WO2016044771A1 - Inhibiteurs de hat et procédés pour leur utilisation - Google Patents

Inhibiteurs de hat et procédés pour leur utilisation Download PDF

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Publication number
WO2016044771A1
WO2016044771A1 PCT/US2015/051029 US2015051029W WO2016044771A1 WO 2016044771 A1 WO2016044771 A1 WO 2016044771A1 US 2015051029 W US2015051029 W US 2015051029W WO 2016044771 A1 WO2016044771 A1 WO 2016044771A1
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Prior art keywords
dioxothiazolidin
acetamide
compound
difluorocyclohexylidene
thiazolidine
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PCT/US2015/051029
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English (en)
Inventor
Edward A. Kesicki
Arthur F. Kluge
Michael A. Patane
John H. VAN DRIE, Jr.
Ce Wang
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Abbvie Inc.
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Publication of WO2016044771A1 publication Critical patent/WO2016044771A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings

Definitions

  • the present invention generally relates to compounds having activity as inhibitors of HAT enzymes.
  • the compounds find utility in any number of therapeutic applications, including treatment of cancer.
  • chromatin Within the eukaryotic cell nucleus, DNA is condensed and packaged into chromatin.
  • the structural unit of chromatin is a nucleosome, which consists of 147 base pairs of DNA wrapped 1.6 times around a histone core of two H2A-H2B dimers and a H3- H4 tetramer (Kornberg et al, 1999, Cell 98:285-294). Histones undergo extensive post- translational modification, which determines whether a gene is transcriptionally active or inactive (GoU and Bestor, 2002, Genes Dev. 16: 1739-1742; Grant, 2001 , Genome Biol. 2:).
  • Histone acetyltransferases catalyze the acetylation (transfer of an acetyl group) on a ⁇ -amino group of a target lysine side chain within a substrate histone
  • HDACs histone deacetylases
  • HATs are categorized into four major families based on primary sequence homology, shared structural features, and functional roles: Gcn5/PCAF (General control nonrepressed protein 5 and p300 and CBP associated factor); MYST (named for the founding members MOZ, Ybf2/Sas3, Sas2, and Tip60); p300/CBP (protein of 300kDa and CREB Binding Protein); and Rttl09 (Regulator of Tyl Transposition gene production 109).
  • Gcn5/PCAF General control nonrepressed protein 5 and p300 and CBP associated factor
  • MYST named for the founding members MOZ, Ybf2/Sas3, Sas2, and Tip60
  • p300/CBP protein of 300kDa and CREB Binding Protein
  • Rttl09 Regulation of Tyl Transposition gene production 109.
  • p300/CBP has multiple domains including three cysteine-histidine rich domains (CHI, CH2, and CH3), a KIX domain, a bromodomain, and a steroid receptor coactivator interaction domain (SRC-1 interaction domain).
  • CHI, CH2, and CH3 cysteine-histidine rich domains
  • KIX domain a KIX domain
  • bromodomain a bromodomain
  • SRC-1 interaction domain steroid receptor coactivator interaction domain
  • P300 and CBP were originally discovered as binding partners of El A adenoviral protein and cAMP -regulated enhancer binding proteins, respectively (Yee and Branton, 1985, Virology 147: 142-153; Harlow et al, 1986, Mol. Cell Biol. 6: 1579-1589; Chrivia et al, 1993, Nature 365:855-859).
  • P300/CBP was later found to have intrinsic HAT activity (Ogryzko et al., 1996, Cell 87:953-959; Bannister and Kouzarides, 1996, Nature 384:641-643).
  • P300/CBP has been shown to have promiscuous acetyltransferase activity towards > 70 substrates (Wang et al, 2008, Curr. Opin. Struct. Biol.
  • p300 also acts as a scaffold for transcription factors or a bridge to connect the transcription factors and the basal transcriptional machinery to activate transcription (Chan and Thangue, 2001, J. Cell Sci. 114:2363-2373; Chen and Li, 2011, Epigenetics 6:957-961).
  • P300/CBP proteins are involved in many cellular processes, including cell growth, proliferation, and
  • Inhibition of p300/CBP has therapeutic potential in cancer (Iyer et al., 2004, Proc. Natl. Acad. Sci. USA 101 :7386-7391; Stimson et al, 2005, Mol. Cancer Ther. 4: 1521-1532; Zheng et al, 2004, Methods Enzymol. 376: 188-199), cardiac disease (Davidson et al, 2005, Chembiochem. 6:162-170); diabetes mellitus (Zhou et al, 2004, Nat. Med. 10:633-637), and HIV (Varier and Kundu, 2006, Curr. Pharm. Des. 12: 1975- 1993).
  • P300/CBP has also been linked to other diseases, such as fibrosis (Ghosh and Varga, 2007, J. Cell. Physiol. 213:663-671), metabolic syndrome (Bricambert et al., 2010, J. Clin. Invest. 120:4316-4331), and progressive neurodegenerative diseases, such as Huntington Disease (Cong et al, 2005, Mol. Cell. Neurosci. 30: 12-23), Kennedy's disease (Lieberman et al, 2002, Hum. Mol. Genet. 11 : 1967-76), and Alzheimer's disease (Francis et al, 2007, Neurosci. Lett. 413:137- 140).
