WO2024054512A1 - Akt1 modulators - Google Patents

Akt1 modulators Download PDF

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Publication number
WO2024054512A1
WO2024054512A1 PCT/US2023/032104 US2023032104W WO2024054512A1 WO 2024054512 A1 WO2024054512 A1 WO 2024054512A1 US 2023032104 W US2023032104 W US 2023032104W WO 2024054512 A1 WO2024054512 A1 WO 2024054512A1
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phenyl
optionally substituted
pyridin
pharmaceutically acceptable
imidazo
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PCT/US2023/032104
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French (fr)
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Michael David Bartberger
Elena V. DNEPROVSKAIA
Yi Fan
Eric Anthony MURPHY
Xuefeng Zhu
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Alterome Therapeutics, Inc.
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Publication of WO2024054512A1 publication Critical patent/WO2024054512A1/en

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    • 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
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/10—Spiro-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
    • 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 or solvate thereof: wherein:
  • G is O or CR 4 R 5 ;
  • Z 1 is N, C-H, or C-R 9 ;
  • Z 2 is N, C-H, or C-R 3 ;
  • X 1 is O or S
  • X 2 is O or S
  • X 3 is a bond, O, S, N-R 7 ;
  • R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl
  • R 3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;
  • R 4 and R 5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R 4 and R 5 together form an oxo; or R 4 and R 5 join together to form a carbocycle or heterocycle;
  • R 6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R 6 is absent and X 3 and L join together to form a heterocycle;
  • R 7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R 6 and R 7 join together to form a heterocycle;
  • L is selected from -N(R 8 )-, or a divalent radical selected from:
  • R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R 8 and R 6 join to form a ring; or optionally R 8 and R 7 join to form a ring;
  • R 9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
  • One embodiment provides a compound having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof: wherein:
  • G is O or CR 4 R 5 ;
  • Z 1 is N, C-H, or C-R 9 ;
  • Z 2 is N, C-H, or C-R 3 ;
  • X 1 is O or S
  • X 2 is O or S
  • X 3 is a bond, O, S, N-R 7 ;
  • R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;
  • R 4 and R 5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R 4 and R 5 together form an oxo; or R 4 and R 5 join together to form a carbocycle or heterocycle;
  • R 6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R 6 is absent and X 3 and L join together to form a heterocycle;
  • R 7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R 6 and R 7 join together to form a heterocycle;
  • L is selected from -N(R 8 )-, or a divalent radical selected from:
  • R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R 8 and R 6 join to form a ring; or optionally R 8 and R 7 join to form a ring;
  • R 9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate 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 or solvate 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., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., Ci-Cu 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., Ci- C4 alkyl).
  • an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 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 ( /-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, trimethyl silanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O)tR a (
  • an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. 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 (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-1, 4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-l-enyl i.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, trimethyl silanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O)tR a
  • 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.,
  • an alkylene comprises one to three carbon atoms (e.g.,
  • an alkylene comprises one to two carbon atoms (e.g.,
  • an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, 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., C2-C5 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) 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),
  • alkenylene or " alkenyl ene 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., C5-C8 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 , -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), -
  • 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., Ci 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 , -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),
  • 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) rr-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 alkenyl ene 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 (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds).
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.”
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, 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 -0R 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(0)R a , -R b -C(O)OR a , -R b -C(0)N(R a ) 2 , -R b -0-R c -C(0)N(R a ) 2 ,
  • 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.
  • 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, l-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • 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.
  • 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 -
  • A-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, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Huckel 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[6][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 a
  • -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 heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula - O-R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or US')-. 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 bothE 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 toE 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.
  • carboxylic acid bioisostere refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety.
  • Examples of carboxylic acid bioisosteres include, but are not limited to,
  • 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, U C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N , 16 N , 16 0 17Q 14p, 15p, 16p, 17p, 18p, 33 g, 34g, 35 g, 36g, 35Q, 37Q, 79 Br , 81g r 125j are al J contemplated.
  • isotopic substitution with 18 F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • 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.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W ; Varma, Rajender S The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [0056] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • CD3I iodomethane-dj
  • LiAlD4 lithium aluminum deuteride
  • Deuterium gas and palladium catalyst are employed to reduce unsaturated carboncarbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
  • the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 'H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the AKT1 inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • Acid addition salts ofbasic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, -methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.
  • subject or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treatment or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
  • the 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 also known as protein kinase B (PKB)
  • PPKB protein kinase B
  • AKT1, AKT2, and AKT3 is a serine/threonine protein kinase with three isoforms, AKT1, AKT2, and AKT3. While the isoforms are encoded by different genes, they are highly homologous at the protein level and share a conserved domain structure comprising an N-terminal pleckstrin homology (PH) domain, a kinase domain, and a C-terminal regulatory domain comprising a hydrophobic moiety, which includes the regulatory serine residue (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).
  • PH N-terminal pleckstrin homology
  • AKT proteins play a crucial role in major cellular functions including cell cycle progression, cell size, regulation of glucose metabolism, transcription, protein synthesis, genome stability, and neovascularization. AKT proteins can block apoptosis by inactivation of pro- apoptotic proteins, and mediate cellular growth factors, promoting cell survival. AKT is a major downstream effector of nuclear factor-kappaB (NficB), which may link AKT signaling to the nucleus of a cell.
  • NficB nuclear factor-kappaB
  • AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin- responsive tissues, and AKT3 is primarily expressed in brain and testes.
  • a shared phosphorylation site of AKT in the catalytic domain corresponds to a threonine residue; specifically, Thr308 in AKT1, Thr309 in AKT2, and Thr305 in AKT3.
  • a shared phosphorylation site in the C-terminus of the protein c is a serine residue; specifically, Ser473 in AKT1, Ser474 in AKT2, and Ser472 in AKT3.
  • AKT is a key downstream mediator of the phosphoinositide-3 -kinase (PI3K) signaling pathway.
  • PI3Ks are activated by different compounds.
  • PI3Ka, PI3KP, and PI3K8 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).
  • mTOR is a key component in the AKT signaling pathway, which is a downstream member of AKT and important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) to form mTOR complex 2 (mT0RC2), which can directly phosphorylate AKT Ser473. AKT can affect cell survival and growth because it can influence the tuberous sclerosis complex (TSC) 1/2 along the mTORC signaling pathway and inhibit pro-apoptotic proteins or signals.
  • TSC tuberous sclerosis complex
  • 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).
  • Malfunction and mis-regulation of AKT may lead to cancers such as but not limited to breast cancer, gastric carcinoma, glioblastoma, gliosarcomas, head and neck squamous cell carcinoma, ovarian cancer, pancreatic cancer, and prostate cancer.
  • 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
  • the E17K mutation enhances migration of breast cancer cells, and also enhances resistance to chemotherapeutic drugs. However, the E17K mutation can also selectively destroy chemo-resistant tumor-promoting AKT1 quiescent cancer cells, suggesting that the AKT1(E17K) mutation is crucial in the oncogenic/anti-tumor mechanism.
  • 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 [0083] Most AKT inhibitors targeting the ATP binding site are non-selective against the three isoforms, as well as having poor to no selectivity against other structurally similar kinases. Thus, there remains a need to develop new and novel AKT inhibitors. 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 has 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.
  • AKT1 inhibitory compound is provided herein.
  • One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein:
  • G is O or CR 4 R 5 ;
  • Z 1 is N, C-H, or C-R 9 ;
  • Z 2 is N, C-H, or C-R 3 ;
  • X 1 is O or S
  • X 2 is O or S
  • X 3 is a bond, O, S, N-R 7 ;
  • R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;
  • R 4 and R 5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R 4 and R 5 together form an oxo; or R 4 and R 5 join together to form a carbocycle or heterocycle;
  • R 6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R 6 is absent and X 3 and L join together to form a heterocycle;
  • R 7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R 6 and R 7 join together to form a heterocycle;
  • L is selected from -N(R 8 )-, or a divalent radical selected from:
  • R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R 8 and R 6 join to form a ring; or optionally R 8 and R 7 join to form a ring;
  • R 9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
  • One embodiment provides a compound having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof: wherein:
  • G is O or CR 4 R 5 ;
  • Z 1 is N, C-H, or C-R 9 ;
  • Z 2 is N, C-H, or C-R 3 ;
  • X 1 is O or S
  • X 2 is O or S
  • X 3 is a bond, O, S, N-R 7 ;
  • R 1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;
  • R 4 and R 5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R 4 and R 5 together form an oxo; or R 4 and R 5 join together to form a carbocycle or heterocycle;
  • R 6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R 6 is absent and X 3 and L join together to form a heterocycle;
  • R 7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R 6 and R 7 join together to form a heterocycle;
  • L is selected from -N(R 8 )-, or a divalent radical selected from: wherein the asterisk (*) indicates the bond to the squaric acid group;
  • R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R 8 and R 6 join to form a ring; or optionally R 8 and R 7 join to form a ring;
  • R 9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein G is O.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein G is CR 4 R 5 .
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is N.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is C-H.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is C-R 3
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X 1 is O.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X 1 is S.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X 2 is O. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X 2 is O [0093] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X 3 is a bond. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X 3 is O. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X 3 is S. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X 3 is N-R 7 .
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted heteroaryl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridyl. [0095] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted aryl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 4 is hydrogen.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 5 is hydrogen.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 4 and R 5 together form an oxo.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 6 is hydrogen. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 6 is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 6 is optionally substituted C3- C7 cycloalkyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 6 is optionally substituted heterocyclyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 6 is absent and X 3 and L join together to form a heterocycle.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 7 is selected from hydrogen, or optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 6 and R 7 join together to form a heterocycle.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is -N(R 8 )-.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from: [00107] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
  • [00112] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 8 is hydrogen or optionally substituted C1-C6 alkyl.
  • One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.
  • Another embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2.
  • 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, “Modem 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.
  • the AKT1 inhibitory compound described herein is administered as a pure chemical.
  • the AKT1 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • 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), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the AKT1 inhibitory compound as described by Formula (I), or a pharmaceutically acceptable salt or solvate 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 Table 2, or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the AKT1 inhibitory compound as described by Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate 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)).
  • the AKT1 inhibitory compound as described by Formula (I) or Table 1 or Table 2, or pharmaceutically acceptable salt or solvate thereof is formulated for administration by injection.
  • the injection formulation is an aqueous formulation.
  • the injection formulation is a non-aqueous formulation.
  • the injection formulation is an oil-based formulation, such as sesame oil, or the like.
  • the dose of the composition comprising at least one AKT1 inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.
  • 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.
  • Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
  • One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
  • a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
  • One embodiment provides a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a use of a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
  • a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof
  • a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • Provided herein is the method wherein the pharmaceutical composition is administered orally.
  • the method wherein the pharmaceutical composition is administered by injection.
  • One embodiment provides a method of inhibiting a AKT1 enzyme comprising contacting the AKT1 enzyme with a compound of Formula (I) or Table 1 or Table 2. Another embodiment provides the method of inhibiting a AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vivo setting. Another embodiment provides the method of inhibiting a AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vitro setting.
  • 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: ACN acetonitrile
  • NMR nuclear magnetic resonance pH potential of hydrogen a measure of the acidity or basicity of an aqueous solution
  • Step 1 Zc'/'Z-Butyl 4-((3-nitropyridin-2-yl)amino)benzylcarbamate
  • Step 2 Zez'Z-Butyl 4-(2-(2-aminopyridin-3-yl)-3/7-imidazo[4,5-b]pyridin-3- yl)benzylcarbamate
  • Step 3 3-(3-(4-(Aminomethyl)phenyl)-377-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • tert-butyl A-[[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate (350 mg, 840 pmol) in 1,4-dioxane (3 mL) was added 4 M HC1 in 1,4-dioxane (1 mL) at 20 °C. The mixture was stirred at 20°C for 2 hr.
  • the reaction was concentrated under reduced pressure to give a crude product (280 mg, HC1 salt, yield: 95%).
  • the crude was purified by prep-HPLC (Column: Phenomenex luna C18 150 x 25 mm x 10 pm; Condition: water (HCl)-ACN; Begin B: 0; End B: 16; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (mL/min): 25) to give the product (HC1 salt).
  • the product was diluted with 10 mL aqueous NaHCCh and extracted with DCM (10 mL x 3).
  • Step 1 tert-Butyl 4-(4-nitrobenzyl)piperazine-l -carboxylate
  • Step 2 tert-Butyl 4-(4-aminobenzyl)piperazine-l -carboxyl ate
  • Step 3 tert-Butyl 4-(4-((3-nitropyridin-2-yl)amino)benzyl)piperazine-l-carboxylate
  • 2-chl oro-3 -nitro-pyridine 10 g, 63 mmol
  • DMSO 200 mL
  • tert-butyl 4-(4-aminobenzyl)piperazine-l-carboxylate 15.3 g, 52.5 mmol
  • DIEA (13.5 g, 105 mmol
  • Step 4 tert-Butyl 4-(4-(2-(2-Aminopyridin-3 -yl)-3//-imidazo[4, 5-b]pyri din-3 - yl)benzyl)piperazine-l -carboxylate
  • Step 5 3-(3-(4-(Piperazin-l-ylmethyl)phenyl)-3J/-imidazo[4,5-b]pyridin-2-yl)pyridin- 2-amine
  • Step 1 ZezZ-Butyl (l-(4-nitrobenzyl) piperidin-4-yl) carbamate
  • Step 2 tert-Butyl (l-(4-aminobenzyl) piperidin-4-yl) carbamate
  • Step 3 tert-Butyl (l-(4-((3-nitropyri din-2 -yl) amino)benzyl)piperidin-4-yl)carbamate
  • tert-butyl (l-(4-aminobenzyl) piperidin-4-yl) carbamate (30 g, 98.2 mmol) in DMSO (500 mL) were added DIEA (38.1 g, 295 mmol) and 2-chloro-3 -nitro-pyridine (18.7 g, 118 mmol). The mixture was stirred at 100 °C for 16 hr.
  • Step 4 tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-3B-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)carbamate
  • Step 5 3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-3/f-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • Step 1 tert-Butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)benzylcarbamate
  • Step 2 tert-Butyl 7V-[[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
  • Step 3 tert-Butyl A-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
  • Step 4 3-(3-(4-(Aminomethyl)phenyl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • the crude was purified by prep-HPLC (column: Welch Xtimate Cl 8 150 x 25mm x 5 pm; mobile phase: [water (HC1) - ACN]; B%: 5% - 35%, 8min) to give the desired product (HC1 salt).
  • the product was diluted with aqueous NaHCCh (10 mL) and extracted with DCM (10 mL x 3).
  • Step 1 tert-Butyl 4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3//-imidazo[4,5- b]pyri din-3 -yl)benzylcarbamate
  • the mixture was degassed and purged with N2 three times and then stirred at 80 °C for 16 hr under N2 atmosphere.
  • the reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with EtOAc (50 mL x 3).
  • Step 2 A-(3-(3-(4-(Aminomethyl)phenyl)-2-(2-aminopyridin-3-yl)-3/ imidazo[4,5- b]pyridin-5-yl)phenyl)acetamide
  • Step 1 Zc/7-Butyl 4-(4-((6-(3-Acetamidophenyl)-3-nitropyridin-2- yl)amino)benzyl)piperazine- 1 -carboxylate
  • the mixture was degassed and purged with N2 three times and stirred at 60 °C for 16 hr under N2 atmosphere.
  • the reaction mixture was quenched H2O (200 mL) at 25 °C and extracted with CH2Q2 (60 mL x 3).
  • the combined organic layers were washed with brine (100 mL x 2), dried over Na2SC>4, fdtered, and concentrated under reduced pressure.
  • Step 2 zc/7-Butyl 4-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-377- imidazo[4,5-b]pyri din-3 -yl)benzyl)piperazine-l -carboxylate
  • Step 3 A r -(3-(2-(2-Aminopyridin-3-yl)-3-(4-(piperazin-l-ylmethyl)phenyl)-3//- imidazo[4,5-b]pyri din-5 -yl)phenyl)acetamide
  • Step 1 fert-Butyl jV-[[4-[(5-bromo-3-nitro-2-pyridyl)amino]phenyl]methyl]carbamate
  • 5-bromo-2-chloro-3-nitro-pyridine 2.1 g, 9.0 mmol
  • tert-butyl N- [(4-aminophenyl)methyl]carbamate 2 g, 9.0 mmol
  • DIEA 3.5 g, 27.0 mmol
  • Step 2 tert-Butyl 7V-[[4-[2-(2-amino-3-pyridyl)-6-bromo-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
  • Step 3 tert-Butyl A-[[4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
  • Step 4 3-[3-[4-(Aminomethyl)phenyl]-6-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2- amine
  • Step 1 Zc'/'Z-Butyl 4-(4-((5-bromo-3-nitropyridin-2-yl)amino)benzyl)piperazine-l- carboxylate
  • Step 2 Zcz'Z-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-6-bromo-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazine-l -carboxylate
  • tert-butyl 4-[[4-[(5-bromo-3-nitro-2- pyridyl)amino]phenyl]methyl]piperazine-l -carboxylate (10.7 g, 21.6 mmol) in DMSO (60 m ) and methanol (30 m ) were added 2-aminopyridine-3-carbaldehyde (3.2 g, 26 mmol) and NazSzOr (7.5 g, 43.3 mmol).
  • Step 3 tert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-6-phenyl-37T-imidazo[4,5-b]pyridin- 3 -yl)benzyl)piperazine- 1 -carboxylate
  • the mixture was degassed and purged with Nz three times and stirred at 80°C for 16 hr under Nz atmosphere. After cooling to 25°C, the reaction mixture was poured into HzO (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3).
  • Step 4 3-(6-Phenyl-3-(4-(piperazin-l-ylmethyl)phenyl)-3//-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • Step 1 ZezZ-Butyl A-[l-[[4-[(5-bromo-3-nitro-2-pyridyl)amino]phenyl]methyl]-4- piperidyl]carbamate
  • Step 2 tert-Butyl A-[l-[[4-[(3-nitro-5-phenyl-2-pyridyl)amino]phenyl]methyl]-4- piperidyl]carbamate
  • Step 4 3-[3-[4-[(4-Amino-l-piperidyl)methyl]phenyl]-6-phenyl-imidazo[4,5- b]pyri din-2 -yl]pyridin-2-amine
  • Step 1 tert-Butyl 4-[[4-[(6-chloro-3-nitro-2-pyridyl)amino]phenyl]methyl]piperazine- 1 -carboxylate
  • Step 3 tert-Butyl 4-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]piperazine- 1 -carboxylate
  • Step 4 3-[5-Phenyl-3-[4-(piperazin-l-ylmethyl)phenyl]imidazo[4,5-b]pyridin-2- yl]pyridin-2-amine
  • Step 1 tert-Butyl (l-(4-((6-chloro-3-nitropyridin-2-yl)amino)benzyl)piperidin-4- yl)carbamate
  • Step 2 tert-Butyl (l-(4-((3-nitro-6-phenylpyridin-2-yl)amino)benzyl)piperidin-4- yl)carbamate
  • Step 3 Zc/7-Butyl (l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl) carbamate
  • Step 4 3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
  • Step 1 tert-Butyl (l-(4-((6-(3-acetamidophenyl)-3-nitropyridin-2- yl)amino)benzyl)piperidin-4-yl)carbamate
  • reaction mixture was diluted with H2O (50 mL) and extracted with CH CI2 (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over ISfeSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 ⁇ 5% MeOH in CH2CI2) to give tertbutyl A-[l-[[4-[[6-(3-acetamidophenyl)-3-nitro-2-pyridyl]amino]phenyl]methyl]-4- piperidyl]carbamate (1.04 g, yield: 86%) as an orange solid.
  • Step 3 A-(3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-2-(2-aminopyridin-3-yl)- 3H-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
  • Step 1 Methyl 4-((6-chloro-3-nitropyridin-2-yl)amino)benzoate
  • Step 2 Methyl 4-((3-nitro-6-phenylpyridin-2-yl)amino)benzoate
  • Step 3 Methyl 4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzoate
  • Step 1 (4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
  • Step 2 3-(3-(4-(Chloromethyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • Step 1 Zc/'Z-Butyl 6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-
  • Step 2 3-(3-(4-((2,6-Diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-5-phenyl-3J7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 tert-Butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.4]octane-6-carboxylate
  • Step 2 3-(3-(4-((2,6-Diazaspiro[3.4]octan-2-yl)methyl)phenyl)-5-phenyl-3JT- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 ZcvZ-Butyl 4-((2 -hydroxy ethyl)amino)piperi dine- 1 -carboxylate)
  • Step 2 Ze/'Z-Butyl 4-(((benzyloxy)carbonyl)(2-hydroxyethyl)amino)piperidine-l- carboxylate) [00273] To a solution of tert-butyl 4-(2-hydroxyethylamino)piperidine-l -carboxylate (1.0 g, 4.09 mmol) and TEA (828 mg, 8.2 mmol) in CH2Q2 (10 m ) was added CbzCl (698 mg, 4.09 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 hr.
  • Step 1 (7?)-tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)carbamate
  • Step 2 (R)-3-(3-(4-((3-Aminopyrrolidin-l-yl)methyl)phenyl)-5-phenyl-3//- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
  • Step 1 Zc/7-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3 -yl)benzyl)azeti din-3 -yl)carb mate
  • Step 2 3-(3-(4-((3-Aminoazetidin-l-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
  • tert-butyl l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- b]pyridin-3-yl)benzyl)azetidin-3-yl)carbamate (60 mg, 109 pmol) in CH2Q2 (2 m ) was added TFA (770 mg, 6.75 mmol).
