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WO2025207620A1 - Modulateurs d'akt1 - Google Patents

Modulateurs d'akt1

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Publication number
WO2025207620A1
WO2025207620A1 PCT/US2025/021322 US2025021322W WO2025207620A1 WO 2025207620 A1 WO2025207620 A1 WO 2025207620A1 US 2025021322 W US2025021322 W US 2025021322W WO 2025207620 A1 WO2025207620 A1 WO 2025207620A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
pharmaceutically acceptable
compound
solvate
deuteroisotope
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/021322
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English (en)
Inventor
Michael David Bartberger
Yi Fan
Eric Anthony MURPHY
Xuefeng Zhu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alterome Therapeutics Inc
Original Assignee
Alterome Therapeutics Inc
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Filing date
Publication date
Application filed by Alterome Therapeutics Inc filed Critical Alterome Therapeutics Inc
Publication of WO2025207620A1 publication Critical patent/WO2025207620A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—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
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • 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.
  • inhibitors of AKT1 are inhibitors of AKT1, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said inhibitory compounds for the treatment of disease.
  • One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof wherein,
  • Ring A is an optionally substituted monocyclic, bicyclic, or tricyclic heteroaryl; w, x, y, and z are each independently N or C-R 1 ; each R 1 is independently selected from H, D, halogen, or -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 together to form a carbocycle or heterocycle; L is selected from -N(R 4 )-, -O-, or a divalent radical selected from:
  • each R 4 is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R 25 are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R 25 together form an oxo; or two independently selected R 25 join together to form a carbocycle or heterocycle; al is 0, 1, 2, 3, or 4; bl is 0, 1, 2, 3, or 4; cl is 1, 2, 3, or 4; dl is 1, 2, 3, or 4; el is 0, 1, 2, 3, or 4; fl is 0, 1, 2, 3, or 4; provided that e and f are not both 0; gl is 0, 1, 2, 3, or 4; provided that e and g are not both 0; hl is 0, 1, 2, 3, or 4; provided that gl and hl are not both 0; and provided that fl and h
  • 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 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, -NH2, 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;
  • T 1 is N or C-R 10 ;
  • T 2 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 7 is N or C-R 12 ;
  • a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and at least one pharmaceutically acceptable excipient.
  • 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), or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. Another embodiment provides the method wherein the disease or disorder is cancer.
  • Amino refers to the -NH2 radical.
  • Cyano refers to the -CN radical.
  • Niro refers to the -NO2 radical.
  • 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., Ci-C is alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., Ci-C 13 alkyl).
  • an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl).
  • an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl).
  • an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl).
  • an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1 -methylethyl (/.w-propyl), 1 -butyl (//-butyl), 1- methylpropyl (sec-butyl), 2-methylpropyl (/.w-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 , -SIU, -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)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S
  • 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. In certain embodiments, 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 (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-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 , -SIU, -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)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) t R 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, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ⁇ -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., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -Cs 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)tOR a (where t is 1 or 2), -S(O)tOR 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., C2-C8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene).
  • an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 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 , -SIU, -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)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., C2-C5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (e.g., C2-C4 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., Cs-Cs 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 , -SIU, -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)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2),
  • 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) ⁇ -electron system in accordance with the Hiickel 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 ) 2 , -R b
  • Aralkyl refers to a radical of the formula -R c -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.
  • alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • Alkynyl refers to a radical of the formula -R e -aryl, where R e 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.
  • “Aralkoxy” refers to a radical bonded through an oxygen atom of the formula -O-R c -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.
  • 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 (z.e., containing single C-C bonds only) or unsaturated (z.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 (z.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
  • Carbocyclylalkyl refers to a radical of the formula -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.
  • Carbocyclylalkynyl refers to a radical of the formula -R c -carbocyclyl where R c 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.
  • 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. Unless stated otherwise specifically in the specification, 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, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
  • 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 -
  • 'W-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 A-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 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 -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 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, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel 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[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
  • 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(O)R
  • 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 A-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 -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 heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroaryl alkyl 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 (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (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.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n 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).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, n C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 C1, 37 C1, 79 Br, 81 Br, 125 I are all contemplated.
  • isotopic substitution with 18 F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive
  • the compounds disclosed herein have some or all of the J H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • 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.
  • CD3I iodomethane-ds
  • 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.
  • 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.
  • AKT is a key downstream mediator of the phosphoinositide-3 -kinase (PI3K) signaling pathway.
  • PI3Ks are activated by different compounds.
  • PI3Ka, PI3KP, and PI3K5 are activated by extracellular ligands binding to a transmembrane glycoprotein with enzymatic activity, receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • GPCRs G-protein- compound receptors
  • RAS RAS family of GTPases.
  • 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
  • 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. et al., Int J Oncol., 2018; 53(6): 2319-2331).
  • 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).
  • 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.
  • 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).
  • These mutations in the PH structural domain increase the binding of 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.
  • Phosphatidylinositol-3,4,5-triphosphate 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.
  • 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.
  • this target may be useful for targeted treatment of cancers.
  • Prior Art AKT1 Inhibitors [0081] 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. These 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 is provided herein.