  • diseases such as fibrosis (Ghosh and Varga, 2007, J. Cell. Physiol. 213:663-671), metabolic syndrome (Bricambert et al., 2010, J. Clin. Invest. 120:4316-4331), and progressive neurodegenerative diseases, such as Huntington Disease (Cong et al, 2005,
  • the present invention is directed to compounds having activity as HAT inhibitors, including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, and the use of such compounds to treat HAT-related conditions or diseases, such as cancer.
  • compositions comprising a pharmaceutically acceptable carrier or excipient and a compound of structure (I) are provided.
  • a method for treating a HAT dependent condition in a mammal in need thereof comprises administering an effective amount of a pharmaceutical composition comprising a compound of structure (I) to the mammal.
  • a pharmaceutical composition comprising a compound of structure (I)
  • Exemplary conditions which can be treated with the disclosed compounds and compositions include, but are not limited to, cancer, metabolic disease, neurogenerative disorders and inflammation.
  • Amino refers to the -NH 2 radical.
  • Aminosulfonyl refers to the -S(0) 2 NH 2 radical.
  • Carboxyl refers to the -C0 2 H radical.
  • Cyano or “nitrilyl” refers to the -CN radical.
  • Niro refers to the -N0 2 radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), having from one to twelve carbon atoms (Ci-Ci 2 alkyl), from one to eight carbon atoms (Ci-Cs alkyl) or from one to six carbon atoms (Ci- C 6 alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (z ' so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl,
  • Alkenyl refers to an alkyl group which comprises one or more double bonds and has from one to twelve carbon atoms (Ci-Ci 2 alkenyl), from one to eight carbon atoms (Ci-Cg alkenyl) or from one to six carbon atoms (Ci-C 6 alkenyl), and which is attached to the rest of the molecule by a single bond, e.g. , ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted.
  • Alkynyl refers to an alkyl group which comprises one or more triple bonds and has from one to twelve carbon atoms (C 2 -Ci 2 alkynyl), from one to eight carbon atoms (C 2 -C8 alkynyl) or from one to six carbon atoms (C 2 -C 6 alkynyl), and which is attached to the rest of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, which is saturated or unsaturated ⁇ i.e., contains one or more double and/or triple bonds), and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single or double bond and to the radical group through a single or double bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted.
  • Alkenylene is a divalent alkene chain as defined above, comprising one or more carbon-carbon double bonds. Unless stated otherwise specifically in the
  • an alkenylene chain is optionally substituted.
  • Alkynylene is a divalent alkyne chain as defined above, comprising one or more carbon-carbon triple bonds. Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted.
  • Aminoalkylene refers to an alkylene as defined above, wherein the hydrocarbon chain is interrupted by ⁇ i.e., includes) at least one nitrogen atom.
  • the nitrogen atom(s) may be at any position in the hydrocarbon chain, including the terminal ends ⁇ i.e., the nitrogen atom may link the hydrocarbon chain to the rest of the molecule and/or to the radical group).
  • an aminoalkylene group is optionally substituted as described below.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.
  • Alkynyloxy refers to a radical of the formula -OR a where R a is an alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkynyloxy group is optionally substituted.
  • Alkoxyalkyl refers to a radical of the formula -RaORb where R a is alkylene radical as defined above and Rb is an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkoxyalkyl group is optionally substituted.
  • Alkylaminyl refers to a radical of the formula -NHR a or -NR a R a where each R a is, independently, an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylaminyl group is optionally substituted.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include spiro, fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • Aralkyl refers to a radical of the formula -Rb-R c where Rb is an alkylene chain as defined above and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group is optionally substituted.
  • Aryloxy refers to a radical of the formula -ORa where Ra is an aryl radical as defined above, for example phenoxy. Unless stated otherwise specifically in the specification, an aryloxy group is optionally substituted.
  • Carbocyclyl or “carbocyclic ring” refers to a stable monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
  • Carbocycles include cycloalkyls and aryls as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group is optionally substituted.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include spiro, fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
  • Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl,
  • Cycloalkylalkyl refers to a radical of the formula -R b Ri where R b is an alkylene chain as defined above and R d is a cycloalkyl radical as defined above. In certain embodiments, R b is substituted with a further cycloalkyl group, such that the
  • cycloalkylalk ly comprises two cycloalkyl moieties.
  • Cyclopropylalkyl and cyclobutylalkyl are exemplary cycloalkylalkyl groups, comprising at least one cyclopropyl or at least one cyclobutyl group, respectively. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group is optionally substituted.
  • fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g. , trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1 ,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.
  • Haloalkoxy refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1 ,2-difluoroethoxy,
  • Haloalkoxyalkyl refers to a radical of the formula -R a OR b where R a is an alkylene radical as defined above containing one to twelve carbon atoms and R b is a haloalkyl radical as defined above. Unless stated otherwise specifically in the
  • a haloalkoxyalkyl group is optionally substituted.