  • Step 1 tert-Butyl (2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2-azaspiro[4.5]decan-8-yl)carbamate
  • Step 2 2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-azaspiro[4.5]decan-8-amine
  • Step 1 tert-Butyl 7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
  • Step 2 3-(3-(4-((2,7-Diazaspiro[3.5]nonan-7-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 tert-Butyl 8-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decane-2-carboxylate
  • Step 2 3-(3-(4-((2,8-Diazaspiro[4.5]decan-8-yl)methyl)phenyl)-5-phenyl-3//- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 tert-Butyl 6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.4]octane-2-carboxylate
  • Step 2 3-(3-(4-((2,6-Diazaspiro[3.4]octan-6-yl)methyl)phenyl)-5-phenyl-3/f- imidazo[4,5-Z>]pyridin-2-yl)pyridin-2-amine
  • Step 1 tert-Butyl 7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin- 3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
  • Step 2 3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-6]pyridin-2-yl)pyridin-2-amine
  • Step 1 Zcz'Z-Butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin- 3-yl)benzyl)-2,7-diazaspiro[4.5]decane-7-carboxylate
  • Step 2 3-(3-(4-((2,7-Diazaspiro[4.5]decan-2-yl)methyl)phenyl)-5-phenyl-3Z/- imidazo[4,5-6]pyridin-2-yl)pyridin-2-amine
  • Step 1 Zcz'Z-Butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37T-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate
  • Step 2 3-(3-(4-((2,7-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 tert-Butyl (R)-7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
  • Step 2 (R)-3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 tert-Butyl 5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate
  • Step 2 3-(3-(4-((2,5-Diazabicyclo[2.2.2]octan-2-yl)methyl)phenyl)-5-phenyl-3 T- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 tert-butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-/>]pyridin-3- yl)benzyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate
  • Step 2 3-(3-(4-((2,6-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
  • Step 1 tert-Butyl (S)-7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
  • Step 2 (S)-3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl-3 /- imidazo[4,5-Z>]pyridin-2-yl)pyridin-2-amine
  • Step 1 (7?)-fert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-methylpiperazine-l -carboxylate
  • Step 2 (7?)-3-(3-(4-((3-Methylpiperazin-l-yl)methyl)phenyl)-5-phenyl-377- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
  • Step 1 (2A',6/?)-te/7-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,6-dimethylpiperazine-l -carboxylate
  • Step 2 3-(3-(4-(((3S,57?)-3,5-Dimethylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3/f- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 ZerZ-Butyl (2A,67?)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2,6-dimethylpiperazine-l -carboxylate
  • Step 2 3-(3-(4-(((37?,5A)-3,5-Dimethylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3ZZ- imidazo[4,5-6]pyridin-2-yl)pyridin-2-amine
  • Step 1 terLButyl (2S,6S)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3. -imidazo[4,5- b]pyridin-3-yl)benzyl)-2,6-dimethylpiperazine-l -carboxylate
  • Step 2 3-(3-(4-(((3S,5S)-3,5-Dimethylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3rt- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 tert-Butyl 8-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate
  • Step 2 3-(3-(4-((3,8-Diazabicyclo[3.2.1]octan-8-yl)methyl)phenyl)-5-phenyl-3JT- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 tert-Butyl 3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 3-(3-(4-((3,8-Diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)-5-phenyl-3 T- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
  • Step 1 tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-6]pyridin- 3-yl)benzyl)azepan-4-yl)carbamate
  • Step 2 l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5-Z>]pyridin-3- yl)benzyl)azepan-4-amine
  • Step 1 tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-6]pyridin- 3 -yl)benzyl)azepan-3 -yl)carbamate
  • Step 2 l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-Z>]pyridin-3- yl)benzyl)azepan-3 -amine
  • Step 1 tert-Butyl (lS,4S)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 2 3-(3-(4-(((lS,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)methyl)phenyl)-5- phenyl-3//-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine
  • Step 1 tert-Butyl (lR,4R)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 2 3-(3-(4-(((lR,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)methyl)phenyl)-5- phenyl-3//-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine
  • Step 1 tert-Butyl 4-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-327-imidazo[4,5-b]pyridin- 3-yl)benzyl)amino)piperidine-l -carboxylate
  • Step 2 3-(5-Phenyl-3-(4-((piperidin-4-ylamino)methyl)phenyl)-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
  • Step 2 3-(5-Phenyl-3-(4-((piperidin-4-yloxy)methyl)phenyl)-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
  • Step 1 Ze/7-Butyl (A)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-(hydroxymethyl)piperazine-l -carboxylate
  • Step 2 (7?)-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-2-yl)methanol
  • Step 1 tert-Butyl (5)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2-(hydroxymethyl)piperazine-l -carboxylate
  • Step 2 (S)-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-2-yl)methanol
  • Step I Zc/Z-Butyl (S)-(l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)(methyl)carbamate
  • Step 2 (S)-3-(3-(4-((3-(Methylamino)pyrrolidin-l-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
  • the mixture was duilted with H2O (5 mL).
  • the pH of the mixture was adjusted to about 8 with NaHCCh (aq) and the mixture was extrated with CH2CI2 (10 mL x 2).
  • the combined organic layers were washed with brine (10 mL x 2), dried over N 2SO4, filtered and concentrated under reduced pressure.
  • Step 1 /c/7-Butyl (4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3 -yl)benzyl)piperazin- 1 -yl)carb amate
  • Step 2 4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-Z>]pyridin-3- yl)benzyl)piperazin- 1 -amine
  • Step 1 tert-Butyl (3aA,6aS)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(l//)-carboxylate
  • Step 2 3-(3-(4-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(17/)-yl)methyl)phenyl)- 5-phenyl-32/-imidazo[4,5-/>]pyridin-2-yl)pyridin-2-amine
  • Step 1 4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3-yl)-?7- methoxy-JV-methy lb enzami de
  • Step 2 l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3ff-imidazo[4,5-b]pyridin-3- yl)phenyl)ethan- 1 -one
  • Step 3 l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5-b]pyridin-3- yl)phenyl)ethan- 1 -ol
  • Step 4 3-(3-(4-(l-Chloroethyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • Step 5 Zc/7-Butyl (l-(l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)phenyl)ethyl)piperidin-4-yl)(methyl)carbamate
  • Step 6 3-(3-(4-(l-(4-(Methylamino)piperidin-l-yl)ethyl)phenyl)-5-phenyl-3Zf- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3 /-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)(ethyl)carbamate
  • Step 2 3-(3-(4-((4-(Ethylamino)piperidin-l-yl)methyl)phenyl)-5-phenyl-3Z7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 Benzyl 4-(cyclopropylamino)piperidine-l-carboxylate
  • Step 2 Benzyl 4-((tert-butoxycarbonyl)(cyclopropyl)amino)piperidine-l -carboxylate
  • benzyl 4-(cyclopropylamino)piperidine-l -carboxylate 580 mg, 2.11 mmol
  • THF 10 mL
  • H2O 5 rnL
  • Na CC 672 mg, 6.34 mmol
  • Boc)2O 554 mg, 2.54 mmol
  • Step 3 tert-Butyl cyclopropyl(piperidin-4-yl)carbamate
  • Step 4 tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin- 3-yl)benzyl)piperidin-4-yl)(cyclopropyl)carbamate
  • Step 5 3-(3-(4-((4-(Cyclopropylamino)piperidin-l-yl)methyl)phenyl)-5-phenyl-3//- imidazo[4,5-Z>]pyridin-2-yl)pyridin-2-amine
  • Step 1 Benzyl 4-((terZ-butoxycarbonyl)amino)piperazine-l -carboxylate
  • Step 2 Benzyl 4-((ter/-butoxycarbonyl)(methyl)amino)piperazine-l -carboxylate
  • benzyl 4-((tert-butoxycarbonyl)amino)piperazine-l-carboxylate 1.2 g, 3.58 mmol
  • THF 10 mb
  • NaH 429 mg, 60% purity
  • CH3I 1.02 g, 7.16 mmol
  • Step 3 tert-Butyl methyl(piperazin-l-yl)carbamate
  • Step 4 tert-Butyl (4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperazin-l-yl)(methyl)carbamate
  • Step 5 4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- y 1 )benzy I j-A-m ethy I pi perazi n- 1 -amine
  • Step 1 tert-Butyl (2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2-azaspiro[3.5]nonan-7-yl)carbamate
  • Step 2 2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-azaspiro[3.5]nonan-7-amine
  • Step 1 tert-Butyl 9-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
  • Step 2 3-(3-(4-((3,9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-5-phenyl-3J7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 2 3-(3-(4-((3,9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-5-phenyl-3J7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 1 Benzyl 4-((terZ-butoxycarbonyl)amino)piperidine-l-carboxylate
  • Step 2 Benzyl 4-((ter/-butoxycarbonyl)(methyl-d3)amino)piperidine-l -carboxylate
  • benzyl 4-(te/7-butoxycarbonylamino)piperidine- l -carboxylate 13 g, 38.9 mmol
  • NaH 4.66 g, 117 mmol
  • CD3I 16.5 g, 117 mmol
  • Step 3 ZcrZ-Butyl (methyl-d3)(piperidin-4-yl)carbamate
  • Step 4 zcz'Z-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)(methyl-d3)carbamate
  • Step 5 3-(3-(4-((4-((Methyl-d3)amino)piperidin-l-yl)methyl)phenyl)-5-phenyl-3H- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
  • Step 1 Zcrt-Butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3rt-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate
  • Step 2 3-(3-(4-((2,8-Diazaspiro[4.5]decan-2-yl)methyl)phenyl)-5-phenyl-3rt- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Example 1 3-(4-(4-(2-(2-Aminopyri din-3 -yl)-37/-imidazo[4,5-b]pyri din-3 - yl)benzyl)piperazin- 1 -yl)-4-methoxycy cl obut-3-ene- 1,2-dione
  • Example 2 3-((4-(2-(2-Aminopyridin-3-yl)-3Z7-imidazo[4,5-b]pyridin-3- yl)benzyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
  • Example 3 3-((l-(4-(2-(2-Aminopyridin-3-yl)-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
  • Example 4 3-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Zf-imidazo[4,5-b]pyridin-3- yl)benzyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
  • Example 5 3-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z7-imidazo[4,5-b]pyridin-3- yl)benzyl)amino)-4-hydroxycyclobut-3-ene-l, 2-dione
  • Example 4 To a solution of Example 4 (200 mg, 398 pmol) in EtOH (4 mL) at 0 °C was added NaOH (79.5 mg, 1.99 mmol) in H2O (2 mL) dropwise. The reaction mixture was stirred at 25 °C for 16 hr. The mixture was concentrated under reduced pressure.
  • Example 6 JV-(3-(2-(2-Aminopyridin-3-yl)-3-(4-(((2-methoxy-3,4-dioxocyclobut-l-en- l-yl)amino)methyl)phenyl)-3//-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
  • Example 7 JV-(3-(2-(2-Aminopyridin-3-yl)-3-(4-((4-(2-methoxy-3,4-dioxocyclobut-l- en-l-yl)piperazin-l-yl)methyl)phenyl)-3/7-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
  • Example 8 JV-(3-(2-(2-Aminopyridin-3-yl)-3-(4-((4-((2-methoxy-3,4-dioxocyclobut-l- en-l-yl)amino)piperidin-l-yl)methyl)phenyl)-3//-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
  • Example 9 3-(4-(4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-methoxycy cl obut-3-ene- 1,2-dione
  • Example 10 3-((l-(4-(2-(2-Aminopyridin-3-yl)-6-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
  • Example 11 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-isopropoxycy cl obut-3-ene- 1,2-dione
  • Example 12 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-ethoxycyclobut-3-ene-l, 2-dione
  • Example 13 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(methoxy-d3)cyclobut-3-ene- 1,2-dione
  • Example 14 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(cyclopentyloxy)cyclobut-3-ene-l, 2-dione
  • Example 15 2-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-3-(cyclopentyloxy)-4-thioxocyclobut-2-en-l-one
  • Example 16 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(cyclopentyloxy)cyclobut-3-ene-l,2-dithione
  • Example 17 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
  • Example 18 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-hydroxycyclobut-3-ene-l, 2-dione
  • Example 17 To a solution of Example 17 (100 mg, 170 pmol) in EtOH (1 mL) was added NaOH (20.5 mg, 512 pmol) in 0.5 mL H2O at 0 °C. The mixture was stirred at 25 °C for 16 hr. The reaction was concentrated under reduced pressure.
  • Example 19 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(dimethylamino)cyclobut-3-ene- 1,2-dione
  • Example 17 To a solution of Example 17 (50 mg, 85.4 pmol) in DMSO (0.15 m ) was added N- methylmethanamine (2 M in THF, 650 pL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure.
  • Example 20 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z7-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(methylamino)cyclobut-3-ene-l, 2-dione
  • Example 17 To a solution of Example 17 (50 mg, 85.4 pmol) in MeOH (0.5 mL) and CHCI3 (0.5 mL) was added MeNH2 (1.0 mL, 30% purity in ethanol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure.
  • Example 21 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-methoxycy cl obut-3-ene- 1,2-dione
  • Example 22 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-hydroxycyclobut-3-ene- 1,2-dione
  • Example 21 To a solution of Example 21 (200 mg, 350 pmol) in EtOH (4 mL) at 0 °C was added NaOH (42 mg, 1.05 mmol) in H2O (0.8 mL) dropwise. The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure.
  • Example 23 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-(methoxy-d3)cyclobut-3-ene-l, 2-dione
  • Example 24 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-ethoxycy cl obut-3-ene- 1,2-dione
  • Example 25 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin- 1 -yl)-4-isopropoxycyclobut-3 -ene- 1 ,2-dione
  • Example 26 3-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin- 1 -yl)-4-(cyclopentyloxy)cyclobut-3-ene- 1 ,2-dione
  • Example 27 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
  • Step 1 3-[3-[4-[[4-(methylamino)-l-piperidyl]methyl]phenyl]-5-phenyl-imidazo[4,5- b]pyridin-2-yl]pyridin-2-amine
  • Step 2 3-(3-(4-((4-(Methylamino)piperidin-l-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 3 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
  • Example 28 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzoyl)piperidin-4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
  • Step 1 4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3ff-imidazo[4,5-b]pyridin-3-yl)benzoic acid
  • Step 1 4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3ff-imidazo[4,5-b]pyridin-3-yl)benzoic acid
  • Step 2 tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3 /-imidazo[4,5-b]pyridin- 3-yl)benzoyl)piperidin-4-yl)carbamate
  • Step 3 (4-Aminopiperidin-l-yl)(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyri din-3 -yl)phenyl)m ethanone
  • Step 4 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3rt-imidazo[4,5-b]pyridin-3- yl)benzoyl)piperidin-4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
  • 4-dimethoxycy cl obut-3-ene- 1,2-dione 34.8 mg, 0.245 mmol.
  • Example 29 (S)-3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-3-yl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
  • Step 1 (S)-to7-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-3-yl)carbamate
  • Step 2 (S)-3-(3-(4-((3-Aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
  • Step 3 (S)-3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperi din-3 -yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
  • Example 30 (S)-3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyri din-3 -yl)benzyl)pyrrolidin-3-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
  • Example 31 3-(9-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,9-diazaspiro[5.5]undecan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
  • Step 1 Zc/7-Butyl 9-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-
  • Step 2 3-(3-(4-(2,9-Diazaspiro[5.5]undecan-9-ylmethyl)phenyl)-5-phenyl-37T- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 3 3-(9-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,9-diazaspiro[5.5]undecan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
  • Example 32 3-((l-(4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3Z7-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
  • Step 1 (4-((5-Bromo-3-nitropyridin-2-yl)amino)phenyl)methanol
  • Step 2 (4-((3-Nitro-5-phenylpyridin-2-yl)amino)phenyl)methanol
  • Step 3 (4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3B-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
  • Step 4 3-(3-(4-(Chloromethyl)phenyl)-6-phenyl-3Z/-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • Step 5 tert-Butyl (l-(4-(2-(2-aminopyri din-3 -yl)-6-phenyl-37/-imidazo[4, 5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)(methyl)carbamate
  • Step 6 3-(3-(4-((4-(Methylamino)piperidin-l-yl)methyl)phenyl)-6-phenyl-377- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
  • Step 7 3-((l-(4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione

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Abstract

Provided herein are inhibitors of AKT1, pharmaceutical compositions comprising the inhibitory compounds, and methods for using the AKT1 inhibitory compounds for the treatment of disease.

Description

AKT1 MODULATORS
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application No. 63/375,023 filed September 08, 2022, which is incorporated herein by reference in its entirety.
BACKGROUND
[0002] AKT is a protein kinase and mediates cell survival and proliferation by inhibiting pathways which promotes apoptosis. AKT signaling cascade dysfunction is observed in several cancer types and may be associated with tumor aggressiveness. Additionally, malfunction of AKT typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis. Pharmaceutical agents with the ability to modulate AKT1 activity would be useful in the treatment of disease, such as cancer.
BRIEF SUMMARY OF THE INVENTION
[0003] Provided herein are inhibitors of AKT1, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said inhibitory compounds for the treatment of disease.
[0004] One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000002_0001
wherein:
G is O or CR4R5;
Z1 is N, C-H, or C-R9;
Z2 is N, C-H, or C-R3;
X1 is O or S;
X2 is O or S;
X3 is a bond, O, S, N-R7;
R1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;
R4 and R5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R4 and R5 together form an oxo; or R4 and R5 join together to form a carbocycle or heterocycle;
R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R6 is absent and X3 and L join together to form a heterocycle;
R7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R6 and R7 join together to form a heterocycle;
L is selected from -N(R8)-, or a divalent radical selected from:
Figure imgf000003_0001
Figure imgf000004_0001
wherein the asterisk (*) indicates the bond to the squaric acid group;
R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R8 and R6 join to form a ring; or optionally R8 and R7 join to form a ring;
R9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
[0005] One embodiment provides a compound having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000004_0002
wherein:
G is O or CR4R5; Z1 is N, C-H, or C-R9;
Z2 is N, C-H, or C-R3;
X1 is O or S;
X2 is O or S;
X3 is a bond, O, S, N-R7;
R1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;
R4 and R5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R4 and R5 together form an oxo; or R4 and R5 join together to form a carbocycle or heterocycle;
R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R6 is absent and X3 and L join together to form a heterocycle;
R7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R6 and R7 join together to form a heterocycle;
L is selected from -N(R8)-, or a divalent radical selected from:
Figure imgf000005_0001
Figure imgf000006_0001
wherein the asterisk (*) indicates the bond to the squaric acid group;
R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R8 and R6 join to form a ring; or optionally R8 and R7 join to form a ring;
R9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
[0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. [0007] 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 or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer.
INCORPORATION BY REFERENCE
[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.
DETAILED DESCRIPTION OF THE INVENTION
[0009] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.
Definitions
[0010] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0011] " Amino" refers to the -NH2 radical.
[0012] "Cyano" refers to the -CN radical. [0013] "Nitro" refers to the -NO2 radical. [0014] " Oxa" refers to the -O- radical. [0015] "Oxo" refers to the =0 radical. [0016] " Thioxo" refers to the =S radical. [0017] " Imino" refers to the =N-H radical. [0018] " Oximo" refers to the =N-OH radical.
[0019] "Hydrazino" refers to the =N-NH2 radical.
[0020] "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., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., Ci-Cu alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., Ci- C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, 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 ( /-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethyl silanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, 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.
[0021] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
[0022] "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 (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-1, 4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethyl silanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
[0023] "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. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, 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. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
[0024] "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. In certain embodiments, 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). In other embodiments, 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., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
[0025] "Alkenylene" or " alkenyl ene 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. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, 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., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
[0026] "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. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, 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., Ci 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). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).
[0027] "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) rr-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. Unless stated otherwise specifically in the specification, the term "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, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb- OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rc substituents is unsubstituted unless otherwise indicated.
[0028] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
[0029] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenyl ene group.
[0030] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain. [0031] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula - O-Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group
[0032] "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. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "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, -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb- N(Ra)2, -Rb-C(0)Ra, -Rb-C(O)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb- S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rc substituents is unsubstituted unless otherwise indicated.
[0033] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
[0034] "Carbocyclylalkynyl" refers to a radical of the formula -Rc-carbocyclyl where Rc is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
[0035] "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, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
[0036] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.
[0038] "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). Examples of such 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-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "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, - Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb- C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rc substituents is unsubstituted unless otherwise indicated.
[0039] "A-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. [0040] " 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.
[0041] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
[0042] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the 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. [0043] "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. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Huckel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7, 8,9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1.6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 177-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7, 8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "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, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb- S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rc substituents is unsubstituted unless otherwise indicated.
[0044] " -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.
[0045] "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. [0046] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
[0047] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula - O-Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the 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.
[0048] 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 US')-. 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 bothE 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. The term “geometric isomer” refers toE or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
[0049] As used herein, “carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,
Figure imgf000019_0001
[0050] 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 presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000020_0001
[0051] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, nC, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such 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.
[0052] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure.
[0053] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, UC, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 160 17Q 14p, 15p, 16p, 17p, 18p, 33 g, 34g, 35 g, 36g, 35Q, 37Q, 79Br, 81gr 125j are alJ contemplated. In some embodiments, isotopic substitution with 18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [0054] In certain embodiments, the compounds disclosed herein have some or all of the JH atoms replaced with 2H 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.
[0055] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W ; Varma, Rajender S The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [0056] 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.
[0057] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-dj (CD3I), are readily available and may be employed to transfer a deuteriumsubstituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.
Figure imgf000021_0001
[0058] Deuterium-transfer reagents, such as lithium aluminum deuteride (Li AID4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.
Figure imgf000021_0002
[0059] Deuterium gas and palladium catalyst are employed to reduce unsaturated carboncarbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
Figure imgf000022_0001
[0060] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 'H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
[0061] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the AKT1 inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
[0062] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1- 19 (1997)). Acid addition salts ofbasic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
[0063] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, -methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra. [0064] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.
[0065] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.
[0066] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
AKT1 Protein and Function
[0067] AKT, also known as protein kinase B (PKB), is a serine/threonine protein kinase with three isoforms, AKT1, AKT2, and AKT3. While the isoforms are encoded by different genes, they are highly homologous at the protein level and share a conserved domain structure comprising an N-terminal pleckstrin homology (PH) domain, a kinase domain, and a C-terminal regulatory domain comprising a hydrophobic moiety, which includes the regulatory serine residue (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).
[0068] AKT proteins play a crucial role in major cellular functions including cell cycle progression, cell size, regulation of glucose metabolism, transcription, protein synthesis, genome stability, and neovascularization. AKT proteins can block apoptosis by inactivation of pro- apoptotic proteins, and mediate cellular growth factors, promoting cell survival. AKT is a major downstream effector of nuclear factor-kappaB (NficB), which may link AKT signaling to the nucleus of a cell.
[0069] AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin- responsive tissues, and AKT3 is primarily expressed in brain and testes. A shared phosphorylation site of AKT in the catalytic domain corresponds to a threonine residue; specifically, Thr308 in AKT1, Thr309 in AKT2, and Thr305 in AKT3. A shared phosphorylation site in the C-terminus of the protein cis a serine residue; specifically, Ser473 in AKT1, Ser474 in AKT2, and Ser472 in AKT3.
