WO2025006902A2 - Synthèse et caractérisation in vitro de chimères ciblant la protéolyse (protacs) pour la dégradation de l'adn méthyltransférase 1 (dnmt1) - Google Patents

Synthèse et caractérisation in vitro de chimères ciblant la protéolyse (protacs) pour la dégradation de l'adn méthyltransférase 1 (dnmt1) Download PDF

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WO2025006902A2
WO2025006902A2 PCT/US2024/036042 US2024036042W WO2025006902A2 WO 2025006902 A2 WO2025006902 A2 WO 2025006902A2 US 2024036042 W US2024036042 W US 2024036042W WO 2025006902 A2 WO2025006902 A2 WO 2025006902A2
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compound
amino
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mmol
linker
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WO2025006902A3 (fr
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Jun Qi
Priscilla LIOW
Tingjian WANG
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Dana Farber Cancer Institute Inc
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Dana Farber Cancer Institute Inc
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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
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings
    • 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

Definitions

  • DNMT1 Deoxyribonucleic acid methyl transferase 1
  • DNA methylation is a well-studied mechanism of epigenetic regulation, affecting the transcription of crucial genes, and DNA hyper- or hypo-methylation has been found to be associated with a number of human diseases including cancer
  • Existing drugs for DNMT1 dysregulation, such as decitabine and 5-azacytidine are highly toxic, and cancer cells often develop drug resistance.
  • a first aspect of the present disclosure is directed to a compound of formula I, (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
  • DNMT1 Targeting Ligand is of Formula TL-I or TL-2:
  • R1 is NR 3 R 4 ;
  • R 3 is H or methyl ,
  • R 3 and R 4 together with the nitrogen atom to which they are atached, form an optionally substituted 6-rnembered heterocyclyl, or
  • R 3 and R 4 together with the nitrogen atom to which they are attached, form an optionally substituted 6-membered heterocyclyl which is also bound to the linker;
  • Rs and Rc are independently H, optionally substituted alkyd, or ;
  • « is a bond between the DNMT1 Targeting Ligand and the Linker, provided that there is only one bond between the DNMT1 Targeting Ligand and the Linker; the linker represents a moiety that connects covalently the degron and the targeting ligand; and the Degron is of Formula DI, D2, or D3: wherein
  • Q is CH 2 or C(O);
  • Xi is O. NH, CH 2 , or C-C;
  • R7 is H or optionally substituted C 1 -C 6 alkyl, or
  • R 10 and R 11 are both H, or R 10 and R 11 , together with the carbon atom to which they are attached, form cyclopropyl;
  • R12 is H, fluoro, cyano, orNMe2; and wherein ' is a bond between the Degron and the Linker, provided that there is only one bond between the Degron and the Linker.
  • Another aspect of the present disclosure is directed to a pharmaceutical composition containing a therapeutically effective amount of a compound offormulal or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • a further aspect of the presen t disclosure is directed to a method of treating a disease or disorder involving (characterized or mediated by) aberrant DNMT1 activity, that includes administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof
  • compounds of formula I are believed to promote the degradation of DNMT1 via cells’ Ubiquitin/Proteasome System, whose function is to routinely identify' and remove damaged proteins. After destruction of an DNMT1 protein molecule, the degrader is released and continues to be active. Therefore, by' engaging and exp1oiting the body’s own natural protein disposal system, compounds of the present disclosure may represent a potential improvement over current small molecule inhibitors of DNMT1. Therefore, effective intracellular concentrations of the degraders may' be significantly lower than for small molecule DNMT1 inhibitors.
  • FIG. 1 is a Western Blot showing that compounds 1-4 degraded DNMT1 in HL60 cells at indicated concentrations.
  • FIG. 2 is a Western Blot showing that compounds 5-8 degraded DNMT1 in HL60 cells at indicated concentrations.
  • FIG. 3 is a Western Blot showing that compounds 9-12 degraded DNMTl in HL60 cells at indicated concentrations.
  • FIG. 4 is a Western Blot showing that compounds 13-16 degraded DNMTl in HL60 cells at indicated concentrations.
  • FIG. 5 is a Western Blot showing that compounds 17-19 degraded DNMTl in HL60 cells at indicated concentrations.
  • FIG. 6 is a Western Blot showing that compounds 20-23 degraded DNMTl in HL60 cells at indicated concentrations.
  • FIG. 7 is a Western Blot showing that compound 20 degraded DNMTl in HL60 cells at indicated concentrations.
  • FIG. 8 is a Western Blot show ing that compound 20 degraded DNMT I in Jurkat cells at indicated concentrations.
  • FIG. 9 is a Western Blot showing that compound 20 degraded DNMTl in A172 cells at indicated concentrations.
  • FIG. 10 is a Western Blot showing that compound 20 (that contains a cereblon (CRBN)-targeted degron) degraded DNMTl in M0LM13 ch2.2 (left). The extent of degradation of DNMTl relative to M0LM13 CRBN KO (light) cells illustrates that the degradation is CRBN-dependent.
  • CRBN cereblon
  • FIG. 11 is a Western Blot showing that compound 20 (3 uM) degraded DNMTl in HL60 cells at indicated time points.
  • FIG. 12 is a Western Blot showing that compounds 26 and 27 degraded DNMTl in HL60 cells at indicated concentrations.
  • transitional term “ccmprising,” which is synonymous with “’including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
  • the transitional phrase “consisting of' excludes any element, step, or ingredient not specified in the claim.
  • the transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the disclosure.
  • alkyl refers to a saturated linear or branched-cham monovalent hydrocarbon radical.
  • the alkyl radical is a C 1 -C 6 group.
  • the alkyl radical is a Co-C 6 , Co-C 5 , Co-C 3 , C 1 -C 6 , C1-C 5 , C1-C 4 or C1-C 3 group (wherein Co alkyl refers to a bond).
  • alkyl groups include methyl, ethyl, 1 -propyl, 2-propyl, i-propyl, 1 -butyl, 2-methyl-l-propyl, 2-butyl, 2-methyl-2-propyl, 1- pentyl, n-pentyl, 2-pentyI, 3-pentyl, 2-methy1-2-buty1, 3-methyI-2-butyl, 3-methyl-l -butyl, 2- methyl- 1 -butyl, 1 -hexyl, 2 -hexyl, 3-hexyl.
  • an alkyd group is a C1-C 3 alkyl group. In some embodiments, an alkyd group is a C1-C 2 alkyl group In some embodiments, an alkyl group is a methyl group.
  • alkylene 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, containing no unsaturation and having from one to 18 carbon atoms, for examp1e, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain may' be attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the alkylene group contains one to 15 carbon atoms (C1- C15 alkylene).
  • the alkylene group contains one to 12 carbon atoms (C1- C 12 alkylene).
  • the alkylene group contains one to 10 carbon atoms (1t- C10 alkylene) In some embodiments, the alkylene group contains one to 8 carbon atoms (C1- C8 alkylene). In other embodiments, an alkylene group contains one to 5 carbon atoms (C1-C 5 alkylene). In other embodiments, an alkylene group contains one to 4 carbon atoms (C1-C 4 alkylene). In other embodiments, an alkylene contains one to three carbon atoms (C1-C 3 alkylene). In other embodiments, an alkylene group contains one to two carbon atoms (C1-C 2 alkylene). In other embodiments, an alkylene group contains one carbon atom (Ci alkylene).
  • alkenyl refers to a linear or branched-chain monovalent hydrocarbon radical with at least one carbon-carbon double bond.
  • An alkenyl includes radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • the alkenyl radical is a C 2 -C18 group
  • the alkenyl radical is a C 2 -C15, C 2 -C 12 , C 2 -C10, Cz-Cn, C 2 -C 6 or C 2 -C? group.
  • Examp1es include ethenyl or vinyl, prop-l-enyl, prop-2-enyl, 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3- enyl, buta- 1,3-dienyl, 2-methylbula-l,3-diene. hex-1 -enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa- 1,3-dienyl.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon trip1e bond
  • the alkynyl radical is a C 2 -C18 group.
  • the alkynyl radical is
  • Examples include ethynyl prop-l-ynyl, prop-2- ynyL but-l -ynyl, but-2-ynyl and but-3-ynyl.
  • alkoxy ’1 or ‘"alkoxy'’ as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto, and which is the point of attachment.
  • the alkoxy! group is methoxy, ethoxy, propyloxy, or teri-butoxy .