  • One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof: wherein,
  • 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 together to form a carbocycle or heterocycle;
  • L is selected from -N(R 4 )-, -O-, or a divalent radical selected from:
  • each R 4 is independently selected from H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 carbocyclyl; each R 25 are independently H, D, halogen, -OH, -CN, or optionally substituted C1-C6 alkyl; or two R 25 together form an oxo; or two independently selected R 25 join together to form a carbocycle or heterocycle; al is 0, 1, 2, 3, or 4; bl is 0, 1, 2, 3, or 4; cl is 1, 2, 3, or 4; dl is 1, 2, 3, or 4; el is 0, 1, 2, 3, or 4; fl is 0, 1, 2, 3, or 4; provided that e and f are not both 0; gl is 0, 1, 2, 3, or 4; provided that e and g are not both 0; hl is 0, 1, 2, 3, or 4; provided that gl and hl are not both 0; and provided that fl and h
  • 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 9a is selected from hydrogen, -OH, -NH2, 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;
  • T 1 is N or C-R 10 ;
  • T 2 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 7 is N or C-R 12 ;
  • Another embodiment provides the compound of Formula (I), having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is: wherein,
  • R 5 is optionally substituted aryl, or optionally substituted heteroaryl
  • a 1 is selected from N, C-H, or C-R 23 ;
  • a 2 is selected from N, C-H, or C-R 24 ;
  • R 21 , R 22 , R 23 , and R 24 are independently selected from H, D, halogen, -OR 26 , -SR 26 , -N(R 26 )2, - CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R 26 , - CON(R 26 )2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R 26 is independently H or optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ila),
  • Another embodiment provides the compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 1 is N. Another embodiment provides the compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 2 is C-H. Another embodiment provides the compound of Formula (Ila), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 21 and R 22 are H. [0088] Another embodiment provides the compound of Formula (I), having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is: wherein,
  • R 5 is optionally substituted aryl, or optionally substituted heteroaryl
  • a 1 is selected from N, C-H, or C-R 23 ;
  • Another embodiment provides the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Illa), acceptable salt, solvate, or deuteroisotope thereof, wherein A 1 is N.
  • Another embodiment provides the compound of Formula (Illa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 2 is C-H.
  • Another embodiment provides the compound of Formula (Illa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 21 and R 22 are H.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IV-i), wherein Ring A is: wherein,
  • R 5 is optionally substituted aryl, or optionally substituted heteroaryl
  • Another embodiment provides the compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (IVb),
  • a 8 is selected from N, C-H, or C-R 32 ;
  • R 23 , R 24 , R 27 , R 28 , R 31 , and R 32 are independently selected from H, D, halogen, -OR 26 , - SR 26 , -N(R 26 ) 2 , -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, - CO2R 26 , -CON(R 26 )2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R 26 is independently H, -OH, - ⁇ (optionally substituted C1-C6 alkyl), or optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), having the structure of Formula (VI), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is: wherein,
  • R 5 is optionally substituted aryl, or optionally substituted heteroaryl
  • a 1 is selected from N, C-H, or C-R 23 ;
  • a 2 is selected from N, C-H, or C-R 24 ;
  • a 3 is selected from N, C-H, or C-R 27 ;
  • a 4 is selected from N, C-H, or C-R 28 ;
  • a 7 is selected from N, C-H, or C-R 31 ;
  • a 8 is selected from N, C-H, or C-R 32 ;
  • R 23 , R 24 , R 27 , R 28 , R 31 , and R 32 are independently selected from H, D, halogen, -OR 26 , -SR 26 , - N(R 26 ) 2 , -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R 26 , -CON(R 26 )2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R 26 is independently H or optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), having the structure of Formula (VII), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is: wherein,
  • R 5 is optionally substituted aryl, or optionally substituted heteroaryl
  • a 1 is selected from N, C-H, or C-R 23 ;
  • a 2 is selected from N, C-H, or C-R 24 ;
  • a 9 is selected from N, C-H, or C-R 33 ;
  • a 10 is selected from N, C-H, or C-R 34 ;
  • R 23 , R 24 , R 33 and R 34 are independently selected from H, D, halogen, -OR 26 , -SR 26 , -N(R 26 )2, - CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R 26 , - CON(R 26 )2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or
  • R 33 and R 34 together form -(C(R 36 ) 2 )tl-NHCO-(C(R 36 ) 2 )t2-; tl is 0, 1, or 2; t2 is 0, 1, or 2; provided that at least one of tl or t2 is not 0; each R 26 is independently H or optionally substituted C1-C6 alkyl; and each R 36 is independently H, halogen, or optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), having the structure of Formula (VIII), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is: wherein,
  • a 5 is selected from N, C-H, or C-R 29 ;
  • R 29 , R 30 and R 35 are independently selected from H, D, halogen, -OR 26 , -SR 26 , -N(R 26 )2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R 26 , -CON(R 26 )2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R 26 is independently H or optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (Villa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof,
  • Another embodiment provides the compound of Formula (Villa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 5 is C-H. Another embodiment provides the compound of Formula (Villa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 6 is C-H. Another embodiment provides the compound of Formula (Villa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 11 is C-H.
