WO2025250545A1 - Modulateurs d'akt1 - Google Patents

Modulateurs d'akt1

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Publication number
WO2025250545A1
WO2025250545A1 PCT/US2025/031050 US2025031050W WO2025250545A1 WO 2025250545 A1 WO2025250545 A1 WO 2025250545A1 US 2025031050 W US2025031050 W US 2025031050W WO 2025250545 A1 WO2025250545 A1 WO 2025250545A1
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Prior art keywords
optionally substituted
compound
pharmaceutically acceptable
solvate
deuteroisotope
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Pending
Application number
PCT/US2025/031050
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English (en)
Inventor
Michael David Bartberger
Yi Fan
Eric Anthony MURPHY
Xuefeng Zhu
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Alterome Therapeutics Inc
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Alterome Therapeutics Inc
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Publication of WO2025250545A1 publication Critical patent/WO2025250545A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • AKT1 MODULATORS CROSS-REFERENCE [0001] This application claims the benefit of US Provisional Application No. 63/652,278 filed May 28, 2024, which is incorporated by reference in its entirety herein.
  • BACKGROUND [0002] AKT is a protein kinase and mediates cell survival and proliferation by inhibiting pathways which promotes apoptosis. AKT signaling cascade dysfunction is observed in several cancer types and may be associated with tumor aggressiveness. Additionally, malfunction of AKT typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis. Pharmaceutical agents with the ability to modulate AKT1 activity would be useful in the treatment of disease, such as cancer.
  • One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof: wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R 1 ; each R 1 is independently H, D, halogen, -CN; R 2 and R 3 are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R 2 and R 3 together form an oxo; or R 2 and R 3 join to form a carbocycle or heterocycle; R 5 and R 6 are each independently selected from the group consisting of H, D, -OR 17 , - SR 17 ,
  • each R 4 is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: Q 2 is O or S; Q 3 is a bond, O, S, N-R 9a ; R
  • One embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof: wherein, R is optionally substituted
  • each R 4 is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: Q 1 is O or S; Q 2 is O or S; Q 3 is a bond, O, S, N
  • T 1 is N or C-R 10 ;
  • T 2 is N or C-R 10 ;
  • T 3 is N or C-R 10 ;
  • T 4 is N or C-R 10 ;
  • T 5 is O, S, or N-R 11 ;
  • each R 10 is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl;
  • each R 11 is hydrogen, or optionally substituted C1-C6 alkyl;
  • T 6 is N or C-R 12 ;
  • T 7 is N or C-R 12 ;
  • T 8 is N or C-R 12 ;
  • each R 12 is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally
  • One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I)-(III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. Another embodiment provides the method wherein the disease or disorder is cancer.
  • an agent includes a plurality of such agents
  • the cell includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.
  • ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • the term "about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.
  • Oxa refers to the -O- radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl).
  • an alkyl comprises one to two carbon atoms (e.g., C 1 -C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1- methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , - C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a
  • an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms.
  • the alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2),
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl comprises two to six carbon atoms.
  • an alkynyl comprises two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , - C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2),
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, c ontaining no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C 1 alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene).
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , - C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2),
  • alkenylene or "alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkenylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkenylene).
  • an alkenylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C 2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkenylene).
  • an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , - C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , - N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2),
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene).
  • an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , - C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , - N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p–electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , - R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -O-R c - C(O)N(R a
  • Aralkyl refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Aralkenyl refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • "Aralkynyl” refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds).
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.”
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)- N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -O-R c -C(O)N(R a ) 2 , -R b -
  • Carbocyclylalkyl refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkynyl refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula –O- R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems.
  • the heteroatoms in the heterocyclyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocyclyl radical is partially or fully saturated.
  • the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
  • heterocyclyl radicals include, but are not limited to, d ioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxoxo
  • heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b - C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -O-R c -
  • N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- p iperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.
  • C-heterocyclyl or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
  • a C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
  • Heterocyclylalkyl refers to a radical of the formula –Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
  • Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula –O- R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p–electron system in accordance with the Hückel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl (benzothion
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula –Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula –O- R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure.
  • this disclosure includes both E and Z geometric i somers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • tautomeric equilibrium includes: [0051]
  • the compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions such as iodomethane-d3 (CD3I) are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.
  • Deuterium-transfer reagents such as lithium aluminum deuteride (LiAlD4)
  • LiAlD4 lithium aluminum deuteride
  • Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
  • the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms.
  • the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material. [0061] "Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the AKT1 inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.
  • salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid.
  • Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.
  • the term “subject” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • AKT1 Protein and Function [0067] AKT, also known as protein kinase B (PKB), is a serine/threonine protein kinase with three isoforms, AKT1, AKT2, and AKT3. While the isoforms are encoded by different genes, they are highly homologous at the protein level and share a conserved domain structure comprising an N-terminal pleckstrin homology (PH) domain, a kinase domain, and a C-terminal regulatory domain comprising a hydrophobic moiety, which includes the regulatory serine residue (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).
  • PH N-terminal pleckstrin homology
  • AKT proteins play a crucial role in major cellular functions including cell cycle progression, cell size, regulation of glucose metabolism, transcription, protein synthesis, genome stability, and neovascularization. AKT proteins can block apoptosis by inactivation of pro-apoptotic proteins, and mediate cellular growth factors, promoting cell survival.
  • AKT is a major N X ⁇ W ⁇ ][OKV OPPOM]X[ XP W ⁇ MUOK[ PKM]X[&TKYYK6 #APk6$% ⁇ RSMR VKb USWT 5>F ⁇ SQWKUSWQ ]X ]RO nucleus of a cell.
  • AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin-responsive tissues, and AKT3 is primarily expressed in brain and testes.
  • a shared phosphorylation site of AKT in the catalytic domain corresponds to a threonine residue; specifically, Thr308 in AKT1, Thr309 in AKT2, and Thr305 in AKT3.
  • a shared phosphorylation site in the C- terminus of the protein c is a serine residue; specifically, Ser473 in AKT1, Ser474 in AKT2, and Ser472 in AKT3.
  • the AKT cascade can be activated by RTKs and G-protein-compound receptors (GPCRs), along with other signals including integrins, B cell receptors, T cell receptors, and cytokine receptors.
  • GPCRs G-protein-compound receptors
  • AKT1 Mechanism AKT is activated by a second phosphorylation at the regulatory serine residue, Ser473.