  • An “ether’ is two hydrocarbyl groups covalently linked by an oxygen atom Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -0-alkenyl, and -O-alkynyl.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • cyclic group broadly refers to any group that used alone or as part of a larger moiety, contains a saturated, partially saturated or aromatic ring system e.g., carbocyclic (cycloalkyl. cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl and heteroaiyl groups. Cyclic groups may have one or more (e.g., fused) ring systems. Therefore, for example, a cyclic group can contain one or more carbocyclic, heterocyclic, aryl or heteroaryl groups.
  • carbocyclic refers to a group that used alone or as part of a larger moiety, contains a saturated, partially unsaturated, or aromatic ring system having 3 to 12 carbon atoms, that is alone or part of a larger moiety (e.g., an alkcarbocyclic group).
  • carbocyclyl includes mono-, bi-, tri-, fused, bridged, and spiroring systems, and combinations thereof.
  • carbocyclyl includes 3 to 10 carbon atoms ( C 3-10 ).
  • carbocyclyl includes 3 to 6 carbon atoms (C 6 -C 6 ).
  • carbocyclyl includes 5 to 6 carbon atoms (C 6 -C 6 ). In some embodiments, carbocyclyl, as a bicycle, includes C 6 -Cio. In another embodiment, carbocyclyl. as a spiro system, includes C 5 -C 11 .
  • monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cy clopent-1 -enyl, l-cyclopent-2-enyl, l-cyclopent-3- enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyI, l -cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and phenyl; bicyclic carbocyclyls having 7 to 11 ring atoms include [ 4,3], [4,4], [4.5], [5,5], [5,6] or [6.6] ring systems, such as for examp1e bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane
  • spiro carbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro [2.5] octane and spiro[4.5]decane.
  • the tenn carbocyclyl includes aryl ring systems as defined herein.
  • the term carbocycyl also includes cycloalkyl rings (e.g.. saturated or partially unsaturated mono-, bi-, or spirocarbocycles).
  • the terra carbocyclic group also includes a carbocyclic ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e g., aryl or heterocyclic rings), where the radical or point of attachment is on the carbocyclic ring.
  • a carbocyclic ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e g., aryl or heterocyclic rings), where the radical or point of attachment is on the carbocyclic ring.
  • carbocyclic also embraces carbocyclyl alkyl groups which as used herein refer to a group of the formula — R c -carbocycly1 where R c is an alkylene chain.
  • the terra carbocyclic also embraces carbocyclylalkoxy groups which as used herein refer to a group bonded through an oxygen atom of the formula — O— R c -carbocyclyl where R c is an alkylene chain.
  • the term “and” used alone or as part of a larger moiety' refers to a group that includes monocyclic, bicyclic or tn cyclic, carbon ring system, that includes fused rings, wherein at least one ring in the system is aromatic
  • the aralkoxy group is a benzoxy group.
  • aryl may be used interchangeably with the terra "aryl ring".
  • aryl includes groups having 6-12 carbon atoms.
  • aryl includes groups having 6-10 carbon atoms
  • Examp1es of aryl groups include phenyl, naphthyl, biphenyl, 1, 2,3,4- tetrahydronaphthalenyl, and the like, which may be substituted or independently substituted by one or more substituents described herein.
  • a particular aryl is phenyl.
  • an aryl group includes an ary l ring fused to one or more (e.g. 1, 2 or 3) different cyclic groups (e g. , carbocyclic mags or heterocyclic rings), where the radical or point of attachment is on the aryl ring.
  • aryl embraces aralkyl groups (e.g.. benzyl) which as disclosed above refer to a group of the formula -R c -aryl where R c is an alkylene chain such as methylene or ethylene.
  • R c is an alkylene chain such as methylene or ethylene.
  • the aralkyl group is an optionally substituted benzyl group.
  • aryl also embraces aralkoxy groups which as used herein refer to a group bonded through an oxygen atom of the formula — O — R c — aryl where R° is an alkylene chain such as methylene or ethylene.
  • heterocyclyl refers to a “carbocyclyl” that used alone or as part of a larger moiety, contains a saturated, partially unsaturated or aromatic ring system, wherein one or more (e.g., 1. 2, 3, 4, or 5) carbon atoms have been rep1aced with a heteroatom or heteroatom-containing group (e.g., O, N. N(O), S. S(O), or S(O)2).
  • heterocyclyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof.
  • a heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system.
  • a heterocyclyl refers to a saturated ring system, such as a 3- to 12- membered saturated heterocyclyl ring system.
  • a heterocyclyl refers to a heteroaryl ring system, such as a 5- to 12-membered heteroaryl ring system.
  • the term heterocyclyl also includes C 2 -C 8 heterocycloalkyl, which is a saturated or partially unsaturated mono-, bi-, or spiro-ring system containing 2-8 carbons and one or more (e g., 1. 2, or 3) heteroatoms.
  • a heterocyclyl group includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and one to 5 ring atoms is a heteroatom such as nitrogen, sulfur or oxygen.
  • heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from O, N, and S.
  • heterocyclyl includes 4- to 6-membered monocycles having one or more heteroatoms selected from O, N. and S.
  • heterocyclyl includes 3-membered monocycles.
  • heterocyclyl includes 4-membered monocycles.
  • heterocyclyl includes 5- to 6-membered monocycles. In some embodiments, the heterocyclyl group includes 0 to 3 double bonds. Tn any of' the foregoing embodiments, heterocyclyl includes 1 , 2, 3 or 4 heteroatoms. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO?.), and any nitrogen heteroatom may optionally be substituted (e.g., methyl, isopropyl) and/or quaternized (e.g., [NRsf'Cl", [NR 4 ]*0H’).
  • Representative examples of heterocyclyls include oxiranyl, aziridinyl, thiiranyl.
  • azetidinyl oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl.
  • pyrrolidinyl dihydro-lH- pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl.
  • 1,1-dioxohexahydrothiopyranyl examples include thiazolyl (e.g., thiazol-2-yl), thiadiazolyl (e.g., l,3,4-thiadiazol-5-yl and 1 ,2,4-thiadiazol-5- yl), oxazolyl (e.g, oxazol-2-yl), and oxadiazolyl (e.g., l,3,4-oxadiazol-5-yl and 1,2,4- oxadiazol-5-yl).
  • thiazolyl e.g., thiazol-2-yl
  • thiadiazolyl e.g., l,3,4-thiadiazol-5-yl and 1 ,2,4-thiadiazol-5- yl
  • oxazolyl e.g, oxazol-2-yl
  • oxadiazolyl e.g., l,3,4-oxadia
  • Example of 5-membered heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl (e.g., imidazol-2-yl), triazolyl (e.g , l,3.4-triazol-5-yl. l,2,3-triazol-5-yl. and l,2,4-triazol-5-yl), and tetrazolyl (e.g. , 1H-tetrazol-5-yl).
  • Representative examples of benzo-fused .5-membered heterocyclyls include benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
  • Example of 6-membered heterocyclyls containing one to three nitrogen atoms and optionally a sulfur or oxygen atom are pyridyl (e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl), py rimidyl (e.g, pyrimid-2-yl and pyrimid-4-yl), triazinyl (e.g., 1 ,3,4-triazin-2-yl and l,3,5-triazin-4-yl), pyridazinyl (e.g.. pyridazin-3-yl), and pyrazinyl.
  • pyridyl e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl
  • py rimidyl e.g, pyrimid-2-yl and pyrimid-4-yl
  • a heterocyclic group includes a heterocyclic ring fused to one or more (e.g., 1 or 2) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heterocyclic ring, and in some embodiments wherein the point of attachment is a heteroatom contained in the heterocyclic ring.
  • heterocyclic embraces N-heterocyclyl groups which as used herein refer to a heterocyclyl group containing at least one nitrogen atom and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a nitrogen atom in the heterocyclyl group.
  • Representative examp1es of N-heterocyclyl groups include 1- morpholinyl, 1-piperidmyl, 1-piperazinyl. 1-pyrrohdinyl. 1-pyrazolidinyl, 1 -imidazolmyl and 1-imidazolidinyl.
  • heterocyclic also embraces C -heterocyclyl groups which as used herein refer to a heterocyclyl group containing at least one heteroatom and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a carbon atom in the heterocyclyl group.
  • Representative examp1es of C-heterocyclyl radicals include 2- or 3- morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl.