  • Another embodiment provides the compound of Formula (I), having the structure of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Ring A is wherein,
  • a 1 is selected from N, C-H, or C-R 23 ;
  • a 2 is selected from N, C-H, or C-R 24 ;
  • a 12 is selected from N-H, or CR 38 R 39 ;
  • a 13 is selected from N-H, or CR 40 R 41 ;
  • a 14 is selected from N-H, or CR 42 R 43 ;
  • a 15 is selected from N-H, or CR 44 R 45 ;
  • R 23 , R 24 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , and R 45 are independently selected from H, D, halogen, -OR 26 , -SR 26 , -N(R 26 )2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R 26 , -CON(R 26 )2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 38 and R 39 join to form an oxo
  • R 39 and R 40 join to form a bond
  • R 40 and R 41 join to form an oxo
  • R 41 and R 42 join to form a bond
  • R 42 and R 43 join to form an oxo
  • R 43 and R 44 join to form a bond
  • Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 12 is C-H2. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 13 is C-H2. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 14 is C-H2. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 15 is C-H2.
  • Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 12 is N-H. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 13 is N-H. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 14 is N-H. Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 15 is N-H.
  • Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 38 and R 39 join to form an oxo.
  • Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 39 and R 40 join to form a bond.
  • Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 40 and R 41 join to form an oxo.
  • Another embodiment provides the compound of Formula (IX), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 41 and R 42 join to form a bond.
  • R 5 is optionally substituted aryl, or optionally substituted heteroaryl
  • a 2 is selected from N, C-H, or C-R 24 ;
  • R 21 , R 22 , R 23 , and R 24 are independently selected from H, D, halogen, -OR 26 , -SR 26 , - N(R 26 )2, -CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, -CO2R 26 , -CON(R 26 )2, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Xa),
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein A 2 is C-H.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 21 and R 22 are H.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 5 is optionally substituted aryl.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 5 is optionally substituted phenyl.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 5 is optionally substituted heteroaryl.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa),or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 5 is optionally substituted pyridine.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R 2 and R 3 are H.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 0.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein n is 1.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is:
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is selected from:
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: [00124] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is -N(R 4 )-.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:
  • 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, -NH2, 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.
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), 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 any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III),
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein LCG is:
  • 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 Cl- 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 any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), 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 any one of Formula (I), (II), (Ila), (III),
  • Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein L is: [00135] Another embodiment provides the compound of any one of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a
  • One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 1.
  • Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • 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) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.
  • the AKT1 inhibitory compound as described by Formula (I), (II), (Ila), (III), (Illa), (IV), (IVa), (IVb), (V), (Va), (VI), (VII), (VIII), (Villa), (IX), (X) or (Xa), 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
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, 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 a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.
  • the AKT1 inhibitory compound as described by Table 1, 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. See, e.g, Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • 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.
  • One embodiment provides the method wherein the cancer is Type II endometrial cancer.
  • Another embodiment provides the method wherein the cancer is Type II endometrial papillary serous carcinoma.
  • Another embodiment provides the method wherein the cancer is Type II endometrial clear cell carcinoma.
  • Another embodiment provides the method wherein the cancer is Type II endometrial undifferentiated carcinoma.
  • Another embodiment provides the method wherein the cancer is Type II endometrioid carcinoma.
  • MSI microsatellite instability
  • MMR DNA mismatch repair
  • TMB tumor mutational burden
  • Another embodiment provides the method wherein the cancer is HER2-.
  • Another embodiment provides the method wherein the cancer is prostate neuroendocrine cancer. Another embodiment provides the method wherein the cancer is prostate small cell neuroendocrine cancer. Another embodiment provides the method wherein the cancer is prostate large cell carcinoma. Another embodiment provides the method wherein the cancer is prostate transitional cell carcinoma. Another embodiment provides the method wherein the cancer is prostate sarcoma.
  • One embodiment provides the method wherein the cancer is lung cancer.
  • One embodiment provides the method wherein the cancer is non-small cell lung cancer.
  • One embodiment provides the method wherein the cancer is non-squamous non-small cell lung cancer.
  • One embodiment provides the method wherein the cancer is squamous non-small cell lung cancer.
  • One embodiment provides the method wherein the cancer is colon cancer.
  • One embodiment provides the method wherein the cancer is anal cancer.
  • One embodiment provides the method wherein the cancer is pancreatic cancer. Another embodiment provides the method wherein the cancer is exocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is neuroendocrine pancreatic cancer. [00209] One embodiment provides the method wherein the cancer is thyroid cancer.
  • One embodiment provides the method wherein the cancer is ovarian cancer. Another embodiment provides the method wherein the cancer is epithelial ovarian cancer. Another embodiment provides the method wherein the cancer is serous epithelial ovarian cancer. Another embodiment provides the method wherein the cancer is endometrioid ovarian cancer. Another embodiment provides the method wherein the cancer is clear cell ovarian cancer. Another embodiment provides the method wherein the cancer is mucinous ovarian cancer.
  • One embodiment provides the method wherein the cancer is adenoid cystic carcinoma. [00217] One embodiment provides the method wherein the cancer is renal cell cancer.
  • One embodiment provides the method wherein the cancer is acute myeloid leukemia. [00221] One embodiment provides the method wherein the cancer is cancer of unknown primary. [00222] One embodiment provides the method wherein the cancer is locally advanced.
  • One embodiment provides the method wherein the patient exhibits Type I diabetes, diabetes requiring insulin, diabetes requiring metformin or another oral hypoglycemic agent, or pre-diabetes treated with metformin or another oral hypoglycemic agent.
