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WO2025240834A1 - Agents de dégradation chimique ciblant nsd2, compositions et méthodes d'utilisation associées - Google Patents

Agents de dégradation chimique ciblant nsd2, compositions et méthodes d'utilisation associées

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Publication number
WO2025240834A1
WO2025240834A1 PCT/US2025/029715 US2025029715W WO2025240834A1 WO 2025240834 A1 WO2025240834 A1 WO 2025240834A1 US 2025029715 W US2025029715 W US 2025029715W WO 2025240834 A1 WO2025240834 A1 WO 2025240834A1
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Prior art keywords
compound
alkyl
cyclopropyl
cancer
oxo
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Pending
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PCT/US2025/029715
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English (en)
Inventor
Jon Loren Collins
Ronan Patrick HANLEY
Lindsey Ingerman JAMES
John Raymond TABOR
Andrew W. Stamford
Tongkun LIU
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University of North Carolina at Chapel Hill
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University of North Carolina at Chapel Hill
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Publication of WO2025240834A1 publication Critical patent/WO2025240834A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • NSD2-TARGETED CHEMICAL DEGRADERS AND COMPOSITIONS AND METHODS OF USE THEREOF FIELD OF THE INVENTION The present invention is directed to nuclear receptor-binding SET domain-containing 2 (NSD2)-targeted protein degradation ligands and pharmaceutical compositions thereof and their utility as anti-cancer agents.
  • NSD2 nuclear receptor-binding SET domain-containing 2
  • the present invention is directed to nuclear receptor-binding SET domain-containing 2 (NSD2)-targeted protein degradation ligands and pharmaceutical compositions thereof and their utility as anti-cancer agents.
  • NSD2 Nuclear receptor-binding SET domain-containing 2
  • MMSET multiple myeloma SET domain
  • WHSC1 Wolf-Hirschhorn syndrome candidate 1
  • NSD2 is also required for efficient non-homologous end-joining and homologous recombination, two canonical DNA repair pathways (Shah, M. Y. et al. Oncogene, 35, 5905-5915, 2016; Zhang, J. et al., Cancer Discov., 9, 1306-1323).
  • NSD2 has multiple protein-protein interaction (PPI) modules with known or potential chromatin reading functions, including five PHD (plant homeodomain) and two PWWP (proline-tryptophan-tryptophan-proline) domains (Bennet, R. L. et al.
  • NSD2 The isolated N-terminal PWWP domain of NSD2 (NSD2-PWWP1) binds H3K36 di- and trimethylated nucleosomes; this interaction presumably is mediated by a conserved aromatic cage and stabilizes NSD2 at chromatin (Sankaran, S. M. et al., J. Biol. Chem.291, 8465-8474, 2016). Mutation of the aromatic cage residues abrogates NSD2-PWWP1 binding to nucleosomal H3K36me2, but has only modest effect on global H3K36 methylation level in cells. However, H3K36 methylation has been shown to be abolished upon mutation of the second PHD domain (PHD2)(Huang, Z. et al.
  • NSD2 is aberrantly expressed, amplified or somatically mutated in multiple types of cancer, leading to increased methylation of lysine 36 of histone 3 (H3K36) (Kuo, A. J., et al. Mol. Cell, 44, 609-620, 2011) and subsequent proliferation.
  • H3K36 histone 3
  • high expression of the NSD2 protein has been demonstrated in different human cancer types, including bladder, brain, gastrointestinal, lung, liver, ovary, skin, uterus, breast, prostate and glioblastoma.
  • NSD2 is among the most frequently mutated genes in pediatric cancer genomes.
  • the NSD2 SET domain variant, E1099K was identified in both acute lymphoblastic leukemia tumors and cell lines with increased H3K36me2 that lack the t (4; 14) translocation.
  • NSD2 is also among the most frequently mutated genes found in mantle cell lymphoma tumors, where both E1099K and T1150A variants are observed.
  • the E1099K variant has also been reported in chronic lymphocytic leukemia (CLL), lung and stomach cancers.
  • CLL chronic lymphocytic leukemia
  • NSD2 upregulation is associated with aggressive tumor behavior and poor prognosis.
  • Due to growing occurrence of drug resistance to current traditional anticancer drugs employed in treating such cancer there has been an ongoing need for improving such anti-cancer therapies and/or developing new treatment options, which can act via different cellular mechanisms to combat cancers.
  • One of such new treatment options involves the NSD2 enzyme, which represents a promising target for anti-cancer therapy.
  • SUMMARY Provided herein are compounds, which can bind to the NSD2 enzyme in the non-active site and degrade the enzyme.
  • a compound of Formula (I): A compound of Formula (I): Formula (I) or any pharmaceutically acceptable salt and/or stereoisomer thereof, wherein: Q is selected from the group consisting of R 1 is –cyclopropyl or -isopropyl; R 1a is hydrogen or (C 1 -C 6 ) alkyl; R 2a and R 2b , in each instance, are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 1 - C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, ⁇ CN, ⁇ NH 2 , and ⁇ OH; A is selected from the group consisting of:
  • Another aspect of the disclosure is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier(s).
  • Another aspect of the disclosure is directed to a method for treating a disease or condition that is treatable by inhibition of nuclear SET-domain-containing protein (NDS2), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, prodrug, or a pharmaceutical composition as disclosed herein.
  • the disease is cancer.
  • DESCRIPTION OF THE DRAWINGS Fig.1 shows the NSD2 protein architecture of the three splicing isoforms NSD2-long, NSD2- short, and REIIBP.
  • NSD2 nuclear receptor-binding SET domain-containing 2
  • H3K36 histone 3
  • NSD2 is a potent oncoprotein and has been implicated as a therapeutic target for a variety of cancers.
  • Recent research efforts suggest that in addition to its catalytic SET domain, NSD2 contains several PWWP and PHD methyl-lysine (Kme) reader domains, which are thought to be critical in propagating H3K36me2 and recruiting NSD2 to its oncogenic genes.
  • Various NSD2 antagonists have been prepared to date (WO2021/026803; WO2021/028854; and Dilworth, D. et al., bioRxiv, March 7, 2021).
  • the disclosed compounds are NSD2 targeted compounds exhibiting potent NSD2 binding affinity while simultaneously demonstrating efficient degradation of the target protein (i.e., NSD2).
  • NSD2 degraders Pharmaceutical compositions containing these NSD2 degraders and methods of use thereof are described further in more detail below.
  • alkyl group refers to a saturated hydrocarbon radical containing 1 to 8, 1 to 6, 1 to 4, or 5 to 8 carbons. In some embodiments, the saturated radical contains more than 8 carbons.