[0070] AKT is a key downstream mediator of the phosphoinositide-3 -kinase (PI3K) signaling pathway. PI3Ks are activated by different compounds. For example, PI3Ka, PI3KP, and PI3K8, are activated by extracellular ligands binding to a transmembrane glycoprotein with enzymatic activity, receptor tyrosine kinases (RTKs). In contrast, PI3Ky is activated by G-protein- compound receptors (GPCRs) and by RAS family of GTPases.
[0071] 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.
AKT1 Mechanism
[0072] 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).
[0073] mTOR is a key component in the AKT signaling pathway, which is a downstream member of AKT and important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) to form mTOR complex 2 (mT0RC2), which can directly phosphorylate AKT Ser473. AKT can affect cell survival and growth because it can influence the tuberous sclerosis complex (TSC) 1/2 along the mTORC signaling pathway and inhibit pro-apoptotic proteins or signals. [0074] 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. Studies have shown that the AKT signaling cascade have frequent malfunctions in various cancers, and may be associated with tumor aggressiveness (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331). Malfunctions of AKT typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Malfunction and mis-regulation of AKT may lead to cancers such as but not limited to breast cancer, gastric carcinoma, glioblastoma, gliosarcomas, head and neck squamous cell carcinoma, ovarian cancer, pancreatic cancer, and prostate cancer.
[0075] Additionally, AKT1 has been found to be involved in invasion and migration of cancerous cells (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Researchers found that silencing the AKT1 isoform can abrogate specific types of cancer cell migration However, there have been other studies which have demonstrated that activated AKT1 resulted in less metastatic propensity for lung metastatic lesion cells and breast cancer cells. AKT1 has also been identified as a key protein involved in angiogenesis, lung cancer, and tumorigenesis. [0076] Furthermore, overexpression of AKT has been correlated to resistance to chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel. Thus, there remains a need to find AKT inhibitors given its role in cell survival and cancer proliferation.
[0077] Recently, it has been found that the AKT1 gene mutation E17K can affect cell growth, proliferation, survival, and migration of breast cancer cells, colorectal cancer cells, and ovarian cancer cells (Chen, Y. et al., Front Cell Dev Biol., 2020; 8: 573599). 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.
[0078] The E17K mutation enhances migration of breast cancer cells, and also enhances resistance to chemotherapeutic drugs. However, the E17K mutation can also selectively destroy chemo-resistant tumor-promoting AKT1 quiescent cancer cells, suggesting that the AKT1(E17K) mutation is crucial in the oncogenic/anti-tumor mechanism.
[0079] 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.
[0080] 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.
[0081] The AKT1(E17K) mutation also causes rapid conformational changes in the AKT1 PH structural domain. The conformational changes to this domain result in a 4.5-fold increase in its membrane localization, which can result in excessive phosphorylation. The AKT1(E17K) mutation can also result in enhanced subcellular localization by increasing the transient expression
[0082] Given the conformational and signaling effects of the AKT1(E17K) mutation, this target may be useful for targeted treatment of cancers.
Prior Art AKT1 Inhibitors [0083] Most AKT inhibitors targeting the ATP binding site are non-selective against the three isoforms, as well as having poor to no selectivity against other structurally similar kinases. Thus, there remains a need to develop new and novel AKT inhibitors. These ATP targeting inhibitors are classified as aminofurazans, azepane derivatives, isoquinoline-5-sulfonamides, phenylpyrazole derivatives, thiophene carboxamide derivatives, and thiazole carboxamide derivatives.
[0084] There are also ATP non-competitive AKT inhibitors which are allosteric modulators which has 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.
Novel AKT1 Inhibitory Compounds
[0085] In one aspect, provided herein is a AKT1 inhibitory compound.
[0086] One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000027_0001
wherein:
G is O or CR4R5;
Z1 is N, C-H, or C-R9;
Z2 is N, C-H, or C-R3;
X1 is O or S;
X2 is O or S;
X3 is a bond, O, S, N-R7;
R1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; R4 and R5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R4 and R5 together form an oxo; or R4 and R5 join together to form a carbocycle or heterocycle;
R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R6 is absent and X3 and L join together to form a heterocycle;
R7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R6 and R7 join together to form a heterocycle;
L is selected from -N(R8)-, or a divalent radical selected from:
Figure imgf000028_0001
Figure imgf000029_0001
wherein the asterisk (*) indicates the bond to the squaric acid group;
R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R8 and R6 join to form a ring; or optionally R8 and R7 join to form a ring;
R9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
[0087] One embodiment provides a compound having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000029_0002
wherein:
G is O or CR4R5;
Z1 is N, C-H, or C-R9;
Z2 is N, C-H, or C-R3;
X1 is O or S; X2 is O or S;
X3 is a bond, O, S, N-R7;
R1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;
R4 and R5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R4 and R5 together form an oxo; or R4 and R5 join together to form a carbocycle or heterocycle;
R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R6 is absent and X3 and L join together to form a heterocycle;
R7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R6 and R7 join together to form a heterocycle;
L is selected from -N(R8)-, or a divalent radical selected from:
Figure imgf000030_0001
Figure imgf000031_0001
wherein the asterisk (*) indicates the bond to the squaric acid group;
R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R8 and R6 join to form a ring; or optionally R8 and R7 join to form a ring;
R9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
[0088] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein G is O. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein G is CR4R5.
[0089] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z1 is N.
[0090] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z2 is C-H. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z2 is C-R3
[0091] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X1 is O. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X1 is S.
[0092] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X2 is O. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X2 is O [0093] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X3 is a bond. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X3 is O. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X3 is S. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X3 is N-R7.
[0094] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted heteroaryl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridyl. [0095] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R2 is optionally substituted aryl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl.
[0096] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 together form an oxo.
[0097] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R6 is optionally substituted C1-C6 alkyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R6 is optionally substituted C3- C7 cycloalkyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R6 is optionally substituted heterocyclyl. Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R6 is absent and X3 and L join together to form a heterocycle.
[0098] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, or optionally substituted C1-C6 alkyl.
[0099] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R6 and R7 join together to form a heterocycle.
[00100] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is -N(R8)-.
[00101] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000033_0001
[00102] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000033_0002
[00103] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000033_0003
[00104] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000033_0004
[00105] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000033_0005
[00106] Another embodiment provides the compound of Formula (I), or pharmaceutically
Figure imgf000033_0006
acceptable salt or solvate thereof, wherein L is selected from: [00107] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000034_0001
[00108] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000034_0002
[00109] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000034_0003
[00110] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000034_0004
[00111] Another embodiment provides the compound of Formula (I), or pharmaceutically
Figure imgf000034_0005
acceptable salt or solvate thereof, wherein L is selected from:
[00112] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R8 is hydrogen or optionally substituted C1-C6 alkyl.
[00113] One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.
Table 1
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
[00114] Another embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2.
Table 2
Figure imgf000059_0002
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Preparation of Compounds
[00115] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K ), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).
[00116] 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, "Modem 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. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional 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, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modem Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
[00117] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.
Pharmaceutical Compositions
[00118] In certain embodiments, the AKT1 inhibitory compound described herein is administered as a pure chemical. In other embodiments, the AKT1 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
[00119] Provided herein is a pharmaceutical composition comprising at least one AKT1 inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) 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.
[00120] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
[00121] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
[00122] In certain embodiments, the AKT1 inhibitory compound as described by Formula (I), or a pharmaceutically acceptable salt or solvate 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.
[00123] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof.
[00124] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
[00125] In certain embodiments, the AKT1 inhibitory compound as described by Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate 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.
[00126] 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. In some embodiments, suitable nontoxic solid carriers are used which 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
[00127] In some embodiments, the AKT1 inhibitory compound as described by Formula (I) or Table 1 or Table 2, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like. [00128] The dose of the composition comprising at least one AKT1 inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.
[00129] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, 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.
[00130] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
Methods of Treatment
[00131] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00132] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
[00133] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.
[00134] One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
[00135] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
[00136] One embodiment provides a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00137] One embodiment provides a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
[00138] One embodiment provides a pharmaceutical composition comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cancer or neoplastic disease.
[00139] One embodiment provides a use of a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
[00140] In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof In some embodiments is provided a method of treating cancer, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 or Table 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. [00141] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.
[00142] One embodiment provides a method of inhibiting a AKT1 enzyme comprising contacting the AKT1 enzyme with a compound of Formula (I) or Table 1 or Table 2. Another embodiment provides the method of inhibiting a AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vivo setting. Another embodiment provides the method of inhibiting a AKT1 enzyme, wherein the AKT1 enzyme is contacted in an in vitro setting.
[00143] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.
EXAMPLES
I. Chemical Synthesis
[00144] In some embodiments, 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: ACN acetonitrile
°C degrees Celsius
3H chemical shift in parts per million downfield from tetramethyl silane
DCM dichloromethane (CH2CI2)
DIAD diisopropyl azodicarboxylate
DIEA diisopropylethylamine DMF dimethylformamide
DMSO dimethylsulfoxide
EA ethyl acetate
EtOAc ethyl acetate
ESI electrospray ionization
Et ethyl g gram(s) h hour(s)
HPLC high performance liquid chromatography
Hz hertz
J coupling constant (in NMR spectrometry)
LCMS liquid chromatography mass spectrometry
H micro m multiplet (spectral); meter(s); milli
M molar
M+ parent molecular ion
Me methyl
MsCl methanesulfonyl chloride
MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter
MS mass spectrometry nm nanometer(s)
NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution
PE petroleum ether
RT room temperature s singlet (spectral) t triplet (spectral)
SFC Supercritical fluid chromatography
T temperature
TFA trifluoroacetic acid THF tetrahydrofuran
TPP Triphenylphosphine
Experimental Procedures
[00145] Intermediate 1 : 3-(3-(4-(Aminomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-
2-amine
Figure imgf000069_0001
[00146] Step 1 : Zc'/'Z-Butyl 4-((3-nitropyridin-2-yl)amino)benzylcarbamate
[00147] To a solution of 2-chl oro-3 -nitro-pyridine (7.0 g, 44.2 mmol) and ZcvZ-butyl 7V-[(4- aminophenyl)methyl]carbamate (9.8 g, 44.2 mmol) in DMSO (100 mL) was added DIEA (11.4 g, 88.3 mmol). The mixture was stirred at 80 °C for 12 hr. The reaction mixture was diluted with H2O (100 mL) at 25 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was triturated with (petroleum ether: EtOAc = 10: 1) to give tert- butyl A-[[4-[(3-nitro-2-pyridyl)amino]phenyl]methyl]carbamate (13.9 g, yield: 91%) as a red solid. MS: m/z = 344.8 [M + H]+. XH NMR (400 MHz, Dimethyl sulfoxide-^) 59.90 (s, 1H), 8.49 (dd, .7 = 8.4, 1.6 Hz, 1H), 8.45 (dd, J = 4.4, 1.6 Hz, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.35 (t, J = 6.0 Hz, 1H), 7.19 (d, J= 8.4 Hz, 2H), 6.93 (dd, J= 8.4, 4.4 Hz, 1H), 4.07 (d, J= 6.0 Hz, 2H), 1.36 (s, 9H).
[00148] Step 2 : Zez'Z-Butyl 4-(2-(2-aminopyridin-3-yl)-3/7-imidazo[4,5-b]pyridin-3- yl)benzylcarbamate
[00149] To a solution of tert-butyl A-[[4-[(3-nitro-2-pyridyl)amino]phenyl]methyl]carbamate (10 g, 29.0 mmol) in MeOH (70 mL) and DMSO (140 mL) were added 2-aminopyridine-3- carbaldehyde (3.9 g, 31.9 mmol) and Na2S2O4 (10.1 g, 58.1 mmol). The mixture was stirred at 100 °C for 12 hr. After cooling to room temperature, the reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (400 mL x 2). The combined organic layers were washed with brine (400mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (Eluent of 1~2% MeOH in CH2CI2) to give Zert-butyl 4-(2-(2-aminopyridin-3-yl)-37/-imidazo[4,5-b]pyridin-3- yl)benzylcarbamate (5.7 g, yield: 44%) as a red solid. MS: m/z = 417.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-fifc) 8 8.31 (dd, J= 4.8, 1.2 Hz, 1H), 8.20 (dd, J= 8.0, 1.2 Hz, 1H), 7.99 (dd, J= 4.8, 1.6 Hz, 1H), 7.49 ( t, J= 6.0 Hz, 1H), 7.41 - 7.36 (m, 5H), 7.21 (dd, J = 7.6, 1.6 Hz, 1H), 6.99 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 4.21 (d, J= 6.0 Hz, 2H), 1.41 (s, 9H).
[00150] Step 3: 3-(3-(4-(Aminomethyl)phenyl)-377-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine [00151] To a solution of tert-butyl A-[[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate (350 mg, 840 pmol) in 1,4-dioxane (3 mL) was added 4 M HC1 in 1,4-dioxane (1 mL) at 20 °C. The mixture was stirred at 20°C for 2 hr. The reaction was concentrated under reduced pressure to give a crude product (280 mg, HC1 salt, yield: 95%). The crude was purified by prep-HPLC (Column: Phenomenex luna C18 150 x 25 mm x 10 pm; Condition: water (HCl)-ACN; Begin B: 0; End B: 16; Gradient Time (min): 10; 100%B Hold Time (min): 2; Flow Rate (mL/min): 25) to give the product (HC1 salt). The product was diluted with 10 mL aqueous NaHCCh and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO-i, filtered and concentrated under reduced pressure to give 3-(3-(4-(Aminomethyl)phenyl)-3//-imidazo[4,5-b]pyridin-2-yl)pyridin- 2-amine (Intermediate 1, 70.0 mg, yield: 95%) as a light-yellow solid. MS: m/z = 317.1 [M + H]+. XH NMR (400 MHz, Dimethylsulfoxide-^) 5 8.31 (dd, J= 4.8, 1.2 Hz, 1H), 8.19 (dd, J = 8.0, 1.2 Hz, 1H), 7.99 (dd, J= 4.8, 1.6 Hz, 1H), 7.47 (d, J= 8.4 Hz, 2H), 7.40 - 7.33 (m, 3H), 7.22 (dd, J= 7.6, 2.0 Hz, 1H), 6.98 (br s, 2H), 6.40 (dd, J= 7.6, 4.8 Hz, 1H), 3.79 (s, 2H), 1.82 (br s, 2H).
[00152] Intermediate 2: 3-(3-(4-(Piperazin-l-ylmethyl)phenyl)-3/7-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
Figure imgf000070_0001
[00153] Step 1 : tert-Butyl 4-(4-nitrobenzyl)piperazine-l -carboxylate
[00154] To a solution of l-(bromomethyl)-4-nitrobenzene (25 g, 116 mmol) in ACN (250 mL) were added tert-butyl piperazine- 1 -carboxylate (25.8 g, 139 mmol) and JGCCL (31.9 g, 231 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 hr. The reaction mixture was filtered and concentrated to give tert-butyl 4-(4-nitrobenzyl)piperazine-l -carboxylate (37 g, yield: 99%) as a white solid, which was used in the next step without further purification. MS: m/z = 322.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfbxide-cZe) 5 8.19 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 3.62 (s, 2H), 3.32 - 3.36 (m, 4H), 2.38-2.28 (m, 4H), 1.39 (s, 9H).
[00155] Step 2: tert-Butyl 4-(4-aminobenzyl)piperazine-l -carboxyl ate
[00156] To a solution of tert-butyl 4-(4-nitrobenzyl)piperazine-l-carboxylate(20 g, 62.2 mmol) in EtOH (150 mL) and H2O (50 mL) were added Fe (17.3 g, 311 mmol) and NH4CI (13.3 g, 249 mmol) at 25 °C. The mixture was stirred at 90 °C for 2 hr. The reaction mixture was filtered and concentrated to give tert-butyl 4-(4-aminobenzyl)piperazine-l -carboxylate (17 g, crude) as a yellow oil, which was used in the next step without further purification. MS: m/z = 292.9 [M+ H]+.
[00157] Step 3 : tert-Butyl 4-(4-((3-nitropyridin-2-yl)amino)benzyl)piperazine-l-carboxylate [00158] To a solution of 2-chl oro-3 -nitro-pyridine (10 g, 63 mmol) in DMSO (200 mL) were added tert-butyl 4-(4-aminobenzyl)piperazine-l-carboxylate(15.3 g, 52.5 mmol) and DIEA (13.5 g, 105 mmol) at 25 °C. The mixture was stirred at 80 °C for 12 hr. The reaction mixture was concentrated, diluted with H2O (200 mL) and extracted with CH2CI2 (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 10-30% EtOAc in petroleum ether) to give tert-butyl 4-(4-((3- nitropyridin-2-yl)amino)benzyl)piperazine-l-carboxylate (11g, yield: 45%) as a red solid. MS: m/z = 413.9 [M + H]+. XH NMR (400 MHz, Dimethylsulfoxide-tL) 89.95 (s, 1H), 8.48-8.58 (m, 2H), 7.60 (d, J= 8.4 Hz, 2H), 7.29 (d, J= 8.4 Hz, 2H), 6.98 (dd, J= 8.4, 4.8 Hz, 1H), 3.46 (s, 2H), 3.29 - 3.32 (m, 4H), 2.29 - 2.35 (m, 4H), 1.39 (s, 9H).
[00159] Step 4: tert-Butyl 4-(4-(2-(2-Aminopyridin-3 -yl)-3//-imidazo[4, 5-b]pyri din-3 - yl)benzyl)piperazine-l -carboxylate
[00160] To a solution of tert-butyl 4-(4-((3-nitropyridin-2-yl)amino)benzyl)piperazine-l- carboxylate (10 g, 24.1 mmol) in DMSO (200 mL) were added 2-aminopyridine-3-carbaldehyde (3.54 g, 29.0 mmol) and Na2S2O4 (12.6 g, 72.5 mmol) at 25 °C. The mixture was stirred at 100 °C for 14 hr. The reaction mixture was poured into H2O (500 mL) and extracted with CH2CI2 (200 mL x 2). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (Eluent of 10-30% MeOH in CH2CI2) to give 4-(4-(2-(2-Aminopyri din-3 -yl)- 3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-l-carboxyla (4.9 g, yield: 42%) as a red solid. MS: m/z = 486.2 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-^) 8 8.33 (dd, J= 4.8, 1.2 Hz, 1 H), 8.20 (dd, J= 8.0, 1.2 Hz, 1 H), 7.99 (dd, J= 4.8, 2.0 Hz, 1 H), 7.43 - 7.48 (m, 2 H), 7.36 - 7.42 (m, 3 H), 7.16 (dd, J= 7.6, 1.6 Hz, 1 H), 7.00 (br s, 2 H), 6.38 (dd, J= 7.6, 4.8 Hz, 1 H), 3.56 (s, 2 H), 3.33 - 3.37 (m, 4 H), 2.32 - 2.38 (m, 4 H), 1.40 (s, 9 H).
[00161] Step 5: 3-(3-(4-(Piperazin-l-ylmethyl)phenyl)-3J/-imidazo[4,5-b]pyridin-2-yl)pyridin- 2-amine
[00162] To a solution of ZerZ-butyl 4-(4-(2-(2-aminopyridin-3-yl)-3J -imidazo[4,5-b]pyridin-3- yl)benzyl)piperazine-l -carboxylate (2 g, 4.12 mmol) in CH2CI2 (10 mL) was added dropwise TFA (4.62 g, 40.5 mmol) at 25 °C. The mixture was stirred at 25 °C for 3hr. The reaction mixture was concentrated The residue was poured into water (50 mL). The pH of the mixture was adjusted to about 8 with saturated NaHCCh (aq). The resulting mixture was extracted with CH2CI2 (100 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated to give 3-(3-(4-(Piperazin-l-ylmethyl)phenyl)-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine (1.43 g, yield: 90%) as an off-white solid. The solid (100 mg) was triturated with EtOAc (3 mL) at 25 °C for 1 hr and filtered. The filter cake was collected to give 3-(3-(4-(Piperazin-l-ylmethyl)phenyl)-377-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 2, 24.5 mg, yield: 90%). MS: m/z = 386.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-zfc) 8 8.33 (d, J= 4.0 Hz, 1H), 8.22 (d, J= 8.0 Hz, 1H), 8.00 (d, J= 3.2 Hz, 1H), 7.35 - 7.52 (m, 5H), 7.18 (d, J = 7.2 Hz, 1H), 7.00 (br s, 2H), 6.40 (dd, d, J= 7.8, 4.8 Hz, 1H), 3.63 (s, 2H), 3.16-3.01 (m, 4H), 2.63-2.48 (ms, 4H).
[00163] Intermediate 3: 3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
Figure imgf000072_0001
[00164] Step 1 : ZezZ-Butyl (l-(4-nitrobenzyl) piperidin-4-yl) carbamate
[00165] To a solution of l-(bromomethyl)-4-nitro-benzene (108 g, 499 mmol) in ACN (1.5 L) were added K2CO3 (149 g, 1.1 mol) and Zez'Z-butyl A-(4-piperidyl)carbamate (100 g, 499 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give ZcvZ-butyl (l-(4-nitrobenzyl) piperidin-4- yl)carbamate (167 g, crude) as a yellow solid, which was used in the next step without further purification. MS: m/z = 335.9 [M + H]+. 'H NMR (400 MHz, Chloroform-c7) 8 8.16 (d, J= 8.8 Hz, 2H), 7.49 (d, J= 8.8 Hz, 2H), 4.44 (br s, 1H), 3.56 (s, 2H), 3.52 - 3.42 (m, 1H), 2.77 - 2.74 (m, 2H), 2.16 - 2.10 (m, 2H), 1.93 - 1.90 (m, 2H), 1.43 (s, 9H), 1.42 - 1.36 (m, 2H).