  • Known phosphorylating agents of AKT at Ser473 include, but are not limited to PDK-1, integrin- linked kinase (ILK), members of the PI3K-related kinase (PIKK) family, and mammalian target of rapamycin (mTOR) (Nitulescu, G. M.
  • mTOR is a key component in the AKT signaling pathway, which is a downstream member of AKT and an important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) to form mTOR complex 2 (mTORC2), which can directly phosphorylate AKT Ser473.
  • RICTOR rapamycin-insensitive companion of mTOR
  • mTORC2 mTOR complex 2
  • AKT can affect cell survival and growth because it can influence the tuberous sclerosis complex (TSC) 1/2 along the mTORC signaling pathway and inhibit pro-apoptotic proteins or signals.
  • AKT is known as a survival kinase and mediates cell survival and proliferation by inhibiting pathways including, but not limited to Bcl2 and MDM2, which promotes apoptosis.
  • Bcl2 and MDM2 promotes apoptosis.
  • Malfunctions of AKT typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270).
  • AKT1 has been found to be involved in invasion and migration of cancerous cells (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). researchers found that silencing the AKT1 isoform can abrogate specific types of cancer cell migration. However, there have been other studies which have demonstrated that activated AKT1 resulted in less metastatic propensity for lung metastatic lesion cells and breast cancer cells.
  • AKT1 has also been identified as a key protein involved in angiogenesis, lung cancer, and tumorigenesis.
  • overexpression of AKT has been correlated to resistance to chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel.
  • chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel.
  • chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel.
  • the AKT1 gene mutation E17K can affect cell growth, proliferation, survival, and migration of breast cancer cells, colorectal cancer cells, and ovarian cancer cells (Chen, Y. et al., Front Cell Dev Biol., 2020; 8: 573599).
  • AKT1 to Phosphatidylinositol-3,4,5- triphosphate (PIP3) lipid ligand, which accelerates transfer of AKT from the cytoplasm to the cell membrane through formation of hydrogen bonds. Transfer of AKT into the cell membrane allows it to be further phosphorylated. Once fully activated, AKT can return to the cytoplasm, or go to the nucleus or other intracellular sites, and phosphorylate other substrate proteins to regulate cell function.
  • PIP3 Phosphatidylinositol-3,4,5- triphosphate
  • a major pathway that activates PI3K-AKT signaling pathway is somatic cell mutations, with the E17K mutation being the highest frequency of AKT1 mutations. It is nearly exclusively present in AKT1.
  • the AKT1(E17K) is a recurrent somatic cell mutation predominantly in breast cancer, ovarian cancer, meningioma, and Proteus syndrome.
  • AKT1(E17K) mutations mediate the PI3K-AKT signaling cascade by expanding PIP lipid specificity, which causes conformational changes. This also enhances subcellular localization to accelerate localization of the PH structural domain to the plasma membrane.
  • the E17K mutation increases PIP3 binding specificity by 7-fold and phosphatidylinositol-(4,5)- bisphosphate (PIP2) by 100-fold.
  • PIP2 phosphatidylinositol-(4,5)- bisphosphate
  • the AKT1(E17K) mutation also causes rapid conformational changes in the AKT1 PH structural domain. The conformational changes to this domain result in a 4.5-fold increase in its membrane localization, which can result in excessive phosphorylation.
  • the AKT1(E17K) mutation can also result in enhanced subcellular localization by increasing the transient expression. [0082] Given the conformational and signaling effects of the AKT1(E17K) mutation, this target may be useful for targeted treatment of cancers.
  • Prior Art AKT1 Inhibitors [0083] Most AKT inhibitors targeting the ATP binding site are non-selective against the three isoforms, as well as having poor to no selectivity against other structurally similar kinases. Thus, there remains a need to develop new and novel AKT inhibitors.
  • ATP targeting inhibitors are classified as aminofurazans, azepane derivatives, isoquinoline-5-sulfonamides, phenylpyrazole derivatives, thiophene carboxamide derivatives, and thiazole carboxamide derivatives.
  • ATP non-competitive AKT inhibitors which are allosteric modulators which have greater specificity than the ATP targeting inhibitors.
  • Many of these allosteric modulator inhibitors are classified as purine derivatives, thiourea derivatives, alkylphospholipids, sulfonamides, 2,3-diphenylquinoxaline analogs, and indole-3-carbinol derivatives.
  • an AKT1 inhibitory compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof: wherein, R is optionally substituted aryl, or optionally substituted heteroaryl; w, x, y, and z are each independently N or C-R 1 ; each R 1 is independently H, D, halogen, -CN; R 2 and R 3 are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or R 2 and R 3 together form an oxo; or R 2 and R 3 join to form a carbocycle or heterocycle; R 5 and R 6 are each independently selected from the group consisting of H, D, -OR 17 , - SR 17 , -NH 2 , -CN, halogen, -CO2R 17 ,
  • each R 4 is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: Q 1 is O or S; Q 2 is O or S; Q 3 is a bond, O, S, N
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z 1 is C-R 7 .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z 2 is N.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z 2 is C-R 8 .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 1 is O.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 1 is N(R 18 ). Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 1 is C(R 19 )(R 20 ). [0090] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 2 is O. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 2 is N(R 18 ).
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 2 is C(R 19 )(R 20 ).
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 3 is C(R 19 )(R 20 ).
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 7 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 8 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is H. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is an optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is an optionally substituted C1-C2 alkyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is -CH 3 .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is - CH 2 CH 3 .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is -CD3.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 19 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 20 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein m is 0. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein m is 1. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein m is 2. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein m is 3.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 5 and R 6 are each independently selected from the group consisting of H, D, -OR 17 , -SR 17 , -NH 2 , -CN, halogen, -CO 2 R 17 , CON(R 17 ) 2 , optionally substituted C1-C6 alkyl, or optionally substituted C3-C7 carbocyclyl.
  • R 5 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 6 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 5 and R 6 are each independently selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 5 and R 6 together form an oxo.
  • R is optionally substituted aryl, or optionally substituted heteroaryl
  • w, x, y, and z are each independently N or C-R 1
  • each R 1 is independently H, D, halogen, -CN
  • R 2 and R 3 are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl
  • R 2 and R 3 together form an oxo
  • R 2 and R 3 join to form a carbocycle or heterocycle
  • Z 3 is N or C-R 22
  • X 4 is O or S
  • R 21 and R 22 are each independently selected from the group consisting of H, D, -OR 17 , -SR 17 , -NH 2 , -CN, halogen, -CO 2 R 17 , CON(R 17 ) 2 , optionally
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z 3 is C-R 22 .