  • alkyl group is structurally similar to a noncyclic alkane compound modified by the removal of one hydrogen from the noncyclic alkane and the substitution therefore of a non-hydrogen group or radical.
  • Alkyl group radicals can be branched or unbranched. Lower alkyl group radicals have 1 to 4 carbon atoms. Higher alkyl group radicals have 5 to 8 carbon atoms.
  • alkyl, lower alkyl, and higher alkyl group radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl, t butyl, amyl, t amyl, n-pentyl, n-hexyl, i-octyl and like radicals.
  • suitable carbonyl moieties include, but are not limited to, those found in ketones and aldehydes.
  • cycloalkyl refers to a hydrocarbon with 3-8 members or 3-7 members or 3-6 members or 3-5 members or 3-4 members and can be monocyclic or bicyclic.
  • the ring may be saturated or may have some degree of unsaturation.
  • Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent.
  • cycloalkyl group examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
  • aryl refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system.
  • Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent.
  • aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.
  • heteroaryl refers to an aromatic 5-10 membered ring systems where the heteroatoms are selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated). Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent.
  • heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.
  • alkoxy refers to a moiety of the formula —OR a where Ra is an alkyl group as defined herein containing one to twelve carbon atoms.
  • haloalkyl refers to an alkyl group, as defined herein, that is substituted by one or more halo atoms, as defined herein, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCF 3 , —CHFCHF 2 , — CHFCH 2 F, —CHFCH 3 , —CF 2 CF 3 , —CF 2 CHF 2 , —CF 2 CH 2 F, —CF 2 CH 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CH 3 , —CH 2 CHFCH 3 , 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • haloalkyl group is optionally substituted.
  • alkynyl used alone or as part of another group, refers to unsaturated linear or branched hydrocarbon radical that contains one triple bond.
  • the hydrocarbon radical contains at least 2 carbon atoms, but preferably contains 3 to 20 carbon atoms.
  • substituted refers to a moiety (such as heteroaryl, aryl, cycloalkyl, alkyl, and/or alkenyl) wherein the moiety is bonded to one or more additional organic or inorganic substituent radicals.
  • the substituted moiety comprises 1, 2, 3, 4, or 5 additional substituent groups or radicals.
  • Suitable organic and inorganic substituent radicals include, but are not limited to, halogen, hydroxyl, cycloalkyl, aryl, substituted aryl, heteroaryl, heterocyclic ring, substituted heterocyclic ring, amino, mono-substituted amino, di-substituted amino, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkyl carboxamide, substituted alkyl carboxamide, dialkyl carboxamide, substituted dialkyl carboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, alkoxy, substituted alkoxy or haloalkoxy radicals, wherein the terms are defined herein.
  • the organic substituents can comprise from 1 to 4 or from 5 to 8 carbon atoms.
  • the substituent radicals may be the same or different.
  • the term “unsubstituted” refers to a moiety (such as heteroaryl, aryl, alkenyl, and/or alkyl) that is not bonded to one or more additional organic or inorganic substituent radical as described above, meaning that such a moiety is only substituted with hydrogens.
  • substitution or “substituted with” includes the implicit proviso that such structures and substitution are in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • subject broadly refers to any animal, including but not limited to, human and non-human animals (e.g., dogs, cats, cows, horses, sheep, poultry, fish, crustaceans, etc.).
  • patient typically refers to a subject that is being treated for a disease or condition.
  • the term “effective amount” refers to the amount of a composition sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the terms “administration” and “administering” refer to the act of giving a drug, prodrug, or other agent, or therapeutic treatment to a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs.
  • Exemplary routes of administration to the human body can be through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, rectal, vaginal, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.) and the like.
  • co-administration and “co-administering” refer to the administration of at least two agent(s) (e.g., NSD2 inhibitor and one or more additional therapeutics) or therapies to a subject.
  • the co-administration of two or more agents or therapies is concurrent.
  • a first agent/therapy is administered prior to a second agent/therapy.
  • the formulations and/or routes of administration of the various agents or therapies used may vary.
  • the appropriate dosage for co-administration can be readily determined by one skilled in the art.
  • the respective agents or therapies are administered at lower dosages than appropriate for their administration alone.
  • co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent(s), and/or when co-administration of two or more agents results in sensitization of a subject to beneficial effects of one of the agents via co-administration of the other agent.
  • a potentially harmful agent e.g., toxic
  • the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.
  • pharmaceutically acceptable refers to compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject.
  • pharmaceutically acceptable carrier refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like.
  • compositions also can include stabilizers and preservatives.
  • carriers, stabilizers and adjuvants see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. (1975), incorporated herein by reference in its entirety.
  • pharmaceutically acceptable salt refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention, which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof.
  • salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.
  • the term “prevent”, “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.
  • a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the term a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • anticancer agent or antineoplastic agent, refers to a therapeutic agent that is useful for treating or controlling the growth of cancerous cells.
  • NSD2 degraders and methods of use thereof for the treatment of disease, such as cancers and other diseases dependent on the activity of NSD2.
  • the compounds disclosed herein comprise a compound of Formula (I): Formula (I) or any pharmaceutically acceptable salt and/or stereoisomer thereof, wherein: Q is selected from the group consisting of R 1 is –cyclopropyl or -isopropyl; R 1a is hydrogen or (C 1 -C 6 ) alkyl; R 2a and R 2b , in each instance, are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 1 - C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, ⁇ CN, ⁇ NH 2 , and ⁇ OH; A is selected from the group consisting of:
  • R 1a is hydrogen. In some embodiments, R 1a is (C 1 -C 6 ) alkyl. In some embodiments, R 1 is -cyclopropyl. In some embodiments, R 1 is -isopropyl. In some embodiments, R1a is hydrogen and R1 is -cyclopropyl. In some embodiments, comprises one of more of the following: In some embodiments, Q is selected from the group consisting of
  • R 1a is hydrogen; R 1 is -cyclopropyl and Q is selected from R 1a is hydrogen; R 1 is -cyclopropyl; Q is selected from
  • R 1a is (C 1 -C 6 ) alkyl and R 1 is -cyclopropyl.
  • R 1a is -CH 3 and R 1 is -cyclopropyl.
  • R 1a is -CH 3 and R 1 is -cyclopropyl
  • Q is selected from the group consisting , wherein R 2a and R 2b are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, and halogen. In some embodiments, . In some embodiments, i
  • B is -C-
  • R3f is -H and L1 is .