  • the AKT1 inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
  • NMR nuclear magnetic resonance pH potential of hydrogen a measure of the acidity or basicity of an aqueous solution PE petroleum ether
  • Step 1 4-(((tert-Butyldimethylsilyl)oxy)methyl)benzonitrile
  • Step 2 l-(4-(((/er/-Butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one
  • Step 3 2-(4-(((/cz7-Butyldimethylsilyl)oxy)methyl)phenyl)-5-chl oro-3 -phenyl- 1,6-naphthyri dine
  • l-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one 450 mg, 1.32 mmol
  • K2CO3 913 mg, 6.61 mmol
  • 4-amino-2- chloronicotinaldehyde (228 mg, 1.45 mmol
  • Step 4 8-(4-(Hydroxymethyl)phenyl)-9-phenyl-[l,2,4]triazolo[3,4-f][l,6]naphthyridin-3(2J7)- one
  • Step 5 8-(4-(Chloromethyl)phenyl)-9-phenyl-[l,2,4]triazolo[3,4-f][l,6]naphthyridin-3(2J7)-one
  • 8-(4-(hydroxymethyl)phenyl)-9-phenyl-[l,2,4]triazolo[3,4-f][l,6]naphthyridin- 3(2J7)-one (30 mg, 81.4 pmol) in CH2CI2 (6 mL) was added SOCI2 (0.3 mL). The mixture was stirred at 25 °C for 0.5 hr. The reaction was concentrated under reduced pressure to give the title compound (Intermediate 1, 34.5 mg, HC1 salt) as a yellow solid.
  • MS: m/z 386.9, 388.9 [M + H] + .
  • Step 1 tert-Butyl 4-((2-cyanopyrimidin-4-yl)amino)piperidine-l -carboxylate
  • Step 1 tert-Butyl 4-(2-cyanopyrimidin-4-yl)piperazine-l -carboxylate
  • Step 1 Methyl 4-(phenylethynyl)benzoate A mixture of methyl 4-bromobenzoate (20 g, 93.0 mmol), ethynylbenzene (11.4 g, 112 mmol), NH3 H2O (186 mmol, 25.6 mL, 28% purity), Pd(PPh 3 ) 2 C12 (6.53 g, 9.30 mmol) and Cui (3.54 g, 18.6 mmol) in THF (200 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 35 °C for 16 hr under N2 atmosphere. The mixture was filtered through Celite at 25 °C and concentrated under reduced pressure.
  • Step 5 7-(4-(Chloromethyl)phenyl)-6-phenyl-1H-imidazo[4,5-g]quinoxaline
  • Step 1 2-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-3-phenyl- l ,6-naphthyridine
  • Step 2 2-(4-(((/ez7-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,6-naphthyridine 6-oxide
  • a solution of 2-(4-(((/ez7-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l ,6-naphthyridine (170 mg, 398 pmol) in CH2Q2 (30 mL) was degassed and purged with N2 three times.
  • zzz-CPBA 89.0 mg, 438 pmol, 85% purity
  • Step 3 2-(4-(Hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6J7)-one
  • Step 4 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6J7)-one
  • Step 3 2-(4-(Chloromethyl)phenyl)-3-phenylimidazo[l,2-b]pyridazine
  • Step 2 4-((l-(4-Bromobenzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • l-bromo-4-(chloromethyl)benzene (6.47 g, 26.7 mmol, HC1 salt) and Intermediate 2 (8.48 g, 26.7 mmol, TFA salt) in DMF (70 mL)
  • K2CO3 (18.5 g, 134 mmol
  • Nal 802 mg, 5.35 mmol
  • Step 3 4-((l-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile
  • Step 1 (Z)- l -(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-3-(dimethylamino)-2- phenylprop-2-en- 1 -one
  • Step 2 4-(5-Oxo-3-phenyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)benzyl acetate
  • Step 3 2-(4-(Hydroxymethyl)phenyl)-3-phenyl-7,8-dihydro-l,6-naphthyridin-5(6J7)-one
  • 4-(5-oxo-3-phenyl-5,6,7,8-tetrahydro-l,6-naphthyridin-2-yl)benzyl acetate 60 mg, 161 pmol
  • MeOH MeOH
  • THF (1 mL
  • H2O 1 mL
  • K2CO3 66.8 mg, 483 pmol, 3 eq
  • Step 4 2-(4-(Chloromethyl)phenyl)-3-phenyl-7,8-dihydro-l,6-naphthyridin-5(6J7)-one
  • Step 3 2-(4-(((/ ⁇ 77-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl- l ,6-naphthyridine-7- carboxamide
  • Step 5 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamide
  • 2-(4-(hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamide 100 mg, 281 pmol
  • SOCI2 0.5 mL
  • the reaction was concentrated under reduced pressure to give the title compound (Intermediate 16, 115 mg, HC1 salt) as a yellow solid.
  • MS: m/z 374.0, 376.0 [M + H] + .
  • Intermediate 17 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,7-naphthyridine-6- carb oxami de
  • Step 1 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-6-chl oro-3 -phenyl- 1,7-naphthyri dine
  • l-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one 500 mg, 1.47 mmol, refer to Intermediate 1 for detail procedures
  • DMF 5 mL
  • K2CO3 203 mg, 1.47 mmol
  • tert-butyl (6-chloro-4-formylpyridin-3-yl)carbamate 377 mg, 1.47 mmol.