  • Heterocyclyl or “heterocyclic ring” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroatoms are selected from oxygen and sulfur
  • the heterocyclic ring i.e., the atoms which form the ring
  • the heterocyclic ring i.e., the atoms which form the ring
  • heterocyclyl radical are a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include spiro, fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l ,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a N-heterocyclyl group is optionally substituted.
  • Heterocyclylalkyl refers to a radical of the formula -R b R e where R b is an alkylene chain as defined above and R e is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include spiro, fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroatom may be a member of an aromatic or non-aromatic ring, provided at least one ring in the heteroaryl is aromatic. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl,
  • benzothiazolyl benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[3 ⁇ 4][l,4]dioxepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,
  • 1-oxidopyrimidinyl 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group is optionally substituted.
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group is optionally substituted.
  • Heteroarylalkyl refers to a radical of the formula -R b R f where R b is an alkylene chain as defined above and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group is optionally substituted.
  • Hydroxylalkyl is an alkyl radical as defined above substituted with one or more hydroxyl radicals. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted.
  • Hydroxylalkynyl is an alkynyl radical as defined above substituted with one or more hydroxyl radicals. Unless stated otherwise specifically in the specification, a hydroxylalkynyl group is optionally substituted.
  • Nitrilylalkyl is an alkyl radical as defined above substituted with one or more nitrilyl radicals. Unless stated otherwise specifically in the specification, a nitrilyalkyl group is optionally substituted.
  • Thioalkyl refers to a radical of the formula -SR a where R a is an alkyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group is optionally substituted.
  • substituted used herein means any of the above groups (e.g., alkyl, alkylene, alkeneylene, alkynylene, aminoalkylene, alkenyl, alkynyls, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkylaminyl, alkylsulfonyl, alkylsulfonimidoyl,
  • Substituted also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple -bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • a higher-order bond e.g., a double- or triple -bond
  • nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • substituted includes any of the above groups in which one or more hydrogen atoms are replaced
  • R g and R h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N- heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
  • Substituted further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or
  • heteroarylalkyl group may also be optionally substituted with one or more of the above substituents.
  • a "linker” is a moiety that joins one portion of a molecule to another portion.
  • Linkers range in length (i.e., the length of the longest contiguous chain of atoms) from about one atom to about 20 atoms, from about one atom to about 10 atoms, from about 1 atom to about 5 atoms or from about 1 atom to about 3 atoms.
  • the linkers described herein are covalently bound to each portion of the molecule and each of the atoms within the linker form a covelent bond with an adjacent atom.
  • Atoms within a linker moiety can vary and are typically selected from C, H, O, N, S and P.
  • the linker moiety is an optionally substituted alkylene, aminoalkylene, alkenylene, alkynylene or amidyl moiety, although other linker moieties are included in various other embodiments.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by so lvo lysis to a biologically active compound of the invention.
  • prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).
  • a discussion of prodrugs is provided in Higuchi, T., et al, A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the invention and the like.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F,
  • Radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
  • Certain isotopically-labelled compounds of structure (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon- 14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Accordingly, certain embodiments include compounds of structure (I) which include one or more deuterium substitutions at various positions.
  • Isotopically-labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Preparations and Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • Embodiments of the invention disclosed herein are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes.
  • the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products are typically identified by administering a radiolabeled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2- dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2- hydroxyethanesul
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine,
  • dicyclohexylamine lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine,
  • N-ethylpiperidine polyamine resins and the like.
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • a “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • Effective amount refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of a HAT related condition or disease in the mammal, preferably a human.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
  • disease and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present invention includes tautomers of any said compounds.
  • A is a 6, 7 or 8-membered carbocyclic or heterocyclic ring, the heterocyclic ring consisting of carbon and one or more heteroatoms selected from O and S;
  • X is -S- or -NH-
  • L is absent or a linker moiety
  • R 1 is aryl, heteroaryl or cycloalkyl
  • R 2 is H, D or Ci-C 6 alkyl.
  • compounds of structure (I) include the proviso that
  • R 1 is not /?-aminosulfonylphenyl or / ⁇ -fluorophenyl when A is unsubstituted cyclohexyl, R 2 is H and X is -S-.
  • compounds having the following structures are not included within the scope of compounds of structure (I), although such compounds are included within certain embodiments of the disclosed methods:
  • A is a 6, 7 or 8- membered carbocyclic ring. In some embodiments, A is cyclohexyl. In other words,
  • A is cycloheptyl. In some other embodiments, A is cyclooctyl.
  • A is a 6, 7 or 8- membered heterocyclic ring, such as a pyranyl or thiopyranyl ring.
  • the compound has the following structure (II)
  • Z is -C(R 5 )(R 6 )-, -0-, -S- or -S(0) 2 -;
  • R 3 , R 4 , R 5 and R 6 are each independently selected from H, D, hydroxyl, halo, carboxyl, nitrilyl, Ci-C 6 alkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy,
  • R 3 and R 4 or R 5 and R 6 join to from oxo or a heterocyclic or carbocyclic ring, and wherein R 3 and R 4 are bound to the same or different carbon atoms;
  • n 1, 2 or 3.
  • L is absent.
  • L is present.