  • n is an integer selected from 3, 4, and 5.
  • R 3f is -H.
  • R 3f is -H; and L 1 is , wherein wherein B is -C-.
  • R 1a is hydrogen; R 1 is -cyclopropyl; .
  • the compounds disclosed herein are compounds of Formula (II): Formula (II) or a pharmaceutically acceptable salt thereof and/or stereoisomer thereof, wherein: R 2a and R 2b are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or halogen; A is selected from the group consisting of
  • R 3a, R 3b R 3c , R 3d , R 3e , R 3f and R 3g are each independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, and halogen;
  • B is -C- or -N-;
  • Z 1 and Z 2 are independently selected from -H, -OH, -NH 2 , -CN, -CF 3 , CD 3 , halogen, (C 1 - C 6 )alkyl, -
  • A is .
  • A is ;
  • R 3a is -CH 3 ; and
  • A is .
  • A is , wherein L1 is .
  • L 1 is
  • A is .
  • A is embodiments, wherein X is -O-; and n is 4, 5, 6 or 7.
  • A is selected from the group consisting of .
  • –O(C 1 -C 6 )alkyl is -OCH 3 or -OCH 2 CH 3 .
  • (C 1 -C 6 alkyl) is - CH 3 .
  • B is -C- and Z 1 and Z 2 are (C1-C6 alkyl).
  • Z 1 and Z 2 are both - CH 3 .
  • Z 1 is -H and Z 2 is -CH 3 .
  • R 3f is -H
  • B is -N-
  • R 1 is -H
  • B is -N-
  • R 1 and R 2 are both -H.
  • Preferred embodiments include the following: Embodiment 1: A compound of Formula (I): Formula (I) or any pharmaceutically acceptable salt and/or stereoisomer thereof, wherein: Q is selected from the group consisting of
  • R 1 is –cyclopropyl or -isopropyl;
  • R 1a is hydrogen or (C 1 -C 6 ) alkyl;
  • R 2a and R 2b in each instance, are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 1 - C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, halogen, ⁇ CN, ⁇ NH 2 , and ⁇ OH;
  • A is selected from the group consisting of:
  • Embodiment 2 The compound of embodiment 1, wherein R 1a is hydrogen.
  • Embodiment 3 The compound of embodiment 1 or embodiment 2, wherein R 1 is cyclopropyl.
  • Embodiment 4 The compound of any one of the preceding embodiments, wherein Q is selected from the group consisting of Embodiment 5: The compound of any one of the preceding embodiments, wherein the compound is a compound of Formula (II): Formula (II) or a pharmaceutically acceptable salt thereof and/or stereoisomer thereof, wherein: R 2a and R 2b are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or halogen; A is selected from the group consisting of ; wherein R3a, R3b R3c, R3d, R3e, R3f and R3g are each independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloal
  • Embodiment 6 The compound of embodiment 5, wherein A is selected from the group consisting of .
  • Embodiment 8 The compound of embodiment 6 or 7, wherein A is ; X is -CH 2 -, and n is an integer selected from 3, 4, 5, and 6.
  • Embodiment 11 The compound of claim 6, wherein A and L 2 is .
  • Embodiment 14 The compound of embodiment 12 or 13, wherein p is 2 and q is 2.
  • Embodiment 15 The compound of embodiment 12 or 13, wherein p is 1 and q is 3.
  • Embodiment 16 The compound of embodiment 5, wherein A is or and X is -CH 2.
  • Embodiment 17 The compound of embodiment 16, wherein n is an integer selected from 2, 3 and 4.
  • Embodiment 18 The compound of embodiment 5, wherein A is and L 2 is .
  • Embodiment 20 The compound of embodiment 5, wherein A is and L 2 is .
  • Embodiment 24 The compound of embodiment 23, wherein Z 2 is -H or -CH 3 .
  • Embodiment 25 The compound of embodiment 5, wherein A is and L 2 is .
  • Embodiment 26 The compound of embodiment 5, wherein A is .
  • Embodiment 28 The compound of embodiment 26, wherein n is 4, 5, 6 or 7.
  • a compound of any one of Formula (I) and (II) may be selected from the compound listed in Table 1. Compounds of Formula (I) and (II) that are not listed in Table 1 are also within the scope herein. Table 1:
  • the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography and/or recrystallization or by the forming diastereomers and separation thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981). Stereoisomers may also be obtained by stereoselective synthesis using synthetic methods known in the art.
  • the compounds disclosed herein are enantiomers having an enantiomeric excess (% ee) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the compounds disclosed herein are disateremores having a diatereomeric excess (% de) of at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99.5%. In some embodiments, the compounds disclosed herein are present as enantiomeric or diastereomeric mixtures. The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts. Active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In some embodiments, the compounds described herein may be formed as, and/or used as, pharmaceutically acceptable salts.
  • the type of pharmaceutical acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenes
  • compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • the compounds and salts described herein include isotopically-labeled compounds.
  • isotopically-labeled compounds are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most common in nature.
  • isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, respectively.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
  • the compounds or salts described herein is a prodrug.
  • the compounds described herein may be formed as, and/or used as, prodrugs.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Examples, without limitation, of a prodrug would be a compound described herein, which is administered as an ester or an amide (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid and/or amine, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) or amino acid (natural or unnatural) bonded to an acid group or an amine group where the peptide or amino acid is metabolized to reveal the active moiety.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration.
  • the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • prodrugs of the compound are designed. (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p.
  • the compounds disclosed herein bind to NSD2 and exhibit a dissociation constant (Kd) ranging from about 1 nM to about 500 nM, from about 1 nM to about 400 nM, from about 1 nM to about 300 nM, from about 1 nM to about 200 nM, from about 1 nM to about 100 nM, from about 1 nM to about 75 nM, from about 1 nM to about 50 nM, from about 1 nM to about 25 nM, or from about 1 nM to about 10 nM.
  • Kd dissociation constant
  • the disclosed compounds exhibit a Kd of less than about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 100 nM, about 75 nM, about 50 nM, about 25 nM, or less than about 10 nM.
  • the compounds disclosed herein degrade enzyme NSD2 in cells at concentrations ranging from about 1 microM to about 10 ⁇ M (i.e., at a concentration of less than about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 ⁇ M).
  • the compounds disclosed herein are present at a concentration that is at least 10 ⁇ M.
  • the compound degrades enzyme NSD2 in such a manner that less than about 100%, about 75%, about 50%, about 25%, or less than about 10% of the enzyme remains intact after a certain time period of exposure.