[00166] Step 2: tert-Butyl (l-(4-aminobenzyl) piperidin-4-yl) carbamate
[00167] To a solution of tert-butyl (l-(4-nitrobenzyl) piperidin-4-yl)carbamate (109 g, 325 mmol) in EtOH (500 mL) and H2O (150 m ) were added Fe (91 g, 1.6 mol) and NH4CI (174 g, 3.3 mol). The mixture was stirred at 85°C for 2 hr. The reaction mixture was filtered. The filtrate was concentrated under pressure to remove most of the EtOH. The residue was diluted with H2O (500 mL) and extracted with CH2CI2 (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl (l-(4-aminobenzyl) piperidin-4-yl) carbamate (80 g crude) as a yellow solid. MS: m/z = 306.2 [M + H]+. ’H NMR (400 MHz, Chloroform-t/) 5 7.14 (d, J= 8.0 Hz, 2H), 6.64 (d, J= 8.0 Hz, 2H), 4.51 (br d, J= 6.0 Hz, 1H), 3.80 - 3.59 (m, 2H), 3.55 (s, 2H), 3.51 - 3.39 (m, 1H), 2.95 - 2.93 (m, 2H), 2.25 - 2.20 (m, 2H), 1.96 - 1.93 (m, 2H), 1.72 - 1.54 (m, 2H), 1.42 (s, 9H).
[00168] Step 3: tert-Butyl (l-(4-((3-nitropyri din-2 -yl) amino)benzyl)piperidin-4-yl)carbamate [00169] To a solution of tert-butyl (l-(4-aminobenzyl) piperidin-4-yl) carbamate (30 g, 98.2 mmol) in DMSO (500 mL) were added DIEA (38.1 g, 295 mmol) and 2-chloro-3 -nitro-pyridine (18.7 g, 118 mmol). The mixture was stirred at 100 °C for 16 hr. The reaction mixture was quenched with H2O (500 mL) at 20 °C and extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tert-butyl (l-(4-((3-nitropyridin-2-yl) amino) benzyl) piperidin-4-yl) carbamate (30 g, yield: 71%) as a yellow solid. MS: m/z = 428.2 [M + H]+. H NMR (400 MHz, Chloroform-^ 8 10.10 (s, 1H), 8.51 (dd, J= 8.0, 1.6 Hz, 1H), 8.47 (dd, J = 8.4, 1.6 Hz, 1H), 7.58 (d, J= 8.4 Hz, 2H), 7.32 (d, J= 8.4 Hz, 2H), 6.81 (dd, J= 8.4, 4.4 Hz, 1H), 4.44 (br s, 1H), 3.47 (s, 2H), 3.44 - 3.34 (m, 1H), 2.82 - 2.79 (m, 2H), 2.13 - 2.05 (m, 2H), 1.93 - 1.89 (m, 2H), 1.43 (s, 9H), 1.39 - 1.37 (m, 2H).
[00170] Step 4: tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-3B-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)carbamate
[00171] To a solution of (12.5 g, 29.2 mmol) in DMSO (500 mL) were added Na2S2O4 (15.3 g, 87.7 mmol) and 2-aminopyridine-3-carbaldehyde (4.3 g, 35.1 mmol). The mixture was stirred at 100 °C for 16 hr. The reaction mixture was quenched with H2O (1000 mL) at 20 °C and extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tertbutyl (l-(4-(2-(2-aminopyridin-3-yl)-3/f-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)carbamate (5.5 g, yield: 38%) as a yellow solid. MS: m/z = 500.2 [M + H]+. 'H NMR (400 MHz, Chloroform-tZ) 8 8.46-8.37 (m, 1H), 8.12 - 8.02 (m, 2H), 7.48 (d, J= 8.0 Hz, 2H), 7.34 - 7.28 (m, 3H), 7.07 (dd, J= 8.0, 4.0 Hz, 1H), 6.62 (br s, 2H), 6.33 (dd, J= 7.6, 4.8 Hz, 1H), 4.46 (br d, J= 6.0 Hz, 1H), 3.56 (s, 2H), 3.49 - 3.47(m, 1H), 2.84 (br d, J= 11.2 Hz, 2H), 2.14 (t, J = 12.0 Hz, 2H), 1.93 (br d, J = 11.2 Hz, 2H), 1.45 (s, 9H), 1.51-1.38 (m, 2H).
[00172] Step 5: 3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-3/f-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
[00173] A solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-3/f-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)carbamate (2.0 g, 4.0 mmol) in HCl/l,4-di oxane (4M, 20 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was quenched with aq. NaHCCL (30 mL) at 20°C. MeOH was added, filtered. The filtrate was freeze-dried to give 3-(3-(4-((4-aminopiperidin-l- yl)methyl)phenyl)-3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 3, 1.45 g, yield: 91%) as a yellow solid. MS: m/z = 400.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t g) 8 8.37 - 8.28 (m, 1H), 8.19 (dd, J= 8.0, 4.0 Hz, 1H), 7.99 - 7.97 (m, 1H), 7.47 - 7.32 (m, 5H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.36 (dd, J= 6.8, 4.0 Hz, 1H), 3.50 (s, 2H), 3.27 - 3.23(m, 1H), 2.75 (br d, J= 10.8 Hz, 2H), 2.00 (t, J= 10.8 Hz, 2H), 1.72 ( d, J= 10.8 Hz, 2H), 1.39 -1.31 (m, 2H).
[00174] Intermediate 4: 3-(3-(4-(Aminomethyl)phenyl)-5-phenyl-37/-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
Figure imgf000074_0001
[00175] Step 1 : tert-Butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)benzylcarbamate
[00176] To a solution of 2, 6-di chi oro-3 -nitro-pyridine (2.0 g, 10.4 mmol) and tert-butyl A-[(4- aminophenyl)methyl]carbamate (2.3 g, 10.4 mmol) in DMSO (25 mL) was added DIEA (4.0 g, 31.1 mmol). The mixture was stirred at 80 °C for 12 hr. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na SCU, filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tert-butyl A-[[4-[(6-chloro-3-nitro-2- pyridyl)amino]phenyl]methyl]carbamate (2.4 g, yield: 44%) as a red solid. MS: m/z = 400.9 [M + Na]+. 'H NMR (400 MHz, Dimcthylsulfoxidc^) 8 10.10 (s, 1H), 8.53 (d, J= 8.8 Hz, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.40 (t, J= 6.0 Hz, 1H), 7.25 (d, J= 8.4 Hz, 2H), 6.99 (d, J= 8.8 Hz, 1H), 4.13 (<7, J= 6.0 Hz, 2H), 1.40 (s, 9H).
[00177] Step 2: tert-Butyl 7V-[[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
[00178] To a solution of tert-butyl A-[[4-[(6-chloro-3-nitro-2- pyridyl)amino]phenyl]methyl]carbamate (2.0 g, 5.3 mmol) in DMSO (30 mL) and MeOH (15 mL) were added 2-aminopyridine-3-carbaldehyde (0.7 g, 5.8 mmol) and Na2S2C>4 (1.8 g, 10.6 mmol). The mixture was stirred at 100 °C for 16 hr. The reaction mixture was quenched with H2O (50 mL) at 25°C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over NazSO^ filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tert-butyl A-[[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]carbamate (1.4 g, yield: 51%) as a yellow solid. MS: m/z = 451.0 [M + H]+. 'H NMR (400 MHz, Di methyl sulfoxide-^) 8 8.26 (d, J= 8.4 Hz, 1H), 7.99 (dd, J = 4.8, 1.6 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.38 (s, 4H), 7.21 (dd, J= 7.6, 1.6 Hz, 1H), 6.91 (br s, 2H), 6.40 (dd, J= 7.6, 4.8 Hz, 1H), 4.22 (d, J= 6.0 Hz, 2H), 1.41 (s, 9H).
[00179] Step 3: tert-Butyl A-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
[00180] To a solution of tert-butyl A-[[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]carbamate (500 mg, 1.1 mmol) and phenylboronic acid (270 mg, 2.2 mmol,) in 1,4-dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)Ch (81.1 mg, 111 pmol) and CS2CO3 (1.1 g, 3.3 mmol). The mixture was degassed and purged with N2 three times and stirred at 80 °C for 16 hr under N2 atmosphere. After cooling to 20 °C, the reaction was diluted with EtOAc (10 mL), filtered through celite and extracted with H2O (10 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 10-35% EtOAc in petroleum ether) to give terLbutyl A-[[4-[2-(2-amino-3-pyridyl)-5-phenyl- imidazo[4,5-b]pyri din-3 -yl]phenyl]methyl]carbamate (126 mg, yield: 21%) as a brown solid. MS: m/z = 493.2 [M + H]+.
[00181] Step 4: 3-(3-(4-(Aminomethyl)phenyl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
[00182] A solution of tert-butyl Ar-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin- 3-yl]phenyl]methyl]carbamate (126 mg, 256 pmol) in HCl/l,4-di oxane (4 M, 1 mL) was stirred at 25 °C for 2 hr. The solvent was removed under reduced pressure to give a crude product (84 mg, yield: 84%). The crude was purified by prep-HPLC (column: Welch Xtimate Cl 8 150 x 25mm x 5 pm; mobile phase: [water (HC1) - ACN]; B%: 5% - 35%, 8min) to give the desired product (HC1 salt). The product was diluted with aqueous NaHCCh (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over NazSCU, filtered, and concentrated under reduced pressure to give 3-(3-(4- (aminomethyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 4, 32.2 mg, yield: 84%) as a light-yellow solid. MS: m/z = 393.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-r/g) 8 8.26 (d, J= 8.4 Hz, 1H), 8.04 - 7.96 (m, 4H), 7.54 - 7.49 (m, 2H), 7.49 - 7.43 (m, 2H), 7.43 - 7.35 (m, 3H), 7.21 (dd, J= 7.6, 1.6 Hz, 1H), 6.98 (br s, 2H), 6.41 (dd, J= 7.6, 4.8 Hz, 1H), 3.82 (s, 2H).
[00183] Intermediate 5: A-(3-(3-(4-(Aminomethyl)phenyl)-2-(2-aminopyridin-3-yl)-3Zf- imidazo[4,5-b]pyri din-5 -yl)phenyl)acetamide
Figure imgf000076_0001
[00184] Step 1 : tert-Butyl 4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3//-imidazo[4,5- b]pyri din-3 -yl)benzylcarbamate
[00185] To a solution of tert-butyl A-[[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]carbamate (refer to Intermediate 4 for detail procedures, 3.5 g, 7.8 mmol) and (3-acetamidophenyl)boronic acid (2.8 g, 15.5 mmol) in 1,4-dioxane (30 mL) and H2O (6 mL) were added Pd(dppf)C12 (568 mg, 776 pmol) and CS2CO3 (7.6 g, 23.3 mmol). The mixture was was degassed and purged with N2 three times and then stirred at 80 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over JSfeSCU, filtered, and concentrated under reduced pressure to give tert-butyl A-[[4-[5-(3-acetamidophenyl)-2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate (2.43 g, yield: 57%), which was used in the next step without further purification. MS: m/z = 550.1 [M + H]+.
[00186] Step 2: A-(3-(3-(4-(Aminomethyl)phenyl)-2-(2-aminopyridin-3-yl)-3/ imidazo[4,5- b]pyridin-5-yl)phenyl)acetamide
[00187] A solution of Zert-butyl A-[[4-[5-(3-acetamidophenyl)-2-(2-amino-3- pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]carbamate (8.0 g, 14.6 mmol) in HCl/1,4- dioxane (4 M, 20 mL) was stirred at 25 °C for 2 hr The solvent was removed under reduced pressure to give a crude product (6.4 g, HC1 salt, yield: 90%). The crude (250 mg, HC1 salt) was diluted with aqueous NaHCCL (10 mL) and extracted with CH2CI2 (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give A-(3-(3-(4-(aminomethyl)phenyl)-2-(2-aminopyridin-3-yl)-3//- imidazo[4,5-b]pyri din-5 -yl)phenyl)acetamide (Intermediate 5, 86.7 mg, yield: 90% ) as a lightyellow solid. MS: m/z = 450.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-cA) 8 10.08 (s, 1H), 8.26 (d, ./= 8.4 Hz, 1H), 8.10 (s, 1H), 8.00 (dd, J= 4.8, 1.6 Hz, 1H), 7.84 (d, J= 8.4 Hz, 1H), 7.68 (d, J= 8.0Hz, 1H), 7.65 (d, J= 8.0 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.45 - 7.35 (m, 3H), 7.20 (dd, J= 7.6, 1.6 Hz, 1H), 6.94 (br s, 2H), 6.41 (dd, J= 7.6, 4.8 Hz, 1H), 3.82 (s, 2H), 2.06 (s, 3H).
[00188] Intermediate 6: A-(3-(2-(2-Aminopyri din-3 -yl)-3-(4-(piperazin-l-ylmethyl)phenyl)-
3H-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
Figure imgf000077_0001
[00189] Step 1 : Zc/7-Butyl 4-(4-((6-(3-Acetamidophenyl)-3-nitropyridin-2- yl)amino)benzyl)piperazine- 1 -carboxylate [00190] To a solution of Zez'Z-butyl 4-[[4-[(6-chloro-3-nitro-2- pyridyl)amino]phenyl]methyl]piperazine-l -carboxylate (2.78 g, 5.39 mmol) and (3- acetamidophenyl)boronic acid (1.93 g, 10.78 mmol) in 1,4-dioxane (30 mL) and H2O (6 mL) were added K2CO3 (2.24 g, 16.2 mmol) and Pd(dppf)C12 (789 mg, 1.08 mmol). The mixture was degassed and purged with N2 three times and stirred at 60 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched H2O (200 mL) at 25 °C and extracted with CH2Q2 (60 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SC>4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 50-100% EtOAc in petroleum ether) to give Zez'Z-Butyl 4-(4-((6-(3- Acetamidophenyl)-3-nitropyridin-2-yl)amino)benzyl)piperazine-l-carboxylate (2.81 g, yield: 83%) as a red solid. MS: m/z = 547.1 [M+H]+. 'H NMR (400 MHz, Chloroform- ) 8 10.19 (s, 1H), 8.42 (d, J= 8.8 Hz, 1H), 8.19 (br s, 1H), 7.68-7.60 (m, 4H), 7.47 (d, J= 9.2 Hz, 1H), 7.34- 7.27 (m, 2H), 7.17-7.12 (m, 1H), 3.43 (s, 2H), 3.35 (br t, J= 4.8 Hz, 4H), 2.32 (br t, J= 4.8 Hz, 4H), 2.11 (s, 3H), 1.36 (s, 9H).
[00191] Step 2: zc/7-Butyl 4-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-377- imidazo[4,5-b]pyri din-3 -yl)benzyl)piperazine-l -carboxylate
[00192] To a solution of 2-aminopyridine-3-carbaldehyde (2.3 g, 18.9 mmol) and Zcz'Z-Butyl 4- (4-((6-(3-Acetamidophenyl)-3-nitropyridin-2-yl)amino)benzyl)piperazine-l -carboxylate (9.5 g, 17.2 mmol) in DMSO (100 mL) was added Na2S20r (8.97 g, 51.5 mmol). The mixture was degassed and purged with N2 three times and stirred at 60 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched with H2O (400 mL) at 25 °C and extracted with CH2CI2 (400 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give Zez'Z-Butyl 4-(4-(5-(3- acetamidophenyl)-2-(2-aminopyridin-3-yl)-3Z/-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-l- carboxylate (9.67 g, crude) as a red solid, which was used in the next step without further purification. MS: m/z = 619.2 [M+H]+.
[00193] Step 3: Ar-(3-(2-(2-Aminopyridin-3-yl)-3-(4-(piperazin-l-ylmethyl)phenyl)-3//- imidazo[4,5-b]pyri din-5 -yl)phenyl)acetamide
[00194] A solution of Zcz'Z-Butyl 4-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3/7- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-l -carboxylate (0.4 g, 370 pmol, crude) in HCl/l,4-dioxane (4M, 5 mL) and 1,4-dioxane (1 mL) was degassed and purged with N2 three times and stirred at 25 °C for 4 hr under N2 atmosphere. The reaction mixture was filtered. The filter cake was washed with 1,4-dioxane (10 mL x 2) and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenom enex Luna C 18 200*40mm*10pm; mobile phase: [water (HCl)-ACN]; B%: l%-30%, 10min) to give /V-(3-(2- (2-aminopyridin-3-yl)-3-(4-(piperazin-l-ylmethyl)phenyl)-3//-imidazo[4,5-b]pyri din-5- yl)phenyl)acetamide (Intermediate 6, 244 mg HC1 salt, yield: 68%) as a yellow solid. MS: m/z = 519.2 [M+H]+. 'H NMR (400 MHz, Dim ethyl sulfoxidc-rL) 8 10.05 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.99 (dd, J= 4.8, 1.6 Hz, 1H), 7.86 (d, J= 8.4 Hz, 1H), 7.66 (d, J= 8.0 Hz,
2H), 7.50 - 7.33 (m, 5H), 7.14 (dd, J= 7.6, 1.2 Hz, 1H), 7.00 (br s, 2H), 6.37 (dd, J= 7.6, 4.8 Hz, 1H), 3.52 (s, 2H), 2.77-2.67 (m, 4H), 2.41-2.27 (m, 4H), 2.05 (s, 3H).
[00195] Intermediate 7: 3-[3-[4-(aminomethyl)phenyl]-6-phenyl-imidazo[4,5-b]pyridin-2- yl]pyridin-2-amine
Figure imgf000079_0001
[00196] Step 1 : fert-Butyl jV-[[4-[(5-bromo-3-nitro-2-pyridyl)amino]phenyl]methyl]carbamate [00197] To a solution of 5-bromo-2-chloro-3-nitro-pyridine (2.1 g, 9.0 mmol) and tert-butyl N- [(4-aminophenyl)methyl]carbamate (2 g, 9.0 mmol) in DMSO (20 mL) was added DIEA (3.5 g, 27.0 mmol) The mixture was stirred at 80 °C for 12 hr. After cooling to 20 °C, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over NazSCU, filtered, and concentrated under reduced pressure to give tert-butyl A-[[4-[(5-bromo-3-nitro-2- pyridyl)amino]phenyl]methyl]carbamate (3.5 g crude, yield: 92%) as a red solid. MS: m/z = 367.6, 368.6 [M + H]+. 'H NMR (400 MHz, Chloroform-^/)) 8 10.02 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.49 (d, J= 2.0 Hz, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.32 (d, J= 8.0 Hz, 2H), 4.84 (br s, 1H), 4.32 (d, J= 5.2 Hz, 2H), 1.47 (s, 9H).
[00198] Step 2: tert-Butyl 7V-[[4-[2-(2-amino-3-pyridyl)-6-bromo-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
[00199] To a solution of tert-butyl 2V-[[4-[(5-bromo-3-nitro-2- pyridyl)amino]phenyl]methyl]carbamate (3 g, 7.1 mmol) and 2-aminopyridine-3-carbaldehyde (952 mg, 7.8 mmol) in DMSO (30 mL) and MeOH (15 mL) was added NazS2O4 (2.5 g, 14.2 mmol). The mixture was stirred at 1OO°C for 12 hr. After cooling to 20 °C, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na SCU, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~l% MeOH in CH2CI2) to give ter/-butyl-A-[[4-[2-(2-amino-3-pyridyl)-6-bromo-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]carbamate (1.7 g, yield: 36%) as a yellow solid. MS: m/z = 495.9, 496.9 [M + H]+. 'H NMR (400 MHz, Chloroform-^) 8 8.40 (d, J = 2.0 Hz, 1H), 8.22 (d, J= 2.0 Hz, 1H), 8.08 (dd, J= 4.8, 2.0 Hz, 1H), 7.46 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.4 Hz, 2H), 7 10 (dd, J= 8.0, 2.0 Hz, 1H), 6.63 (br s, 2H), 6.41 - 6.34 (m, 1H), 4.93 (br s, 1H), 4.42 (d, J= 5.6 Hz, 2H), 1.48 (s, 9H).
[00200] Step 3: tert-Butyl A-[[4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
[00201] To a solution of tert-butyl A-[[4-[2-(2-amino-3-pyridyl)-6-bromo-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]carbamate (500 mg, 1.0 mmol) and phenylboronic acid (246 mg, 2.0 mmol) in toluene (5 mL) and EtOH (5 mL) were added NaHCCh (254 mg, 3.0 mmol) and Pd(PPh3)4 (233 mg, 202 pmol). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 12 hr under N2 atmosphere. After cooling to 20 °C, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with saturated NaHCOi solution (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~l% MeOH in CH2CI2) to give tert-butyl A-[[4-[2-(2-amino-3- pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]carbamate (340 mg, 62% yield) as a brown solid. MS: m/z = 493.1 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-tC)) 8 8.61 (d, J= 2.0 Hz, 1H), 8.45 (d, J= 2.0 Hz, 1H), 8.01 - 7.99 (m, 1H), 7.77 (d, J= 7.2 Hz, 2H), 7.63 - 7.59 (m, 4H), 7.54 - 7.52 (m, 2H), 7.39 (d, J= 5.2 Hz, 2H), 7.23 (dd, J= 7.6, 2.0 Hz, 1H), 7.04 (br s, 2H), 6.40 (dd, J= 7.6, 5.2Hz, 1H), 4.21 (d, J= 6.0 Hz, 2H), 1.40 (s, 9H).
[00202] Step 4: 3-[3-[4-(Aminomethyl)phenyl]-6-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2- amine
[00203] To a solution of tert-butyl A-[[4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]carbamate (340 mg, 690 pmol, 1.0 eq) in 1,4-dioxane (5 mL) was added HCl/dioxane (5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give the crude (297 mg, HC1 salt, yield: 96%). The residue was purified by prep-HPLC (column: Welch Xtimate Cis 150 x 25mm x 5pm; mobile phase: [water (HCl)-ACN]; B%: 3%-33%, 8min) and dissociated with NaHCCh to give 3-[3-[4- (aminomethyl)phenyl]-6-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (Intermediate 7, 83.8 mg, yield: 96%) as an off-white solid. MS: m/z = 393.1 [M + H]+. 'll NMR (400 MHz, Dimethylsulfoxide-z/e)) 8 8.62 (d, J= 2.0 Hz, 1H), 8.46 (d, J= 2.0 Hz, 1H), 8.00 (dd, J= 4.8, 2.0 Hz, 1H), 7.78 (d, J= 7.2 Hz, 2H), 7.56 - 7.46 (m, 5H), 7.45 - 7.35 (m, 4H), 7.26 (dd, J= 8.0, 2.0 Hz, 1H), 7.04 (s, 2H), 6.44 - 6.39 (m, 1H), 3.80 (s, 2H).