  • Step 2 Ethyl 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,7-naphthyridine-6- carb oxy late
  • Step 3 2-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-3-phenyl- l ,7-naphthyridine-6- carboxamide
  • Step 1 4-(4-(4-Bromobenzyl)piperazin-l-yl)pyrimidine-2-carbonitrile
  • Step 2 4-(4-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)piperazin-l-yl)pyrimidine- 2-carbonitrile
  • Step 1 /c/V-Butyl 4-(2-cyanopyrimidin-4-yl)-l,4-diazepane-l -carboxylate
  • Step 1 tert-Butyl (l-(4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperidin-4- yl)carbamate
  • Step 2 l -(4-(6-Phenyl- IT/-imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperidin-4-amine
  • Step 1 Methyl 4-(3-phenylpyrido[2,3-Z>]pyrazin-2-yl)benzoate & methyl 4-(2-phenylpyrido[2,3- Z>]pyrazin-3 -yl)benzoate
  • Step 2 (4-(3-Phenylpyrido[2,3-Z>]pyrazin-2-yl)phenyl)methanol & (4-(2-phenylpyrido[2,3- Z>]pyrazin-3 -yl)phenyl)m ethanol
  • Step 3 2-(4-(Chloromethyl)phenyl)-3-phenylpyrido[2,3-Z>]pyrazine & 3-(4- (chloromethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine
  • Step 1 tert-Butyl 6-(2-cyanopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate
  • Step 1 tert-Butyl 7-(2-cyanopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
  • Step 1 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l,5-naphthyridine
  • Step 3 2-(4-(Chloromethyl)phenyl)-3-phenyl-l,5-naphthyridine
  • Step 2 Ethyl 2-(4-(((/er/-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2- a]pyrimidine-7-carboxylate
  • Step 3 2-(4-(((/er/-Butyldimethylsilyl)oxy)methyl)phenyl)-3-phenylimidazo[l,2-a]pyrimidine- 7-carboxamide
  • Step 1 l-Methyl-7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-one
  • Step 2 6-Bromo-l -methyl -7-phenyl-3,4-dihydro-l,5-naphthyridin-2(U7)-one
  • Step 2 7-Chloro-3-(4-fluorophenyl)-l,6-naphthyridin-2(177)-one
  • Step 3 Methyl 3-(4-fluorophenyl)-2-oxo-l,2-dihydro-l,6-naphthyridine-7-carboxylate
  • TEA 7-chloro-3-(4-fluorophenyl)-l,6-naphthyridin-2(U7)-one
  • TEA 7-chloro-3-(4-fluorophenyl)-l,6-naphthyridin-2(U7)-one
  • TEA 684 pL, 4.91 mmol
  • Pd(dppf)C12 360 mg, 492 pmol
  • Step 4 Methyl 2-chloro-3-(4-fluorophenyl)-l,6-naphthyridine-7-carboxylate
  • Step 5 Methyl 3-(4-fluorophenyl)-2-(4-(hydroxymethyl)phenyl)-l,6-naphthyridine-7- carb oxy late
  • Step 6 3-(4-Fluorophenyl)-2-(4-(hydroxymethyl)phenyl)-l,6-naphthyridine-7-carboxamide
  • methyl 3-(4-fluorophenyl)-2-(4- (hydroxymethyl)phenyl)-l,6-naphthyridine-7-carboxylate 140 mg, 361 pmol
  • NHLMeOH 7M, 4 mL
  • Step 7 2-(4-(Chloromethyl)phenyl)-3-(4-fluorophenyl)-l,6-naphthyridine-7-carboxamide
  • Step 1 7-Bromo-2-(4-(((/c/7-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl- l ,5-naphthyridine
  • l-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan-l-one 1.3 g, 3.82 mmol, refer to Intermediate 1 for detail procedures
  • 3- amino-5-bromopicolinaldehyde (921 mg, 4.58 mmol) and K2CO3 (2.64 g, 19.1 mmol).
  • Step 3 Methyl 2-amino-5-bromo-6-(4-(((/c/7-butyldimethylsilyl)oxy)methyl)phenyl)nicotinate
  • NBS 3.82 g, 21.5 mmol
  • Step 4 Methyl 2-amino-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-phenylnicotinate
  • phenylboronic acid (1.57 g, 12.9 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) were added Pd(dppf)C12 (786 mg, 1.07 mmol) and CS2CO3 (10.5 g, 32.2 mmol).
  • Step 5 Methyl 2-bromo-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-phenylnicotinate
  • methyl 2-amino-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5- phenylnicotinate (1 g, 2.23 mmol) in CH2Br2 (10 mL) were added slowly tert-butyl nitrite (460 mg, 4.46 mmol) and A-benzyl-A,A-diethylethanaminium bromide (910 mg, 3.34 mmol) in an ice bath.
  • Step 6 Methyl (£)-6-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-(2-ethoxyvinyl)-5- phenylnicotinate
  • Step 8 2-(4-(Chloromethyl)phenyl)-3-phenyl-5J/-pyrano[4,3-Z>]pyridin-5-one
  • Step 1 6-Bromo-2-phenylpyrido[2,3-Z>]pyrazin-3-ol
  • Step 4 Methyl 3-(4-(hydroxymethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxylate
  • Step 5 3-(4-(Hydroxymethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxamide
  • Step 6 3-(4-(Chloromethyl)phenyl)-2-phenylpyrido[2,3-Z>]pyrazine-6-carboxamide
  • Step 1 2-(4-(Hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxylic acid
  • Step 2 2-(4-(Hydroxymethyl)phenyl)-7V-methoxy-3-phenyl-l,6-naphthyridine-7-carboxamide
  • 2-(4-(hydroxymethyl)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxylic acid 100 mg, 281 pmol
  • O-methylhydroxylamine 46.9 mg, 561 pmol, HC1 salt
  • EtOAc 5 mL
  • T4P 404 mg, 561 pmol, 50% purity in EtOAc
  • DIEA 109 mg, 842 pmol
  • Step 3 2-(4-(Chloromethyl)phenyl)-A-methoxy-3-phenyl-l,6-naphthyridine-7-carboxamide
  • 2-(4-(hydroxymethyl)phenyl)-A-methoxy-3-phenyl-l,6-naphthyridine-7- carboxamide 90 mg, 234 pmol
  • SOCI2 0.5 mL
  • the pH of the reaction mixture was adjusted to about 7 ⁇ 8 at 0 °C with solid K2CO3.