  • the disclosed compounds degrade enzyme NSD2 and exhibit a DC50 (compound concentration at which 50% of the NSD2 protein is degraded) ranging from about 0.1 ⁇ M to about 5 ⁇ M, from about 0.1 ⁇ M to about 4 ⁇ M, from about 0.1 ⁇ M to about 3 ⁇ M, from about 0.1 ⁇ M to about 2 ⁇ M, from about 0.1 ⁇ M to about 1 ⁇ M, from about 0.1 ⁇ M to about 0.5 ⁇ M and from about 0.1 ⁇ M to about 0.25 ⁇ M.
  • DC50 compound concentration at which 50% of the NSD2 protein is degraded
  • the disclosed compounds degrade enzyme NSD2 and exhibit a DC50 (compound concentration at which 50% of the NSD2 protein is degraded) of less than about 5 ⁇ M, about 4 ⁇ M, about 3 ⁇ M, about 2 ⁇ M, about 1 ⁇ M, about 0.75 ⁇ M, about 0.50 ⁇ M, about 0.25 ⁇ M, or less than about 0.1 ⁇ M.
  • DC50 compound concentration at which 50% of the NSD2 protein is degraded
  • an IC 50 of >10 ⁇ M means compounds exhibit activities of 10 ⁇ M and higher; an IC 50 of >2 ⁇ M means compounds exhibit activities of 2 ⁇ M and higher but less than 10 ⁇ M; an IC 50 of >1 ⁇ M means compounds exhibit activities of 1 ⁇ M and higher but less than 2 ⁇ M; an IC 50 of >0.75 ⁇ M means compounds exhibit activities of 0.75 ⁇ M and higher but less than 1 ⁇ M; an IC 50 of >0.5 ⁇ M means compounds exhibit activities of 0.5 ⁇ M and higher but less than 0.75 ⁇ M; an IC 50 of >0.25 ⁇ M means compounds exhibit activities of 0.25 ⁇ M and higher but less than 0.5 ⁇ M; and an IC 50 of ⁇ 0.25 ⁇ M means compounds exhibit activities of less than 0.25 ⁇ M.
  • a DC 50 of >10 ⁇ M means compounds exhibit degradation activities of 10 ⁇ M and higher; a DC 50 of ⁇ 0.5 ⁇ M means compounds exhibit degradation activities of less than 0.5 ⁇ M but higher than 0.1 ⁇ M; a DC 50 of ⁇ 0.1 ⁇ M means compounds exhibit degradation activities of less than 0.1 ⁇ M.
  • compounds, prodrugs or salts of Formulae (I) and/or (II) disclosed herein are combined with one or more additional agents to form pharmaceutical compositions.
  • compounds of Formulae (I) and/or (II) are already in the form of a prodrug.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Additional details about suitable excipients for pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A.
  • a pharmaceutical composition refers to a mixture of a compound or salt or prodrug of Formulae (I) and/or (II) with any suitable substituents and functional groups disclosed herein, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated.
  • the mammal is a human.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds or salts of Formula (I) with any suitable substituents and functional groups disclosed herein, can be used singly or in combination with one or more therapeutic agents as components of mixtures (as in combination therapy).
  • compositions described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • parenteral e.g., intravenous, subcutaneous, intramuscular
  • intranasal e.g., buccal
  • topical e.g., topical, rectal, or transdermal administration routes.
  • compositions described herein which include a compound of Formula (I) and/or (II) with any suitable substituents and functional groups disclosed herein, can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, and capsules.
  • One may administer the compounds and/or compositions in a local rather than systemic manner, for example, via injection of the compound directly into an organ or tissue, often in a depot preparation or sustained release formulation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • a targeted drug delivery system for example, in a liposome coated with organ-specific antibody.
  • the liposomes will be targeted to and taken up selectively by the organ.
  • the drug may be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • Pharmaceutical compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • compositions will include at least one compound of Formula (I) disclosed herein, as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • the pharmaceutical solid dosage forms described herein can include a compound of Formulae (I) and/or (II) and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • a compatible carrier such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of the compound described herein.
  • some or all of the particles of the compound described herein are coated. In another embodiment, some or all of the particles of the compound described herein are microencapsulated. In still another embodiment, the particles of the compound described herein are not microencapsulated and are uncoated.
  • Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.
  • Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac- Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrroli
  • Suitable binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose,
  • Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali- metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.
  • stearic acid calcium hydroxide, talc, corn star
  • Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
  • Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.
  • quaternary ammonium compounds e.g., Polyquat 10®
  • Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like.
  • Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as,
  • Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
  • BHT butylated hydroxytoluene
  • sodium ascorbate sodium ascorbate
  • tocopherol sodium ascorbate
  • Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups.
  • compositions described herein may include sweetening agents such as, but not limited to, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaS)
  • compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients.
  • suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels.
  • Nasal dosage forms generally contain large amounts of water in addition to the active ingredient.
  • the nasal dosage form should be isotonic with nasal secretions.
  • the compounds described herein may be in a form as an aerosol, a mist or a powder.
  • compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch.
  • buccal formulations that include compounds described herein may be administered using a variety of formulations, which include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136.
  • the buccal dosage forms described herein can further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa.
  • the buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery of the compound is provided essentially throughout.
  • buccal drug delivery avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver.
  • bioerodible (hydrolysable) polymeric carrier virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the compounds described herein, and any other components that may be present in the buccal dosage unit.
  • the polymeric carrier comprises hydrophilic (water-soluble and water- swellable) polymers that adhere to the wet surface of the buccal mucosa.
  • polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as “carbomers” (Carbopol®, which may be obtained from B.F. Goodrich, is one such polymer).
  • Carbopol® which may be obtained from B.F. Goodrich, is one such polymer.
  • Other components may also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like.
  • the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.
  • Transdermal formulations described herein may incorporate certain pharmaceutically acceptable excipients, which are conventional in the art.
  • formulations suitable for transdermal administration of compounds described herein may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants such as surfactants.
  • Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents.
  • antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.
  • compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally recognized in the field.
  • appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally recognized in the field.
  • Parenteral injections may involve bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions provided herein also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions.
  • compositions provided herein also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • the compounds described herein may be administered topically and are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • the compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • the compounds of Formulae (I) and/or (II) disclosed herein are combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti- nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.
  • the compounds of Formulae (I) and/or (II) disclosed herein are combined with another therapeutic agent capable of inhibiting BRAF, MEK, CDK4/6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof.
  • an agent such as a compound of Formula (I) disclosed herein, is administered in an amount effective for treating the disease or disorder (i.e., a therapeutically effective amount).