  • heterocyclic also embraces heterocyclyl alkyl groups which as disclosed above refer to a group of the formula — RMieterocyclyl where R c is an alkylene chain.
  • heterocyclic also embraces heterocyciyialkoxy groups which as used herein refer to a radical bonded through an oxygen atom of the formula — O--R c -beterocyclyl where R c is an alkylene chain.
  • heteroaryl used alone or as part of a larger moiety (e.g., “heteroarylalkyl” (also “‘heteroaralkyf'), or “heteroatylalkoxy” (also “heteroaralkoxy”)) refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 12 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom.
  • heteroaryl includes 5- to 6- membered monocyclic aromatic groups where one or more ring atoms is 0, N, or S.
  • heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl. oxatriazolyl. pyridyl, pyrimidyl.
  • imidazopyndyl pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetraz.olo[l ,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indolyl, 1 ,3-thiazol-2-yl, l ,3,4-triazol-5-yl, l,3-oxazol-2-yl, I,3,4-oxadiazol-5-yl, 1 ,2,4- oxadiazol-5-yl, l,3,4-thiadiazol-5-yl, lH-tetrazol-5-yl, and l,2,3-triazol-5-yl.
  • heteroaryl also includes groups in which a heteroaryl is fused to one or more cyclic (e.g, carbocyclyl, or heterocyclyl) rings, where the radical or point of attachment is on the heteroaryl ring
  • Nonlimiting examples include indolyl, indolizinyl.
  • a heteroaryl group may be mono-, bi- or tri-cyclic.
  • a heteroaryl group includes a heteroaryl ring fused to one or more (e.g., 1 or 2) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heteroaryl ring, and m some embodiments wherein the point of attachment is a heteroatom contained in the heterocyclic ring
  • heteroaryl embraces N-heteroaiyl groups which as used herein refer to a heteroaryl group as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group.
  • heteroaryl also embraces C -heteroaryl groups which as used herein refer to a heteroaryl group as defined above and where the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group.
  • heteroaryl also embraces heteroarylalkyl groups which as disclosed above refer to a group of the formula — R e -heteroaryl.
  • heteroaryl also embraces heteroaralkoxy (or heteroarylalkoxy) groups which as used herein refer to a group bonded through an oxygen atom of the formula -O— R c - heteroaryl, where R c is an alkylene group as defined above.
  • any of the groups described herein may be substituted or unsubstituted.
  • representative examp1es of substituents may include alkyl (e.g., C 1 -C 6 , Ci-C 5 , C1-C 4 , C1-C 3 , C1-C 2 , C1), substituted alkyl (e.g., substituted C1-C 6 , C1-C 5 , C1-C 4 . C1-C 3 , C1-C 2 , C1), alkoxy (e.g..
  • C 2 substituted alkenyl (e.g. , substituted C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 2 ), alkynyl (e.g., C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 2 ), substituted alkynyl (e.g., substituted C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 2 ), cyclic (e.g., C 3 -C 12 , C 6 -C 6 ), substituted cyclic (e.g., substituted C 3 -C 12 , C 6 -C 6 ), carbocyclic (e.g., C 3 -C 12 , C 5 -C 6 ), substituted carbocyclic (e.g., substituted C 3 -C 12 , C
  • alkylthio e.g., Ci-Ccd. substituted alkylthio (e.g, substituted Ci- C 6 ).
  • arylthio e.g..
  • C 6 -C 12 , Q substituted arylthio (e.g., substituted C 6 -C 12 , C 6 ), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide. sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptide groups. Terminal substituents may include C 5 -C 6 alkyl, halo, hydroxyl, cyano, amino, or amido groups.
  • binding as it relates to interaction between the compound of formula (I) and the targeted protein, which in this disclosure is DNMTl , via the DNMTl targeting ligand, typically refers to an inter-molecular interaction that may be preferential (also referred to herein as “selective”’) in that binding of the compounds of formula (I) with other proteins present in the cell is substantially less and may be functionally insignificant.
  • DNMTl the targeted protein
  • DNMTl targeting ligand typically refers to an inter-molecular interaction that may be preferential (also referred to herein as “selective”’) in that binding of the compounds of formula (I) with other proteins present in the cell is substantially less and may be functionally insignificant.
  • Present compounds preferentially bind and recruit DNMTl for targeted degradation.
  • binding as it relates to interaction between the degron and the E3 ubiquitin ligase, typically refers to an inter-molecular interaction that may or may not exhibit an affinity level that equals or exceeds that affinity between the compound and DNMTl, but is nonetheless sufficient to achieve recruitment of the E3 ubiquitin ligase to DNMTl .
  • DNMTl Targeting Ligand is of Formula TL-1 or TL-2: R 3 and R 4 , together with the nitrogen atom to which they are attached, form an optionally substituted 6-membered heterocyclyl, or R 3 find R 4 , together with the nitrogen atom to which they are attached, form an optionally substituted 6-membered heterocyclyl which is also bound to the linker; R 2 is NH2 or each R 5 is independently H, optionally substituted alkyl, or wherein is a bond between the DNM'11 Targeting Ligand and the Linker, provided that there is only one bond between the DNMT1 Targeting Ligand and the Linker; the linker represents a moiety that connects covalently the degron and the targeting ligand; and the degron represents a moiety that binds an E3 ubiquitin ligase, or a pharmaceutically acceptable salt or stereoisomer thereof
  • the DNMT1 Targeting Ligand is of Formula TL-1 and R 2 is NH 2 .
  • R 1 is NR 3 R 4 , wherein R 3 is H and R 4 is , R 2 is NH 2 , and [0047] Therefore, in some embodiments, the compounds have a structure represented by formula I- la: (I- la), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Ri is NR 3 R 4 , wherein Rs is Me and R 4 is * , R 2 is NHz, and
  • Formula TL-1 is of TL-lb: -lb).
  • the compounds have a structure represented by formula I- lb: (I- lb), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Ri is NR 3 R 4 , wherein Rs and R 4 , together with the nitrogen atom to which they are attached, form an optionally substituted 6-membered heterocyclyl which is also bound to the linker, and Rz is NHz.
  • Ri is NR 3 R 4 , wherein Rs and R 4 , together with the nitrogen atom to which they are attached, form piperidyl, and Formula TL-1 is of TL-lc: [0052] Therefore, in some embodiments, the compounds have a structure represented by formula I-lc: stereoisomer thereof.
  • Ri is NR 3 R 4 , wherein R 3 and R 4 , together with the nitrogen atom to which they are attached, form an optionally substituted 6-membered heterocyclyl.
  • Rr and R 4 together with the nitrogen atom to which they are attached, form optionally substituted piperidyl.
  • piperidyl is substituted with an ammo group.
  • Ri is NR 3 R 4 , wherein Rj and Rr, together with the nitrogen
  • the compounds have a structure represented by formula I- id: pharmaceutically acceptable salt or stereoisomer thereof.
  • the DNMT1 Targeting Ligand is of Formula TL-2, Rs is « , and Rs is H.
  • the compounds have a structure represented by formula I-2a: (I-2a), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the DNMT1 Targeting Ligand is of Formula TL-2, Rs is H or
  • _4 optionally substituted alkyl, and Rr, is 5 .
  • the compounds have a structure represented by formula I-2b: pharmaceutically acceptable salt or stereoisomer thereof.
  • the linker C'L provides a covalent attachment between the targeting ligand and the degron.
  • the linker is of Formula LO: or stereoisomer thereof, wherein pi is an integer selected from 0 to 6; p2 is an integer selected from 0 to 12; p3 is an integer selected from 0 to 12; each W is independently absent, CFh, O, S, NR13, or C(O)NRB; each Ris is independently hydrogen or C 1 -C 6 alkyl;
  • Wi and W2 are independently absent, (CHzh-a, O, NH, or C(O)NRB; and Z 1 and Z 2 are independently absent,
  • Linker is covalently bonded to a Degron via the next to W2, and covalently bonded to a Targeting Ligand via the next to W 1, or the Linker is covalently bonded to a Degron via the next to W 1, and covalently bonded to a Targeting Ligand via the next to W2.
  • p1 is an integer selected from 0 to 4. In some embodiments, p1 is an integer selected from 0 to 2. In some embodiments, p1 is an integer selected from 1 to
  • p2 is an integer selected from 0 to 8. In some embodiments. p2 is an integer selected from 0 to 6. In some embodiments, p2 is an integer selected from 0 to
  • p2 is an integer selected from 1 to 4.