  • the structure and/or length of linker moiety L is not particularly limited, and L is typically chosen to optimize the activity of the compounds of structure (I).
  • L comprises a chain of from one to three contiguous atoms, wherein the atoms are optionally substituted.
  • L consists of a chain of from one to three contiguous atoms, wherein the atoms are optionally substituted.
  • L comprises bonds selected from alkylene, aminoalkylene, alkenylene, alkynylene, carbonyl and amidylene bonds.
  • L consists of bonds selected from alkylene, aminoalkylene, alkenylene, alkynylene, carbonyl and amidylene bonds.
  • L comprises one of the following structures:
  • R' is H or Ci-C 6 alkyl, and m is 1, 2 or 3.
  • L has one of the immediately foregoing structures.
  • the compound has one of the following structures (Ila), (lib), (lie), (lid). (He), (Ilf), (Ilg) or (Ilh):
  • R 3 and R 4 are each H.
  • Z is -C(R 5 )(R 6 )-.
  • Z is -0-, -S- or -S(0) 2 -.
  • the compound has structure (Ila). In other embodiments, the compound has structure (lib). In more embodiments, the compound has structure (He). In still other embodiments, the compound has structure (lid). In yet other embodiments, the compound has structure (He). In some more embodiments, the compound has structure (llf). In yet more embodiments, the compound has structure (llg). In even other embodiments, the compound has structure (Ilh).
  • R 1 is aryl.
  • the aryl is phenyl. In certain more specific embodiments, the phenyl is substituted phenyl. In other embodiments, the phenyl is unsubstituted.
  • R 1 is heteroaryl.
  • the heteroaryl is substituted heteroaryl, and in other embodiments the heteroaryl is unsubstituted heteroaryl.
  • R 1 is cycloalkyl.
  • the cycloalkyl is substituted cycloalkyl.
  • the cycloalkyl is unsubstituted cycloalkyl.
  • R 1 is substituted with one or more substituents selected from D, hydroxyl, oxo, halo, nitro, nitrilyl, carboxyl, amino, amidinyl, formamidyl, aminocarbonyl, aminosulfonyl, alkyl, haloalkyl, alkoxy, alkynyloxy, haloalkoxy, alkylsulfonyl, alkylsulfonimidoyl,
  • alkylsulfonylaminyl alkycarbonylaminyl, alkylphosphoryl, heteroaryl, pyrazolyl, pyrazoleonyl, imidazolyl, imidazoleonyl and triazolyl.
  • R 1 when R 1 is substituted phenyl, R 1 has one of the following structures:
  • R 1 is substituted phenyl
  • R 1 is phenyl substituted with a heteroaryl moiety.
  • R 1 has one of the following structures:
  • R 1 is heteroaryl
  • the heteroaryl is monocyclic heteroaryl.
  • R 1 has one of the following structures:
  • R 1 is heteroaryl
  • the heteroaryl is a fused bicyclic heteroaryl.
  • R 1 has one of the following structures:
  • R 1 is cyclohexyl.
  • R 1 has the following structure:
  • R 1 has one of the following structures:
  • the compound has structure (II); (Ila); (lib); (lie); (lid); (He); (Ilg) or (Ilh), and Z is -C(R 5 )(R 6 )- wherein at least one of R 5 or R 6 is halo.
  • both of R 5 and R 6 are halo.
  • both of R 5 and R 6 are halo, and both of R 5 and R 6 are attached to the same carbon atom.
  • halo is fluoro.
  • halo is chloro.
  • halo is bromo.
  • the compound of structure (I) has the following
  • R 5 and R 6 are each independendently halo.
  • the compound of structure (I) has one of the following structures:
  • R 2 is H. In different of the foregoing embodiments R 2 is CH 3 .
  • n is 1. In other embodiments, n is 2. In still other embodiments, n is 3.
  • X is -S-. In some different embodiments X is -NH-.
  • Some embodiments of the invention also include deuterium substituted compounds of structure (I).
  • the deuterium may be included at various positions in the compound, for example in some embodiments one or more of R 1 , R 2 (when C C 6 alkyl), A and/or L are substituted with one or more deuterium atoms.
  • R 2 is deuterium. While not wishing to be bound by theory, such deuterium substitutions may contribute to advantageous metabolism of the compounds.
  • the compound is a compound selected from one of the compounds in Table 1, for example any one of compounds 1-1 to 141-1.
  • any embodiment of the compounds of structure (I), and substructures thereof, as set forth above, and any specific substituent or value set forth herein for A, L, X, R 1 and/or R 2 in the compounds of structure (I), as set forth above, may be independently combined with other embodiments and/or substituents and/or values of the above variables of compounds of structure (I) to form embodiments of the inventions not specifically set forth above.
  • a list of choices is listed for any particular R group or other variable in a particular embodiment and/or claim, it is understood that each individual choice may be deleted from the particular embodiment and/or claim and that the remaining list of choices will be considered to be within the scope of the invention.
  • the compounds of the present invention may contain one or more asymmetric centers.
  • Compounds as described herein include all stereoisomers. Accordingly, the compounds include racemic mixtures, purified enantiomers, diastereomeric mixtures and purified diastereomers of any of the compounds described herein. Tautomers of any of the compounds described herein are also included within the scope of the invention.