  • the reaction was concentrated under reduced pressure to give the title compound (Intermediate 34, 94 mg).
  • Step 3 I -(4-(((tert-Butyldimethylsilyl)oxy)methyl-d2)phenyl)-2-phenylethan- l -one
  • benzyl magnesium Chloride 8.82 mL, 1 M in THF
  • Step 4 2-(4-(((tert-butyl dirnethylsilyl)oxy)rnethyl-d2)phenyl)-7-chloro-3-phenyl- l ,6- naphthyridine
  • Step 6 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl-t/2)phenyl)-3-phenyl-l,6-naphthyridine-7- carb oxami de
  • Step 7 2-(4-(Hydroxymethyl-d2)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamide
  • 2-(4-(((terLbutyldimethylsilyl)oxy)methyl-t/2)phenyl)-3-phenyl-l,6- naphthyridine-7-carboxamide 565 mg, 1.20 mmol
  • TBAF 3 mL, 1 M in THF
  • the mixture was stirred at 25 °C for 1 hr.
  • the mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 2).
  • the combined organic layers were washed with brine (30 mL x 5), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (426 mg).
  • MS: m/z 358.0 [M + H] + .
  • Step 8 2-(4-(Chloromethyl-t/2)phenyl)-3-phenyl-l,6-naphthyridine-7-carboxamide
  • Step 6 Ethyl 2-hydroxy-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate
  • Step 7 Ethyl 2-chloro-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate
  • Step 8 Ethyl 2-(4-(hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate A mixture of ethyl 2-chloro-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate (100 mg, 306 pmol), (4-(hydroxymethyl)phenyl)boronic acid (46.5 mg, 306 pmol), CS2CO3 (199 mg, 612 pmol), and Pd(dppf)C12 (22.4 mg, 30.6 pmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed, purged with N2 three times, and stirred at 90 °C for 2 hr under N2.
  • Step 1 2-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-7-chloro-5-methyl-3-phenyl- l ,6- naphthyridine
  • Step 2 Ethyl 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-methyl-3-phenyl-l,6- naphthyridine-7-carboxylate
  • Step 3 2-(4-(Hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylic acid
  • ethyl 2-(4-(((/c/7-butyldimethylsilyl)oxy)methyl)phenyl)-5-methyl-3-phenyl- l,6-naphthyridine-7-carboxylate 314 mg, 612 pmol
  • LiOH.J O 89.9 mg, 2.14 mmol
  • Step 4 2-(4-(Hydroxymethyl)phenyl)-A-methoxy-5-methyl-3-phenyl-l,6-naphthyridine-7- carb oxami de
  • Step 1 (4-(6-Bromo-3-phenylquinolin-2-yl)phenyl)methanol
  • l -(4-(((/c/7-butyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan- l -one 500 mg, 1.47 mmol, refer to Intermediate 1 for detail procedures
  • EtOH 10 mL
  • 2- amino-5-bromobenzaldehyde (294 mg, 1.47 mmol)
  • KOH 98.9 mg, 1.76 mmol
  • Step 1 Ethyl (£)-3-(4-amino-6-chloro-5-fluoropyridin-3-yl)acrylate
  • Step 4 7-Chloro-8-fluoro-3-phenyl-l,6-naphthyridin-2-ol
  • Step 6 Ethyl 2-chloro-8-fluoro-3-phenyl-l,6-naphthyridine-7-carboxylate
  • Step 1 (4-Amino-6-chloro-5-fluoropyridin-3-yl)methanol
  • Step 5 7-Chloro-8-fluoro-5-methyl-3-phenyl-l,6-naphthyridin-2-ol
  • Step 6 Ethyl 8-fluoro-2-hydroxy-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate
  • Step 7 Ethyl 2-chloro-8-fluoro-5-methyl-3-phenyl-l,6-naphthyridine-7-carboxylate
  • Step 9 8-Fluoro-2-(4-(hydroxymethyl)phenyl)-5-methyl-3-phenyl-l,6-naphthyridine-7- carb oxami de
  • Step 10 2-(4-(Chloromethyl)phenyl)-8-fluoro-5-methyl-3-phenyl-l,6-naphthyridine-7- carboxamide
  • Step 1 (4-(7-Bromo-6-fluoro-3-phenylquinolin-2-yl)phenyl)methanol
  • Step 2 Methyl 6-fluoro-2-(4-(hydroxymethyl)phenyl)-3-phenylquinoline-7-carboxylate
  • MeOH MeOH
  • Pd(dppf)C12 30 mg, 42 pmol
  • TEA 63 mg, 625 pmol
  • the suspension was degassed, purged with CO three times, and stirred under CO (50 psi) at 50 °C for 16 hr.