  • p3 is an integer selected from 0 to 10, In some embodiments, p3 is an integer selected from 0 to 8. In some embodiments. p3 is an integer selected from 0 to 6. In some embodiments, p3 is an integer selected from 0 to 4. In some embodiments, p3 is an integer selected from 1 to 8. In some embodiments, p3 is an integer selected from 1 to 6. In some embodiments, p3 is an integer selected from 1 to 4.
  • each W is CH 2 . In some embodiments, each W is O.
  • each R 10 is independently hydrogen or methyl.
  • Wi and W 2 are independently absent, CH 2 , (CH 2 ) 2 , (CH 2 )3, NH, C(O)NH, or C(O)NMe.
  • Z 1 and Z 2 are independently absent, -O-, ⁇ N(R 13 )“. -C(O) ⁇ , -C(O)N(R 13 )-, -N(RI I)C(O)-.
  • Formula L0 is of Formula LOa-LOj: represents targeting ligand.
  • the linker includes an alkylene chain (e.g, having 1-18 alkylene units).
  • the linker may include an alkylene chain or a bivalent alkylene chain, either of' which may be interrupted by, and/or terminate (at either or both termini) at least one of 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene or any combination thereof, wherein R' is H or C 1 -C 6 alkyl, wherein the interrupting and the one or both terminating groups mas be the same or different.
  • the linker includes an alkylene chain having 1-18 alkylene units and is interrupted by and/or terminates in -C(O)-, -NH-, -C(0)NH--, --C(O)N(Me)-.
  • the linker includes an alkylene chain having 1-12 alkylene units and is interrupted by and/or terminates in -C(O) ⁇ , -NH-, -C(O)NH-, -C(O)N(Me)-, C 6 carbocyclene, 6-membered heteroarylene or any combination thereof
  • the linker includes an alkylene chain having 1 -6 alkylene units and is interrupted by and/or terminates in -C(O)-, - NH-. --C(O)NH ⁇ . ⁇ C(O)N(Me>”, C 6 carbocyclene, 6-membered heteroarylene or any combination thereof.
  • the linker includes an alkylene chain having 1-3 alkylene units and is interrupted by and/or terminates in -C(O)-, -NH-, -C(O)NH- - C(O)N(Me)--, C 6 ; carbocyclene, 6-membered heteroarylene or any combination thereof, in some embodiments, the linker includes an alkylene chain having 1-18 alkylene units. In some embodiments, the linker includes an alkylene chain having 1 -12 alkylene units. In some embodiments, the linker includes an alkylene chain having 1-6 alkylene units. In some embodiments, the linker includes an alkylene chain having 1-3 alkylene units.
  • Carbocyclene refers to a bivalent carbocycle radical, which is optionally substituted
  • Heterocyclene refers to a bivalent heterocyclyl radical which may be optionally substituted
  • Heteroarylene refers to a bivalent heteroaryl radical which may be optionally substituted.
  • Representative examp1es of linkers that may be suitable for use in the present disclosure include alkylene chains: alkylene chains terminating in various functional groups (as described above), examp1es of which are as follows: alkylene chains interrupted by various functional groups (as described above), examples of which are as follows: alkylene chains interrupted by or terminating with heterocyclene groups, e.g.
  • n are independently an integer from 0-10, examples of which include: alkylene chains interrupted by amide, heterocyclene and/or aryl groups, examp1es of which include: alkylene chains interrupted by heterocyclene and aryl groups, and a heteroatom, examples of which include: 8-9, 9-10, and 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10, and R is H or Cl to C 4 alkyl, an example of which is
  • the linker may include a polyethylene glycol (PEG) chain which may terminate at either or both termini with at least one of C 3-12 carbocyclene, 3- to 12-membered heterocyciene, 5- to 12-membered heteroarylene or any combination thereof, wherein R' is H or Ci-C* alkyl, wherein the one or both terminating groups may be the same or different.
  • PEG polyethylene glycol
  • the linker includes a polyethylene glycol chain having 1-10 PEG units and is interrupted by and/or terminates in -C(O) ⁇ , -NH-, -C(O )NH-, -C(O)N(Me)- , or any combination thereof.
  • the linker includes a polyethylene glycol chain having 1-6 PEG units and is interrupted by and/or terminates in -C(O ⁇ -, --NH-, - C(O)NH- -C(O)N(Me)-, or any combination thereof.
  • the linker includes a polyethylene glycol chain having 1-2 PEG units and is interrupted by and/or terminates in -C(O) ⁇ , -NH-, -C(O)NH-, -C(O)N(Me)-, or any combination thereof.
  • the linker includes a polyethylene glycol chain having 1-10 PEG.
  • the linker includes a polyethylene glycol chain having 1-6 PEG units.
  • the linker includes a polyethylene glycol chain having 1 -2 PEG units.
  • linkers that include a polyethylene glycol chain include: [0079] In some embodiments, the linker containing a polyethylene glycol chain may terminate in a functional group, examples of which are as follows:
  • the linker is represented by any one of structures:
  • compounds of the present disclosure may be represented by any one of the following structures: pharmaceutically acceptable salt or stereoisomer thereof.
  • UPP U biquitin-Proteasome Pathway
  • E3 ubiquitin ligases include over 500 different proteins and are categorized into multip1e classes defined by the structural element of their E3 functional activity.
  • the degron may bind the E3 ligase which is cereblon (CRBN) or von Hippel Lindau (VHL) tumor suppressor.
  • CRBN cereblon
  • VHL von Hippel Lindau
  • the degron that binds cereblon is represented by DI : stereoisomer thereof; wherein
  • Q is CH 2 or C(O):
  • X 1 is O or NH.
  • Q is CH 2 [0086 ] In some embodiments, Q is C :::: O
  • Xi is O.
  • Tn some embodiments, Xi is NH.
  • Xi is CH 2 .
  • Q is CH 2 and Xi is O. In some embodiments, Q is CH 2 and Xj is NH. In some embodiments, Q is CH 2 , and Xi is CH 2 . In some embodiments. Q is CH? and Xi is C C.
  • formula DI is of formula Dla-Dlp:
  • the compounds of the present disclosure may be represented by any of the following structures:
  • the linker includes an alkylene chain having 1 -12 alkylene units and is interrupted by and/or terminates in -C(O) ⁇ , -NH-, -C(O)NH-, -C(O)N(Me)-, C 6 carbocyclene, 6-membered heteroarylene or any combination thereof
  • the linker includes an alkylene chain having 1-6 alkylene units and is interrupted by and/or terminates in -C(())-, - NH-, -C(O)NH ⁇ , -C(O)N(Me) ⁇ , C 6 carbocyclene, 6-membered heteroarylene or any combination thereof.
  • the linker includes an alkylene chain having 1-3 alkylene units and is interrupted by and/or terminates in -C(O)-, -NH-, -C(O)NH--, - C(O)N(Me)-, C 6 carbocyclene, 6-membered heteroarylene or any combination thereof.
  • the linker includes an alkylene chain having 1-12 alkylene units.
  • the linker includes an alkylene chain having 1-6 alkylene units.
  • the linker includes an alkylene chain having 1-3 alkylene units.
  • the linker includes a polyethylene glycol chain having 1-6 PEG units and is interrupted by and/or tenninates in -C(O)-, or any combination thereof In some embodiments, the linker includes a polyethylene glycol chain having 1 -2 PEG units and is interrupted by and/or terminates in -C(O) ⁇ , -NH-, -C(O)NH ⁇ , - C(O)N(Me)--, or any combination thereof. In some embodiments, the linker includes a polyethylene glycol chain having 1-6 PEG units. In some embodiments, the linker includes a polyethylene glycol chain having 1-2 PEG units.
  • the degron may bind the E3 ligase which is von Hippel-Lindau (VI-IL) tumor suppressor, and is represented by D2 or D3 : stereoisomer thereof, wherein:
  • R? is H or optionally substituted Ct-C 6 alkyd, or
  • R 10 and R11 are both H, or R 10 and R 11 , together with the carbon atom to which they are attached, form cyclopropyl:
  • R12 is H, fluoro, cyano, or NMez
  • Y is H, o ⁇ HhA . MebA . or H 2 C' ⁇ ; wherein is a bond between the Degron and the Linker, provided that there is only one bond between the Degron and the Linker.
