sprays.
  • the active ingredients When administered as eye drops or eye wash, the active ingredients are typically dissolved or suspended in suitable carrier, typically a sterile aqueous solvent.
  • suitable carrier typically a sterile aqueous solvent.
  • An appropriate buffer system may be added to prevent pH drift under storage conditions.
  • preservatives may be required to prevent microbial contamination during use.
  • compositions comprising at least one chemical entity may also be administered to the respiratory tract as an aerosol or in a solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the composition typically have diameters of less than 50 microns, for example, less than 10 microns.
  • Packaged pharmaceutical compositions comprising a pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from a disease associated with smooth muscle myosin or non-muscle myosin.
  • the packaged pharmaceutical compositions described herein are also used to treat a patients suffering from a disease associated with smooth muscle myosin selected from hypertension, asthma, chronic obstructive pulmonary disease, bronchoconstrictive disease, glaucoma and other ocular indications, incontinence and other bladder disfunctions, irritable bowel syndrome, p re-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.
  • Also provided is 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 described herein.
  • the method of treating or ameliorating a disease associated with smooth muscle myosin or non-muscle myosin described herein is used to treat diseases selected from hypertension, asthma, chronic obstructive pulmonary disease (COPD), 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.
  • diseases selected from hypertension, asthma, chronic obstructive pulmonary disease (COPD), bronchoconstrictive disease, glaucoma and other ocular indications, incontinence and other bladder disfunctions, irritable bowel syndrome, pre-term labor, esophogial dysmotility, strokes, subarachnoid
  • Also provided is a method of treating or ameliorating a disease associated with airway wall remodeling in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity described herein.
  • smooth muscle myosin is bound to a support and at least one chemical entity is added to the assay.
  • the chemical entity may be bound to the support and the smooth muscle myosin added.
  • Classes of compounds among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells.
  • assays may be used for this purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.), and the like. See, e.g., U.S. Patent No. 6,495,337. EXAMPLES
  • reaction mixture was then heated to 155 0 C for 10 min, cooled to rt, filtered, and purified by RP-HPLC using a mixture of acetonitrile and H 2 O to give tert-butyl methyl(2-(6-methyl-4-oxo-3,4- dihydroquinazolin-2-ylamino)ethyl)carbamate (80 mg, 52%).
  • Screening assays were performed using a pyruvate kinase and lactate dehydrogenase-coupled ATPase assay containing the following reagents: Potassium PIPES (50 mM), MgCI 2 (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 0 C 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), MgCI 2 (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.
  • 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.
  • Compound dose response assays are performed by first preparing a dilution series of test compound, each with an assay mixture containing potassium PIPES, MgCI 2 , KCI 1 ATP, BSA, potassium phosphate, amplex red, PEP, crosslinked smooth muscle actomyosin (subfragment-1), antifoam, and water.
  • the assay is started by adding an equal volume of solution containing potassium Pipes, MgCI 2 , 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 IC 50 is defined as the concentration at which ATPase activity is midway between the top and bottom of the dose response curve.
  • Certain chemical entities described herein have an IC 50 less than 10 ⁇ M; for example, less than 1 ⁇ M.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des entités chimiques qui modulent la myosine des muscles lisses et/ou la myosine non musculaire, des compositions pharmaceutiques et des méthodes de traitement de pathologies et de troubles associés à la myosine des muscles lisses et/ou à la myosine non musculaire.
PCT/US2007/017231 2006-08-02 2007-08-01 Entités chimiques, compositions et méthodes WO2008016666A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120264733A1 (en) * 2008-06-19 2012-10-18 Takanobu Kuroita Heterocyclic compound and use thereof
CN115028619A (zh) * 2014-09-10 2022-09-09 Epizyme股份有限公司 Smyd抑制剂
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11725010B2 (en) 2019-12-02 2023-08-15 Storm Therapeutics Limited Polyheterocyclic compounds as METTL3 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

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US20070135435A1 (en) * 2005-11-02 2007-06-14 Xiangping Qian Certain chemical entities, compositions, and methods
US20070293530A1 (en) * 2006-06-14 2007-12-20 Methylgene Inc. Sulfamide and sulfamate derivatives as histone deacetylase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070135435A1 (en) * 2005-11-02 2007-06-14 Xiangping Qian Certain chemical entities, compositions, and methods
US20070293530A1 (en) * 2006-06-14 2007-12-20 Methylgene Inc. Sulfamide and sulfamate derivatives as histone deacetylase inhibitors

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120264733A1 (en) * 2008-06-19 2012-10-18 Takanobu Kuroita Heterocyclic compound and use thereof
US9045436B2 (en) * 2008-06-19 2015-06-02 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9221836B2 (en) 2008-06-19 2015-12-29 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
CN115028619A (zh) * 2014-09-10 2022-09-09 Epizyme股份有限公司 Smyd抑制剂
US11725010B2 (en) 2019-12-02 2023-08-15 Storm Therapeutics Limited Polyheterocyclic compounds as METTL3 inhibitors
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

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