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 4 is O.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 17 is H.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 17 is optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 21 is selected from the group consisting of H, D, -OR 17 , -SR 17 , -NH 2 , -CN, halogen, -CO2R 17 , CON(R 17 ) 2 , optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 21 is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 22 is selected from the group consisting of H, D, -OR 17 , -SR 17 , -NH 2 , -CN, halogen, -CO2R 17 , CON(R 17 ) 2 , optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 22 is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • R is optionally substituted aryl, or optionally substituted heteroaryl
  • w, x, y, and z are each independently N or C-R 1
  • each R 1 is independently H, D, halogen, -CN
  • R 2 and R 3 are each independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl
  • Z 4 is N or C-R 24
  • X 5 is O or S
  • R 23 and R 24 are each independently selected from the group consisting of H, D, -OR 17 , -SR 17 , -NH 2 , -CN, halogen, -CO 2 R 17 , CON(R 17 ) 2 , optionally substitute
  • each R 4 is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; a1 is 0, 1, 2, 3, or 4; b1 is 0, 1, 2, 3, or 4; c1 is 1, 2, 3, or 4; d1 is 1, 2, 3, or 4; e1 is 0, 1, 2, 3, or 4; f1 is 0, 1, 2, 3, or 4; provided that e and f are not both 0; g1 is 0, 1, 2, 3, or 4; provided that e and g are not both 0; h1 is 0, 1, 2, 3, or 4; provided that g1 and h1 are not both 0; and provided that f1 and h1 are not both 0; p is 1, 2, 3, or 4; q is 0, 1, or 2; LCG is a group selected from the group consisting of: Q 1 is O or S; Q 2 is O or S; Q 3 is a bond, O, S, N
  • Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z 4 is C-R 24 .
  • Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 4 is O.
  • Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 17 is H.
  • Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 17 is optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 23 is selected from the group consisting of H, D, -OR 17 , -SR 17 , -NH 2 , -CN, halogen, -CO2R 17 , CON(R 17 ) 2 , optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl.
  • Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 23 is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 24 is selected from the group consisting of H, D, -OR 17 , -SR 17 , -NH 2 , -CN, halogen, -CO2R 17 , CON(R 17 ) 2 , optionally substituted C1-C6 alkyl, and optionally substituted C3-C7 carbocyclyl.
  • Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 24 is selected from the group consisting of optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted aryl.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted phenyl.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted heteroaryl.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted pyridine.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein w is C-R 1 .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein x is C-R 1 .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein y is C-R 1 .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein z is C-R 1 .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein w, x, y, and z are C-R 1 .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 1 is H.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 2 and R 3 are H.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 0.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 1.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from: [00122]
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 4 is H.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is -N(R 4 )-.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: Q 1 is O or S; Q 2 is O or S; Q 3 is a bond, O, S, N-R 9a ; R 9 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R 9 is absent and Q 3 and L join together to form a heterocycle; and R 9a is selected from hydrogen, -OH, -NH 2 , optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R 9 and R 9a join together to form a heterocycle.
  • LCG is: Q 1 is O or S; Q 2 is O or S; Q 3 is a bond, O, S, N-R 9a
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: T 1 is N or C-R 10 ; T 2 is N or C-R 10 ; T 3 is N or C-R 10 ; T 4 is N or C-R 10 ; T 5 is O, S, or N-R 11 ; each R 10 is independently selected from hydrogen, deuterium, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, and optionally substituted aryl; and each R 11 is hydrogen, or optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: [00133]
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: T 6 is N or C-R 12 ; T 7 is N or C-R 12 ; T 8 is N or C-R 12 ; each R 12 is independently selected from hydrogen, halogen, -OH, -SH, optionally substituted C1-C6 alkoxy, -S-(optionally substituted C1-C6 alkyl), -CN, optionally substituted C1-C6 alkyl, optionally substituted amino, optionally substituted C1-C6 alkenyl, and optionally substituted aryl.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: wherein each R 13 , R 14 , R 15 , and R 16 is independently selected from H, F, CN, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted alkoxy.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 13 is H.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 14 is H.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 15 is H.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a YRK[VKMO ⁇ ]SMKUUb KMMOY]KLUO ⁇ KU]% ⁇ XU_K]O% X[ NO ⁇ ]O[XS ⁇ X]XYO ]RO[OXP% ⁇ RO[OSW ?7; S ⁇ &7hA' [00141]
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 4 is H.
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: .
  • Another embodiment provides the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z 1 is N.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z 1 is C-R 7 .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 7 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z 2 is N.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z 2 is C-R 8 .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 8 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 1 is N(R 18 ).
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is an optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is an optionally substituted C1-C2 alkyl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is -CH3.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is -CH2CH3.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is - CD 3 .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 18 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 2 is O.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X 3 is C(R 19 )(R 20 ).
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 19 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 20 is H. [00155] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein m is 1. [00156] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 5 and R 6 together form an oxo. [00157] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted aryl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R is optionally substituted phenyl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein w, x, y, and z are C-R 1 .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 1 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 2 and R 3 are H.
  • [00161] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 0. [00162] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: . [00163] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 4 is H. [00164] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is: .
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 13 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 14 is H.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 15 is H.
  • One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 1. Table 1
  • Another embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 2.
  • Table 2
  • compositions [00176]
  • the AKT1 inhibitory compound described herein is administered as a pure chemical.
  • the AKT1 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising at least one AKT1 inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s)
  • One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition
  • a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.
  • the AKT1 inhibitory compound as described by Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.
  • the AKT1 inhibitory compound as described by Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • the AKT1 inhibitory compound as described by Formula (I)-(III), or Table 1 or 2, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof is formulated for administration by injection.
  • the injection formulation is an aqueous formulation.
  • the injection formulation is a non-aqueous formulation.
  • the injection formulation is an oil-based formulation, such as sesame oil, or the like.
  • the dose of the composition comprising at least one AKT1 inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [00188] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • One embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.
  • One embodiment provides a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a use of a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
  • a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.
  • a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.
  • One embodiment provides a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a use of a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
  • a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.
  • a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Table 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is administered orally.
  • the pharmaceutical composition is administered by injection.
  • One embodiment provides a method of inhibiting an AKT1 enzyme comprising contacting the AKT1 enzyme with a compound of Formula (I)-(III), or Table 1 or 2.
  • Another embodiment provides the method of inhibiting an AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vivo setting.
  • Embodiment 1 A method of treating a cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (I), (II), (III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.