[00204] Intermediate 8: 3-(6-Phenyl-3-(4-(piperazin-l-ylmethyl)phenyl)-3/f-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
Figure imgf000081_0001
[00205] Step 1 : Zc'/'Z-Butyl 4-(4-((5-bromo-3-nitropyridin-2-yl)amino)benzyl)piperazine-l- carboxylate
[00206] To a solution of 5-bromo-2-chloro-3-nitro-pyridine (10 g, 42.1 mmol) in DMSO (100 mL) were added ZcvZ-butyl 4-[(4-aminophenyl)methyl]piperazine-l-carboxylate (11 g, 30.2 mmol) and DIEA (11.7 g, 94.8 mmol). The mixture was stirred at 80 °C for 12 hr. After cooling to 20 °C, the reaction mixture was poured into H2O (100 mL). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3). The combined organic layers were dried over anhydrous NazSCU, filtered, and concentrated to dryness. The crude was purified by silica gel flash chromatography (Elute of 10-50% EtOAc in petroleum ether) to give ZcvZ-butyl 4-[[4-[(5-bromo-3-nitro-2- pyridyl)amino]phenyl]methyl]piperazine-l -carboxylate (10.7 g, yield: 43%) as a brown solid. MS: m/z = 493.8 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-^) 8 9.93 (s, 1H), 8.67 (d, J= 2.4 Hz, 1H), 8.60 (d, J= 2.4 Hz, 1H), 8.50 (dd, J= 10.0, 2.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.29 (d, J= 8.0 Hz, 1H), 3.46 (s, 2H), 3.32 - 3.28 (m, 4H), 2.32 - 2.30 (m, 4H), 1.39 (s, 9H).
[00207] Step 2 : Zcz'Z-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-6-bromo-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazine-l -carboxylate [00208] To a solution of tert-butyl 4-[[4-[(5-bromo-3-nitro-2- pyridyl)amino]phenyl]methyl]piperazine-l -carboxylate (10.7 g, 21.6 mmol) in DMSO (60 m ) and methanol (30 m ) were added 2-aminopyridine-3-carbaldehyde (3.2 g, 26 mmol) and NazSzOr (7.5 g, 43.3 mmol). The reaction mixture was stirred at 100 °C for 16 hr. After cooling to 25 °C, the reaction mixture was diluted with HzO (100 mL) and extracted with CH2CI2 (100 mL x 3) and brine (100 mL x 2 times). The combined organic phases were dried over NazSCh, filtered, and concentrated under reduced pressure. tert-Butyl 4-[[4-[2-(2-amino-3-pyridyl)-6- bromo-imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]piperazine-l-carboxylate (7.6 g, yield: 62%) was obtained as a red oil. MS: m/z = 565.9 [M + H]+.
[00209] Step 3 : tert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-6-phenyl-37T-imidazo[4,5-b]pyridin- 3 -yl)benzyl)piperazine- 1 -carboxylate
[00210] To a solution of tert-butyl 4-[[4-[2-(2-amino-3-pyridyl)-6-bromo-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]piperazine-l -carboxylate (5.8 g, 10.3 mmol) and phenylboronic acid (2.5 g, 20.6 mmol) in 1,4-dioxane (100 mL) and HzO (10 mL) were added Pd(dppf)Clz (752 mg, 1.03 mmol) and CS2CO3 (10 g, 30.8 mmol). The mixture was degassed and purged with Nz three times and stirred at 80°C for 16 hr under Nz atmosphere. After cooling to 25°C, the reaction mixture was poured into HzO (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3). The combined organic layers were dried over anhydrous NazSO^ filtered and concentrated under reduced pressure to give tert-butyl 4-[[4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]piperazine-l -carboxylate (2.54 g, yield: 44%) as a brown oil. MS: m/z = 562.4 [M + H]+.
[00211] Step 4: 3-(6-Phenyl-3-(4-(piperazin-l-ylmethyl)phenyl)-3//-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
[00212] A solution of tert-butyl 4-[[4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5-b]pyridin- 3 -yl]phenyl]methyl]piperazine-l -carboxylate (10 g, 17.80 mmol, 1 eq) in HCl/l,4-dioxane (4M, 100 mL) was stirred at 25 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product. The crude was triturated with MeOH (30 mL) at 25 °C for 30 min. The suspension was filtered. The filter cake was washed with MeOH (20 mL) and dried under reduced pressure to give 3-(6-phenyl-3-(4-(piperazin-l-ylmethyl)phenyl)-377- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine (Intermediate 8, 3.7 g, yield: 42%) as a yellow solid. MS: m/z = 462.2 [M + H]+. XHNMR (400 MHz, Dimethylsulfoxide- g) 8 8.63 (d, J= 2.0 Hz, 1H), 8.46 (d, J= 2.0 Hz, 1H), 8.00 (dd, J= 4.8, 1.6 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.52 (dd, J = 7.6, 7.6 Hz, 2H), 7.47 - 7.38 (m, 5H), 7.19 (dd, J= 7.6, 1.6 Hz, 1H), 7.06 (br s, 2H), 6.39 (dd, J = 7.6, 4.8 Hz, 1H), 3.51 (s, 2H), 3.33 - 3.27 (m, 1H), 2.71 (br t, J = 4.4 Hz, 4H), 2.32 (s, 4H). [00213] Intermediate 9: 3-[3-[4-[(4-Amino-l-piperidyl)methyl]phenyl]-6-phenyl-imidazo[4,5- b]pyridin-2-yl]pyridin-2-amine
Figure imgf000083_0001
[00214] Step 1 : ZezZ-Butyl A-[l-[[4-[(5-bromo-3-nitro-2-pyridyl)amino]phenyl]methyl]-4- piperidyl]carbamate
[00215] A mixture of 5-bromo-2-chloro-3-nitro-pyridine (17.1 g, 72 mmol), tert-butyl A-[l-[(4- aminophenyl)methyl]-4-piperidyl]carbamate (22 g, 72 mmol), DIEA (27.9 g, 216 mmol) in DMSO (200 m ) was stirred at 80 °C for 16 hr. After cooling to 25 °C, the mixture was extracted with EtOAc (250 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na SCh, filtered, and concentrated to give tert-butyl A-[l-[[4-[(5- bromo-3-nitro-2-pyridyl)amino]phenyl]methyl]-4-piperidyl]carbamate 32g crude product as black brown solid. MS: m/z = 506.9, 507.9 [M + H]+. 'H NMR (400 MHz, Chloroform-c/) S 10.04 (s, 1H), 8.64 (d, J= 2.0 Hz, 1H), 8.49 (d, J= 2.4 Hz, 1H), 7.53 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.4 Hz, 2H), 4.34 (d, J= 3.2 Hz, 1H), 3.48 (s, 2H), 3.46-3.35 (m, 1H), 2.82 (br d, J = 12.0 Hz, 2H), 2.10 (t, J= 10.8 Hz, 2H), 1.91 (br d, J= 11.2 Hz, 2H), 1.44 (s, 9H).
[00216] Step 2: tert-Butyl A-[l-[[4-[(3-nitro-5-phenyl-2-pyridyl)amino]phenyl]methyl]-4- piperidyl]carbamate
[00217] A mixture of tert-butyl A-[l-[[4-[(5-bromo-3-nitro-2-pyridyl)amino]phenyl]methyl]-4- piperidyl]carbamate (20 g, 39.5 mmol), phenylboronic acid (4.8 g, 39.5 mmol), K2CO3 (16.4 g, 118.5 mmol), Pd(dppf)C12 (1.4 g, 2.0 mmol) in 1,4-dioxane (250 mL) and H2O (50 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 16 hr under N2 atmosphere. After cooling to 25 °C, the reaction mixture was filtered, diluted with H2O (100 mL) and EtOAc (450 mL). The organic phase was separated, washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 3~4% MeOH in CH2O2) to give tert-butyl -[l-[[4- [(3-nitro-5-phenyl-2-pyridyl)amino]phenyl]methyl]-4-piperidyl]carbamate (8.6 g, yield: 43%) as a red brown soild. MS: m/z = 504.2 [M + H]+. XHNMR (400 MHz, Chloroform - ) 6 10.14 (s, 1H), 8.75 (dd, J= 10.0, 2.0 Hz, 2H), 7.62 (d, J= 8.0, Hz, 2H), 7.57 (d, J= 7.2, Hz, 2H), 7.49 (dd, J= 8.0, 8.0 Hz, 2H), 7.43 - 7.37 (m, 3H), 4.43 (br s, 1H), 3.50 (br s, 2H), 3.49-3.41 (m, 1H), 2.85 - 2.81 (m, 2H), 2.15 - 2.08 (m, 2H), 1.94 - 1.91 (m, 2H), 1.51-1.45 (m, 2H), 1.44 (s, 9H).
[00218] Step 3. tert-Butyl N-[l-[[4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]-4-piperidyl]carbamate
[00219] A mixture of tert-butyl A-[l-[[4-[(3-nitro-5-phenyl-2-pyridyl)amino]phenyl]methyl]-4- piperidyl]carbamate (2.2 g, 4.4 mmol), 2-aminopyridine-3-carbaldehyde (694 mg, 5.7 mmol), NazS2O4 (1.5 g, 8.7 mmol) in DMSO (100 mL) was degassed and purged with Nz three times, The mixture was stirred at 100 °C for 16 hr under N2 atmosphere. After cooling to 25 °C, the reaction mixture was filtered, diluted with H2O (30 mL) and extracted with EtOAc (45 mL). The organic phase was separated, washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 5~6% EtOAc in petroleum ether) to give tert-butyl A-[l-[[4-[2-(2- amino-3-pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]-4-piperidyl]carbamate (700 mg, yield: 28%) as a black brown soild. MS: m/z = 576.2 [M + H]+. 'll NMR (400 MHz, Chloroform- ) 5 8.63 (d, J= 2.0 Hz, 1H), 8.27 (d, J= 2.0 Hz, 1H), 8.07 (dd, J= 5.2, 2.0 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.54 - 7.47 (m, 4H), 7.44 - 7.39 (m, 1H), 7.36 (d, J= 8.4 Hz, 2H), 7.09 (dd, J= 8.0, 2.0 Hz, 1H), 6.65 (br s, 2H), 6.35 (dd, J= 8.0, 4.8 Hz, 1H), 4.45 (br s, 1H), 3.58 (s, 2H), 3.55 - 3.46 (m, 1H), 2.92-2.77 (m, 2H), 2.16 (br t, J= 10 Hz, 2H), 1.95 (br d, J= 11.2 Hz, 2H), 1.63-1.56 (m, 2H), 1.45 (s, 9H).
[00220] Step 4: 3-[3-[4-[(4-Amino-l-piperidyl)methyl]phenyl]-6-phenyl-imidazo[4,5- b]pyri din-2 -yl]pyridin-2-amine
[00221] A mixture of tert-butyl A-[l-[[4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]-4-piperidyl]carbamate (2.4 g, 4.17 mmol) in HCl/l,4-dioxane (4M, 20 mL) and MeOH (4 mL) was stirred at 25 °C for 2 hr. The reaction mixture was filtered to give a residue (2 g HC1 salt, yield: 94.3%). The crude (100 mg) was purified by prep-HPLC (column: Welch Ultimate C18 150 x 25mm x 5pm; mobile phase: [water (FA)-ACN]; B%: 0% to 25%, lOmin) to give 3-[3-[4-[(4-amino-l-piperidyl)methyl]phenyl]-6-phenyl-imidazo[4,5- b]pyridin-2-yl]pyridin-2-amine (Intermediate 9, 26.6 mg, 2HCOOH salt, yield: 94%) as a yellow solid. MS: m/z = 476.1 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-^) 8 8.63 (d, J= 2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.34 (s, 2H), 8.00 (dd, J= 4.8, 1.6 Hz, 1H), 7.78 (d, J= 7.6 Hz, 2H), 7.53 (dd, J= 7.6, 7.6 Hz, 2H), 7.47 - 7.39 (m, 5H), 7.20 (dd, J= 7.6, 1.6 Hz, 1H), 7.04 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.55 (s, 2H), 2.98-2.88 (m, 1H), 2.87-2.80 (m, 2H), 2.09-1.97 (m, 2H), 1.90 - 1.80 (m, 2H), 1.57 - 1.44 (m, 2H).
[00222] Intermediate 10: 3-[5-Phenyl-3-[4-(piperazin-l-ylmethyl)phenyl]imidazo[4,5- b]pyridin-2-yl]pyridin-2-amine
Figure imgf000085_0001
[00223] Step 1 : tert-Butyl 4-[[4-[(6-chloro-3-nitro-2-pyridyl)amino]phenyl]methyl]piperazine- 1 -carboxylate
[00224] To a solution of 2, 6-di chi oro-3 -nitro-pyridine (5.0 g, 25.9 mmol) in 1,4-dioxane (50 mL) were added DIEA (6.7 g, 51.8 mmol) and Zc/7-biityl 4-[(4-aminophenyl)methyl]piperazine- 1-carboxylate (10 8 g, 25.9 mmol). The mixture was stirred at 60 °C for 12 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over NazSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-50% EtOAc in petroleum ether) to give terLbutyl 4-[[4-[(6- chloro-3-nitro-2-pyridyl)amino]phenyl]methyl]piperazine-l-carboxylate (6.1 g, yield: 53%) as a yellow solid. MS: m/z = 447.9 [M + H]+. LH NMR (400 MHz, Chloroform-t/) 8 10.27 (s, 1H), 8.46 (d, J= 8.8 Hz, 1H), 7.61 (d, J= 8.4 Hz, 2H), 7.36 (d, J= 8.4 Hz, 2H), 6.80 (d, J= 8.4 Hz, 1H), 3.52 (s, 2H), 3.48-3.37 (m, 4H), 2.45-2.32 (m, 4H), 1.46 (s, 9H).
[00225] Step 2. tert-Butyl 4-[[4-[(3-nitro-6-phenyl-2-pyridyl)amino]phenyl]methyl]piperazine- 1 -carboxylate
[00226] To a solution of tert-butyl 4-[[4-[(6-chloro-3-nitro-2- pyridyl)amino]phenyl]methyl]piperazine-l -carboxylate (1.0 g, 2.23 mmol) and phenylboronic acid (544 mg, 4.47 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)C12 (327 mg, 0.446 mmol) and K2CO3 (926 mg, 6.7 mmol). The mixture was stirred at 60 °C for 4 hr. The reaction mixture was added with H2O (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography (Eluent of 0~50% EtOAc in petroleum ether) to give tert-butyl 4-[[4- [(3-nitro-6-phenyl-2-pyridyl)amino]phenyl]methyl]piperazine-l-carboxylate (1.0 g, yield: 92%) as a red solid. MS: m/z = 490.1 [M + H]+. 'H NMR (400 MHz, Chloroform-^/) 8 10.31 (s, 1H), 8.59 (d, J= 8.8 Hz, 1H), 8.06-8 04 (m, 2H), 7.73 (d, J= 8.4 Hz, 2H), 7.52-7.44 (m, 3H), 7.37 (d, J= 8.4 Hz, 2H), 7.3 (d, J= 8.4 Hz, 1H), 3.54 (s, 2H), 3.52-3.37 (m, 4H), 2.49-2.37 (m, 4H), 1.46 (s, 9H).
[00227] Step 3: tert-Butyl 4-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]piperazine- 1 -carboxylate
[00228] To a solution of 2-aminopyridine-3-carbaldehyde (269 mg, 2.21 mmol) and tert-butyl 4-[[4-[(3-nitro-6-phenyl-2-pyridyl)amino]phenyl]methyl]piperazine-l-carboxylate (900 mg, 1.84 mmol) in DMSO (10 mL) was added NazSzCh (960 mg, 5.52 mmol) at 15 °C. The mixture was stirred at 100 °C for 20 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (80 mL x 3). The combined organic layers were washed with brine (80 mL x 3), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tertbutyl 4-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]piperazine-l -carboxylate (600 mg, yield: 58%) as a yellow solid. MS: m/z = 562.1 [M + H]+. fll NMR (400 MHz, Chloroforme d 8.13 (d, J = 8.4 Hz, 1H), 8.06 (dd, J= 5.2, 2.0 Hz, 1H), 8.03-8.01 (m, 2H), 7.81 (d, J= 8.4 Hz, 1H), 7.51-7.49 (m, 2H), 7.48-7.35 (m, 5H), 7.10 (dd, J= 9.6, 2.0 Hz, 1H), 6.66 (br s, 2H), 6.36 (dd, J= 8.0, 4.0 Hz, 1H), 3.64 (s, 2H), 3.53-3.42 (m, 4H), 2.55-2.42 (m, 4H), 1.47 (s, 9H).
[00229] Step 4: 3-[5-Phenyl-3-[4-(piperazin-l-ylmethyl)phenyl]imidazo[4,5-b]pyridin-2- yl]pyridin-2-amine
[00230] A solution of tert-butyl 4-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin- 3 -yl]phenyl]methyl]piperazine-l -carboxylate (400 mg, 712 pmol) in HCl/l,4-di oxane (4M, 8 mL) was stirred at 25 °C for 4 hr. The reaction was filtered and concentrated under reduced pressure to give 3-[5-phenyl-3-[4-(piperazin-l-ylmethyl)phenyl]imidazo[4,5-b]pyridin-2- yl]pyridin-2-amine (450 mg, HC1) as a yellow solid, which was used in the next step without further purification. The crude (200 mg) was purified by prep-HPLC (column: Waters xbridge 150*25mm 10pm;mobile phase: [water(NH4HCO3)-ACN];B%: 19%-49%, 9min) to give 3-[5- Phenyl-3-[4-(piperazin-l-ylmethyl)phenyl]imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (Intermediate 10, 49.7 mg) as a yellow solid. MS: m/z = 462.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- e) 8 8.27 (d, J= 8.4 Hz, 1H), 8.04-7.97 (m, 4H), 7.48-7.39 (m, 8H), 7.15 (dd, J= 8.0, 2.0 Hz, 1H), 7.03 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.53 (s, 2H), 2.74-2.66 (m, 4H), 2.38-2.27 (m, 4H).
[00231] Intermediate 11 : 3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
Figure imgf000087_0001
[00232] Step 1 : tert-Butyl (l-(4-((6-chloro-3-nitropyridin-2-yl)amino)benzyl)piperidin-4- yl)carbamate
[00233] To a solution of 2, 6-di chi oro-3 -nitro-pyridine (3.0 g, 15.5 mmol) and /e/Z-butyl 7V-[1- [(4-aminophenyl)methyl]-4-piperidyl]carbamate (4.8 g, 15.6 mmol) in 1,4-dioxane (100 mL) was added DIEA (6.0 g, 46.6 mmol). The mixture was stirred at 50 °C for 12 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~5% MeOH in CH2Q2) to give tert-butyl A-[l-[[4-[(6-chloro-3-nitro-2- pyridyl)amino]phenyl]methyl]-4-piperidyl]carbamate (4.6 g, yield: 64%) as an orange solid.
MS: m/z = 462.1 [M + H]+. 'H NMR (400 MHz, Chloroform- ) 5 10.26 (s, 1H), 8.46 (d, J = 8.8 Hz, 1H), 7.60 (d, J= 8.8 Hz, 2H), 7.34 (d, J= 8.4 Hz, 2H), 6.79 (d, J= 8.4 Hz, 1H), 4.42 (br s, 1H), 3.48 (s, 2H), 3.48 - 3.39 (m, 1H), 2.82 (br d, J= 10.8 Hz, 2H), 2.10 (br t, J= 10.8 Hz, 2H), 1.92 (br d, J= 10.8 Hz, 2H), 1.50-1.40 (m, 2H).1.44 (s, 9H).
[00234] Step 2 : tert-Butyl (l-(4-((3-nitro-6-phenylpyridin-2-yl)amino)benzyl)piperidin-4- yl)carbamate
[00235] A mixture of tert-butyl A-[l-[[4-[(6-chloro-3-nitro-2-pyridyl)amino]phenyl]methyl]-4- piperidyl]carbamate (1.0 g, 2.20 mmol), phenylboronic acid (528 mg, 4.30 mmol), Pd(dppf)C12 (158 mg, 0.216 mmol) and K2CO3 (898 mg, 6.50 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 12 hr under N2 atmosphere. After cooling to 25 °C, the reaction mixture was diluted with H2O and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~7% MeOH in CH2CI2) to give tert- butyl 7V-[l-[[4-[(3-nitro-6-phenyl-2-pyridyl)amino]phenyl]methyl]-4-piperidyl]carbamate (1.1 g, yield: 96%) as a yellow solid. MS: m/z = 504.1 [M + H]+. 'H NMR (400 MHz, Chloroform-c/) 8 10.31 (s, 1H), 8.59 (d, J= 8.8 Hz, 1H), 8.09 - 8.02 (m, 2H), 7.72 (d, J= 8.4 Hz, 2H), 7 51 - 7.47 (m, 3H), 7.36 (d, J= 8.8 Hz, 1H), 7.30 (d, J= 8.8 Hz, 1H), 4.52 - 4.37 (m, 1H), 3.52 (s, 2H), 3.51 - 3.42 (m, 1H), 2.85 (br d, J= 11.2 Hz, 2H), 2.12 (br t, J= 10.8 Hz, 2H), 1.93 (br d, J = 11.0 Hz, 2H), 1.50 - 1.40 (m, 2H). 1.44 (s, 9H).
[00236] Step 3: Zc/7-Butyl (l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl) carbamate
[00237] A solution of tert-butyl A-[l-[[4-[(3-nitro-6-phenyl-2-pyridyl)amino]phenyl]methyl]-4- piperidyl]carbamate (200 mg, 0.397 mmol), 2-aminopyridine-3-carbaldehyde (53.4 mg, 0.437 mmol) and Na2S2O4 (207 mg, 1.2 mmol) in DMSO (6 mL) was stirred at 100 °C for 18 hr. After cooling to 25 °C, the reaction mixture was diluted with DCM (40 mL). The organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~7% MeOH in CH2Q2) to give tert-butyl A-[l-[[4-[2-(2-amino-3-pyridyl)-5-phenyl- imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]-4-piperidyl]carbamate (100 mg, yield: 40%) as a yellow solid. MS: m/z = 576.2 [M + H]+.