  • a therapeutically effective amount can be an amount that is capable of at least partially treating, preventing or reversing a disease or disorder.
  • the dose required to obtain an effective amount may vary depending on the agent, formulation, disease or disorder, and individual to whom the agent is administered. Determination of effective amounts may also involve in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. Effective amounts may also be based in in vivo animal studies. An agent can be administered prior to, concurrently with and subsequent to the appearance of symptoms of a disease or disorder.
  • an agent is administered to a subject with a family history of the disease or disorder, or who has a phenotype that may indicate a predisposition to a disease or disorder, or who has a genotype which predisposes the subject to the disease or disorder.
  • the compositions described herein are provided as pharmaceutical and/or therapeutic compositions.
  • the pharmaceutical and/or therapeutic compositions of the present disclosure can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Administration can be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders can be desirable.
  • Compositions and formulations for parenteral, intrathecal or intraventricular administration can include sterile aqueous solutions that can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.
  • compositions of the present disclosure include, but are not limited to, solutions, emulsions, and liposome containing formulations. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids.
  • the pharmaceutical and/or therapeutic formulations which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical/nutriceutical industries. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • compositions of the present disclosure can be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas.
  • the compositions of the present disclosure can also be formulated as suspensions in aqueous, non-aqueous, oil-based, or mixed media. Suspensions can further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran.
  • the suspension can also contain stabilizers.
  • the pharmaceutical compositions can be formulated and used as foams.
  • compositions include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative. Dosing and administration regimes are tailored by the clinician, or others skilled in the pharmacological arts, based upon well-known pharmacological and therapeutic considerations including, but not limited to, the desired level of therapeutic effect, and the practical level of therapeutic effect obtainable.
  • the compounds are administered to a subject at a dose of about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone. Dosing may be once per day or multiple times per day for one or more consecutive days.
  • Methods of Treatment The present disclosure provides compounds and methods for binding to and/or inhibiting the activity of the NSD2 enzyme. In some embodiments, the present disclosure provides compounds and methods that degrade the NSD2 enzyme. Inhibition of NSD2 activity may be assessed and demonstrated by a wide variety of ways known in the art.
  • Non-limiting examples include measure (a) a direct decrease in NSD2 activity; (b) a decrease in cell proliferation and/or cell viability; (c) an increase in cell differentiation; (d) a decrease in the levels of downstream targets of NSD2 activity; and (e) decrease in tumor volume and/or tumor volume growth rate. Kits and commercially available assays can be utilized for determining one or more of the above. Binding of compounds disclosed herein to the NSD2 enzyme can be determined using known methods in the arts, such as, but not limited to Surface Plasmon Resonance (SPR).
  • SPR Surface Plasmon Resonance
  • the disclosure provides compounds and methods for treating a subject suffering from a disease, comprising administering a compound, prodrug or salt described herein, for example, a compound, prodrug or salt of Formulae (I) and/or (II) disclosed herein, to the subject.
  • the disease is selected from a disease associated with NSD2 expression (e.g., aberrant expression, overexpression, etc.) and/or activity (e.g., cancer).
  • the disease is mediated by NSD2 activity and/or expression (e.g., aberrant expression, overexpression, etc.).
  • the disease or condition is treatable by inhibition of and/or degradarion of the NDS2 enzyme.
  • the method comprises treating a disease or condition that is treatable by inhibition of NDS2 by administering to a subject in need thereof a therapeutically effective amount of a compound, prodrug, or a salt thereof of Formulae (I) and/or (II) or a pharmaceutical composition as disclosed herein.
  • the disclosure provides a method for treating cancer in a subject, comprising administering a compound, prodrug or salt described herein, for example, a compound, prodrug or salt of Formulae (I) and/or (II) disclosed herein, to the subject.
  • the cancer is mediated by a NSD2 expression (e.g., aberrant expression, overexpression, etc.) and/or activity.
  • the disclosure provides method of treating a disease in a subject, wherein the method comprises determining if the subject has an NSD2-mediated condition (e.g., cancer) and administering to the subject a therapeutically effective dose of a compound, prodrug or salt described herein, for example, a compound, prodrug or salt of Formulae (I) and/or (II) as disclosed herein. Determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) NSD2 can be undertaken by assessing the nucleotide sequence encoding NSD2 or by assessing the amino acid sequence of NSD2.
  • an NSD2-mediated condition e.g., cancer
  • PCR-RFLP polymerase chain reaction- restriction fragment length polymorphism
  • PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
  • MASA mutant allele-specific PCR amplification
  • direct sequencing primer extension reactions
  • electrophoresis oligonucleotide ligation assays
  • hybridization assays TaqMan assays
  • SNP genotyping assays high resolution melting assays and microarray analyses.
  • Methods for detecting an NSD2 protein are known by those of skill in the art. These methods include, but are not limited to, detection using a binding agent, e.g., an antibody, specific for NSD2, protein electrophoresis and Western blotting, and direct peptide sequencing. Methods for determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) NSD2 or is mediated by NSD2 activity can use a variety of samples.
  • the sample is taken from a subject having a tumor or cancer.
  • the sample is taken from a subject having a cancer or tumor.
  • the sample is a fresh tumor/cancer sample.
  • the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA. In certain embodiments, the disclosure provides a method of inhibiting NSD2 activity in a sample, comprising administering the compound or salt described herein to said sample comprising NSD2. The disclosure provides methods for treating a disease by administering a compound, prodrug, or salt of Formulae (I) and/or (II) disclosed herein, to a subject suffering from the disease, wherein the compound binds to NSD2 and/or inhibits NSD2 activity.
  • the compound covalently binds to NSD2. In some embodiments, the compound noncovalently binds to NSD2. In some embodiments, the compound degrades the NSD2 enzyme.
  • the disclosure also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to the mammal a therapeutically effective amount of a compound, prodrug, or salt of Formulae (I) and/or (II) with any suitable substituents and functional groups disclosed herein.
  • the method relates to the treatment of cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers, e.g., Lymphoma and Kaposi's Sarcoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic duct
  • cancer such
  • the method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hypertrophy (BPH).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hypertrophy (BPH).
  • BPH benign prostatic hypertrophy
  • the method relates to the treatment of leukemia, hematologic malignancy, solid tumor cancer, prostate cancer, e.g., castration-resistant prostate cancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bone sarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma, liver cancer, e.g., hepatocellular carcinoma, or
  • Subjects that can be treated with compounds of Formulae (I) and/or (II) disclosed herein, or pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or enantiomer of the compounds, according to the methods of this disclosure include, for example, subjects that have been diagnosed as having acute myeloid leukemia, acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS-related cancers, e.g., Lymphoma and Kaposi's Sarcoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocy
  • subjects that are treated with the compounds of the disclosure include subjects that have been diagnosed as having a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hypertrophy (BPH).