  • Embodiment 2 A method of treating a cancer in a patient in need thereof, comprising administering to the patient a compound of Table 1, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.
  • Embodiment 3 A method of treating a cancer in a patient in need thereof, comprising administering to the patient a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, selected from the group consisting of: 4-((1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-(4-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient: (a) a compound of Formula (I), (II), (III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof; and (b) at least one oncology therapeutic selected from an endocrine therapy, a hormonal therapy, an aromatase inhibitor, a selective estrogen receptor modulator (SERM) therapy, a selective estrogen receptor degrader (SERD) therapy, an anti-androgen, an androgen deprivation therapy, a taxane, a platinum agent, an anthracycline, an anti-metabolite, an alkylating agent, a microtubule affecting agent, an immune checkpoint inhibitor, a kinase inhibitor, a phosphatidylinositol 3-kinase (PI3K) inhibitor, a human epidermal growth factor receptor 2 (HER2) inhibitor, an antibody, a poly-ADP ribo
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient: (a) a compound of Table 1, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof; and (b) at least one oncology therapeutic selected from an endocrine therapy, a hormonal therapy, an aromatase inhibitor, a selective estrogen receptor modulator (SERM) therapy, a selective estrogen receptor degrader (SERD) therapy, an anti-androgen, an androgen deprivation therapy, a taxane, a platinum agent, an anthracycline, an anti-metabolite, an alkylating agent, a microtubule affecting agent, an immune checkpoint inhibitor, a kinase inhibitor, a phosphatidylinositol 3-kinase (PI3K) inhibitor, a human epidermal growth factor receptor 2 (HER2) inhibitor, an antibody, a poly-ADP ribose polymerase (PARP)
  • PARP poly-ADP
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient: (a) a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, selected from the group consisting of: 4-((1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-(4-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyri
  • Embodiment 8 The method of embodiment 10, wherein the endocrine therapy, a hormonal therapy, a SERM therapy, a SERD therapy, an aromatase inhibitor, or an androgen deprivation therapy is selected from megestrol, exemestane, anastrozole, letrozole, tamoxifen, torimifene, raloxifene, fulvestrant, camizestrant, elacestrant, amcenestrant, giredestrant, imlunestrant, rintodestrant, SHR9549, ZN-c5, D0502, vepdegrestrant, palazestrant, AC682, DT2216, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide, abiraterone, buserelin, goserelin, leuprorelin, triptorelin, degarelix, or re
  • FIG. 13 The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an anthracycline.
  • FIG. 14 The method of embodiment 16, wherein the anthracycline is selected from doxorubicin or epirubicin.
  • FIG. 15 The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an anti-metabolite.
  • the anti-metabolite is selected from methotrexate, fluorouracil, pemetrexed, irinotecan, topotecan, capecitabine or gemcitabine.
  • FIG. 17 The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an alkylating agent.
  • the alkylating agent is selected from ifosfamide, trabectedin, cyclophosphamide, melphalan, or dacarbazine.
  • the microtubule affecting agent is selected from ixabepilone, viborelbine, or eribulin.
  • FIG. 21 The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is an immune checkpoint inhibitor.
  • FIG. 22 The method of embodiment 24, wherein the immune checkpoint inhibitor is selected from a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a TIGIT inhibitor, or a bi-specific PD-1/CTLA4 inhibitor.
  • the CTLA-4 inhibitor is selected from ipilimumab or tremelimumab.
  • PD-1 inhibitor is selected from spartalizumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, dostarlimab, retifanlimab, or toripalimab.
  • the bi-specific PD-1/CTLA4 inhibitor is selected from AK104, MGD019, XmAb20717, or MEDI5752.
  • Embodiment 26 The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a kinase inhibitor.
  • kinase inhibitor is selected from lenvatinib, pazopanib, imatinib, sorafenib, or Congressometinib.
  • PI3K inhibitor is selected from copanlisib, alpelisib, idelalisib, duvelisib, or umbralisib.
  • the HER2 inhibitor is selected from lapatinib, neratinib, tucatinib, pyrotinib, or afatinib.
  • the HER2 inhibitor is selected from lapatinib, neratinib, tucatinib, pyrotinib, or afatinib.
  • the HER2 inhibitor is selected from lapatinib, neratinib, tucatinib, pyrotinib, or afatinib.
  • the HER2 inhibitor is selected from lapatinib, neratinib, tucatinib, pyrotinib, or afatinib.
  • the HER2 inhibitor is selected from lapatinib, neratinib, tucatinib,
  • Embodiment 34 The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a PARP inhibitor.
  • the PARP inhibitor is selected from olaparib, rucaparib, talazoparib, or niraparib.
  • ADC antibody drug conjugate
  • the antibody drug conjugate is selected from ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, sacituzumab govitecan, disitamab vedotin, tisotumab vedotin, raludotatug deruxtecan, ARX-788, datopotamab deruxtecan, patritumab deruxtecan, ladiratuzumab vedotin, HS-20089, pertuzumab, or margetuximab.
  • RAF inhibitor is vemurafenib, dabrafenib, encorafenib, tovorafenib, naporafenib, belvarafenib, or exarafenib.
  • RAF inhibitor is vemurafenib, dabrafenib, encorafenib, tovorafenib, naporafenib, belvarafenib, or exarafenib.
  • MEK inhibitor is binimetinib, cobimetinib, trametinib, selumetinib, pimasertib, complicatometinib, IMM-1-104, or NST-628.
  • Embodiment 52 The method of any one of embodiments 7-9, wherein at least one oncology therapeutic is a CDK inhibitor.
  • the CDK inhibitor is selected from palbociclib, abemaciclib, ribociclib, tagtociclib, ebvaciclib, lerociclib, PF-07220060, BLU- 222, INX-315, or AVZO-021.
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient: (a) a compound of Formula (I), (II), (III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof; and (b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine.
  • a compound of Formula (I), (II), (III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof comprising administering to the patient: (a) a compound of Formula (I), (II), (III), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof; and (b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine.
  • TIL tumor-infiltrating lymphocytes
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient: (a) a compound of Table 1, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof; and (b) at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine.
  • a compound of Table 1 or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof
  • at least one oncology therapeutic selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine selected from CAR-T therapy, tumor-infiltrating lymphocytes (TIL) or a neoantigen vaccine.
  • a method of treating a cancer in a patient in need thereof comprising administering to the patient: (a) a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, selected from the group consisting of: 4-((1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-((1-(4-(1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile; 4-(4-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyri
  • Embodiment 63 The method of embodiment 60, wherein the cancer is a triple negative breast cancer (TNBC).