  • the compounds are mixtures of different enantiomers (e.g., R and S) or different diastereomers.
  • the compounds are pure (or enriched) enantiomers or diastereomers.
  • the chiral carbons are not always depicted in the compounds; however, the present invention includes all stereoisomers (pure and mixtures) of all compounds of Structure I.
  • General Reaction Scheme I illustrates an exemplary method of making compounds of this invention, i.e., compound of structure (I), wherein R 1 , R 2 , A, L and X are as defined above and "LG" is a leaving group (e.g., halogen, mesylate and the like). Variations of General Reaction Scheme I and alternative methods of making the compounds are derivable by one of ordinary skill in the art.
  • General Reaction Scheme I depicts only one of many methods available for preparation of compounds of structure (I) and various changes can be made to the exemplified method (e.g., protecting groups, order of synthetic steps, etc.) for preparation of compounds of structure (I).
  • Three exemplary methods for preparing various substructures of compounds of structure (I) e.g., where A is carbocyclic and X is S) are provided in General Reaction Scheme II.
  • compounds of structure xi (a compound of structure (I)) can be prepared by route 1. Namely, thiazolidinedione v is reacted with ketone vi under catalytic conditions with KF-AI2O3 to form vii. vii is then reacted with bromoacetic acid viii to form ix. Compound xi is then formed by reaction of ix with amine x (where R" is H or Ci-C 6 alkyl). Alternatively, xi may be prepared via route 2. According to route 2, amine x is reacted with bromoacetyl bromide xii to form xiii. Reaction of xiii with vii under basic conditions then yields xi.
  • starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and
  • Suitable protecting groups include hydroxy, amino, mercapto and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl, aryl or arylalkyl),
  • protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.
  • Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley.
  • the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
  • the compounds of the present invention may be administered as a raw chemical or may be formulated as pharmaceutical compositions.
  • the present invention is directed to a
  • composition comprising a pharmaceutically acceptable carrier or excipient and a compound having the following structure (I):
  • A is a 6, 7 or 8-membered carbocyclic or heterocyclic ring, the heterocyclic ring consisting of carbon and heteroatoms selected from -O- and -S-;
  • X is -S- or -NH-: L is absent or a linker moiety;
  • R 1 is aryl, heteroaryl or cycloalkyl
  • R 2 is H or Ci-C 6 alkyl.
  • the compound of structure (I) is any one of the compounds described above in the section entitled “Compounds.” In other embodiments, the compound is selected from a compound in Table 1.
  • the compound of structure (I) is present in the composition in an amount which is effective to treat a particular disease or condition of interest. Accordingly, in certain embodiments the compound is present in an amount sufficient to inhibit HAT activity, and preferably with acceptable toxicity to the patient.
  • HAT activity of compounds of structure (I) can be determined by one skilled in the art, for example, as described in the Examples below. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • parenteral as used herein includes subcutaneous injections, intravenous,
  • compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition
  • administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.
  • a pharmaceutical composition of the invention may be in the form of a solid or liquid.
  • the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
  • the pharmaceutical composition When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide;
  • sweetening agents such as sucrose or saccharin
  • a flavoring agent such as peppermint, methyl salicylate or orange flavoring
  • a coloring agent such as peppermint, methyl salicylate or orange flavoring
  • the pharmaceutical composition When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
  • a liquid carrier such as polyethylene glycol or oil.
  • the pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for oral administration or for delivery by injection, as two examples.
  • preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • the liquid pharmaceutical compositions of the invention may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediammetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred adjuvant.
  • a liquid pharmaceutical composition of the invention intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained.
  • the pharmaceutical composition of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Thickening agents may be present in a pharmaceutical composition for topical administration.
  • the composition may include a transdermal patch or iontophoresis device.
  • the pharmaceutical composition of the invention may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug.
  • the composition for rectal administration may contain an oleaginous base as a suitable non-irritating excipient.
  • bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
  • the pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients may be encased in a gelatin capsule.
  • the pharmaceutical composition of the invention in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound.
  • Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
  • the pharmaceutical composition of the invention may consist of dosage units that can be administered as an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols.
  • compositions of the invention may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
  • the compounds of the invention are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.
  • Compounds of the invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents.
  • Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation.
  • a compound of the invention and the other active agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations.
  • the compounds of the invention and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
  • the disclosed compounds are useful for inhibiting the activity of p300/CBP and/or can be useful in analyzing p300/CBP signaling activity in model systems and/or for preventing, treating, or ameliorating of a symptom associated with a disease, disorder, or pathological condition involving p300/CBP, preferably one afflicting humans.
  • a compound which inhibits the activity of p300/CBP will be useful in preventing, treating, ameliorating, or reducing the symptoms or progression of cancer, cardiac disease, metabolic disease, fibrotic disease, inflammatory disease, or viral infections.
  • the present invention provides methods for inhibiting p300/CBP comprising administering the compounds described herein in a therapeutically effective amount to a subject in need thereof.
  • a subject may be a human, non-human primate, rodent, canine, feline, ungulate, bovine, equine, or other species.