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin, e.g., psoriasis, restenosis, or prostate, e.g., benign prostatic hypertrophy (BPH).
  • BPH benign prostatic hypertrophy
  • the disclosure provides methods of inhibiting NSD2 activity in a subject including but not limited to rodents and mammals, e.g., humans, by administering to the subject an effective amount of a compound of Formulae (I) and/or (II) disclosed herein.
  • the present disclosure is directed to methods of inhibiting NSD2 activity in an in vitro and in vivo testing environment, which a skilled artisan would be familiar with.
  • the percentage of inhibition of the NSD2 enzyme in vitro and/or in vivo is at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • the disclosure provides methods of inhibiting NSD2 activity in a cell by contacting the cell with an amount of a compound as disclosed herein sufficient to inhibit the activity.
  • the disclosure provides methods of inhibiting NSD2 activity in a tissue by contacting the tissue with an amount of a compound, prodrug or salt of Formulae (I) and/or (II) as disclosed herein, sufficient to inhibit the NSD2 activity in the tissue.
  • the disclosure provides methods of inhibiting NSD2 activity in an organism (e.g., mammal, human, etc.) by contacting the organism with an amount of a compound, prodrug or salt of Formulae (I) and/or (II) as disclosed herein, sufficient to inhibit the NSD2 activity in the organism.
  • the methods disclosed herein re directed to compounds that are able to degrade the NSD2 enzyme.
  • methods of degrading the NSD2 enzyme comprises contacting the NSD2 with an effective amount of a compound, prodrug or salt of Formulae (I) and/or (II) disclosed herein (e.g., by contacting a cell, tissue, or organ that expresses NSD2).
  • the disclosure provides methods of degarding the NSD2 enzyme in a subject including but not limited to rodents and mammals, e.g., humans, by administering to the subject an effective amount of a compound of Formulae (I) and/or (II) disclosed herein.
  • the percentage of degradation of the NSD2 enzyme is at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • the compositions containing the compounds or salts thereof described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease, in an amount sufficient to cure or at least partially arrest the symptoms of the disease.
  • compositions containing the compounds or salts thereof described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.”
  • prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating clinician.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02-about 5000 mg per day, in some embodiments, about 1-about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • EXAMPLES General Chemistry Procedures Reactions were carried out using conventional glassware. All reagents and solvents were used as received unless otherwise stated. Reagents were of 95% purity or greater, and solvents were reagent grade unless otherwise stated. Any anhydrous solvents used were purchased as “anhydrous” grade and used without further drying. “Room” or ambient temperature varied between 20-25 °C.
  • Analytical thin layer chromatography was carried out using glass plates pre-coated with silica gel (Merck) impregnated with fluorescent indicator (254 nm). TLC plates were visualized by illumination with a 254 nm UV lamp. Analytical LCMS data for all compounds were acquired using an Agilent 1260 Infinity II system with the UV detector set to 254 nm. Samples were injected ( ⁇ 25 ⁇ L) onto an Agilent ZORBAX Eclipse Plus C18, 600 Bar, 4.6 x 50 mm, 1.8 ⁇ M column at 25 °C.
  • Preparative HPLC was performed as follows unless otherwise noted: Preparative HPLC was performed using an Agilent Prep 1200 series with the UV detector set to 220 nm and 254 nm. Samples were injected onto either a Phenomenex Luna 250 x 30 mm (5 ⁇ m) C18 column, a Phenomenex Luna 250 x 50mm (10 ⁇ m) C18 column, a Phenomenex Luna 80 x 40mm (3 ⁇ m) C18 column, or a Phenomenex Luna 75 x 30 mm (5 ⁇ m) C18 column at rt.
  • Example 1 General Procedures
  • General Procedure A For the coupling of aliphatic amines or anilines with achiral carboxylic acids To a scintillation vial charged with a stirbar was added carboxylic acid (1 Eq), EDC (1.5 – 2 Eq), HOAt (1.5 – 2 Eq) and DMF or MeCN (0.5 – 4 mL). The mixture was left to stir at room temperature for 30 minutes. To the vial was then added amine/aniline (1 – 1.9 Eq) followed by triethylamine (3 – 4 Eq). The reaction was stirred at room temperature for 24 (aliphatic amines) or 48 (anilines) hours.
  • Step 2 To the sulfonate ester was then added di-tert-butyl iminodicarbonate (1.2 Eq), Cs 2 CO 3 (1.5 Eq) and DMF (2.5 – 5 mL). The reaction was heated to 70 ⁇ C and stirred overnight.
  • Example 2 Synthesis of N-(4-((2-(6-Amino-3,3-dimethylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 53).
  • reaction mixture was stirred at 25 o C for 16 h. Upon completion (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse phase prep HPLC purification (method: A: 0.1% formic acid in water, B: ACN, column: C18), to afford tert-butyl N- [4,4-dimethyl-6-(6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-6-oxo-hexyl]carbamate (150 mg, 0.328 mmol, yield 85%) as a pale-yellow gum.
  • reaction mixture was stirred at 25 o C for 16 h. Upon completion (monitored by LCMS), the reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse phase prep HPLC purification (method A: 0.1% formic acid in water, B: ACN, column:C18) to afford tert-butyl N-[6-[6-[[4-[[cyclopropyl-(3-oxo-4H-1,4-benzoxazine-7- carbonyl)amino]methyl]benzoyl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-4,4-dimethyl-6-oxo- hexyl]carbamate (160 mg, 0.202 mmol, yield 61%) as pale-yellow gum.
  • reaction mixture was stirred at 25 o C for 16 h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 ⁇ 20 mL). The combined organic extracts were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • Example 12 Synthesis of N-(4-((4-((3-(2-aminoethoxy)propyl)carbamoyl)phenyl) carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 91).
  • Step 91 Prepared using Intermediate C according to above-described procedures to afford compound 91 (29.3 mg, 41.9 ⁇ mol, 28.6 %).
  • Example 14 Synthesis of N-(4-((4-((2-(2- (aminooxy)ethoxy)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (compound 207).
  • Intermediate C According to above-described procedures to afford compound 207 (0.99 mg, 1.4 ⁇ mol, 3.3 %) as a white solid.