  • TNBC triple negative breast cancer
  • Embodiment 64 The method of embodiment 60, wherein the cancer is an invasive breast cancer.
  • Embodiment 65 The method of any one of embodiments 1-59, wherein the cancer is uterine cancer.
  • Embodiment 66 The method of embodiment 68, wherein the cancer is uterine sarcoma.
  • Embodiment 67 The method of embodiment 68, wherein the cancer is endometrial cancer.
  • Embodiment 68 The method of embodiment 68, wherein the cancer is Type I endometrial cancer.
  • Embodiment 69 The method of embodiment 68, wherein the cancer is Type II endometrial cancer.
  • Embodiment 70 The method of embodiment 72, wherein the cancer is Type II endometrial papillary serous carcinoma.
  • Embodiment 71 The method of embodiment 72, wherein the cancer is Type II endometrial clear cell carcinoma.
  • Embodiment 72 The method of embodiment 72, wherein the cancer is Type II endometrial undifferentiated carcinoma.
  • Embodiment 73 The method of embodiment 72, wherein the cancer is Type II endometrioid carcinoma.
  • MSI microsatellite instability
  • MMR DNA mismatch repair
  • TMB tumor mutational burden
  • Embodiment 76] The method of embodiment 68, wherein the cancer is HER2-.
  • the method of embodiment 80, wherein the cancer is a cervical squamous cell carcinoma.
  • Embodiment 80 The method of any one of embodiments 1-59, wherein the cancer is prostate cancer.
  • Embodiment 81 The method of embodiment 83, wherein the cancer is prostate adenocarcinoma.
  • Embodiment 82 The method of embodiment 83, wherein the cancer is prostate neuroendocrine cancer.
  • Embodiment 83 The method of embodiment 83, wherein the cancer is prostate small cell neuroendocrine cancer.
  • Embodiment 84 The method of embodiment 83, wherein the cancer is prostate large cell carcinoma.
  • Embodiment 85 The method of embodiment 83, wherein the cancer is prostate transitional cell carcinoma.
  • Embodiment 98 The method of any one of embodiments 1-59, wherein the cancer is a meningioma.
  • Embodiment 99 The method of any one of embodiments 1-59, wherein the cancer is a glioma.
  • Embodiment 100 The method of any one of embodiments 1-59, wherein the cancer is pancreatic cancer.
  • Embodiment 101 The method of embodiment 103, wherein the cancer is exocrine pancreatic cancer.
  • Embodiment 102 The method of embodiment 103, wherein the cancer is neuroendocrine pancreatic cancer.
  • Embodiment 103 The method of any one of embodiments 1-59, wherein the cancer is thyroid cancer.
  • Embodiment 104 The method of any one of embodiments 1-59, wherein the cancer is myxofibrosarcoma.
  • Embodiment 105 The method of any one of embodiments 1-59, wherein the cancer is parotid gland cancer.
  • Embodiment 106 The method of any one of embodiments 1-59, wherein the cancer is esophageal cancer.
  • Embodiment 107 The method of any one of embodiments 1-59, wherein the cancer is stomach cancer.
  • Embodiment 108 The method of any one of embodiments 1-59, wherein the cancer is skin cancer.
  • Embodiment 109 The method of embodiment 111, wherein the cancer is nonmelanoma skin cancer.
  • Embodiment 122 The method of any one of embodiments 1-59, wherein the cancer is acute myeloid leukemia.
  • Embodiment 123 The method of any one of embodiments 1-59, wherein the cancer is cancer of unknown primary.
  • Embodiment 124 The method of any one of embodiments 1-59, wherein the cancer is locally advanced.
  • Embodiment 125 The method of any one of the preceding embodiments, wherein the cancer is metastatic.
  • Embodiment 126 The method of any one of the preceding embodiments, wherein the method is adjuvant therapy following surgical resection.
  • Embodiment 143 The method of any one of the preceding embodiments, wherein the oral administration occurs once per day, twice per day, three times per day, every other day, or one to six days per week.
  • Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.
  • Step 2 Methyl 4-(2-oxo-2-phenylacetyl)benzoate F X K ⁇ XU ⁇ ]SXW XP VO]RbU -&#YROWbUO]RbWbU$LOWcXK]O #.) VQ% +*+ lVXU$ SW 8@EB #+ V?$ ⁇ O[O added Pd(OAc)2 #*, VQ% .0'2 lVXU$ KWN 7 ⁇ 6[ #*,') VQ% 2)'/ lVXU$' FRO VSa] ⁇ [O ⁇ K ⁇ ⁇ ]S[[ON at 125 °C for 2 hr.
  • Step 2 4-(Piperidin-4-ylamino)pyrimidine-2-carbonitrile
  • tert-Butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-1-carboxylate 110 V Q% ,/+ lVXU$ SW 87@ #, V?$ ⁇ K ⁇ KNNON F:5 #0/0 VQ% /'0, VVXU$' FRO VSa] ⁇ [O ⁇ K ⁇ stirred at 25 °C for 1 hr.
  • the reaction mixture was concentrated under reduced pressure.
  • the title compound (Intermediate 5, 120 mg, yield: 100%, TFA salt) was used in the next step without further purification.
  • Step 2 Ethyl 2-((3-nitro-5-phenylpyridin-2-yl)oxy)acetate
  • ethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate 850 mg, 2.79 mmol
  • phenylboronic acid 408 mg, 3.34 mmol
  • Pd(dppf)Cl2 #+)- VQ% +02 lVXU$% KWN 7 ⁇ 2CO3 (2.72 g, 8.36 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was degassed and purged with N2 three times, and the mixture was stirred at 90 °C for 2 hr under N 2 atmosphere.
  • Step 3 7-Phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one
  • ethyl 2-((3-nitro-5-phenylpyridin-2-yl)oxy)acetate 450 mg, 1.49 mmol
  • Fe 416 mg, 7.44 mmol
  • the reaction mixture was degassed, purged with N 2 three times, and stirred at 70 °C for 3 hr under N 2 .
  • the reaction mixture was concentrated under reduced pressure. After trituration with 1 N HCl (20 mL) at 25 °C for 30 mins, the title compound (284 mg, yield: 84%) was obtained as a gray solid.
  • Step 4 6-Bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one
  • 7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H$&XWO #.) VQ% ++* lVXU$ SW 8@: #* V?$ ⁇ K ⁇ KNNON A6E #01'0 VQ% --+ lVXU$ ⁇ UX ⁇ Ub' FRO VSa] ⁇ [O ⁇ K ⁇ NOQK ⁇ ON% Y ⁇ [QON ⁇ S]R N2 three times, and stirred at 80 °C for 1 hr under N2.