  • the degron is of formula D2,
  • R7 and Rs are both H
  • R7 is H and Rs is methyl
  • R7 is optionally substituted C1-C 3 alkyl and Rs is H.
  • R7 is optionally substituted C1-C 3 alkyl and Rs is methyl.
  • R? and Rs. together with the carbon atom to which they are attached, form cyclopropyl.
  • Y is H.
  • Ry is C(0)CR 10 RiiRi2.
  • R 10 , R11, and R12 are H.
  • Re and Rv, together with the carbon atom to which they are attached, form cyclopropyl and Rs is H, fluoro, cyano, or Nhte.
  • Rs is fluoro, cyano, or NMe?..
  • R 10 and Ru together with the carbon atom to which they are attached, form cyclopropyl and Ri2 is fluoro, cyano, orNMea.
  • Ry is C(0)CR 10 R 11 Ri2, wherein R 10 and R 11 , together with the carbon atom to which they are attached, form cyclopropyl and R12 is fluoro, cyano, or NMei.
  • R9 is .
  • Y is H, and R? and Rs are H.
  • Ry is , Y is H. R? is H, and Rs is methyl.
  • Ry is .
  • Y is H
  • R7 is optionally substituted CJ-CS alkyl
  • Rs is H.
  • Ry is , Y is H, R? is optionally substituted C1-C 3 alkyl, and Rs is H.
  • R 9 IS is , Y is H, and R7 and Rs, together with the carbon atom to which they are attached, form cyclopropyl.
  • formula D2 is of formula D2a-D2o:
  • the degron is of formula D3
  • the degron of formula D3 is of formula D3a-D3g: r stereoisomer thereof.
  • the compounds of the present disclosure may be represented by any of the following structures:
  • the linker includes an alkylene chain having 1 -12 alkylene units and is interrupted by and/or terminates in -C(O)-, -NH-, - C(O)NH- ⁇ C(O)N(Me) ⁇ , C 6 carbocyclene, 6-membered heteroarylene or any combination thereof.
  • the linker includes an alkylene chain having 1-6 alkylene units and is interrupted by and/or terminates in -C(O)-, -NH-, -C(O)NH- -C(O)N(Me)- C 6 carbocyclene, 6-membered heteroarylene or any combination thereof.
  • the linker includes an alkylene chain having 1-3 alkylene units and is interrupted by and/or terminates in -C(O)-, -Nil-, -C(O)NH- -C(O)N(Me)-, C 6 carbocyclene, 6-membered heteroarylene or any combination thereof.
  • the linker includes an alkylene chain having 1-12. alkylene units.
  • the linker includes an alkylene chain having 1-6 alkylene units.
  • the linker includes an alkylene chain having 1-3 alkylene units.
  • compounds of the present disclosure are represented by any one of the following structures:
  • Compounds of the present disclosure may be in the form of a free acid or free base, or a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt of the compounds of this disclosure can be formed, for examp1e, by reaction of an appropriate free base of a compound of the disclosure and an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art. See. for example. Gould, P. L.. "Salt selection for basic drugs," International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R. J., et al., “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge. S. M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19, (1977).
  • stereoisomer may have at least one chiral center and thus may be in the form of a stereoisomer, which as used herein, embraces all isomers of individual compounds that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers which include the ( R- ) or (S-) configurations of the compounds), mixtures of mirror image isomers (physical mixtures of the enantiomers, and racemates or racemic mixtures) of compounds, geometric (cis/trans or E/Z, R/S) isomers of compounds and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • the chiral centers of the compounds may undergo epimerization in vivo, thus, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Accordingly, the compounds of the present disclosure may be made and used in the form of individual isomers and substantially free of other isomers, or in the form of a mixture of various isomers, e.g., racemic mixtures of stereoisomers.
  • the compound of formula (I) is an isotopic derivative in that it has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • the compound includes deuterium or multip1e deuterium atoms
  • the term “compound” embraces isotopic derivatives
  • Compounds of formula (I) may also be in the form of N-oxides, crystalline forms (also known as polymorphs), co-ciy sials, active metabolites of the compounds having the same type of activity, prodrugs, tautomers, and unsolvated as well as solvated (e.g.. hydrated) forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, of the compounds.
  • crystalline forms also known as polymorphs
  • co-ciy sials active metabolites of the compounds having the same type of activity
  • prodrugs tautomers
  • unsolvated e.g.. hydrated
  • the compounds of formula (I) may be prepared by crystallization under different conditions and may exist as one or a combination of polymorphs of the compound.
  • different polymorphs may be identified and-'or prepared using different solvents, or different mixtures of solvents for recrystallization, by performing crystallizations at different temperatures, or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraclogram and/or other known techniques.
  • the pharmaceutical composition comprises a co-crystal of a compound of formula (I).
  • co-crystal refers to a stoichiometric multi-component system comprising a compound of formula (I) and a co-crystal former wherein the compound of formula (I) and the co-crystal former are connected by non-covalent interactions.
  • co-crystal former refers to compounds which can form intermolecular interactions with a compound of formula (I) and co-crystallize with it.
  • Representative examp1es of co-crystal formers include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans- cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2- hexanoic acid, 2-hydroxy caproic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4 ’-bipyridine p-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl-4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogal lol, phloroglucinol, hydroxy quinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etofylline, and phenobarbit
  • the present disclosure is directed to a method for making a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the compounds or pharmaceutically acceptable salts or stereoisomers thereof may be prepared by any process known to be app1icable to the preparation of chemically related compounds, ’Tire compounds of the present disclosure will be better understood in connection with the synthetic schemes that described in various working examples that illustrate nonlimiting methods by which the compounds of the disclosure may be prepared.
  • compositions that includes a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable earner refers to a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present disclosure to mammals.
  • Suitable carriers may include, for examp1e, liquids (both aqueous and non-aqueous alike, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g. semi-solids), and gases, that function to cany' or transport the compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a carrier is “acceptable” in the sense of being physiologically inert to and compatible with the other ingredients of the formulation and not injurious to the subject or patient.
  • the composition may also include one or more pharmaceutically acceptable excipients.
  • compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers may be formulated into a given type of composition in accordance with conventional pharmaceutical practice such as conventional mixing, dissolving, granulating, dragee-ma.kmg, levigating, emulsifying, encapsulating, entrapping and compression processes (see, e.g. , Remington: The Science and Practice of Pharmacy (20th ed.), ed. A R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. S warbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York), each of which is incorporated herein by reference in us entirety.
  • the type of formulation depends on the mode of administration which may include enteral (e g., oral, buccal, sublingual and rectal), parenteral (e.g , subcutaneous (s.cf intravenous (i.v.), intramuscular (i.m.), and intrastemal injection, or infusion techniques, intra-ocular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, interdermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation) and topical (e.g. transdermal).
  • enteral e g., oral, buccal, sublingual and rectal
  • parenteral e.g , subcutaneous (s.cf intravenous (i.v.), intramuscular (i.m.), and intrastemal injection, or infusion techniques, intra-ocular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal,
  • the most appropriate route of administration will depend upon a variety of factors including, for examp1e, the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • parenteral (e.g , intravenous) administration may also be advantageous in that the compound may be administered relatively quickly such as in the case of a single-dose treatment and/or an acute condition.
  • the compounds are formulated for oral or intravenous administration (e.g , systemic intravenous injection).
  • compounds of formula (I) may be formulated into solid compositions (e.g, powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g, solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups and elixirs); semi-solid compositions (e.g, gels, suspensions and creams); and gases (e.g., propellants for aerosol compositions).
  • Compounds may also be formulated for rapid, intermediate or extended release.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate and an additional earner or excipient such as a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as.
  • the dosage form may also include buffering agents.
  • Solid compositions of a similar type may also be emp1oyed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings. They may further contain an opacifying agent.
  • compounds of formula (I) may be formulated in a hard or soft gelatin capsule.
  • excipients that may be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, lactose anhydrous, microcrystalline cellulose and croscarmellose sodium.
  • Gelatin shells may include gelatin, titanium dioxide, iron oxides and colorants.
  • Liquid dosage forms for oral administration include solutions, suspensions, emulsions, micro-emulsions, syrups and elixirs.
  • the liquid dosage forms may contain an aqueous or non-aqueous carrier (depending upon the solubility of the compounds) commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylfonnamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty’ acid esters of sorbitan, and mixtures thereof.