  • Example 35 Synthesis of N-(4-((2-(6-aminohexanoyl)isoindolin-5-yl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 2,2,2-trifluoroacetate (Compound 221).
  • Compound 221 Prepared using a modified Intermediate D according to above-described procedures to afford compound 221 (55 mg, 77 ⁇ mol, 92 %) as a white solid.
  • Example 41 Synthesis of N-(4-((3-(6-aminohexanoyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide 2,2,2-trifluoroacetate (compound 25). Prepared using a modified Intermediate D according to above-described procedures to afford compound 25 (25.45 mg, 34.50 ⁇ mol, 57 %) as a white solid.
  • Example 68 Synthesis of N-(4-((2-(7-Aminoheptanoyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 7-yl)carbamoyl)benzyl)-N-cyclo propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 78).
  • compound 78 Prepared using a modified Intermediate D according to above- described procedures to afford compound 78 (40.0 mg, 0.0625 mmol, 38% yield) as an off-white solid.
  • Example 72 Synthesis of N-((3-((2-(6-aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)methyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 99). Prepared using a modified Intermediate A according to above-described procedures to afford compound 99 (65 mg, 0.1078 mmol, 68 % yield) as an off-white solid.
  • Example 74 Synthesis of N-((5-((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)thiophen-2-yl)methyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 72). Prepared using a modified Intermediate D according to above-described procedures to afford compound 72 (30.0 mg, 0.0484 mmol, 38% yield) as an off-white solid.
  • Example 76 Synthesis of N-(4-(((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)methyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 74).
  • compound 74 preparedd using a modified Intermediate D according to above- described procedures to afford compound 74 (43.0 mg, 0.0716 mmol, 49% yield) as an off-white solid.
  • Example 78 Synthesis of N-(4-(3-((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)oxetan-3-yl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 116). Prepared using a modified Intermediate D according to above- described procedures to afford compound 116 (45.0 mg, 0.0703 mmol, 40% yield) as pale-yellow solid.
  • Example 80 Synthesis of (S)-N-(1-(4-((2-(6-Aminohexanoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)phenyl)ethyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide hydrochloride (compound 111). Prepared using Intermediate D according to above- described procedures to afford compound 111 (22.0 mg, 0.0351 mmol, 85% yield) as an off-white solid.
  • Example 84 Synthesis of N-(4-((2-(6-Amino-5,5-dimethylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 16). Prepared using Intermediate A according to above-described procedures to afford compound 16 (150 mg, 0.233 mmol, 52% yield) as off-white solid.
  • Example 86 Synthesis of (R)-N-(4-((2-(6-Amino-3-methylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 134). Prepared using Intermediate D according to above-described procedures to afford compound 134 (60.0 mg, 0.0953 mmol, 18% yield) as an off- white solid.
  • Example 88 Synthesis of (S)-N-(4-((2-(6-Amino-5-methylhexanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 138). Prepared using Intermediate D according to above-described procedures to afford compound 138 (72.0 mg, 0.115 mmol, 26% yield) as an off- white solid.
  • Example 96 Synthesis of (E)-N-(4-((2-(6-Aminohex-4-enoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (compound 55). Prepared using Intermediate A according to above-described procedures to afford compound 55 (60.0 mg, 0.0987 mmol, 78% yield) as a white solid.
  • Example 98 Synthesis of N-(4-((2-(3-((1S,2R)-2-(Aminomethyl)cyclopropyl)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 94). Prepared using Intermediate A according to above-described procedures to afford compound 94 (35.0 mg, 0.0558 mmol, 34% yield) as an off- white solid.
  • Example 101 Synthesis of N-(4-((2-(3-((2-Aminoethyl)amino)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 45). Prepared using Intermediate A according to above-described procedures to afford compound 45 (30.0 mg, 0.0484 mmol, 39% yield) as an off- white solid.
  • Example 103 Synthesis of N-(4-((2-(3-((2-aminoethyl)thio)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 49). Prepared using Intermediate A according to above-described procedures to afford compound 49 (50.0 mg, 0.0793 mmol, 36% yield) as an off- white solid.
  • Example 105 Synthesis of N-(4-((2-(3-((2-Aminoethyl)sulfonyl)propanoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (compound 44). Prepared using Intermediate A according to above-described procedures to afford compound 44 (35.46 mg, 0.0532 mmol, 34% yield) as off-white solid.
  • Example 109 Synthesis of 4-((N-Cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamido)methyl)benzoic acid (Intermediate A) To a stirred solution of methyl 4-formylbenzoate (1.00 eq, 10.00 g, 60.9 mmol) and cyclopropylamine (1.20 eq, 5.2 mL, 73.1 mmol) in methanol (100 mL) was added acetic acid (0.143 eq, 0.50 mL, 8.73 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred at 25 o C for 5 h.
  • Example 110 Synthesis of N-(4-((4-((2-(2- Aminoethoxy)ethyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carboxamide (229).
  • Intermediate A Prepared using Intermediate A according to above- described procedures to afford compound 229 (80.0 mg, 0.132 mmol, 93% yield) as pale-yellow solid.
  • LCMS (ESI, +ve mode) expected m/z for C 31 H 34 N 5 O 6 [M+H] 572.6, found 572.2.
  • Example 111 Synthesis of N-(4-((4-((6-Aminohexyl)carbamoyl)phenyl)carbamoyl)benzyl)-N- cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 2).
  • Compound 2 Prepared using Intermediate A according to above-described procedures to afford compound 2 (30.0 mg, 0.0513 mmol, 18% yield) as an off-white solid.
  • LCMS (ESI, +ve mode) expected m/z for C 33 H 38 N 5 O 5 [M+H] 584.6, found 584.2.
  • Example 112 Synthesis of N-(4-((2-((4-Aminobutyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin- 7-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 3). Prepared using Intermediate A according to above-described procedures to afford compound 3 (54.0 mg, 0.0882 mmol, 62% yield) as an off-white solid.
  • Example 113 Synthesis of N-(4-((2-((4-Aminobutyl)(methyl)carbamoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 4). Prepared using Intermediate A according to above-described procedures to afford compound 4 (50.0 mg, 0.0796 mmol, 59% yield) as an off-white solid.
  • Example 119 Synthesis of N-(4-((3-(5-Aminopentyl)-4-oxo-2,3,4,5-tetrahydro-1H- benzo[d]azepin-7-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 47). Prepared using Intermediate A according to above-described procedures to afford compound 47(15.0 mg, 0.0244 mmol, 25% yield) as an off-white solid.