  • certain embodiments are directed to a method for treating a HAT dependent condition in a mammal in need thereof, the method comprising
  • a pharmaceutical composition as described above i.e., a pharmaceutical composition comprising any one or more compound of structure (I), for example any one or more compounds from Table 1
  • the condition is cancer, metabolic disease, neurogenerative disorders or inflammation.
  • the condition is cancer.
  • cancers including solid tumors and leukemias are amenable to the compositions and methods disclosed herein.
  • Types of cancer that may be treated include, but are not limited to: adenocarcinoma of the breast, prostate, and colon; all forms of bronchogenic carcinoma of the lung; myeloid; melanoma; hepatoma;
  • cancers e.g., Walker, basal cell, basosquamous, Brown-Pearce, ductal, Ehrlich tumor, Krebs 2, merkel cell, mucinous, non-small cell lung, oat cell, papillary, scirrhous, bronchiolar, bronchogenic, squamous cell, and transitional cell.
  • carcinoma e.g., Walker, basal cell, basosquamous, Brown-Pearce, ductal, Ehrlich tumor, Krebs 2, merkel cell, mucinous, non-small cell lung, oat cell, papillary, scirrhous, bronchiolar, bronchogenic, squamous cell, and transitional cell.
  • Additional types of cancers that may be treated include: histiocytic disorders;
  • leukemia leukemia; histiocytosis malignant; Hodgkin's disease; immunoproliferative small; non- Hodgkin's lymphoma; plasmacytoma; reticuloendotheliosis; melanoma; chondroblastoma; chondroma; chondrosarcoma; fibroma; fibrosarcoma; giant cell tumors; histiocytoma; lipoma; liposarcoma; mesothelioma; myxoma; myxosarcoma; osteoma; osteosarcoma; chordoma; craniopharyngioma; dysgerminoma; hamartoma; mesenchymoma;
  • cancers mesonephroma; myosarcoma; ameloblastoma; cementoma; odontoma; teratoma; thymoma; trophoblastic tumor.
  • adenoma cholangioma
  • cholesteatoma cholesteatoma
  • cyclindroma a type of cancers that are also contemplated as amenable to treatment: adenoma; cholangioma; cholesteatoma; cyclindroma;
  • cystadenocarcinoma cystadenoma; granulosa cell tumor; gynandroblastoma; hepatoma; hidradenoma; islet cell tumor; Leydig cell tumor; papilloma; Sertoli cell tumor; theca cell tumor; leimyoma; leiomyosarcoma; myoblastoma; myomma; myosarcoma; rhabdomyoma; rhabdomyosarcoma; ependymoma; ganglioneuroma; glioma; medulloblastoma;
  • cancers meningioma; neurilemmoma; neuroblastoma; neuroepithelioma; neurofibroma; neuroma; paraganglioma; paraganglioma nonchromaffin.
  • the types of cancers that may be treated also include, but are not limited to, angiokeratoma; angiolymphoid hyperplasia with eosinophilia; angioma sclerosing; angiomatosis; glomangioma; hemangioendothelioma; hemangioma; hemangiopericytoma; hemangiosarcoma; lymphangioma;
  • lymphangiomyoma lymphangiosarcoma; pinealoma; carcinosarcoma; chondrosarcoma; cystosarcoma phyllodes; fibrosarcoma; hemangiosarcoma; leiomyosarcoma; leukosarcoma; liposarcoma; lymphangiosarcoma; myosarcoma; myxosarcoma; ovarian carcinoma;
  • rhabdomyosarcoma sarcoma
  • neoplasms neoplasms
  • nerofibromatosis neoplasms
  • cervical dysplasia rhabdomyosarcoma
  • the present disclosure provides for methods of treating colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, CNS cancer, renal cancer, prostate cancer, ovarian cancer, leukemia, or breast cancer.
  • Another aspect of the present disclosure provides for using the p300/CBP inhibitory compositions disclosed herein to treat, prevent, or ameliorate a symptom associated with a chronic inflammatory disorder or condition, including but not limited to asthma, inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic obstructive pulmonary disease, rheumatoid arthritis, and psoriasis.
  • a chronic inflammatory disorder or condition including but not limited to asthma, inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic obstructive pulmonary disease, rheumatoid arthritis, and psoriasis.
  • Another aspect of the present disclosure provides for methods of treating, preventing, or ameliorating a symptom associated with a viral infection, including, but not limited to human immunodeficiency virus, hepatitis C virus, and human papilloma virus.
  • Yet another aspect of the present disclosure provides for methods of treating, preventing, or ameliorating a symptom associated with metabolic disease, including but not limited to: obesity, hepatic steatosis, dyslipidemia, hypertension, coronary heart disease, hepatic inflammation, and diabetes mellitus type 2.