[00238] Step 4: 3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
[00239] A solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)carbamate (200 mg, 0.347 mmol) in HCl in 1,4-dioxane (4 M, 2 mL) was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 24% - 54%, 8 min) to give 3-(3-(4-((4- aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 11, 120 mg, yield: 72 %) as a light-yellow solid. MS: m/z = 476.2 [M + H]+. 'H NMR (400 MHz, Chloroform- ) 8 8.12 (d, J= 8.4 Hz, 1H), 8.05 (dd, J= 5.2, 1.6 Hz, 1H), 8.01 (d, J= 7.2 Hz, 2H), 7.79 (d, J= 8.4 Hz, 1H), 7.50 - 7.35 (m, 7H), 7.09 (dd, J= 7.6, 1.2 Hz, 1H), 6.61 (br s, 2H), 6.35 (dd, J= 7.6, 4.8 Hz, 1H), 3.58 (s, 2H), 2.88 (br d, J= 11.6 Hz, 2H), 2.75 - 2.65 (m, 1H), 2.09 (br t, J= 11.6 Hz, 2H), 1.83 (br d, ./- 11.6 Hz, 2H), 1.49 - 1.38 (m, 2H).
[00240] Intermediate 12: 7V-(3-(3-(4-((4-Aminopiperidin-l-yl)methyl)phenyl)-2-(2- aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
Figure imgf000089_0001
[00241] Step 1 : tert-Butyl (l-(4-((6-(3-acetamidophenyl)-3-nitropyridin-2- yl)amino)benzyl)piperidin-4-yl)carbamate
[00242] A mixture of tert-butyl A-[l-[[4-[(6-chloro-3-nitro-2-pyridyl)amino]phenyl]methyl]-4- piperidyl]carbamate (1.0 g, 2.16 mmol), (3-acetamidophenyl)boronic acid (773 mg, 4.32 mmol), Pd(dppf)Ch (158 mg, 0.216 mmol) and K2CO3 (895 mg, 6.48 mmol) in H2O (2 mL) and 1,4- di oxane (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 100°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with CH CI2 (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over ISfeSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~5% MeOH in CH2CI2) to give tertbutyl A-[l-[[4-[[6-(3-acetamidophenyl)-3-nitro-2-pyridyl]amino]phenyl]methyl]-4- piperidyl]carbamate (1.04 g, yield: 86%) as an orange solid. MS: m/z = 561.1 [M + H]+. 'H NMR (400 MHz, Chloroform-^ 8 10.30 (s, 1H), 8.57 (d, J= 8.8 Hz, 1H), 8.26 (br s, 1H), 7.79 (d, J= 8.0 Hz, 1H), 7.72 (d, J= 8.4 Hz, 2H), 7.63 - 7.57 (m, 1H), 7.47 - 7.35 (m, 4H), 7.28 (d, J = 8.8 Hz, 1H), 4.44 (br s, 1H), 3.51 (s, 2H), 3.44 - 3.48 (m, 1H), 2.93 - 2.78 (m, 2H), 2.23 (s, 3H), 2.13 (br t, J= 10.4 Hz, 2H), 1.93 (br d, J= 11.2 Hz, 2H), 1.52 - 1.45 (m, 2H), 1.44 (s, 9H). [00243] Step 2: tert-Butyl (l-(4-((3-nitro-6-phenylpyridin-2-yl)amino)benzyl)piperidin-4- yl)carbamate
[00244] A solution of tert-butyl A-[l-[[4-[[6-(3-acetamidophenyl)-3-nitro-2- pyridyl]amino]phenyl]methyl]-4-piperidyl]carbamate (950 mg, 1.69 mmol), 2-aminopyridine-3- carbaldehyde (228 mg, 1.9 mmol) and Na2SO4 (590 mg, 3.4 mmol) in DMSO (12 mL) was stirred at 100 °C for 18 hr. After cooling to 25 °C, the reaction mixture was diluted with CH2CI2 (50 mL), washed with H2O (50 mL) and brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~7% MeOH in CH2CI2) to give tert-butyl A-[ 1 -[[4-[5-(3- acetamidophenyl)-2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]-4- piperidyl]carbamate (536 mg, yield: 50%) as a yellow solid. MS: m/z = 633.3 [M + H]+. 'H NMR (400 MHz, Chloroform-tf) 5 8.11 (d, J= 8.4 Hz, 1H), 8.06 (dd, J= 4.8, 2.0 Hz, 1H), 8.00 (br s, 1H), 7.78 (d, J= 8.4 Hz, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.49 (br s, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.40 - 7.34 (m, 3H), 7.05 (dd, J= 8.0, 1.6 Hz, 1H), 6.60 (br s, 2H), 6.33 (dd, J= 7.6, 4.8 Hz, 1H), 4.47 (br s, 1H), 3.58 (s, 2H), 3.51 - 3.48 (m, 1H), 2.85 (br d, J = 11.2 Hz, 2H), 2.18 - 2.16 (m, 2H), 2.14 (s, 3H), 1.94 (br d, J= 10.8 Hz, 2H), 1.49 - 1.47 (m, 2H), 1.45 (s, 9H).
[00245] Step 3: A-(3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-2-(2-aminopyridin-3-yl)- 3H-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
[00246] A solution of tert-butyl A-[l-[[4-[5-(3-acetamidophenyl)-2-(2-amino-3- pyridyl)imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]-4-piperidyl]carbamate (300 mg, 474 pmol) in HCl/l,4-di oxane (4 M, 2 mL) was stirred at 25 °C for 2 hr. The reaction mixture was added NaHCCh to adjust the pH to abount 8, and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried by NazSCL, filtered and concentrated under reduced pressure to give A-(3-(3-(4-((4-aminopiperidin-l-yl)methyl)phenyl)-2-(2- aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide (Intermediate 12, 134 mg, yield: 53%) as a yellow solid. MS: m/z = 533.2 [M + H]+. LH NMR (400 MHz, Chloroform-^/) 8 8.13 (d, J= 8.4 Hz, 1H), 8.07 (dd, J= 4.8, 1.6 Hz, 1H), 8.02 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.48 (d, J= 8.4 Hz, 2H), 7.42 - 7.37 (m, 4H), 7.08 (d, J= 6.8 Hz, 1H), 6.61 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 3.59 (s, 2H), 2.90 (br d, J = 11.2 Hz, 2H), 2.77 - 2.67 (m, 1H), 2.20 (s, 3H), 2.12 (br t, J= 11.2 Hz, 2H), 1.85 (br d, J = 11.2 Hz, 2H), 1.49 - 1.41 (m, 2H).
[00247] Intermediate 13: Methyl 4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyri din-3 -yl)benzoate
Figure imgf000090_0001
[00248] Step 1 : Methyl 4-((6-chloro-3-nitropyridin-2-yl)amino)benzoate
[00249] To a solution of methyl 4-aminobenzoate (5 g, 33.1 mmol) in DMSO (50 mL) were added 2,6-dichloro-3-nitro-pyridine (7.66 g, 39.7 mmol) and DIEA (12.82 g, 99.2 mmol). The mixture was stirred at 80 °C for 16 hr. After cooling to 20 °C, the reaction mixture was poured into H2O (100 mL) and extracted with CH2CI2 (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na SCh, filtered, and concentrated under reduced pressure. The crude was triturated with EtOAc at 25 °C for 30 min to give methyl 4- [(6-chloro-3-nitro-2-pyridyl)amino]benzoate (8 g, yield: 51%) as a yellow solid MS: m/z = 307.8 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-^) 8 10.25 (s, 1H), 8.57 (d, J= 8.4 Hz, 1H), 7.97 (d, J= 8.8 Hz, 2H), 7.79 (d, J= 8.8 Hz, 2H), 7.12 (d, J= 8.4 Hz, 1H), 3.85 (s, 3H).
[00250] Step 2: Methyl 4-((3-nitro-6-phenylpyridin-2-yl)amino)benzoate
[00251] To a solution of methyl 4-[(6-chloro-3-nitro-2-pyridyl)amino]benzoate (45 g, 146 mmol) and phenylboronic acid (21.4 g, 176 mmol) in 1,4-dioxane (500 mL) and H2O (100 mL) were added Pd(dppf)C12 (10.7 g, 14.6 mmol) and CS2CO3 (143 g, 439 mmol). The mixture was degassed and purged with N2 three times and stirred at 80 °C for 16 hr under N2 atmosphere. The reaction mixture was poured into H2O (500 mL) and extracted with CH2CI2 (500 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over anhydrous NazSC , filtered, and concentrated. The crude was triturated with EtOAc at 25 °C for 30 min to give methyl 4-[(3-nitro-6-phenyl-2-pyridyl)amino]benzoate (35.2 g, yield: 69%) as a red solid. MS: m/z = 350.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-fifc) 810.25 (s, 1H), 8.62 (d, J= 8.8 Hz, 1H), 8.15 - 8.10 (m, 2H), 8.00 (d, J= 8.4 Hz, 2H), 7.92 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 8.8 Hz, 1H), 7.59 - 7.54 (m, 3H), 3.86 (s, 3H).
[00252] Step 3: Methyl 4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzoate
[00253] To a solution of methyl 4-[(3-nitro-6-phenyl-2-pyridyl)amino]benzoate (15 g, 42.9 mmol) in DMSO (150 mL) were added 2-aminopyridine-3-carbaldehyde (6.29 g, 51.5 mmol) and Na2S2O4 (15 g, 85.9 mmol). The reaction mixture was heated to 100°C for 16 hr. After cooling to 25 °C, the reaction mixture was diluted with H2O (200 mL) and extracted with CH2CI2 (200ml x 3). The combined organic layers were washed with brine (200ml x 2), dried over NazSCfi, filtered, and concentrated under reduced pressure. The crude was triturated with CH2CI2 at 25°C for 30 min to give methyl 4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzoate (Intermediate 13, 12 g, yield: 66%) as a yellow solid. MS: m/z = 422.0 [M + H]+. 'H NMR (400 MHz, Di methyl sulfoxide-^) 8 8.29 (d, J= 8.0 Hz, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.07 - 8.00 (m, 4H), 7.67 (d, J= 8.8 Hz, 2H), 7.49 - 7.44 (m, 2H), 7.42 - 7.38 (m, 1H), 7.23 (dd, J= 7.6, 1.6Hz, 1H), 6.89 (br s, 2H), 6.46 (dd, J= 7.6, 4.8 Hz, 1H), 3.90 (s, 3H). [00254] Intermediate 14: 3-(3-(4-(Chloromethyl)phenyl)-5-phenyl-37/-imidazo[4,5-b]pyridin- 2-yl)pyridin-2-amine
Figure imgf000092_0001
[00255] Step 1 : (4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
[00256] To a solution of Intermediate 13 (2.5 g, 5.9 mmol) in THF (25 mL) was added LiAlHi (450 mg, 11.9 mmol) at 0 °C. After addition, the resulting mixture was stirred at 25 °C for 2 hr. After cooling to 0 °C, the reaction mixture was quenched with H2O (100 mL) and 15% aqueous NaOH (30 mL). The reaction mixture was filtered and concentrated to give [4-[2-(2-amino-3- pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]methanol (1.87 g, yield: 80%) as a yellow solid, which was used in the next step without further purification. MS: m/z = 394.1 [M + H]+.
[00257] Step 2: 3-(3-(4-(Chloromethyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
[00258] To a solution of [4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methanol (2.3 g, 5.9 mmol) in CH2CI2 (25 mL) was added SOCI2 (2.1 g, 17.5 mmol). The mixture was stirred at 40°C for 1 hr. The reaction mixture was filtered and concentrated to give 3-(3-(4-(Chloromethyl)phenyl)-5-phenyl-3Z/-imidazo[4, 5-b]pyri din-2 -yl)pyridin-2-amine (Intermediate 14, 1.71 g, yield: 71%) as a yellow solid. MS: m/z = 412.0 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tL) 8 8.29 (d, J= 8.4 Hz, 1H), 8.12 (d, J= 8.4 Hz, 2H), 8.07 - 8.00 (m, 4H), 7.67 (d, J= 8.4 Hz, 2H), 7.50 - 7.44 (m, 2H), 7.42 - 7.37 (m, 1H), 7.24 (d, J= 7.2 Hz, 1H), 6.88 (br s, 2H), 6.46 (dd, J= 4.8, 7.6 Hz, 1H), 3.90 (s, 2H).
[00259] Intermediate 15: 3-(3-(4-((2,6-Diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000092_0002
[00260] Step 1 : Zc/'Z-Butyl 6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-
3-yl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [00261] To a solution of Intermediate 14 (200 mg, 486 pmol) in MeCN (3 mL) were added K2CO3 (268 mg, 1.94 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (106 mg, 534 pmol) and Nal (7.28 mg, 48 pmol) at 25 °C. The reaction mixture was stirred at 80 °C for 3 hr. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 - 7% MeOH in CH2CI2) to give tertbutyl 6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (150 mg, yield: 54%) as a yellow solid. MS: m/z = 574.6 [M + H]+.
[00262] Step 2: 3-(3-(4-((2,6-Diazaspiro[3.3]heptan-2-yl)methyl)phenyl)-5-phenyl-3J7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00263] To a solution of tert-butyl 6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg, 261 pmol) in CH2CI2 (3 mL) was added TFA (1.54 g, 13.5 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated to give 3-(3-(4-((2,6-diazaspiro[3.3]heptan-2- yl)methyl)phenyl)-5-phenyl-3Z/-imidazo[4,5-/>]pyridin-2-yl)pyridin-2-amine (Intermediate 15, 120 mg, TFA salt, yield: 81%) as a yellow solid. MS: m/z = 474.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-cfc) 5 8.26 (d, J= 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.49 - 7.44 (m, 2H), 7.42 - 7.37 (m, 5H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 6.99 (br s, 2H), 6.39 (dd, J= 8.0, 5.2 Hz, 1H), 3.58 (s, 2H), 3.56 (s, 4H), 3.25 (s, 4H), 1.23 (s, 1H).
[00264] Intermediate 16: 3-(3-(4-((2,6-Diazaspiro[3.4]octan-2-yl)methyl)phenyl)-5-phenyl-3Z7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
Figure imgf000093_0001
[00265] Step 1 : tert-Butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.4]octane-6-carboxylate
[00266] To a solution of Intermediate 14 (200 mg, 485 pmol) in MeCN (3 mL) were added K2CCb (268 mg, 1.94 mmol), tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (113 mg, 534 pmol) and Nal (7.28 mg, 48 pmol) at 25 °C. The reaction mixture was stirred at 80 °C for 3 hr. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 - 7% MeOH in CH2Q2) to give tertbutyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,6- diazaspiro[3.4]octane-6-carboxylate (150 mg, yield: 53%) as a yellow solid. MS: m/z = 588.3 [M + H]+.
[00267] Step 2: 3-(3-(4-((2,6-Diazaspiro[3.4]octan-2-yl)methyl)phenyl)-5-phenyl-3JT- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00268] To a solution of tert-butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,6-diazaspiro[3.4]octane-6-carboxylate (150 mg, 255 pmol) in CH2CI2 (3 mL) was added TFA (1.54 g, 13.5 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was poured into water (20 mL). The resulting mixture was washed with CH2CI2 (50 mL x 2). The pH of the aqueous phase was adjusted to 8 by NaHCCh. The resulting mixture was extracted with CH2Q2 (50 mL x 2). The combined organic phases were dried over anhydrous ISteSCh, filtered and concentrated to give 3-(3-(4-((2,6- diazaspiro[3.4]octan-2-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyri din-2 -yl)pyridin-2- amine (Intermediate 16, 104 mg, yield: 14%) as a yellow solid. MS: m/z = 488.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/s) 8 8.26 (d, J= 8.4 Hz, 1H), 8.06 - 7.95 (m, 4H), 7.51 - 7.36 (m, 7H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 6.99 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.63 (s, 2H), 3.16 - 3.10 (m, 4H), 2.88 (s, 2H), 2.74 (t, J = 6.8 Hz, 2H), 1.82 (t, J = 6.8 Hz, 2H), 1.25 - 1.22 (m, 1H).
[00269] Intermediate 17: Benzyl (2-hydroxyethyl)(piperidin-4-yl)carbamate)
Figure imgf000094_0001
[00270] Step 1 : ZcvZ-Butyl 4-((2 -hydroxy ethyl)amino)piperi dine- 1 -carboxylate) [00271] A mixture of ze/'Z-butyl 4-oxopiperidine-l-carboxylate (20 g, 100 mmol), 2- aminoethanol (12.3 g, 201 mmol), CH3COOH (6.0 g, 100 mmol) and Na(OAc)3BH (53 g, 251 mmol) in CH2CI2 (200 mL) was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched with 3 M NaOH (150 mL) at 0 °C, diluted with H2O (50 mL), and extracted with CH2CI2 (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over NazSC filtered, and concentrated under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2CI2 = 0% to 15%), ZcvZ-butyl 4-((2-hydroxyethyl)amino)piperidine-l -carboxylate (36 g, yield: 33%) was obtained as a colorless oil. 'H NMR (400 MHz, Chloroform -c/) 84.02 (br s, 2H), 3.62 (t, J= 4.8 Hz, 2H), 2.85 - 2.66 (m, 4H), 2.62 - 2.55 (m, 1H), 2.13 (br s, 2H), 1.85 - 1.82 (m, 2H), 1.43 (s, 9H), 1.31 - 1.15 (m, 2H).
[00272] Step 2 : Ze/'Z-Butyl 4-(((benzyloxy)carbonyl)(2-hydroxyethyl)amino)piperidine-l- carboxylate) [00273] To a solution of tert-butyl 4-(2-hydroxyethylamino)piperidine-l -carboxylate (1.0 g, 4.09 mmol) and TEA (828 mg, 8.2 mmol) in CH2Q2 (10 m ) was added CbzCl (698 mg, 4.09 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, fdtered, and concentrated under reduced pressure. After purified by silica gel flash chromatography (EtOAc in petroleum ether = 0 ~ 70%), tertebutyl 4-(((benzyloxy)carbonyl)(2-hydroxyethyl)amino)piperidine-l -carboxylate) (1.2 g, yield: 78%) was obtained as a light-yellow solid. LH NMR (400 MHz, Cliloroforni-t/) 87.38 - 7.33 (m, 5H), 5.16 (s, 2H), 4.70 (d, J= 6.0 Hz, 1H), 4.24 - 4.12 (m, 2H), 4.10 - 3.93 (m, 1H), 3.72 - 3.69 (m, 2H), 3.38 - 3.36 (m, 2H), 2.79 - 2.65 (m, 2H), 1.80 - 1.61 (m, 4H), 1.45 (s, 9H). [00274] Step 3: Benzyl (2-hydroxyethyl)(piperidin-4-yl)carbamate)
[00275] A solution of tert-butyl 4-[benzyloxycarbonyl(2-hydroxyethyl)amino]piperidine-l- carboxylate (900 mg, 2.38 mmol) in HCl/l,4-di oxane (4 M, 4 mL) was stirred at 25 °C for 2 hr. The solvent was removed under reduced pressure. Benzyl (2-hydroxyethyl)(piperidin-4- yl)carbamate) (Intermediate 17, 750 mg HC1 salt, yield: 100%) was obtained as a white solid. The crude product was used in the next step without further purification. MS: m/z = 279.2 [M + H]+.
[00276] Intermediate 18: (J?)-3-(3-(4-((3-Aminopyrrolidin-l-yl)methyl)phenyl)-5-phenyl-3//- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
Figure imgf000095_0001
[00277] Step 1 : (7?)-tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)carbamate
[00278] To a solution of Intermediate 14 (50 mg, 121 pmol) in DMF (0.5 mL) were added tertbutyl A-[(3A)-pyrrolidin-3-yl]carbamate (24.8 mg, 133 pmol), Nal (1.82 mg, 12.1 pmol) and K2CO3 (33.5 mg, 242 pmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was diluted with H2O (5 mL) and filtered to give (7?)-tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)- 5-phenyl-5Z/-imidazo[4,5-b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)carbamate (60 mg, yield: 88%) as a yellow solid, which was used in the next step without further purification. MS: m/z = 562.3 [M + H]+. [00279] Step 2: (R)-3-(3-(4-((3-Aminopyrrolidin-l-yl)methyl)phenyl)-5-phenyl-3//- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
[00280] To a solution of (A)-tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3J7- imidazo[4,5-b]pyri din-3 -yl)benzyl)pyrrolidin-3-yl)carbamate (60 mg, 106 pmol) in CH2CI2 (2 mb) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 20 °C for 2 hr The reaction mixture was concentrated under reduced pressure to give a crude product (TFA salt). The crude was used in the next step without further purification.
[00281] The crude was quenched with sat. NaHCCL (5 mL) and extracted with CH2CI2 (10 mL x 3). The combined organic layers were washed with brine (5 ml), dried over Na2SCU, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (CH2Q2: MeOH = 10: l) to give (A)-3-(3-(4-((3-aminopyrrolidin-l-yl)methyl)phenyl)-5-phenyl-3/f- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine(Intermediate 18, 7.7 mg) as a light-yellow powder. MS: m/z = 462.3 [M + H]+. XHNMR (400 MHz, Dimethylsulfoxide- d6) 8 8.27 (d, J= 8.0 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.52 - 7.44 (m, 6H), 7.43 - 7.34 (m, 1H), 7.6 (dd, J= 7.6, 2.0 Hz, 1H), 7.00 (br s, 2H), 6.40 (dd, J= 8.0, 5.2 Hz, 1H), 3.69 (s, 2H), 3.60 - 3.57 (m, 2H), 2.75 - 2.66 (m, 2H), 2.46 - 2.40 (m, 1H), 2.18 - 2.08 (m, 1H), 1.66 - 1.56 (m, 1H).
[00282] Intermedi te 19: 3 -(3 -(4-((3 - Aminoazetidin- 1 -yl)methyl)phenyl)-5 -pheny 1-3//- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
Figure imgf000096_0001
[00283] Step 1 : Zc/7-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3 -yl)benzyl)azeti din-3 -yl)carb mate
[00284] A solution of Intermediate 14 (50 mg, 121 pmol) in DMF (0.5 mL) were added tert- butyl A-(azetidin-3-yl)carbamate (23.0 mg, 133 pmol), Nal (1.82 mg, 12.1 pmol) and K2CO3 (33.5 mg, 242 pmol) was stirred at 80 °C for 2 hr. The reaction mixture was diluted with H2O (5 mL) and filtered to give terz-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)azetidin-3-yl)carbamate (60 mg, yield: 90%) as a yellow solid, which was used in the next step without further purification. MS: m/z = 548.3 [M + H]+.