  • Example 122.5 Synthesis of N-(4-((4-(4-(7-Aminoheptyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4- triazol-1-yl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 58). Prepared using Intermediate A according to above-described procedures to afford compound 58 (60.0 mg, 0.0918 mmol, 31% yield) as an off- white solid.
  • Example 126 Synthesis of N-(4-((2-(4-(3-Aminopropyl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 75). Prepared using Intermediate A according to above-described procedures to afford compound 75 (2.0 mg, 0.00310 mmol, 05% yield) as an off- white solid.
  • Example 134 Synthesis of N-(4-((4-((6-Amino-5,5- dimethylhexyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 132).
  • Compound 132 Prepared using Intermediate C according to above-described procedures to afford compound 132 (50.0 mg, 0.0812 mmol, 72% yield) as an off- white solid.
  • LCMS (ESI, +ve mode) expected m/z for C 35 H 42 N 5 O 5 [M+H] 612.7, found 612.3.
  • Example 135 Synthesis of N-(4-((4-((6-Amino-2,2- dimethylhexyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 133).
  • Intermediate C Prepared using Intermediate C according to above-described procedures to afford compound 133 (50.0 mg, 0.0809 mmol, 47% yield) as an off- white solid.
  • LCMS (ESI, +ve mode) expected m/z for C 35 H 42 N 5 O 5 [M+H] 612.7, found 612.2.
  • Example 136 Synthesis of N-(4-((4-((6-Amino-6- methylheptyl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 136).
  • Compound 136 Prepared using Intermediate C according to above-described procedures to afford compound 136 (35.0 mg, 0.0572 mmol, 51% yield) as an off- white solid.
  • LCMS (ESI, +ve mode) expected m/z for C 35 H 42 N 5 O 5 [M+H] 612.73, found 612.3.
  • Example 137 Synthesis of N-(4-((4-((7-Amino-2-methylheptan-2- yl)carbamoyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 137).
  • Intermediate A Prepared using Intermediate A according to above-described procedures to afford compound 137 (5.0 mg, 0.00780 mmol, 7% yield) as an off- white solid.
  • LCMS (ESI, +ve mode) expected m/z for C 35 H 42 N 5 O 5 [M+H] 612.73, found 612.2.
  • Example 138 Synthesis of N-(4-((4-(1-(6-Amino-N- methylhexanamido)cyclopropyl)phenyl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 139).
  • Intermediate A Prepared using Intermediate A according to above-described procedures to afford compound 139 (66.0 mg, 0.105 mmol, 20.96% yield) as an off-white solid.
  • LCMS (ESI, +ve mode): Expected m/z for C 36 H 42 N 5 O 5 [M+H] 624.74, found 624.4.
  • Example 139 Synthesis of N-(4-((4-((6-Aminohexyl)carbamoyl)phenyl)carbamoyl)-3- methylbenzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (Compound 141).
  • Compound 141 Prepared using a variant of Intermediate A according to above-described procedures to afford compound 141 (20.0 mg, 0.0328 mmol, 12.73% yield) as an off-white solid.
  • LCMS (ESI, +ve mode): Expected m/z for C 34 H 40 N 5 O 5 [M+H] 598.7, found 598.4.
  • Example 140 Synthesis of N-(4-((2-(4-Aminobutyl)-1-oxo-1,2,3,4-tetrahydropyrazino[1,2- a]indol-8-yl)carbamoyl)-3-methylbenzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (Compound 142). Prepared using a variant of Intermediate A according to above-described procedures to afford compound 142 (10.0 mg, 0.0156 mmol, 19.16% yield) as an off-white solid.
  • Example 145 Synthesis of N-cyclopropyl-N-(4-((2-(4-formylbenzoyl)-1,2,3,4- tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] oxazine- 7-carboxamide (Compound 167).
  • 4-(1,3-dioxolan-2-yl)benzoic acid was prepared according to General Procedure A/Workup B using (methyl 4-formylbenzoate) (100.0 mg, 1.0 Eq, 609.2 ⁇ mol), ethane-1,2-diol (189.1 mg, 170.0 ⁇ L, 5.0 Eq, 3.046 mmol), 4-methylbenzenesulfonic acid (11.7 mg, 90% Wt, 0.1 Eq, 60.92 ⁇ mol), and Toluene (3.0 mL).
  • the product was purified by prep-HPLC (5-100% ACN in H 2 O + 0.1% formic acid) to give N-cyclopropyl-N-(4-((2-(4-formylbenzoyl)-1,2,3,4-tetrahydroisoquinolin- 6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro-2H-benzo[b] [1,4] oxazine-7-carboxamide (UNC10415667) (17 mg, 27.06 ⁇ mol, 10.7% over 2 steps) as a white solid.
  • Example 147 Synthesis of N-(4-((2-(4-acetylbenzoyl)-1,2,3,4-tetrahydroisoquinolin-6- yl)carbamoyl)benzyl)-N-cyclopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7- carboxamide (Compound 168) To a scintillation vial was added 4-acetylbenzoic acid (12.9 mg, 1.3 Eq, 78.5 ⁇ mol), N-cyclopropyl- 3-oxo-N-(4-((1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-7-carboxamide (30.0 mg, 1 Eq, 60.4 ⁇ mol), EDC (23.2 mg, 2 Eq, 121 ⁇ mol),
  • the reaction mixture was stirred at 23°C for 4 hours.
  • the reaction was poured in to water and was extracted with 10 % MeOH in DCM (3 x 50 mL). The organic layers were combined and washed with brine once (30 ml), dried over sodium sulfate, filtered, and concentrated to get the crude compound.
  • the reaction mixture was stirred at 23°C for 1 hour.
  • the reaction was poured in to water to give the solid as the crude product.
  • the crude product was purified by prep-HPLC (5-100% ACN in H2O + 0.1% formic acid) to give N-cyclopropyl-N-(4-((2-(5- formylfuran-2-carbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl) carbamoyl) benzyl)-3-oxo-3,4-dihydro- 2H-benzo[b] [1,4] oxazine-7-carboxamide (15.0 mg, 24.26 ⁇ mol, 24.0%) as a white solid.

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Abstract

La présente invention concerne des réactifs de dégradation protéique ciblant la protéine à domaine SET de liaison aux récepteurs nucléaires 2 (NSD2) ainsi que des compositions pharmaceutiques de ceux-ci et leur utilité comme agents anticancéreux.
PCT/US2025/029715 2024-05-17 2025-05-16 Agents de dégradation chimique ciblant nsd2, compositions et méthodes d'utilisation associées Pending WO2025240834A1 (fr)

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