  • Fibrotic diseases and disorders include, for example, radiation-induced pneumonitis, radiation fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, interstitial lung disease, myocardial infarction, ischemic stroke, ischemic kidney disease, transplant rejection, Leishmaniasis, type I diabetes, rheumatoid arthritis, chronic hepatitis, cirrhosis, inflammatory bowel disease, Crohn's disease, scleroderma, keloid, post-operative fibrosis, chemotherapy induced fibrosis (e.g., chemotherapy induced pulmonary fibrosis or ovarian cortical fibrosis), nephrogenic systemic fibrosis, retroperitoneal fibrosis, myelofibrosis, mediastinal fibrosis, cystic fibrosis
  • Another aspect of the present disclosure provides for methods of treating, preventing, or ameliorating a symptom associated with cardiac disease, including but not limited to cardiac hypertrophy and heart failure.
  • the present disclosure also relates to methods of treating, preventing, or ameliorating a symptom associated with a disease, disorder, or pathological condition involving p300/CBP comprising administering the compounds described herein in a therapeutically effective amount to a subject in need thereof as part of a combination therapy. It is apparent to a person of skill in the medical arts that agent(s) administered with the p300/CBP compounds disclosed herein are selected based upon the subject's disease, disorder, or pathological condition.
  • various embodiments of the present disclosure are directed to a method for treating a HAT dependent condition in a mammal in need thereof, the method comprising administering an effective amount of the pharmaceutical composition described herein (i.e., as described in the foregoing section entitled “Pharmaceutical Compositions and Administration”).
  • the condition is cancer, metabolic disease, neurogenerative disorders or inflammation.
  • the condition is cancer (e.g., the various cancers described herein above).
  • the compound is a compound as described in the foregoing section entitled “Compounds,” including the exemplary compounds provided in Table 1.
  • HAT assay kits for detecting HAT activity are well known in the art, and a variety of HAT assay kits are commercially available.
  • filter-binding assays measure the transfer of radiolabeled acetate from acetyl-CoA to protein
  • continuous, spectroscopic enzyme coupled assays link the HAT reaction to the reduction of NAD+ by pyruvate or a-ketoglutarate dehydrogenase (Berndsen and Denu, 2005, Methods 36:321- 333).
  • compounds disclosed herein may be screened by using a radiolabel that is incorporated into a biotinylated form of the substrate as a result of an enzymatic reaction (i.e., acetylation).
  • the reaction contents are then incubated on a specially manufactured multi-well plate (Perkin-Elmer), where the wells have been precoated with avidin and a scintillant.
  • beads precoated with avidin and scintillant may be used instead of plates.
  • the tight interaction of biotin-avidin complexes brings the radiolabel on the reaction product in close proximity to the scintillant, resulting in emission of a light signal.
  • the need for the proximity of the radiolabel to the scintillant to generate a signal enables a rapid readout without elaborate post-assay work up.
  • the interference from unreacted (hence free) radiolabel is minimal.
  • P300 HAT can acetylate all four core histones (HI A, H1B, H3, and H4), with acetylation occurring predominantly on the N-terminal amino acid residues.
  • a p300 HAT assay in SPA format was designed using a substrate (Biotin-C6- GRGKGGKGLGKGGAK) comprising a synthetic peptide of 15 amino acids derived from the N-terminus of human H4 (GRGKGGKGLGKGGAK (SEQ ID NO:l)) that is chemically attached to biotin with an amino hexanoic acid linker (C6).
  • the synthetic peptide was re-suspended in nanopure water; adjusted to pH 7.0 with concentrated NaOH; and subjected to amino acid analysis to estimate purity and concentration.
  • Tritiated acetylCoA was diluted with cold acetylCoA (in water) as needed and used in the assay.
  • P300 HAT in various forms full length and truncated was used as catalyst in the assay.
  • Compounds to be tested were dissolved in neat DMSO to make lOmM stocks and diluted further to make 4X stocks in lOmM HEPES, pH 7.8 with 20% DMSO. The final concentration of DMSO in assays was kept at 5%.
  • the assay was performed in a volume of 40 ⁇ 1 in a polypropylene 96 well plate.
  • a typical reaction (40 ⁇ 1) contained: lOOmM HEPES, pH 7.9, lOOmM KC1, lmM DTT, 50 ⁇ g/ml BSA, p300 HAT (0.2-5 nM), 0.01% Triton-X-100, 12.5 ⁇ biotinylated substrate peptide, 5% DMSO, and acetylated CoA (0.2 ⁇ to 0.6 ⁇ , set at IX Km app of acetylCoA).
  • 2X reaction mixture buffer ion, salt, substrate peptide, DTT, BSA, detergent, and enzyme
  • 20 ⁇ 1 of 2X reaction mixture buffer ion, salt, substrate peptide, DTT, BSA, detergent, and enzyme
  • the reaction was initiated by the addition of 10 ⁇ of 4X acetylCoA and quenched with 120 ⁇ 1 of 0.5N HC1 at required time intervals.
  • the contents ( ⁇ 160 ⁇ 1) were delivered to the SPA plate coated with avidin and scintillant, incubated for 1 hr, and light emission was counted in a TOP COUNT Microplate scintillation and luminescence counter (Perkin Elmer).
  • HeLa and HEK 293 were maintained and passaged in EMEM (ATCC, Manassas, VA) supplemented with 10% heat inactivated FBS, and were kept in a humidified incubator at 37°C and 5% C0 2 .