[00285] Step 2: 3-(3-(4-((3-Aminoazetidin-l-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine [00286] To a solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- b]pyridin-3-yl)benzyl)azetidin-3-yl)carbamate (60 mg, 109 pmol) in CH2Q2 (2 m ) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 20 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give 3-(3-(4-((3-aminoazetidin-l-yl)methyl)phenyl)-5- phenyl-3/f-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 19, 31 mg, TFA salt, yield: 53%). The crude product was used in the next step without further purification. MS: m/z = 448.2 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide- d6 5 8.26 (d, J = 8.4 Hz, 1H), 8.04 - 7.96 (m, 4H), 7.49 - 7.36 (m, 7H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 7.00 (br s, 2H), 6.39 (dd, J= 8.0, 4.8 Hz, 1H), 3.61 (s, 2H), 3.52 - 3.48 (m, 2H), 3.47 - 3.38 (m, 3H), 2.72 - 2.65 (m, 2H).
[00287] Intermediate 20: 2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-azaspiro[4.5]decan-8-amine
Figure imgf000097_0001
[00288] Step 1 : tert-Butyl (2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2-azaspiro[4.5]decan-8-yl)carbamate
[00289] To a solution of Intermediate 14 (100 mg, 243 pmol) in CH3CN (8 mL) were added tert-butyl 2-azaspiro[4.5]decan-8-ylcarbamate (55.6 mg, 219 pmol), Nal (3.64 mg, 24.3 pmol) and K2CO3 (134 mg, 971 pmol). The mixture was stirred at 80 °C for 2 hr. The mixture was concentrated under reduced pressure. The mixture was purified by silica gel flash chromatography (Eluent of 0 - 12% MeOH in CH2CI2) to give te/7-butyl (2-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)-2-azaspiro[4.5]decan-8- yl)carbamate (64 mg, yield: 42%) as a yellow solid. MS: m/z = 630.5 [M + H]+.
[00290] Step 2: 2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-azaspiro[4.5]decan-8-amine
[00291] To a solution of tert-butyl (2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-azaspiro[4.5]decan-8-yl)carbamate (80 mg, 127 pmol) in CH2CI2 (1 mL) was added TFA (29 mg, 254 pmol). The mixture was stirred at 25 °C for 2 hr. The mixture was duilted with H2O (5 mL) and extrated by CH2CI2 (5 mL x 2). The pH of aqueous phase was adjusted to about 8 with NaHCCF (aq). The aqueous layer was extrated with CH2Q2 (5 mL x 2). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give 2-(4-(2-(2-Aminopyri din-3- yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3-yl)benzyl)-2-azaspiro[4.5]decan-8-amine (Intermediate 20, 10.9 mg, yield: 16%) as a light-yellow solid. MS: m/z = 530.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- e) 88.26 (d, J= 8.8 Hz, 1H), 8.06 - 7.94 (m, 4H), 7.50 - 7.37 (m, 7H), 7.15 (d, J= 7.2 Hz, 1H), 7.03 (br s, 2H), 6.44 - 6.32 (m, 1H), 4.40 - 4.36 (m, 1H), 4.18 - 4 09 (m, 6H), 1.65 - 1.45 (m, 6H), 1.31 - 1.22 (m, 4H)
[00292] Intermediate 21: 3-(3-(4-((2,7-Diazaspiro[3.5]nonan-7-yl)methyl)phenyl)-5-phenyl- 37/-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000098_0001
[00293] Step 1 : tert-Butyl 7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
[00294] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) and tert-butyl 2,7- diazaspiro[3.5]nonane-2-carboxylate (660 mg, 2.92 mmol) in ACN (20 mL) were added Nal (36.4 mg, 243 pmol) and K2CO3 (671 mg, 4.86 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was concentrated. The residue was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tert-butyl 7-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,7-diazaspiro[3.5]nonane- 2-carboxylate (570 mg, yield: 39%) as a light-yellow solid, which was used in the next step without further purification. MS: m/z = 602.3 [M + H]+.
[00295] Step 2: 3-(3-(4-((2,7-Diazaspiro[3.5]nonan-7-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00296] A solution of tert-butyl 7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (490 mg, 814 pmol) in HCl in 1,4-di oxane (4M, 9 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated. The residue was purified by /jrep-HPLC (column: Waters xbridge 150 * 25 mm 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 32% - 62%, 8 min). 3-(3-(4-((2,7- Diazaspiro[3.5]nonan-7-yl)methyl)phenyl)-5-phenyl-37/-imidazo[4,5-b]pyri din-2 -yl)pyridin-2- amine (Intermediate 21, 300 mg, yield: 74%) was obtained as a light-yellow oil. MS: m/z = 502.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- e) 8 8.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.49 - 7.39 (m, 7H), 7.18 - 7.12 (dd, J= 7.6, 1.6 Hz, 1H), 7.02 (br s, 2H), 6.36 (dd, J= 7.6, 5.2 Hz, 1H), 3.58 - 3.41 (m, 6H), 2.38 - 2.26 (m, 4H), 1.71 - 1.68 (m, 4H). [00297] Intermediate 22: 3-(3-(4-((2,8-Diazaspiro[4.5]decan-8-yl)methyl)phenyl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000099_0001
[00298] Step 1 : tert-Butyl 8-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decane-2-carboxylate
[00299] To a solution of Intermediate 14 (250 mg, 607 pmol) in DMF (2 mb) were added tert- butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (160 mg, 668 pmol), Nal (9.10 mg, 60.7 pmol) and K2CO3 (252 mg, 1.82 mmol). The resulting mixture was stirred at 80 °C for 16 hr. The reaction mixture was poured into H2O (5 mb) and extracted with EtOAc (10 mb x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~65% EtOAc in petroleum ether) to give tert-butyl 8-(4-(2-(2-aminopyridin-3-yl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (200 mg, yield: 53%) as a yellow solid. MS: m/z = 616.2 [M + H]+.
[00300] Step 2: 3-(3-(4-((2,8-Diazaspiro[4.5]decan-8-yl)methyl)phenyl)-5-phenyl-3//- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00301] To a solution of tert-butyl 8-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (280 mg, 455 pmol) in dioxane (1 mL) was added 4M HC1 in 1,4-dioxane (2 mb). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated, extracted with CH2Q2 (15 mL), washed with saturated NaHCCh (5 mL) aqueous solution. The organic layer was separated, dried over Na2SC>4, filtered, and concentrated under reduced pressure to give 3-(3-(4-((2,8-diazaspiro[4.5]decan-8- yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 22, 200 mg, yield: 85%). MS: m/z = 516.3 [M + H]+. 'll NMR (400 MHz, Methanol-^) 8 8.18 (d, J= 8.4 Hz, 1H), 8.02 (d, J= 7.2 Hz, 2H), 7.97 (dd, J= 4.8, 1.6 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.45 - 7.34 (m, 5H), 7.31 (dd, J= 6.8, 1.6 Hz, 1H), 6.45 (dd, J= 7.6, 4.8 Hz, 1H), 3.62 (s, 2H), 3.10 (t, J= 7.2 Hz, 2H), 2.85 (s, 2H), 2.50 (m, 4H), 1.75 (t, J= 72 Hz, 2H), 1.65 ( t, J= 5.6 Hz, 4H).
[00302] Intermediate 23: 3-(3-(4-((2,6-Diazaspiro[3.4]octan-6-yl)methyl)phenyl)-5-phenyl-3Z/- imidazo[4,5-6]pyridin-2-yl)pyridin-2-amine
Figure imgf000100_0001
[00303] Step 1 : tert-Butyl 6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.4]octane-2-carboxylate
[00304] To a solution of Intermediate 14 (200 mg, 486 pmol), tert-butyl 2,6- diazaspiro[3.4]octane-2-carboxylate (113 mg, 534 pmol) in DMF (2 mL) were added Nal (7.28 mg, 48.6 pmol) and K2CO3 (134 mg, 971 pmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was poured into H2O (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~60% EtOAc in petroleum ether) to give tert-butyl 6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (127 mg, yield: 45%) as a yellow solid. MS: m/z = 588.4 [M + H]+.
[00305] Step 2: 3-(3-(4-((2,6-Diazaspiro[3.4]octan-6-yl)methyl)phenyl)-5-phenyl-3/f- imidazo[4,5-Z>]pyridin-2-yl)pyridin-2-amine
[00306] To a solution of tert-butyl 6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (60 mg, 103 pmol) in CH2Q2 (2 mL) was added TFA (47 mg, 408 pmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 3-(3-(4-((2,6-diazaspiro[3.4]octan-6- yl)methyl)phenyl)-5-phenyl-3Z/-imidazo[4,5-/>]pyridin-2-yl)pyridin-2-amine (54 mg, TFA salt, yelid: 90%). Then saturated NaHCCF aqueous solution (10 mL) was added to adjust pH to around 9. The mixture was extracted with CH2Q2 (5 mL x 3). The combined organic layers were dried over Na2SO-i, filtered and concentrated under reduced pressure to give 3-(3-(4-((2,6- diazaspiro[3.4]octan-6-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-2-yl)pyridin-2- amine (Intermediate 23, 17.6 mg, free base) as a yellow solid. MS: m/z = 488.3 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.18 (d, J= 8.4 Hz, 1H), 8.06 - 7.89 (m, 4H), 7.51 (d, J= 8.0 Hz, 2H), 7.45 - 7.40 (m, 3H), 7.39 - 7.30 (m, 3H), 6.48 (dd, J= 7.6, 5.2 Hz, 1H), 3.99 (d, J= 2.4 Hz, 2H), 3.72 (s, 2H), 2.87 (s, 2H), 2.71 - 2.61 (m, 2H), 2.18 (t, J= 7.2 Hz, 2H), 1.28 - 1.25 (m, 2H).
[00307] Intermediate 24: 3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl- 37/-imidazo[4,5-Z>]pyridin-2-yl)pyridin-2-amine
Figure imgf000101_0001
[00308] Step 1 : tert-Butyl 7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin- 3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
[00309] To a solution of Intermediate 14 (1.5 g, 3.6 mmol) and tert-butyl 2,7- diazaspiro[4.4]nonane-2-carboxylate (988 mg, 4.4 mmol) in DMF (10 mL) were added Nal (273 mg, 1.82 mmol) and K2CO3 (1.0 g, 7.3 mmol). The mixture was stirred at 80 °C for 1 hr. Then the reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, fdtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography (Eluent of 0-98% EtOAc in petroleum ether) to give tert-butyl 7-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-/>]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane- 2-carboxylate (640 mg, yield: 30%) as a yellow solid. MS: m/z = 602.4 [M + H]+ .
[00310] Step 2: 3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-6]pyridin-2-yl)pyridin-2-amine
[00311] A solution of tert-butyl 7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (590 mg, 980 pmol) in HCl in 1,4-di oxane (4 M, 5 mL) was stirred at 25 °C for 0.5 hr. The mixture was concentrated, washed with CH2CI2 (3 mL), and concentrated under reduced pressure to give 3-(3-(4-((2,7- diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-2-yl)pyri din-2- amine (Intermediate 24, 452 mg, HC1 salt, yield: 86%) as a yellow solid. MS: m/z = 502.3 [M + H]+. JH NMR (400 MHz, Dimethylsulfoxide-rL) 8 11.93 (br s, 1H), 9.88 - 9.48 (m, 2H), 8.60 - 8.35 (m, 2H), 8.38 (d, J= 8.4 Hz, 1H), 8.16 (dd, J= 6.4, 1.6 Hz, 1H), 8.08 - 8.05 (m, 3H), 7.98 - 7.83 (m, 3H), 7.66 (d, J= 8.4 Hz, 2H), 7.52 - 7.40 (m, 3H), 7.02 - 6.92 (m, 1H), 4.54 - 4.43 (m, 2H), 3.64 - 3.47 (m, 2H), 3.43 - 3.27 (m, 3H), 3.25 - 3.18 (m, 3H), 2.31 - 2.14 (m, 2H), 2.11 - 1.96 (m, 2H).
[00312] Intermediate 25: 3-(3-(4-((2,7-Diazaspiro[4.5]decan-2-yl)methyl)phenyl)-5-phenyl- 3//-imidazo[4,5-6]pyridin-2-yl)pyridin-2-amine
Figure imgf000102_0001
[00313] Step 1 : Zcz'Z-Butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin- 3-yl)benzyl)-2,7-diazaspiro[4.5]decane-7-carboxylate
[00314] To a solution of Intermediate 14 (1.5 g, 3.6 mmol) and Zcz'Z-butyl 2,8- diazaspiro[4.5]decane-8-carboxylate (1.0 g, 4.4 mmol) in DMF (10 mL) were added Nal (273 mg, 1.8 mmol) and K2CO3 (1.5 g, 11 mmol). The mixture was stirred at 80 °C for 1 hr. After cooling to 20 °C, the reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-85% EtOAc in petroleum ether) to give ZcvZ-butyl 2-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.5]decane- 7-carboxylate (1.2 g, yield: 53%) as a yellow solid. MS: m/z = 616.1 [M + H]+.
[00315] Step 2: 3-(3-(4-((2,7-Diazaspiro[4.5]decan-2-yl)methyl)phenyl)-5-phenyl-3Z/- imidazo[4,5-6]pyridin-2-yl)pyridin-2-amine
[00316] A solution of Zc/'Z-butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.5]decane-7-carboxylate (240 mg, 390 pmol) in HCl/1,4- dioxane (4 M, 2 mL) was stirred at 25 °C for 0.5 hr. The mixture was concentrated and washed with CH2CI2 (3 mL), then concentrated under reduced pressure. 3-(3-(4-((2,7- Diazaspiro[4.5]decan-2-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-ft]pyridin-2-yl)pyridin-2- amine (Intermediate 25, 188 mg, HC1 salt, yield: 88%) was obtained as a yellow solid. MS: m/z = 516.4 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.32 (d, J= 8.4 Hz, 1H), 8.09 - 8.00 (m, 4H), 7.93 (d, J = 8.4 Hz, 2H), 7.89 (d, J= 7.2 Hz, 1H), 7.72 (d, J= 8.0 Hz, 2H), 7.49 - 7.37 (m, 3H), 6.99 - 6.85 (m, 1H), 4.62 (d, J= 11.6 Hz, 2H), 3.78 - 3.72 (m, 1H), 3.65 - 3.47 (m, 2H), 3.44 . 3.38 (m, 1H), 3.35 (s, 2H), 3.18 - 3.13 (m, 2H), 2.26 - 2.13 (m, 1H), 2.11 - 2.01 (m, 1H), 1.95 - 1.86 (m, 4H).
[00317] Intermediate 26: 3-(3-(4-((2,7-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000103_0001
[00318] Step 1 : Zcz'Z-Butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37T-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate
[00319] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) in MeCN (10 mL) were added K2CO3 (1.0 g, 7.28 mmol), Nal (109 mg, 728 pmol), and Zez'Z-butyl 2,7-diazaspiro[3.5]nonane-7- carboxylate (604 mg, 2.67 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 1~5% MeOH in CH2CI2). Zc/'Z-Butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (775 mg, yield: 53%) was obtained as a yellow solid. MS: m/z = 602.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-z4) 6 8.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.49 - 7.39 (m, 7H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 6.99 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.68 (s, 2H), 3.26 - 3.22 (m, 4H), 3.01 (s, 4H), 1.64 - 1.58 (m, 4H), 1.38 (s, 9H).
[00320] Step 2: 3-(3-(4-((2,7-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00321] A solution of ZezZ-butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,7-diazaspiro[3 5]nonane-7-carboxylate (350 mg, 582 pmol) in 4 M HC1 in 1,4-di oxane (4 mL) was stirred at 25 °C for 2 hr. The reaction was concentrated under reduced pressure to give 3-(3-(4-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-5-phenyl-377- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine (Intermediate 26, 270 mg, HC1 salt, yield: 86%) as a yellow solid. MS: m/z = 502.3 [M + H]+. 'H NMR (400 MHz, Dim ethyl sulfoxide- y) 8 11.79 - 11.63 (m, 1H), 9.00 - 8.82 (m, 2H), 8.36 (d, J= 8.8 Hz, 1H), 8.33 - 8.18 (m, 1H), 8.13 (dd, J = 6.8, 1.2 Hz, 1H), 8.04 - 8.08 (m, 3H), 7.83 - 7.75 (m, 3H), 7.65 (d, J= 8.4 Hz, 2H), 7.52 - 7.46 (m, 2H), 7.45 - 7.39 (m, 1H), 6.92 - 6.83 (m, 1H), 4.50 (d, J= 6.0 Hz, 2H), 3.96 (d, J= 6.0 Hz, 4H), 3.07 - 3.10 (m, 2H), 2.95 - 3.02 (m, 2H), 2.10 - 2.17 (m, 2H), 1.97 - 2.04 (m, 2H).
[00322] Intermediate 27: (R)-3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5- phenyl-37/-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine
Figure imgf000104_0001
[00323] Step 1 : tert-Butyl (R)-7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
[00324] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) in DMF (10 mL) were added K2CO3 (671 mg, 4.86 mmol) and tert-butyl (R)-2,7-diazaspiro[4.4]nonane-2-carboxylate (604 mg, 2.67 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with CH2Q2 (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over ISfeSCL, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (Eluent of 1~5% MeOH in CH2Q2) to give tert-butyl (R)-7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//- imidazo[4,5-b]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (920 mg, yield: 63%) as a yellow solid. MS: m/z = 602.6 [M + H]+.
[00325] Step 2: (R)-3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00326] A solution of tert-butyl (R)-7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (700 mg, 1.16 mmol) in 4 M HC1 and 1,4-di oxane (7 mL) was stirred at 25 °C for 2 hr. The reaction was concentrated under reduced pressure to give (R)-3-(3-(4-((2,7-diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 27, 600 mg, HC1 salt, yield: 96%) as a yellow solid. MS: m/z = 502.3 [M + H]+. LHNMR (400 MHz, Dimethylsulfoxide-t/s) 8 12.00 - 11.77 (m, 1H), 9.73 - 9.52 (m, 2H), 8.58 - 8.44 (m, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.16 (dd, J =6.0, 1.6 Hz, 1H), 8.04 - 8.09 (m, 3H), 7.92 - 7.85 (m, 3H), 7.66 (d, J= 8.4 Hz, 2H), 7.52 - 7.46 (m, 2H), 7.45 - 7.40 (m, 1H), 7.00 - 6.92 (m, 1H), 4.57 - 4.41 (m, 2H), 3.50-3.58 (m, 4H), 3.41 - 3.33 (m, 2H), 3.25 - 3.22 (m, 2H), 2.28 - 2.13 (m, 2H), 2.10 - 1.97 (m, 2H).
[00327] Intermediate 28: 3-(3-(4-((2,5-Diazabicyclo[2.2.2]octan-2-yl)methyl)phenyl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000105_0001
[00328] Step 1 : tert-Butyl 5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate
[00329] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) and tert-butyl 2,5- diazabicyclo[2.2.2]octane-2-carboxylate (567 mg, 2.67 mmol) in MeCN (10 mL) were added K2CO3 (1.0 mg, 7.28 mmol) and Nal (109 mg, 728 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with CH2CI2 (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over ISfeSCL, fdtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 0 - 5% MeOH in CH2CI2) to give tert-butyl 5-(4-(2-(2-aminopyridin- 3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane-2- carboxylate (700 mg, yield: 45%) as a yellow solid. MS: m/z = 588.3 [M + H]+. JH NMR (400 MHz, Dim ethyl sulfoxide-tL) 88.26 (d, J= 8.4 Hz, 1H), 8.06 - 7.95 (m, 4H), 7.54 - 7.36 (m, 7H), 7.15 (dd, J= 8.0, 1.6 Hz, 1H), 7.02 (s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.94 - 3.72 (m, 3H), 3.69 - 3.54 (m, 1H), 3.27 - 3.20 (m, 1H), 3.17 (d, J= 5.2 Hz, .0.5H), 2.90 - 2.86 (m, 0.5H), 2.84 - 2.79 (m, 2H), 2.07 - 1.95 (m, 1H), 1.78 - 1.69 (m, 2H), 1.63 - 1.52 (m, 1H), 1.45 - 1.37 (d, J = 9.6 Hz, 9H).
[00330] Step 2: 3-(3-(4-((2,5-Diazabicyclo[2.2.2]octan-2-yl)methyl)phenyl)-5-phenyl-3 T- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00331] A solution of tert-butyl 5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (50 mg, 85 pmol) in 4 M HC1 in 1,4-di oxane (1 mL) was stirred at 25 °C for 2 hr. The mixture was filtered. The collected solid was washed with 1,4-dioxane (10 mL x 2) and dried under reduced pressure to give 3-(3-(4-((2,5-diazabicyclo[2.2.2]octan-2-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine (Intermediate 28, 44.9 mg, yield: 99%) as a yellow solid. MS: m/z = 488.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-^) 8 12.11 - 11.44 (m, 1H), 10.27 - 9.61 (m, 2H), 8.56 - 8.40 (m, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.15 (dd, J = 6.0, 1.2 Hz, 1H), 8.10 - 7.99 (m, 5H), 7.86 (dd, J= 7.2, 1.2 Hz, 1H), 7.68 (d, J= 8.4 Hz, 2H), 7.51 - 7.46 (m, 2H), 7.46 - 7.40 (m, 1H), 6.91 (dd, J= 7.6, 6.4 Hz, 1H), 4.62 (br s, 2H), 4.01 - 3.79 (m, 4H), 3.76 - 3.70 (m, 2H), 2.21 (m, 2H), 1.97 - 1.80 (m, 2H). [00332] Intermediate 29: 3-(3-(4-((2,6-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000106_0001
[00333] Step 1 : tert-butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-/>]pyridin-3- yl)benzyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate
[00334] To a solution of Intermediate 14 (1.1 g, 2.67 mmol) and tert-butyl 2,6- diazaspiro[3.5]nonane-6-carboxylate (725 mg, 3.20 mmol) in MeCN (15 mL) were added K2CO3 (1.11 g, 8.01 mmol) and Nal (120 mg, 801 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (30 mL) at 25 °C and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 1~4% MeOH in CH2CI2) to give tert-butyl 2-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,6-diazaspiro[3.5]nonane- 6-carboxylate (900 mg, yield: 56%) as a yellow solid. MS: m/z = 602.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-cL) 88.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.95 (m, 4H), 7.50 - 7.35 (m, 6H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 3.69 (s, 2H), 3.45 (s, 2H), 3.30 - 3.20 (m, 2H), 3.10 - 3.00 (m, 2H), 2.87 - 2.75 (m, 2H), 2.52 - 2.50 (m, 2H), 1.70 - 1.62 (m, 2H), 1.49 - 1.41 (m, 2H), 1.38 (s, 9H).