  • Oral compositions may also include an excipients
  • Injectable preparations for parenteral administration may include sterile aqueous solutions or oleaginous suspensions. They may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for examp1e, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be emp1oyed are water, Ringer's solution. U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be emp1oyed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the effect of the compound may be prolonged by slowing its absorption, which may be accomp1ished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility.
  • Prolonged absorption of the compound from a parenterally administered formulation may also be accomplished by suspending the compound in an oily vehicle.
  • compounds of formula (I) may be administered in a local rather than systemic manner, for examp1e, via injection of the conjugate directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for examp1e subcutaneously or intramuscularly) or by intramuscular injection.
  • injectable depot forms are made by forming microencapsule matrices of the compound in a biodegradable polymer, e.g., poly lactidepolyglycolides. poly(orthoesters) and poly(anhydrides). The rate of release of the compound may be controlled by varying the ratio of compound to polymer and the nature of the particular polymer emp1oyed.
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • the compound is delivered in a targeted drug delivery system, for examp1e, in a liposome coated with organ-specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • compositions may be formulated for buccal or sublingual administration, examp1es of which include tablets, lozenges and gels.
  • the compounds of formula (I) may be formulated for administration by inhalation.
  • Various forms suitable for administration by inhalation include aerosols, mists or powders.
  • Pharmaceutical compositions may be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoroniethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoroniethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit of a pressurized aerosol may be determined by providing a valve to deliver a metered amount.
  • capsules and cartridges including gelatin for example, for use in an inhaler or insufflator, may be formulated containing a powder mix of
  • Compounds of formula (I) may be formulated for topical administration which as used herein, refers to administration intradermally by injection of the formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.
  • Representative examples of carriers useful in formulating compounds for topical app1ication include solvents (e.g. alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline).
  • Creams, for examp1e may be formulated using saturated or unsaturated fatly acids such as stearic acid, palmitic acid, oleic acid, paimito-oleic acid, cetyl, or oleyl alcohols Creams may also contain a non-ionic surfactant such as polyoxy-40-stearate.
  • the topical formulations may also include an excipient, an example of which is a penetration enhancing agent.
  • an excipient an example of which is a penetration enhancing agent.
  • these agents are capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption.
  • a wide variety of compounds have been evaluated as to their effecti veness in enhancing the rate of penetration of drugs through the skin. See. for example. Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds. ), CRC Press, Inc., Boca Raton, Fla.
  • Representative examp1es of penetration enhancing agents include triglycerides (e.g, soybean oil), aloe compositions (e.g, aloe-vera gel), ethyl alcohol, isopropyl alcohol, octoly phenylpoly ethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.
  • triglycerides e.g, soybean oil
  • aloe compositions e.g, aloe-vera gel
  • ethyl alcohol isopropyl alcohol
  • isoctoly phenylpoly ethylene glycol oleic acid
  • polyethylene glycol 400 polyethylene glycol 400
  • propylene glycol N-de
  • excipients that may be included in topical as well as in other types of formulations (to the extent they- are compatible), include preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, skin protectants, and surfactants.
  • Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols.
  • Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxy toluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid.
  • Suitable moisturizers include glycerin, sorbitol, polyethylene glycols, urea, and propylene glycol.
  • Suitable buffering agents include citric, hydrochloric, and lactic acid buffers.
  • Suitable solubilizing agents include quaternary’ ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.
  • Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.
  • Transdermal formulations typically emp1oy transdermal delivery devices and transdermal delivery' patches wherein the compound is formulated in lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Transdermal delivery of the compounds may be accomplished by means of an iontophoretic patch. Transdermal patches may provide controlled delivery' of the compounds wherein the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
  • Absorption enhancers may be used to increase absorption, examples of which include absorbable pharmaceutically acceptable solvents that assist passage through the skin.
  • Ophthalmic formulations include eye drops.
  • Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository' bases such as cocoa butter or other glycerides, as well as synthetic polymers such as poly vinylpyrrolidone, PEG, and the like.
  • compositions for rectal or vaginal administration may also be formulated as suppositories which can be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty' acid glycerides, polyethylene glycol, suppository' waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.
  • suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty' acid glycerides, polyethylene glycol, suppository' waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.
  • the term, "therapeutically effective amount” refers to an amount of a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof; or a composition including a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, effective in producing the desired therapeutic response in a particular patient, in need thereof Therefore, the term “therapeutically effective amount” includes the amount of a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, that when administered, induces a positive modification in the disease or disorder to be treated, or is sufficient to prevent development or progression of the disease or disorder, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject, or which simp1y kills or inhibits the growth of diseased (e.g . cancer, autophagydependent disease (e g., neurodeg eneratrve disorder)) cells, or reduces the amount of DNMT1 in diseased cells.
  • diseased e.g .
  • the total daily dosage of the compounds and usage thereof may be decided in accordance with standard medical practice, e.g., by the attending physician using sound medical judgment.
  • the specific therapeutically effective dose for any particular subject may depend upon a variety of factors including the disease or disorder being treated and the severity thereof (e.g., its present status); the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound emp1oyed; the duration of tire treatment; drugs used in combination or coincidental with the compound; and like factors well known in the medical arts (see, for examp1e, Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001), which is incorporated herein by reference in its entirety.
  • the present disclosure is directed to methods of treating diseases or disorders by reducing the level or activity of DNMT1.
  • the methods entail administration of a therapeutically effective amount of a compound formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof.
  • the diseases or disorders are characterized or mediated by aberrant DNMT1 activity' (e.g., elevated levels of DNMT1 or otherwise functionally abnormal DNMT1, e.g., mutant DNMT1 activity', relative to a non-pathological state).
  • a "disease” is generally regarded as a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject's health continues to deteriorate.
  • a "disorder" in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
  • subject includes all members of the animal kingdom prone to or suffering from the indicated disease or disorder.
  • the subject is a mammal, e.g., a human or a non-human mammal, 'the methods are also app1icable to companion animals such as dogs and cats.
  • a subject “in need of’ treatment according to the present disclosure may be “suffering from or suspected of suffering from” a specific disease or disorder may have been positively diagnosed or otherwise presents with a sufficient number of risk factors or a sufficient number or combination of signs or symptoms such that a medical professional could diagnose or suspect that the subject was suffering from the disease or disorder.
  • subjects suffering from, and suspected of suffering from, a specific disease or disorder are not necessarily two distinct groups.
  • compounds of formula (I) may be useful in the treatment of cell proliferative diseases and disorders.
  • the term “cell proliferative disease or disorder’” refers to the conditions characterized by deregulated or abnormal cell growth, or both, including noncancerous conditions such as neop1asms, precancerous conditions, benign tumors, and cancer.
  • methods of the present disclosure entail treatment of subjects having cell proliferative diseases or disorders of the hematological system, liver, brain, colon, prostate, breast, and head and neck.
  • lymphoma As used herein, “cell proliferative diseases or disorders of the hematological system” include lymphoma, leukemia, myeloid neop1asms, mast cell neoplasms, myelodysp1asia, benign monoclonal gammopathy. lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia.
  • hematologic cancers may therefore include leukemia, multiple myeloma, and lymphoma (including T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin’s lymphoma (NHL).
  • leukemia multiple myeloma
  • lymphoma including T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin’s lymphoma (NHL).
  • NHL include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), cutaneous T-cell lymphoma (CTCL) (including mycosis fungoides and Sezary syndrome), peripheral T-cell lymphoma (PTCL) (including anap1astic large-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma, hepatospienic T-cell lymphoma, epithelial T-cell lymphoma, and gamma-delta T-cell lymphoma), germinal center B-cell-like diffuse large B-cell lymphoma, activated B-cell -like diffuse large B-cell lymphoma, Burkitt’s lymphoma/leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma,
  • DLBCL
  • Examp1es of leukemia include childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, mast cell leukemia, myeloid neoplasms and mast cell neop1asms.
  • acute lymphocytic leukemia e.g., acute myelocytic leukemia
  • acute myeloid leukemia e.g., acute monocytic leukemia
  • chronic lymphocytic leukemia chronic myelocytic leukemia
  • chronic myelogenous leukemia e.g., mast cell leukemia, myeloid neoplasms and mast cell neop1asms.
  • C 6 ll proliferative diseases or disorders of the liver include all forms of cell proliferative disorders affecting the liver.