  • EMEM American Type Culture Collection
  • FBS heat inactivated FBS
  • cells were seeded into BD BioCoatTM 6-well poly-D-lysine coated plates (3 x 10 5 cells per well for HeLa and 6 x 10 5 cells for HEK 293) in 2 ml complete media and incubated overnight at 37°C and 5% C0 2 .
  • siRNA experiments transfections were done the day after seeding.
  • Cells were treated with a mixture of DharmaFECT formulation 1 and 25 pg/mL of p300 siRNA alone, both p300 and CBP siR As, or nontargeting siRNA (Thermo Scientific, Pittsburgh, PA) in complete media overnight. Treatments were aspirated off the following day and replaced with fresh media, and cells were incubated an additional 24 hours. Cells were then treated with HDAC inhibitors and TNF-a as described below.
  • compound dilutions were prepared in complete media from lOmM stock solutions in DMSO. 2 mL of media containing the appropriate concentration of inhibitor were added to each well. The final DMSO concentration in all wells was kept at 0.3 % .
  • Protein of the samples is measured using BCA (Bicinchoninic Acid) Protein assay kit (Thermo Scientific, product # 23227). Protein level is equilibrated among samples and prepared with sample buffer for loading into gels for electrophoresis.
  • Anti-p53 acetyl-Lysine 382 was obtained from Cell Signaling Technology, and anti-total p53 antibody was obtained from Santa Cruz. On the following day, membranes were washed 5x for 5min each time with PBS-T milk and incubated with secondary antibody for 3 hours and washed 5x for 5 min each time. Secondary antibodies linked to horseradish peroxidase , including anti-rabbit IgG and anti-mouse IgG, were obtained from Life Technologies. Detection was done by chemiluminescence and measured with FluorChem imager (Protein Simple).
  • CRE-LUC reporter system has tandem repeats of the CRE transcriptional response element and basic promoter elements to drive the transcription of a downstream reporter gene (luciferase).
  • P300 a transcriptional coactivator, binds CRE and drives the transcription of the downstream genes.
  • Cignal CRE-LUC reporter assay kit Qiagen (CCS- 002L) was used to establish a cell based assay for p300 function.
  • HEK293 cells were purchased from ATCC and cultured in EMEM with 10% HI FBS (ATCC ® 30-2003). To transfect the reporter in HEK 293 cells, Attractene, a transfection reagent from Qiagen (301005) was used.
  • HEK-293 cells were grown in EMEM with 10% FBS to 70% confluency.
  • the cells were harvested and plated in a 96 well Poly D-Lys plate (BIOCOAT ® Becton and Dickinson) with a cell density of 60000 cells/well in 100 of EMEM with 10% HI FBS.
  • the transfection cocktail (provided by the kit) was prepared in plain EMEM with no FBS. Positive control (GFP) and negative control from the kit were included.
  • the plate was treated with 25-50 of transfection cocktail and incubated at 37°C for 18-20 hrs. The next day, the plate was gently tapped over an absorbent pad to remove media.
  • the protocol is identical to CRE-LUC gene reporter assay except Cignal
  • NFkB reporter assay kit from Qiagen (CCS-013L) was used, and human TNF-a (final cone: 5ng/mL in EMEM with 0.4% DMSO and 10% FBS) was used for induction.
  • Table 1 The compounds in Table 1 were tested according to the above procedures. All of the compounds in Table 1 were found to have an IC 50 against HAT p300 of 120 ⁇ or less.
  • Table 2 summarizes the HAT p300 IC 50 data of the exemplary compounds from Table 1.
  • N/A N/A N/A +++ indicates IC 50 of 1 ⁇ or less

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Abstract

La présente invention concerne des composés ayant une structure de formule (I) : ou un stéréoisomère, un tautomère, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci, où A, L, X, R1 et R2, sont tels que définis dans la description. L'invention concerne en outre des compositions pharmaceutiques comprenant de tels composés et des procédés pour traiter différents états ou maladies associés à HAT, comprenant le cancer, par administration de tels composés.
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WO2018022637A1 (fr) 2016-07-25 2018-02-01 Epizyme, Inc. Cancérothérapie associée à crebbp
US11274090B2 (en) 2018-02-16 2022-03-15 Constellation Pharmaceuticals, Inc. P300/CBP HAT inhibitors
WO2022138944A1 (fr) * 2020-12-25 2022-06-30 国立研究開発法人国立がん研究センター Thérapie fondée sur la létalité synthétique dans un cancer à dysfonctionnement du complexe swi/snf
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018022637A1 (fr) 2016-07-25 2018-02-01 Epizyme, Inc. Cancérothérapie associée à crebbp
US11274090B2 (en) 2018-02-16 2022-03-15 Constellation Pharmaceuticals, Inc. P300/CBP HAT inhibitors
US11414384B2 (en) 2018-02-16 2022-08-16 Constellation Pharmaceuticals, Inc. P300/CBP hat inhibitors
WO2022138944A1 (fr) * 2020-12-25 2022-06-30 国立研究開発法人国立がん研究センター Thérapie fondée sur la létalité synthétique dans un cancer à dysfonctionnement du complexe swi/snf

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