  • Step 2 4-((1-(4-Bromobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • 1-bromo-4-(chloromethyl)benzene (6.47 g, 26.7 mmol, HCl salt) and Intermediate 2 (8.48 g, 26.7 mmol, TFA salt) in DMF (70 mL)
  • K 2 CO 3 (18.5 g, 134 mmol
  • NaI 802 mg, 5.35 mmol
  • Step 3 4-((1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile
  • Step 2 4-(Piperazin-1-yl)pyrimidine-2-carbonitrile To a solution of tert-butyl 4-(2-cyanopyrimidin-4-yl)piperazine-1-carboxylate (140 mg, 483 l VXU$ SW 7 ⁇ 2Cl2 (3 mL) was added TFA (767 mg, 6.73 mmol).
  • Step 2 6-(4-(Chloromethyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one
  • 6-(4-(hydroxymethyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)- X WO #*2/ VQ% .2) lVXU$ SW 7 ⁇ 2Cl2 (10 mL) was added SOCl2 (3 mL). The mixture was stirred at 40 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (Intermediate 14, 207 mg, HCl salt) as a yellow solid.
  • Step 2 6-Bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one
  • 1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one 51 mg, 212 l VXU$ SW 8@: #+ V?$ ⁇ K ⁇ KNNON A6E #0.'/ VQ% -+. lVXU$' FRO VSa] ⁇ [O ⁇ K ⁇ NOQK ⁇ ON% purged with N2 three times, and stirred at 80 °C for 4 hr under N2.
  • Step 2 6-Bromo-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one
  • NBS NBS
  • Step 3 1-Ethyl-6-(4-(hydroxymethyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)- one
  • a mixture of 6-bromo-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (340 mg, 1.02 mmol), (4-(hydroxymethyl)phenyl)boronic acid (233 mg, 1.53 mmol), Cs 2 CO 3 (997 mg, 3 .06 mmol), and Pd(dppf)Cl2 #0-'0 VQ% *)+ lVXU$ SW *%-&NSXaKWO #*) V?$ KWN ⁇ 2O (2 mL) was degassed, purged with N2 three times, and stirred under N2 at 90 °C for 16 hr.
  • Step 4 6-(4-(Chloromethyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one
  • SOCl2 0.5 mL
  • Step 2 6-Phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one
  • a mixture of 6-bromo-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one 500 mg, 2.17 mmol
  • phenylboronic acid 265 mg, 2.17 mmol
  • Cs2CO3 2.12 g, 6.52 mmol
  • Pd(dppf)Cl2 159 V Q% +*0 lVXU$ SW *%-&NSXaKWO #*
  • Step 3 4-Ethyl-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one
  • 6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (220 mg, 968 mmol) in MeCN (5 mL) were added EtI (302 mg, 1.94 mmol) and K 2 CO 3 (401 mg, 2.90 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (50 mL) and extracted with CH2Cl2 (50 mL x 3).
  • Step 4 7-Bromo-4-ethyl-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one
  • NBS 126 mg, 705 mmol
  • the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 2).
  • Example 1 4-((1-(4-(2-Oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Example 2 4-((1-(4-(6-Methyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile
  • Example 3 4-((1-(4-(5-Isobutyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile
  • Example 4 4-(4-(4-(5-Isobutyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzyl)piperazin-1- yl)pyrimidine-2-carbonitrile
  • Example 4 was prepared in a manner similar to Example 2.
  • MS: m/z 506.3 [M + H] + .
  • 1 H N MR 400 MHz, Dimethysulfoxide-d6$ g *+'-2 & **'1. #V% * ⁇ $% 1'+.
  • Example 5 4-((1-(4-(1-Methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Example 6 4-(4-(4-(6-Methyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)benzyl)piperazin-1- yl)pyrimidine-2-carbonitrile
  • Example 7 4-(4-(4-(5-Methyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzyl)piperazin-1- yl)pyrimidine-2-carbonitrile
  • Example 8 4-((1-(4-(5-Methyl-6-oxo-3-phenyl-1,6-dihydropyrazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile
  • Example 9 4-(4-(4-(6-Isobutyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)benzyl)piperazin-1- yl)pyrimidine-2-carbonitrile
  • Example 10 4-((1-(4-(6-Isobutyl-5-oxo-3-phenyl-4,5-dihydropyrazin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile
  • Example 10 was prepared in a manner similar to Example 2.
  • MS: m/z 520.2 [M + H] + .
  • 1 H N MR 400 MHz, Chloroform-d$ g 1'+- & 1'). #V% * ⁇ $% 0',.
  • Example 11 4-(4-(4-(2-Oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile
  • Example 11 was prepared in a manner similar to Example 2.
  • MS: m/z 504.2 [M + H] + .
  • Example 12 4-((1-(4-(1-Ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • F X K ⁇ XU ⁇ ]SXW XP W]O[VONSK]O */ #/)
  • VQ% *.1 lVXU$ KWN W]O[VONSK]O .
  • Example 14 6-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-1-ethyl-7- phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one
  • Step 1 tert-Butyl 2-(4-(1-ethyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate
  • F X K ⁇ XU ⁇ ]SXW XP W]O[VONSK]O */ #*.)
  • VQ% ,2/ lVXU$ KWN tert-butyl 2,7-diazaspiro[3.5]nonane- 0&
  • VQ% -0. lVXU% ⁇ 7U ⁇ KU]$ SW 8@: #, V?$ ⁇ O[O KNNON >2CO3 (274 mg, 1.98 VVXU$ KWN AK #**'2 VQ% 02'+ lVXU$' FRO VSa] ⁇ [O ⁇ K ⁇ ⁇ ]S[[ON K] +. d7 PX[ */ R[' FRO [OKM]SXW mixture was quenched with H 2 O (20 mL) at 25 °C and extracted with CH 2 Cl 2 (25 mL x 2).
  • Step 2 6-(4-((2,7-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-1-ethyl-7-phenyl-1H-pyrido[2,3- b][1,4]oxazin-2(3H)-one
  • VQ% *0/ lVXU$ SW 1,4-dioxane (1 mL) was added 2 M HCl in 1,4-dioxane (2 M, 2 mL).
  • Step 3 6-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-1-ethyl-7-phenyl-1H- pyrido[2,3-b][1,4]oxazin-2(3H)-one
  • Example 15 6-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-7-phenyl-1H- pyrido[2,3-b][1,4]oxazin-2(3H)-one
  • Example 15 was prepared in a matter similar to Example 14.