  • C 6 ll proliferative disorders of the liver may include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma and hepatoblastoma), a precancer or precancerous condition of the liver, benign growths or lesions of the liver, and malignant growths or lesions of the liver, and metastatic lesions in tissue and organs in the body other than the liver.
  • C 6 ll proliferative disorders of the liver may include hyperp1asia, metap1asia, and dysp1asia of the liver.
  • C 6 ll proliferative diseases or disorders of the brain include all forms of cell proliferative disorders affecting the brain.
  • C 6 ll proliferative disorders of the brain iivr include brain cancer (e.g., gliomas, glioblastomas, meningiomas, pituitary adenomas, vestibular schwannomas, and primitive neuroectodermal tumors (medulloblastomas)), a precancer or precancerous condition of the brain, benign growths or lesions of the brain, and malignant growths or lesions of the brain, and metastatic lesions in tissue and organs in the body other than the brain.
  • C 6 ll proliferative disorders of the brain may include hyperp1asia, metaplasia, and dysplasia of the brain.
  • cell proliferative diseases or disorders of the colon include all forms of cell proliferative disorders affecting colon cells, including colon cancer, a precancer or precancerous conditions of the colon, adenomatous polyps of the colon and metachronous lesions of the colon.
  • Colon cancer includes sporadic and hereditary colon cancer, malignant colon neop1asms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma.
  • Colon cancer can be associated with a hereditary syndrome such as hereditary' nonpolyposis colorectal cancer, familiar adenomatous polyposis, MYH associated polyposis, Gardner’s syndrome, Peutz- Jeghers syndrome, Turcot’s syndrome and juvenile polyposis.
  • C 6 ll proliferative disorders of the colon may also be characterized by hyperp1asia, metap1asia, or dysp1asia of the colon.
  • C 6 ll proliferative disorders of the prostate include all forms of cell proliferative disorders affecting the prostate.
  • C 6 ll proliferative disorders of the prostate may include prostate cancer, a precancer or precancerous condition of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, and metastatic lesions in tissue and organs in the body other than the prostate
  • C 6 ll proliferative disorders of the prostate may include hyperp1asia, metap1asia, and dysp1asia of the prostate.
  • C 6 ll proliferative disorders of the breast include ail forms of cell proliferative disorders affecting breast cells.
  • C 6 ll proliferative disorders of the breast may include breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast.
  • C 6 ll proliferative disorders of the breast may include hyperp1asia, metap1asia, and dysp1asia of the breast.
  • Compound 2 was prepared from 2-((6-(4-aminopiperidin-l-yl)-3,5-dic5 ), ano-4- ethylpyridin-2-yl)thio)-2-phenylacetamide and 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)eflioxy)propanoic acid using a procedure similar to that used in Examp1e 1.
  • LCMS nv'z 880.82 [M+H] + .
  • Compound 4 was prepared from 2-((6-(4-aminopiperidin-l-yl)-3J-dicyano-4- ethyIpyridin-2-yl)thio)-2-phenylacetamide and 8-((2-(2,6-dioxopiperidin-3-yi)-l,3- dioxoisoindolin-4-y l)ammo)octanoic add using a procedure similar to that used in Examp1e 1.
  • Example 5 Synthesis of N-( 1 -(6-( (2-amino-2-oxo- 1 -phenylethyl)thio)-3.5-dicvano-
  • Compound 5 was prepared from 2-((6-(4-anunopiperidin-l-yl)-3,5-dicyano-4- thylpy ri din-2-yl )thio)-2-pheny 1 acetamide and 10-((2-(2,6-dioxopiperi din-3-yl)- 1,3- dioxoisoindolin-5-yl)amino)decanoic acid using a procedure similar to that used in Example 1 .
  • Compound 6 was prepared from 2-((6-(4-ammopiperidin-l-y[)-3.5-dicyano-4- ethyipyridin-2-yl)thio)-2-phenylacetamide and 12-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)ammo)dodecanoic acid using a procedure similar to that used in Examp1e
  • Example 7 Synthesis of N-( 1 -( 6 ⁇ ( (2-amino-2-oxo- 1 -phenylethyl)thio)-3,5-dicyano- 4-ethylpyridin-2-yl)piperidin-4-yl)-4-((2-(2.6-dioxopiperidin-3-y])-1.3-dioxoisoindolin-4- yDaminoicyclohexane-l -carboxamide (7)
  • Compound 7 was prepared from 2-((6-(4-aminopiperidin-l-yl)-3,5-dicyano-4- ethylpyridin-2-yI)thio)-2-phenyIacetamide and 4-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)arnino)cyclohexane-l-carboxylic acid using a procedure similar to that used in Example 1.
  • Compound 8 was prepared from 2-((6-(4-aniinopiperidin-l-yl)-3,5-dicyano-4-
  • Compound 10 was prepared from 6-amino-A r -(l-(6-((2-amino-2-oxo-l- phenylethyl)thio)-3,5-dicyano-4-eihylpyridin-2-yI)piperidm-4-yl)hexanamide and 4-(((2-(2,6- dioxopiperidin-3-yI)-l ,3-dioxoisoindolin-4-yl)amino)methyl)benzoic acid using a procedure similar to that used in Examp1e 1.
  • LCMS m/z 923 79 [M+H]
  • Examp1e 12 Synthesis of N-(l-(6-((2-amino-2-oxo-l-phenylethyl)thio)-3.5- dicy r aiio-4-ethylpyridin-2-Yl)piperidin-4-yl)-3-(4-(2-((2-(2.6-dioxopiperidin-3-yl)-1.3- dioxoisoindolin-5 -yl)amino)ethyl)piperazin- 1 -yl )pro panamide ( 12 ) yl)amino)ethyl)piperazin-l-yl)propanoate
  • Example 13 Synthesis of N-(l-(6-((2-amino-2-oxo-l-phenylethyl)thio)-3.5- dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-2-((2-(2,6-dioxopiperidin-3-Yl)-1.3- dioxoisoindolin-4-yl)amino)acetamide ( 13)
  • Compound 13 was prepared from 2-((6-(4-aminopiperidin-I-yl)-3,5 ⁇ dicyano-4- ethylpyridin-2-yl)thio)-2 -phenylacetamide and (2-(2,6-dioxopiperidin-3-yl)- 1 ,3- dioxoisoindolin-4-yl)glycine using a procedure similar to that used in Example 1.
  • LCMS m/z 734.49 [M+H] + .
  • Example 14 Synthesis of N-(l-(6-((2-amino-2-oxo-l-phenylethyl)thio)-3.5- dicvano-4-ethylpyridin-2-yl)piperidin-4-yr)-2-(2-((2-(2'6-dioxopiperidin-3-y])-1.3- dioxoisomdoim-4-vDamino)ethoxy)acetamide (
  • Compound 14 was prepared from 2-((6-(4-aminopi peridin- 1 -yl)-3.5-dicyano-4- ethylpyridin-2-yl)thio)-2-phenylacetamide and 2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)ammo)ethoxy)acetic acid using a procedure similar to that used in Examp1e 1.
  • LCMS m/z 778,57 [M+H] + .
  • Example 15 Synthesis of N-(l-(6-((2-amino-2-oxo-l-phenylethyl)thio)-3.5- dicvano-4-ethylpyridin-2-yl)piperidin-4-yl)-3-(2-((2-(2..6-dioxopiperidin-3-yD-L3- dioxoisomdolm-5-yl)amino)ethyl)benzamide (15)
  • Compound 15 was prepared from 2-((6-(4-aminopiperidin-l-yl)-3.5-dicyano-4- ethylpyridin-2-yI)thio)-2-pheny1acetamide and 3-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)ethyl)benzoic acid using a procedure similar to that used m Examp1e 1.
  • LCMS m/z 824.50 [M+H
  • Example 16 Synthesis of N-(l-(6-((2-amino-2-oxo-l-phenylethyl)thio)-3,5- dicvano-4-ethylpyridin-2-yI)piperidin-4-YD-6-((3-('(2-(2,6-dioxopiperidm-3-yl)-L3- dioxoisoindolin-4-yl)amino)propyI)amino)nicotinamide ( 16)
  • Example 17 Synthesis of (2S.4R)-1 -((2S)-2-(6-((1-(6-((2-amino-2-oxo-l- phenylethyl)thio)-3,5-dicvano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)hexanamido)-3,3- dimethylbutanoy’l)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-y’l)phenyl)ethyl)pyrrolidine-2- carboxamide (17)
  • 6-Bromohexanoic acid (390 mg, 2.0 mmol) and trifluoroacetic acid anhydride (1.11 mL. 8 0 mmol) were dissolved in THF (4 ml.,). The solution was stirred at rt for 1 .5 hours, then tert -butanol (2 mL, 34.5 mmol) was added The solution was stirred at rt for 16 hours, then quenched by slowly adding saturated aqueous NaHCOs (15 mL).