  • the reaction was filtered and concentrated under reduced pressure.
  • Step 3 6-Fluoro-2-(4-(hydroxymethyl)phenyl)-3-phenylquinoline-7-carboxamide
  • Step 1 7-Bromo-2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-phenyl-l ,8-naphthyridine
  • l -(4-(((tertb- utyldimethylsilyl)oxy)methyl)phenyl)-2-phenylethan- l -one (1.55 g, 4.55 mmol, refer to Intermediate 1 for detail procedures)
  • 2-amino-6-bromonicotinaldehyde (1.01 g, 5.01 mmol) in z-PrOH (30 mL) was added K2CO3 (3.15 g, 22.8 mmol) at 25 °C.
  • Step 3 7-(4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-6-phenyl- l ,8-naphthyridine-2- carboxamide
  • a mixture of methyl 7-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-phenyl-l,8- naphthyridine-2-carboxylate (120 mg, 248 pmol) in NH3 (7M in MeOH, 3 mL) was stirred at 55 °C for 12 hr.
  • the reaction mixture was concentrated to give the title compound (Intermediate 46, 100 mg, yield: 86%), which was used in the next step directly.
  • MS: m/z 470.1 [M + H] + .
  • Example 1 4-((l-(4-(3-Oxo-9-phenyl-2,3-dihydro-[l,2,4]triazolo[3,4- f] [ 1 ,6]naphthyridin-8-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Example 2 4-(4-(4-(3-Oxo-9-phenyl-2,3-dihydro-[l,2,4]triazolo[3,4- f] [ 1 ,6]naphthyridin-8-yl)benzyl)piperazin- 1 -yl)pyrimidine-2-carbonitrile
  • Example 3 4-((l-(4-(5-Oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile
  • Example 4 4-(4-(4-(5-Oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperazin-l-yl)pyrimidine-2-carbonitrile
  • Example 5 4-(4-(4-(6-Phenyl-l J H-imidazo[4,5-g]quinoxalin-7-yl)benzyl)piperazin-l- yl)pyrimidine-2-carbonitrile
  • Example 7 2-(4-((4-((2-Cyanopyrimidin-4-yl)amino)piperidin-l-yl)methyl)phenyl)-3- phenylimidazo[l,2-b]pyridazine-6-carboxamide
  • Example 8 2-(4-((4-(2-Cyanopyrimidin-4-yl)piperazin-l-yl)methyl)phenyl)-3- phenylimidazo[l,2-b]pyridazine-6-carboxamide
  • Example 10 4-(4-(4-(3-Phenylimidazo[l,2-b]pyridazin-2-yl)benzyl)piperazin-l- yl)pyrimidine-2-carbonitrile
  • Example 11 3-Methoxy-4-((l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)amino)cy cl obut-3-ene- 1,2-dione
  • Step 1 tert-Butyl (l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2-yl)benzyl)piperidin-4- yl)carbamate
  • a solution of Intermediate 6 (116 mg, 334 pmol) and tert-butyl piperidin-4-ylcarbamate (80.4 mg, 401 pmol) in DMF (3 mL) were added Nal (10.0 mg, 66.9 pmol) and K2CO3 (231 mg, 1.67 mmol). The mixture was stirred at 25 °C for 16 hr.
  • Step 2 2-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-3-phenyl-l,6-naphthyridin-5(6rt)-one
  • tert-butyl l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)carbamate (120 mg, 235 pmol) in 1,4-dioxane (1 mL) was added HC1 in 1,4-dioxane (2 M,5 mL). The mixture was stirred at 25 °C for 0.5 hr.
  • Step 3 3-Methoxy-4-((l-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)amino)cy cl obut-3-ene- 1,2-dione
  • Example 17 A-(l-(4-(5-Oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperidin-4-yl)acrylamide
  • Step 1 tert-Butyl 2-(4-(6-carbamoyl-3-phenylimidazo[l,2-Z>]pyridazin-2-yl)benzyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate
  • Example 19 4-((l-(4-(3-Phenylquinoxalin-2-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile
  • Example 20 2-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenyl- l,6-naphthyridin-5(6J7)-one
  • Step 1 tert-Butyl 2-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2-yl)benzyl)-2,7- diazaspiro[3.5]nonane-7-carboxylate
  • Step 3 2-(4-((7-Acryloyl-2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-3-phenyl-l,6- naphthyridin-5(6J7)-one
  • Step 1 2-(4-(((tert-Butyldimethylsilyl)oxy)methyl)phenyl)-A-methyl-3-phenylimidazo[l,2- Z>]pyridazine-6-carboxamide
  • Step 3 2-(4-(Chloromethyl)phenyl)-7V-methyl-3-phenylimidazo[l,2-Z>]pyridazine-6-carboxamide
  • 2-(4-(hydroxymethyl)phenyl)-7V-methyl-3-phenylimidazo[l,2-Z>]pyridazine-6- carboxamide 378 mg, 1.06 mmol
  • CH2Q2 4 mL
  • SOCI2 (1 mL)
  • the reaction mixture was stirred at 25 °C for 1 hr.
  • the reaction mixture was concentrated under reduced pressure to give the title compound (210 mg, yield: 53% for three steps) as a yellow solid, which was used directly in the next step.
  • MS: m/z 377.0, 378.9 [M + H] + .