  • MS: m/z 495.2 [M + H] + .
  • Example 16 4-(4-(4-(1-Methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile
  • Step 1 6-(4-(Hydroxymethyl)phenyl)-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)- one
  • Intermediate 15 250 mg, 783 mmol
  • (4-(hydroxymethyl)phenyl)boronic acid 131 mg, 862 mmol
  • Pd(dppf)Cl2 57.3 mg, 78.3 mmol
  • Cs2CO3 7.35 mmol
  • Step 2 6-(4-(Chloromethyl)phenyl)-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)- one
  • SOCl2 489 mg, 432 mmol
  • Step 3 4-(4-(4-(1-Methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6- yl)benzyl)piperazin-1-yl)pyrimidine-2-carbonitrile
  • 6-(4-(chloromethyl)phenyl)-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin- 2(3H)-one 52 mg, 143 mmol
  • Example 18 4-((1-(4-(3-Oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Step 1 6-Phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one
  • phenylboronic acid (1.76 g, 14.5 mmol
  • Cs2CO3 (12.9 g, 39.5 mmol)
  • Pd(dppf)Cl2 963 mg, 1.32 mmol) in 1,4-dioxane (30 mL) and H 2 O (6 mL) was degassed, purged with N 2 three times, and stirred under N 2 at 90
  • Step 2 7-Bromo-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one T o a solution of 6-phenyl-2H-benzo[b][1,4]oxazin-3(4H$&XWO #*)) VQ% --- lVXU$ SW 8@: #* V?$ ⁇ K ⁇ KNNON A6E #*.1 VQ% 111 lVXU$' FRO VSa] ⁇ [O ⁇ K ⁇ ⁇ ]S[[ON K] +.
  • Example 19 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Step 1 4-Ethyl-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one To a solution of 6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg, 1.33 mmol.
  • Step 2 7-Bromo-4-ethyl-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one T o a solution of 4-ethyl-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H$&XWO #0) VQ% +0/ lVXU$ SW 8@: #* V?$ ⁇ K ⁇ KNNON A6E #21'- VQ% .., lVXU$' FRO VSa] ⁇ [O ⁇ K ⁇ ⁇ ]S[[ON K] +.
  • Step 3 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • a mixture of 7-bromo-4-ethyl-6-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one (90 mg, 271 l VXU$% #**- VQ% +0- lVXU$% 7 ⁇ 2CO3 #+/.
  • Example 20 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Step 1 6-Phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one
  • Step 2 4-Ethyl-6-phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one
  • K2CO3 641 mg, 4.64 mmol
  • iodoethane 483 mg, 3.09 mmol
  • Step 3 7-Bromo-4-ethyl-6-phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one
  • Step 4 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • a mixture of 7-bromo-4-ethyl-6-phenyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (130 mg, 390 lVXU$% W]O[VONSK]O *) #*/- VQ% ,2) lVXU$% 7 ⁇ 2CO3 (381 mg, 1.17 mmol), and Pd(dppf)Cl2 #+1'/ VQ% ,2') lVXU$ SW *%-&NSXaKWO #.
  • Example 23 4-((1-(4-(4-Ethyl-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Example 30 4-((1-(4-(7-Phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazin-6- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Step 1 2-((6-Amino-3-bromopyrazin-2-yl)oxy)ethan-1-ol
  • ethane-1,2-diol 40 mL
  • THF 40 mL
  • NaH 3.07 g, 76.8 mmol, 60% in oil
  • the mixture was stirred at 0 °C for 0.5 hr before 5-bromo-6- chloropyrazin-2-amine (8 g, 38.4 mmol) was added.
  • the resulting mixture was degassed, purged with N2 three times, and stirred under N2 at 70 °C for 16 hr.
  • Step 2 (E)-N'-(5-Bromo-6-(2-hydroxyethoxy)pyrazin-2-yl)-N,N-dimethylformimidamide
  • 2-((6-amino-3-bromopyrazin-2-yl)oxy)ethan-1-ol (8.98 g, 38.4 mmol) in DMF- DMA (45 mL) was degassed, purged with N 2 three times, and stirred under N 2 at 50 °C for 1 hr.
  • the reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (200 mL x 3).
  • Step 3 (E)-N'-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyrazin-6-yl)-N,N-dimethylformimidamide
  • Pd(OAc) 2 862 mg, 3.84 mmol
  • BINAP 4.78 g, 7.68 mmol
  • Cs 2 CO 3 37.5 g, 115 mmol
  • Step 4 2,3-Dihydro-[1,4]dioxino[2,3-b]pyrazin-6-amine
  • EtOH a solution of EtOH (30 mL) in EtOH (30 mL)
  • ethane-1,2-diamine 3.87 g, 64.4 mmol
  • the mixture was degassed, purged with N 2 three times, and stirred under N 2 at 80 °C for 16 hr.
  • Step 5 6-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine
  • Step 7 6-Bromo-7-phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine To a solution of 6-phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazine (390 mg, 1.82 mmol) in DMF (5 mL) was added NBS (1.30 g, 7.28 mmol).
  • Step 8 4-((1-(4-(7-Phenyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyrazin-6-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile
  • Example 31 4-((1-(4-(4-(Methyl-d3)-3-oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3- b][1,4]oxazin-7-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Step 1 4-(Methyl-d 3 )-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one T o a solution of 6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H$&XWO #*-) VQ% /*/ lVXU% [OPO[ to Intermediate 17 for detail procedures) in MeCN (6 mL) were added Cs2CO3 (602 mg, 1.85 mmol) and iodomethane-d3 #*,- VQ% 2
  • Step 2 7-Bromo-4-(methyl-d3)-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one
  • 4-(methyl-d 3 )-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one (150 mg, / *- lVXU$ SW 8@: #+ V?$ ⁇ K ⁇ KNNON A6E #+*2 VQ% *'+, VVXU$' FRO VSa] ⁇ [O ⁇ K ⁇ ⁇ ]S[[ON K] 80 °C for 2 hr.
  • Example 32 4-((1-(4-(3-Oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Step 1 7-Bromo-6-phenyl-2H-pyrazino[2,3-b][1,4]oxazin-3(4H)-one
  • NBS (405 mg, 2.28 mmol).