  • HATU (2.1 mg, 0.00561 mmol) was added to the solution and the mixture was stirred for 15 minutes at rt, then purified by column chromatography (Teledyne ISCO, 4 g silica column) eluting with a gradient of 0% to 20% MeOH in DCM, to give the title compound (0.62 mg, 17.2%).
  • Example 18 Synthesis of (2S.4R)-l ⁇ ((2S)-2-(10-((l-(6-((2-amino-2-oxo-l- phenylethyl)thio)-3,5-dicyano-4-ethylpyridm-2-yl)piperidin-4-Yl)amino)decanamido)-3.3- dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (18)
  • HATU (3.1 mg, 0.00804 mmol) was added and the solution was stirred at rt for 1 hour, then purified by column chromatography’ (Teledyne 1SC0, 4 g silica column) eluting with a gradient of 0 to 15% MeOH/DCM, to give the title compound (3.89 mg, 65 9%).
  • column chromatography Teledyne 1SC0, 4 g silica column
  • Example 20 Synthesis of N-(2-((6-((2-amino-2-oxo-l-phenylethyl)thio)-3,5- dicy , ano-4-ethylpyridin-2-yl)(methyl)ammo)ethyl)-6-((2-(2.6-dioxopiperidin-3-yl)-L3- dioxoisoindolin-4-yl)amino)-N-methylhexanamide (20)
  • HATU 7.0 mg, 0.0185 mmol
  • the mixture was stirred at rt for 15 minutes.
  • the mixture was purified by column chromatography (Teledyne ISCO, 4 g) eluting with a gradient of 50 to 100% EtOAc/hexanes, to give the title compound (4.36 mg, 44.4%).
  • LCMS m/z 798.56
  • Example 22 Synthesis of 2-((6-(4-aminopiperidin-l-yl)-3.5-dicvano-4- ethvipyrklin-2-yDthio)-N-(4-((2-(2,6-dioxoptperidin-3-yl)-1.3-dioxoisoindolin-4- yl)amino)butyl)-2-phenylacetamide (22)
  • N , N' -dicyclohexylcarbodiimide (0.9 mg, 0.00425 mmol) and hydroxybenzotriazole (0.6 mg. 0.00425 mmol) were added and the mixture was stirred at 0°C for 10 minutes.
  • 4-((4-aminobulyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (1.5 mg, 0.00425 mmol) and A'-methylmorpholme (0.47 ⁇ L, 0.00425 mmol) were added and the mixture was allowed to warm to rt.
  • Example 23 Synthesis of 2-((6-(4-aminopiperidin-l-yl)-3.5-dicyano-4- ethylpyridin-2-yl)thio)-N-(4-(((2-(2.6-dioxopiperidin-3-yr)-1.3-dioxoisoindolin-4- yl)amino)methyl )benzyl)-2-phenylacetamide (23) [00269] tert-Butyl ( ⁇ -(3.5-dicyano-6-((2-((4-(((2-(2,6-dioxopiperidm-3-yr)-l .3- dioxoisoindolin-4-yl)amino)methyl)benzyl)amino)-2-oxo-l-phenylethyl)thio)-4-ethylpyridin- 2-yl)piperidin-4-yl)carbamate
  • Example 24 Synthesis of N-(2-((6-((2-amino-2-oxo-l-phenylethyl)thio)-3 till5- dicvano-4-ethvlpyridin-2-yl)(methyl)amino)ethyl)-3-(2-(2-(2-((2-(2.6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4-yl )amino)ethoxy)ethoxy)ethoxy)-N -methylpropanamide (24)
  • Example 26 Synthesis of 2-((6-(4-aminopiperidin-l-vD-3,5-dicvano-4- diylpvridin-2-vl)thio)-N-(2-(2-(2-((2-(2.6-dioxoi i-3-vl)-l ,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)-2-phenylacetamide (26) [00278] tert-Butyl (l-(3, 5-dicyano-6-((2-((2-(2-(2-(2-(2-(2-(2-(2-(2, 6-dioxopiperidin-3-yl)-l .3- dioxoisoindolin-4-yl)amino)ethoxy)ethyl)amino)-2-oxo-l-phenylethyl)thio)-4- ethylpyndin-2-yl)
  • Example 27 Synthesis of 2-((6-(4-aminopipendin-l-yl)-.L5-dicyano-4- ethylpyridin-2-yl)thio)-N-( 10-((2-(2.6-dioxopiperidin-3-vi)- 1 .3-dioxoisoindolin-4- yl)amino)decyl)-2-phenylacetamide (27)
  • Example 28 Synthesis of N-(2-((6-((2-amino-2-oxo-l-phenylethyl)thio)-3,5- dicyano-4-ethylpyridin-2-yl)(methyl)ammo)ethyl)-6-((2-(2.6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)amino)-N-methylhexanamide (28)
  • Examp1e 30 Synthesis of 2-((7-C 6 -((2-(2,6-dioxopiperidin-3-yl)-13- dioxoisoindolin-4-yl)amino)hexanoyl)-2-(4-hvdroxypiperidin-J -yl)-5.6.7,8- tetrahydropyrido[3.4-d]pyrimidin-4-yl)!hio)-2-phenylacetamide (30)
  • Example 31 Synthesis of 2-((7-(10-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindoUn-4-yl)amino)decanoyl)-2-(4-hydroxypiperidin-l-yl)-5.6.7.8- tetrahydropyridor3.4-dlpyrimidin-4-yl)thio)-2 ⁇ phenylacetamide
  • HATU (3.6 mg, 0.00953 mmol) was added and the mixture was stirred at rt for 30 minutes, then purified by column chromatography (Teledyne TSCO, 4 g silica column) eluting with a gradient of 0 to 7% MeOH/DCM, to give the title compound (2.88 mg, 55.0%).
  • LCMS m/z 825 72 i Vi H i
  • Examp1e 32 Synthesis of 2-((3,5-dicvano-6-((8-((2-(2,6-dioxopiperidin-3-yl)-l .3- dioxoisoindolin-4-yl)amino)octyl)ajtnino)-4-ethylpyridin-2-yl)thio)-2 ⁇ phenylacetamide (32)
  • HL60 cells were seeded in 6-well p1ates at 1*10° cells/well and treated with the compound at the indicated concentrations and time.
  • Total protein was extracted from cells using the RIP A buffer (Abeam) supp1emented with the Halt Protease Inhibitor Cocktail (Miilipore®-Sigraa). Samples were loaded to Invitrogen BoltTM Bis-Tris Plus gels (ThermoFisher® Scientific) and transferred to InvitrolonTM PVDF membranes (ThermoFisher®' Scientific) using the Invitrogen BoltTM wet-gel Transfer Device. Immunodetection was performed with standard techniques. The following primary and secondary antibodies were used: anti-DNMTL CRBN and ⁇ -actin (Cell Signaling Technology®), and IRDye secondary antibodies at the concentration recommended by the manufacturer.

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Abstract

L'invention concerne des composés (agents de dégradation) qui ciblent DNMT1 pour la dégradation. L'invention concerne également des compositions pharmaceutiques contenant les composés et des procédés d'utilisation des composés pour traiter des maladies et troubles caractérisés ou médiés par une activité de DNMT1 aberrante.
PCT/US2024/036042 2023-06-29 2024-06-28 Synthèse et caractérisation in vitro de chimères ciblant la protéolyse (protacs) pour la dégradation de l'adn méthyltransférase 1 (dnmt1) Ceased WO2025006902A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP24833014.4A EP4734989A2 (fr) 2023-06-29 2024-06-28 Synthèse et caractérisation in vitro de chimères ciblant la protéolyse (protacs) pour la dégradation de l'adn méthyltransférase 1 (dnmt1)
CN202480042233.XA CN121368481A (zh) 2023-06-29 2024-06-28 用于降解dna甲基转移酶1 (dnmt1)的蛋白水解靶向嵌合体(protacs)的合成和体外表征

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