  • Step 4 2-(4-((4-((2-Cyanopyrimidin-4-yl)amino)piperidin-l-yl)methyl)phenyl)-A-methyl-3- phenylimidazo[l,2-Z>]pyridazine-6-carboxamide
  • Example 27 2-Hydroxy-4-(4-(4-(5-oxo-3-phenyl-5,6-dihydro-l,6-naphthyridin-2- yl)benzyl)piperazin-l-yl)benzaldehyde

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Abstract

L'invention concerne des inhibiteurs d'AKT1, des compositions pharmaceutiques comprenant les composés inhibiteurs, et des méthodes d'utilisation des composés inhibiteurs d'AKT1 pour le traitement d'une maladie.
PCT/US2025/021322 2024-03-27 2025-03-25 Modulateurs d'akt1 Pending WO2025207620A1 (fr)

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US202463715372P 2024-11-01 2024-11-01
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Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2511231A (en) * 1949-03-26 1950-06-13 Eastman Kodak Co 1-cyanophenyl-3-acylamino-5-pyrazolone couplers for color photography
EP0453210A2 (fr) * 1990-04-19 1991-10-23 Zeneca Limited Derivés de pyridine
EP0591891A2 (fr) * 1992-10-06 1994-04-13 Dr. Karl Thomae GmbH Dérivés de benzimidazole comme antagonistes de l'angiotensine II
US20040102360A1 (en) * 2002-10-30 2004-05-27 Barnett Stanley F. Combination therapy
WO2009148887A1 (fr) * 2008-06-03 2009-12-10 Merck & Co., Inc. Inhibiteurs de l'activité akt
WO2010104933A1 (fr) * 2009-03-11 2010-09-16 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
WO2011082270A2 (fr) * 2009-12-30 2011-07-07 Arqule. Inc. Composés imidazopyridinyl-aminopyridine substitués
WO2012168315A1 (fr) * 2011-06-09 2012-12-13 Boehringer Ingelheim International Gmbh Pipéridines substituées à titre de modulateurs de gpr119 pour le traitement des troubles métaboliques
WO2015048567A1 (fr) * 2013-09-26 2015-04-02 Sanford-Burnham Medical Research Institute Modulateurs ebi2 spirocycliques
EP3091016A1 (fr) * 2015-05-05 2016-11-09 Technische Universität Dortmund Inhibiteurs de kinase et leur utilisation dans la thérapie du cancer
WO2018226794A1 (fr) * 2017-06-06 2018-12-13 Cornell University Inhibiteurs covalents spécifiques de l'isozyme akt dérivés de lipides de signalisation redox
WO2021102359A2 (fr) * 2019-11-22 2021-05-27 The Regents Of The University Of California Inhibiteurs de taspase1 et leurs utilisations
WO2022206939A1 (fr) * 2021-04-03 2022-10-06 海南耀臻生物医药科技有限公司 Composé hétérocyclique servant d'inhibiteur de fgfr et son application

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2511231A (en) * 1949-03-26 1950-06-13 Eastman Kodak Co 1-cyanophenyl-3-acylamino-5-pyrazolone couplers for color photography
EP0453210A2 (fr) * 1990-04-19 1991-10-23 Zeneca Limited Derivés de pyridine
EP0591891A2 (fr) * 1992-10-06 1994-04-13 Dr. Karl Thomae GmbH Dérivés de benzimidazole comme antagonistes de l'angiotensine II
US20040102360A1 (en) * 2002-10-30 2004-05-27 Barnett Stanley F. Combination therapy
WO2009148887A1 (fr) * 2008-06-03 2009-12-10 Merck & Co., Inc. Inhibiteurs de l'activité akt
WO2010104933A1 (fr) * 2009-03-11 2010-09-16 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
WO2011082270A2 (fr) * 2009-12-30 2011-07-07 Arqule. Inc. Composés imidazopyridinyl-aminopyridine substitués
WO2012168315A1 (fr) * 2011-06-09 2012-12-13 Boehringer Ingelheim International Gmbh Pipéridines substituées à titre de modulateurs de gpr119 pour le traitement des troubles métaboliques
WO2015048567A1 (fr) * 2013-09-26 2015-04-02 Sanford-Burnham Medical Research Institute Modulateurs ebi2 spirocycliques
EP3091016A1 (fr) * 2015-05-05 2016-11-09 Technische Universität Dortmund Inhibiteurs de kinase et leur utilisation dans la thérapie du cancer
WO2018226794A1 (fr) * 2017-06-06 2018-12-13 Cornell University Inhibiteurs covalents spécifiques de l'isozyme akt dérivés de lipides de signalisation redox
WO2021102359A2 (fr) * 2019-11-22 2021-05-27 The Regents Of The University Of California Inhibiteurs de taspase1 et leurs utilisations
WO2022206939A1 (fr) * 2021-04-03 2022-10-06 海南耀臻生物医药科技有限公司 Composé hétérocyclique servant d'inhibiteur de fgfr et son application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ITO, M. ET AL.: "Discovery of 3-Benzyl-1-(trans-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors", J. MED. CHEM., vol. 61, 2018, pages 7710 - 7728, XP055618079, DOI: 10.1021/acs.jmedchem.8b00683 *
WINN, M ET AL.: "2-(Alkylamino) nicotinic acid and analogs. Potent angiotensin II antagonists", JOURNAL OF MEDICINAL CHEMISTRY, vol. 36, no. 18, 1993, pages 2676 - 2688, XP002281129, DOI: 10.1021/jm00070a012 *

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