  • Step 2 4-((1-(4-(3-Oxo-6-phenyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-7- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • VQ% 0.* lVXU$% 7 ⁇ 2CO3 (734 mg, 2.25 mmol), and Pd(dppf)Cl2 #..') VQ% 0.'* lVXU$ SW *%-&NSXaKWO #*) V?$ KWN ⁇ 2O (2 mL) was degassed, purged with N2 three times, and stirred under N2 at 80 °C for 16 hr.
  • the reaction mixture was quenched with H 2 O (30 mL) at 25 °C and extracted with CH 2 Cl 2 (30 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • NanoBRET NanoBRET Target Engagement
  • TE Target Engagement
  • the NanoBRETTM Target Engagement (TE) Intracellular Kinase Assays are based on the NanoBRETTM System (Promega Corporation), an energy transfer technique designed to measure molecular proximity in living cells.
  • the NanoBRETTM TE Assays measure the apparent affinity of test compounds by competitive displacement of the NanoBRETTM tracer compound, which is a cell permeable molecule engineered to be reversibly bound to a NanoLuc® luciferase-kinase fusion expressed in cells.
  • NanoBRET assay procedure was used to interrogate the compounds against the full length AKT E17K per manufacturers suggestions. Briefly, HEK-293 cells (ATCC Cat # CRL-1573) were used for transfection purposes using FuGENE HD Transfection Reagent (Promega Cat # E2311). All cells were evaluated for viability prior to transfection and optimization of the transfection was done prior to experimentation. Greater than 95% viability was used for all experiments. Following transfection, cells were washed and resuspended in Opti-MEM. NanoBRET assays were performed in white, 384-well plates (Corning) at a density of 2x10 5 cells/well. All example compounds were prepared as concentrated stock solutions in DMSO (Sigma-Aldrich).
  • Example compounds are dissolved in DMSO to make 10 mM stock solution.
  • Example compounds were transferred as 40uL of 10 mM stock solution to a 384 pp-plate (LABCYTE, PP-0200) and diluted in 3-fold, 10-point dilution _SK ][KW ⁇ PO[[SWQ *+ l? MXVYX ⁇ WN SW]X +- l? 8@EB Lb 5Y[SMX] USZ ⁇ SN RKWNUO[' 5 ?KLMb]O ECHO 550 compound dispenser was used to facilitate compound transfer directly to cells. Cells were equilibrated for 2 hr with energy transfer probes and example compound prior to BRET measurements.
  • AKTE17K Promega Cat # NV2421
  • specific probe NaBRET tracer, Promega Cat # N264B
  • tracer dilution buffer 12.5 mM HEPES, 31.25% PEG-400, pH 7.5.
  • the energy transfer probes were added to the cells at concentrations optimized for the target in question (AKT E17K).
  • NanoBRET NanoGlo Substrate Promega Cat # N157D
  • Extracellular Nanoluc Inhibitor Promega Cat # N235C
  • luminescence was measured on Envision Reader (Perkin Elmer) Multimode Luminometer equipped with 450nmBPfilter (donor)and 600nmLPfilter (acceptor), using 0.5 s integration time.
  • Milli-BRET units mBU
  • Apparent tracer affinity values EC50
  • EC50 sigmoidal dose-response (variable slope).
  • Competitive displacement data were then plotted and data were fit to determine the EC50 value for each example compound.
  • Table 4 provides the assay results for select examples. Activity is defined as “+”, for EC 50 greater 600 nanomolar; “++” for EC 50 between 60-600 nanomolar; “+++” for EC50 between 15-60 nanomolar; and “++++”, for EC50 less than 15 nanomolar. Table 4
  • Example 1 Oral capsule
  • the active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.
  • a capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
  • Example 2 Solution for injection
  • the active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq/mL.
  • the examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

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Abstract

L'invention concerne des inhibiteurs d'AKT1, des compositions pharmaceutiques comprenant les composés inhibiteurs, et des procédés d'utilisation des composés inhibiteurs d'AKT1 pour le traitement d'une maladie.
PCT/US2025/031050 2024-05-28 2025-05-27 Modulateurs d'akt1 Pending WO2025250545A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040102360A1 (en) * 2002-10-30 2004-05-27 Barnett Stanley F. Combination therapy
WO2011077098A1 (fr) * 2009-12-23 2011-06-30 Almac Discovery Limited Inhibiteurs de l'activité de l'akt
WO2015200843A1 (fr) * 2014-06-27 2015-12-30 Quanticel Pharmaceuticals, Inc. Inhibiteurs de la déméthylase-1 spécifique de la lysine
WO2024054512A1 (fr) * 2022-09-08 2024-03-14 Alterome Therapeutics, Inc. Modulateurs de akt1
WO2024064026A1 (fr) * 2022-09-19 2024-03-28 Alterome Therapeutics, Inc. Modulateurs d'akt1
WO2024102621A1 (fr) * 2022-11-09 2024-05-16 Alterome Therapeutics, Inc. Modulateurs de akt1
WO2024107565A1 (fr) * 2022-11-14 2024-05-23 Alterome Therapeutics, Inc. Modulateurs de akt1

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040102360A1 (en) * 2002-10-30 2004-05-27 Barnett Stanley F. Combination therapy
WO2011077098A1 (fr) * 2009-12-23 2011-06-30 Almac Discovery Limited Inhibiteurs de l'activité de l'akt
WO2015200843A1 (fr) * 2014-06-27 2015-12-30 Quanticel Pharmaceuticals, Inc. Inhibiteurs de la déméthylase-1 spécifique de la lysine
WO2024054512A1 (fr) * 2022-09-08 2024-03-14 Alterome Therapeutics, Inc. Modulateurs de akt1
WO2024064026A1 (fr) * 2022-09-19 2024-03-28 Alterome Therapeutics, Inc. Modulateurs d'akt1
WO2024102621A1 (fr) * 2022-11-09 2024-05-16 Alterome Therapeutics, Inc. Modulateurs de akt1
WO2024107565A1 (fr) * 2022-11-14 2024-05-23 Alterome Therapeutics, Inc. Modulateurs de akt1

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LENA QUAMBUSCH; INA LANDEL; LAURA DEPTA; JÖRN WEISNER; NIKLAS UHLENBROCK; MATTHIAS P. MÜLLER; FRANZISKA GLANEMANN; KRISTINA ALTHOF: "Covalent‐Allosteric Inhibitors to Achieve Akt Isoform‐Selectivity", ANGEWANDTE CHEMIE, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 131, no. 52, 8 November 2019 (2019-11-08), DE , pages 18999 - 19005, XP071379626, ISSN: 0044-8249, DOI: 10.1002/ange.201909857 *

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