[00335] Step 2: 3-(3-(4-((2,6-Diazaspiro[3.5]nonan-2-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
[00336] A solution of tert-butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (50 mg, 83.1 pmol) in 4 M HC1 in 1,4-dioxane (5 mL) at 25 °C was stirred at 25 °C for 4 hr. The reaction was filtered and concentrated under reduced pressure to give 3-(3-(4-((2,6-diazaspiro[3.5]nonan-2- yl)methyl)phenyl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 29, 37 mg, HC1 salt, yield: 84%) as a yellow solid. MS: m/z = 502.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-<A) 8 8.26 (d, J= 8.4 Hz, 1H), 8.03 - 7.97 (m, 5H), 7.50 - 7.39 (m, 6H), 7.15 (dd, ./ 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 3.66 (s, 2H), 3.04 (d, J = 72 Hz, 2H), 2.85 (d, J= 6.8 Hz, 2H), 2.78 (s, 2H), 2 62 - 2.58 (m, 2H), 1.64- 1.60 (m, 2H), 1.40- 1.35 (m, 2H). [00337] Intermediate 30: (S)-3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5- phenyl-327-imidazo[4,5-Z>]pyri din-2 -yl)pyridin-2-amine
Figure imgf000107_0001
[00338] Step 1 : tert-Butyl (S)-7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
[00339] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) and tert-butyl (S)-2,7- diazaspiro[4.4]nonane-2-carboxylate (659 mg, 2.91 mmol) in DMF (15 mb) was added K2CO3 (671 mg, 4.86 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (50 mL) at 25°C and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 - 5% MeOH in CH2CI2) to give tert-butyl (S)-7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37T- imidazo[4,5-6]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (600 mg, yield: 41%) as a brown solid. MS: m/z = 602.3 [M + H]+. JH NMR (400 MHz, Chloroform-60 3 8.13 (d, J= 8.4 Hz, 1H), 8.07 (dd, J= 4.8, 1.6 Hz, 1H), 8.03 - 8.01 (m, 2H), 7.8 (d, J= 8.4 Hz, 1H), 7.51 - 7.49 (m, 2H), 7.46 - 7.35 (m, 5H), 7.09 (dd, J= 7.6, 1.6 Hz, 1H), 6.59 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 3.80 - 3.70 (m, 2H), 3.50 - 3.20 (m, 4H), 2.80 - 2.50 (m, 4H), 1.95 - 1.80 (m, 4H), 1.46 (s, 9H).
[00340] Step 2: (S)-3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl-3 /- imidazo[4,5-Z>]pyridin-2-yl)pyridin-2-amine
[00341] To a solution of tert-butyl (S)-7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/T- imidazo[4,5-6]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (580 mg, 964 pmol) in 1,4-dioxane (2 mL) was added HCl/l,4-di oxane (4M, 8 mL). The mixture was stirred at 25 °C for 2 hr. The reaction was filtered and concentrated under reduced pressure. (S)-3-(3- (4-((2,7-diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl-37/-imidazo[4,5-Z>]pyridin-2- yl)pyridin-2-amine (Intermediate 30, 500 mg, HC1 salt, yield: 96%) was obtained as a yellow solid. MS: m/z = 502.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tL) 3 11.9 (br s, 1H), 9.80 - 9.66 (m, 2H), 8.66 - 8.50 (m, 2H), 8.38 (d, J= 8.4 Hz, 1H), 8.17 (dd, J= 6.4, 1.6 Hz, 1H), 8.08 - 8.05 (m, 3H), 7.93 - 7.86 (M, 3H), 7.66 (d, J= 8.4 Hz, 2H), 7.54 - 7.40 (m, 3H), 7.00 - 6.95 (m, 1H), 3.55 - 3.50 (m, 1H), 3.40 - 3.17 (m, 8H), 2.33 - 1.95 (m, 5H). [00342] Intermediate 31: (7?)-3-(3-(4-((3-Methylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
Figure imgf000108_0001
[00343] Step 1 : (7?)-fert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-methylpiperazine-l -carboxylate
[00344] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) in DMF (5 mL) were added K2CO3 (671 mg, 4.86 mmol) and (/?)-Zc'/7-butyl 2-methylpiperazine-l -carboxylate (632 mg, 3.16 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with CH2Q2 (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na?SO-i, filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 1~4% MeOH in CH2CI2) to give (/?)-/c/7-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- yl)benzyl)-2 -m ethylpiperazine- 1 -carboxylate (671 mg, yield: 48%) as a yellow solid. MS: m/z = 576.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-fifc) 88.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.95 (m, 4H), 7.51 - 7.38 (m, 7H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.04 (br s, 2H), 6.38 (dd, J = 8.0, 4.8 Hz, 1H), 4.14 - 4.07 (m, 1H), 3.72 - 3.70 (m, 1H), 3.64 (d, J= 13.6 Hz, 1H), 3.49 (d, J = 13.6 Hz, 1H), 3.09 - 2.98 (m, 1H), 2.84 - 2.78 (m, 1H), 2.63 - 2.57 (m, 1H), 2.08 (dd, J= 11.2, 4.0 Hz, 1H), 2.02 - 1.92 (m, 1H), 1.40 (s, 9H), 1.17 (d, J= 6.8 Hz, 3H).
[00345] Step 2: (7?)-3-(3-(4-((3-Methylpiperazin-l-yl)methyl)phenyl)-5-phenyl-377- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
[00346] A solution of (T?)-/e/7-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-methylpiperazine-l -carboxylate (700 mg, 1.22 mmol) in 4 M HC1 in 1,4-di oxane (5 mL) was stirred at 25 °C for 2 hr. The reaction was concentrated under reduced pressure to give product (A)-3-(3-(4-((3-Methylpiperazm-l-yl)methyl)phenyl)-5-phenyl-3J7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine (Intermediate 31, 500 mg, HC1 salt) as a yellow solid. MS: m/z = 476.2 [M + H]+. H NMR (400 MHz, Dimethyl sulfoxide-^) 8 8.27 (d, J= 8.4 Hz, 1H), 8.08 - 7.95 (m, 4H), 7.52 - 7.35 (m, 7H), 7.15 (d, J= 6.0 Hz, 1H), 7.04 (br s, 2H), 6.40 - 6.34 (m, 1H), 3.53 (s, 2H), 2.87 - 2.77 (m, 1H), 2.75 - 2.62 (m, 4H), 2.02 - 1.91 (m, 1H), 1.68 - 1.58 (m, 1H), 0.92 (d, J= 6.0 Hz, 3H). [00347] Intermediate 32: 3-(3-(4-(((35,57?)-3,5-Dimethylpiperazin-l-yl)methyl)phenyl)-5- phenyl-327-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine
Figure imgf000109_0001
[00348] Step 1 : (2A',6/?)-te/7-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,6-dimethylpiperazine-l -carboxylate
[00349] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) and tert-butyl (25',6J?)-2,6- dimethylpiperazine-1 -carboxylate (520 mg, 2.43 mmol) in DMF (10 mL) was added K2CO3 (671 mg, 4.86 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) at 25°C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SCU, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 1~2% MeOH in CH2CI2) to give (25,67?)-ter/-butyl 4-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,6-dimethylpiperazine-l- carboxylate (770 mg, yield: 54%) as a yellow solid, which was used directly in the next step. MS: m/z = 590.4 [M + H]+
[00350] Step 2: 3-(3-(4-(((3S,57?)-3,5-Dimethylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3/f- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00351] To a solution of tert-butyl (25,67?)-4-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]-2,6-dimethyl-piperazine-l -carboxylate (50 mg, 84.9 pmol) in 1,4-dioxane (3 mL) was added HCl/l,4-di oxane (4M, 5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane. The crude was dissolved in H2O (5 mL) and extracted with CH2Q2 (5 mL x 3). The aqueous phase was added NaHCCE and extracted with CH2CI2 (5 mL x 3). The combined organic layers were concentrated to give 3-(3-(4-(((3S,5R)-3,5-dimethylpiperazin-l-yl)methyl)phenyl)-5- phenyl-327-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 32, 34 mg, yield: 82%) as a yellow solid. MS: m/z = 490.1 [M + H]+. LH NMR (400 MHz, Dimethyl sulfoxi de-cL) 6 8.27 (d, J= 8.4 Hz, 1H), 7.97 - 8.04 (m, 4H), 7.42 - 7.48 (m, 6H), 7.37 - 7.42 (m, 1H), 7.15 (dd, J = 7.6, 2.0 Hz, 1H), 7.05 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 3.52 (s, 2H), 2.73 - 2.79 (m, 2H), 2.64 - 2.67 (m, 2H), 1.56 - 1.50 (m, 2H), 0.91 (d, J= 6.0 Hz, 6H). [00352] Intermediate 33: 3-(3-(4-(((37?,5A)-3,5-Dimethylpiperazin-l-yl)methyl)phenyl)-5- phenyl-327-imidazo[4,5-/>]pyri din-2 -yl)pyridin-2-amine
Figure imgf000110_0001
[00353] Step 1 : ZerZ-Butyl (2A,67?)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2,6-dimethylpiperazine-l -carboxylate
[00354] To a solution of Intermediate 14 (1.06 g, 2.57 mmol) and Zc/'Z-butyl (2R,6R)-2,6- dimethylpiperazine- 1 -carboxylate (500 mg, 2.33 mmol) in DMF (10 mb) was added DIEA (905 mg, 7.0 mmol). The mixture was stirred at 80 °C for 16 hr. The mixture was quenched with H2O (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was dried over anhydrous NaiSCh, filtered, and concentrated. The residue was purified by silica gel flash chromatography (Eluent of 0~9% MeOH in CH2CI2) to give zc/7-butyl (27?,67?)-4-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z7-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,6-dimethylpiperazine-l- carboxylate (Intermediate 27, 1 g, yield: 69.4%) as a yellow solid. MS: m/z = 590.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-flfc) 88.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.98 (m, 4H), 7.52 - 7.43 (m, 6H), 7.42 - 7.36 (m, 1H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.04 (br s, 2H), 6.37 (dd, J= 7.6, 4.8 Hz, 1H), 3.83 - 3.74 (m, 2H), 3.65 (d, J= 13.6 Hz, 1H), 3.48 (d, J= 13.6 Hz, 1H), 3.35 - 3.39 (m, 2H), 2.27-2.19 (m, 2H), 1.42 - 1.41 (m, 1H), 1.40 (s, 9H), 1.23 (d, J= 6.4 Hz, 6H). [00355] Step 2: 3-(3-(4-(((37?,5A)-3,5-Dimethylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3ZZ- imidazo[4,5-6]pyridin-2-yl)pyridin-2-amine
[00356] A solution of ZerZ-butyl (27?,6A)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-6]pyri din-3 -yl)benzyl)-2,6-dimethylpiperazine-l -carboxylate (100 mg, 169 pmol) in HCl/l,4-di oxane (4M, 1 mL) was stirred at 25 °C for 0.5 hr. The mixture was filtered to give 3-(3-(4-(((37?,57?)-3,5-dimethylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-2-yl)pyridin-2-amine (Intermediate 33, 84 mg HC1 salt, yield: 95%) as a yellow solid. MS: m/z = 490.2 [M + H]+. XHNMR (400 MHz, Dim ethyl sulfoxidc-cL) 8 12.41 - 11.57 (m, 0.5H), 10.79 - 10.27 (m, 0.5H), 10.07 - 9.71 (m, 1H), 8.65 - 8.51 (m, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.16 (d, J= 6.0 Hz, 1H), 8.11 - 7.95 (m, 4H), 7.93 - 7.82 (m, 3H), 7.68 (d, J= 8.0 Hz, 2H), 7.51 - 7.42 (m, 3H), 7.04 (t, J= 6.8 Hz, 1H), 4.50 - 4.25 (m, 2H), 3.44-3.32 (m, 2H), 3.20-3.01 (m, 2H), 2.91 - 2.87 (m, 1H), 2.75 - 2.71 (m, 1H), 1.60 - 1.31 (m, 6H) [00357] Intermediate 34: 3-(3-(4-(((3S,5S)-3,5-Dimethylpiperazin-l-yl)methyl)phenyl)-5- phenyl-3rt-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine
Figure imgf000111_0001
[00358] Step 1 : terLButyl (2S,6S)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3. -imidazo[4,5- b]pyridin-3-yl)benzyl)-2,6-dimethylpiperazine-l -carboxylate
[00359] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) in DMF (4 m ) were added K2CO3 (671 mg, 4.86 mmol) and tert-butyl (2R,6R)-2,6-dimethylpiperazine-l -carboxylate (624 mg, 2.91 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (10 mL) at 25 °C, diluted with CH2CI2 (6 mb), and washed with H2O (20 mL x 3). The organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tert-butyl (2S,6S)-4-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3rt-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,6-dimethylpiperazine-l- carboxylate (750 mg, yield: 52%) as a yellow solid. MS: m/z = 590.3 [M + H]+. XH NMR (400 MHz, Dimethylsulfoxide-r/g) 88.26 (d, J= 8.4 Hz, 1H), 8.04 - 7.95 (m, 4H), 7.51 - 7.38 (m, 7H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.04 (br s, 2H), 6.38 (dd, J= 8.0, 4.8 Hz, 1H),3.82 - 3.75 (m, 2H), 3.64 (d, J= 13.6 Hz, 1H), 3.47 (d, J= 13.6 Hz, 1H), 2.90 - 2.86 (m, 1H), 2.76 - 2.70 (m, 1H),2.26 - 2.18 (m, 2H), 1.40 (s, 9H), 1.22 (d, J= 6.4 Hz, 6H).
[00360] Step 2: 3-(3-(4-(((3S,5S)-3,5-Dimethylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3rt- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00361] A solution of tert-butyl (2S,6S)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3rt- imidazo[4,5-b]pyri din-3 -yl)benzyl)-2,6-dimethylpiperazine-l -carboxylate (700 mg, 1.19 mmol) in HCl/l,4-di oxane (10 mL) was stirred at 25 °C for 2 hr. The reaction was filtered and concentrated under reduced pressure to give 3-(3-(4-(((3S,5S)-3,5-dimethylpiperazin-l- yl)methyl)phenyl)-5-phenyl-3rt-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 34, 540 mg, HC1 salt, yield: 86%) as a white solid. MS: m/z = 490.6 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-c/e) 8 8.27 (d, J= 8.4 Hz, 1H), 8 08 - 7.95 (m, 4H), 7.52 - 7.35 (m, 7H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 7.04 (br s, 2H), 6.40 - 6.34 (m, 1H), 3.54 (d, J= 14.0 Hz, 1H), 3.45 - 3.40 (m, 1H), 3.10 - 3.04 (m, 2H), 2.41 - 2.33 (m, 2H), 2.06 - 2.00 (m, 2H), 1.04 (d, J= 6.4 Hz, 6H). [00362] Intermediate 35: 3-(3-(4-((3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)phenyl)-5-phenyl-
3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000112_0001
[00363] Step 1 : tert-Butyl 8-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate
[00364] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-3-carboxylate (618 mg, 2.91 mmol) in DMF (15 mL) was added K2CO3 (671 mg, 4.86 mmol). The mixture was stirred at 25 °C for 8 hr. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (30 ml), dried over JSfeSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-10% EtOAc in petroleum ether) to give tert-butyl 8-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/- imidazo[4,5-b]pyridin-3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (956 mg, yield: 67%) as a yellow solid. MS: m/z = 588.2 [M + H]+. H NMR (400 MHz, Dimethylsulfoxide-c/e) 88.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.95 (m, 4H), 7.55 (d, J= 8.4 Hz, 2H), 7.48 - 7.37 (m, 5H), 7.16 (dd, .7 = 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.38 (dd, ./- 7.6, 4.8 Hz, 1H), 3.59 (s, 2H),3.20 - 2.85 (m, 6H), 2.02 - 1.92 (m, 2H), 1.54 - 1.48 (m, 2H), 1.40 (s, 9H).
[00365] Step 2: 3-(3-(4-((3,8-Diazabicyclo[3.2.1]octan-8-yl)methyl)phenyl)-5-phenyl-3JT- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00366] To a solution of tert-butyl 8-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Zf-imidazo[4,5- b]pyridin-3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (600 mg, 1.02 mmol) in 1,4- dioxane (5 mL) was added HCl/l,4-di oxane (4M, 5 mL) at 25 °C. The mixture was stirred at 25 °C for 6 hr. The reaction was filtered and concentrated under reduced pressure to give 3-(3- (4-((3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine (Intermediate 35, 535 mg, HC1 salt) as a light yellow solid. MS: m/z = 488.2 [M + H]+. I I NMR (400 MHz, Dimethylsulfoxide-tA) 8 12.42 (br s, 1H), 10.4 - 10.0 (m, 2H), 8.55 (br s, 1H), 8.38 (d, J= 8.0 Hz, 1H), 8.13 - 8.07 (m, 1H), 8.06 - 8.00 (m, 5H), 7.98 - 7.94 (m, 1H), 7.69 (d, J= 8.0 Hz, 2H), 7.50 - 7.40 (m, 3H), 6.94 (t, J= 7.2 Hz, 1H), 4.39 - 4.33 (m, 2H), 4.01 (s, 2H), 3.95 - 3.89 (m, 3H), 3.42 - 3.39 (m, 3H), 2.47 - 2.38 (m, 2H). [00367] Intermediate 36: 3-(3-(4-((3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000113_0001
[00368] Step 1 : tert-Butyl 3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
[00369] To a solution of Intermediate 14 (500 mg, 1.21 mmol) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (309 mg, 1.46 mmol) in DMF (8 mL) was added K2CO3 (336 mg, 2.43 mmol). The mixture was stirred at 25 °C for 8 hr. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na SO i, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-10% EtOAc in petroleum ether) to give Zc/7-butyl 3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/- imidazo[4,5-b]pyridin-3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, yield: 63%) as a yellow solid. MS: m/z = 588.3 [M + H]+.
[00370] Step 2: 3-(3-(4-((3,8-Diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)-5-phenyl-3 T- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
[00371] To a solution of tert-butyl 3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.766 mmol) in 1,4-dioxane (5 mL) was added HCl/l,4-di oxane (4M, 5 mL) at 25 °C. The mixture was stirred at 25 °C for 6 hr. The reaction was filtered and concentrated under reduced pressure to give 3- (3-(4-((3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)-5-phenyl-3/f-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine (Intermediate 36, 240 mg, HC1 salt) as a light yellow solid. MS: m/z = 488 1 [M + H]+. 1 H NMR (400 MHz, Methanol-^) 58.34 - 8.28 (m, 1H), 8.05 - 7.95 (m, 4H), 7.90- 7.85 (m, 3H), 7.65 (d, ./ 8.0 Hz, 2H), 7.48 - 7.37 (m, 3H), 6.90 (t, J= 6.8 Hz, 1H), 4.35 - 4.25 (m, 4H),3.50 - 3.40 (m, 4H),2.41 (d, J= 8.4 Hz, 2H), 2.25 - 2.16 (m, 2H).
[00372] Intermediate 37: l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3- yl)benzyl)azepan-4-amine
Figure imgf000114_0001
[00373] Step 1 : tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-6]pyridin- 3-yl)benzyl)azepan-4-yl)carbamate
[00374] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) and tert-butyl A-(azepan-4- yl)carbamate (670 mg, 2.67 mmol) in DMF (10 mL) was added DIEA (1.26 g, 9.71 mmol). The mixture was stirred at 80 °C for 16 hr. The mixture was quenched with H2O (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was dried over anhydrous NazSC , filtered and concentrated. The residue was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl- 3//-imidazo[4,5-Z>]pyridin-3-yl)benzyl)azepan-4-yl)carbamate (890 mg, yield: 62%) as a yellow solid. MS: m/z = 590.4 [M + H]+. 'H NMR (400 MHz, Chloroform-d) 88.13 (d, J = 8.4 Hz, 1H), 8.09 - 8.05 (m, 1H), 8.02 (d, J= 7.6 Hz, 2H), 7.80 (d, J= 8.4 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.47 - 7.33 (m, 5H), 7.15 - 7.06 (m, 1H), 6.61 (br s, 2H), 6.35 (dd, J= 7.6, 4.8 Hz, 1H), 5.08 - 4.93 (m, 1H), 3.99 - 3.83 (m, 1H), 3.73 (s, 2H), 2.88 - 2.68 (m, 2H), 2.67 - 2.52 (m, 2H), 2.00 - 1.68 (m, 6H), 1.43 (s, 9H).
[00375] Step 2: l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5-Z>]pyridin-3- yl)benzyl)azepan-4-amine
[00376] A solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z7-imidazo[4,5- Z>]pyri din-3 -yl)benzyl)azepan-4-yl)carbamate (100 mg, 170 pmol) in HC1 in 1,4-di oxane (4M, 1 mL) was stirred at 25 °C for 1 hr. The mixture was filtered to give l-(4-(2-(2-aminopyri din-3 - yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-3-yl)benzyl)azepan-4-amine (Intermediate 37, 80 mg HC1 salt, yield: 89%) as a yellow solid. MS: m/z = 490.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tA) 8 11.56 - 11.29 (m, 1H), 8.37 (J= 8.4 Hz, 1H), 8.36 - 8.18 (m, 3H), 8.14 (J= 7.6 Hz, 1H), 8.12 - 7.97 (m, 3H), 7.96 - 7.80 (m, 3H), 7.67 (d, J= 8.4 Hz, 2H), 7.52 - 7.38 (m, 3H), 6.93 - 6.84 (m, 1H), 4.52 - 4.33 (m, 2H), 3.40 - 3.38 (m, 2H), 3.21 - 3.12 (m, 2H), 3.09 - 2.96 (m, 1H), 2.26 - 1.98 (m, 4H), 1.93 - 1.80 (m, 1H), 1.75 - 1.61 (m, 1H).
[00377] Intermediate 38: l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3- yl)benzyl)azepan-3 -amine
Figure imgf000115_0001
[00378] Step 1 : tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-6]pyridin- 3 -yl)benzyl)azepan-3 -yl)carbamate
[00379] To a solution of Intermediate 14 (800 mg, 1.94 mmol) and tert-butyl ,V-(azepan-3- yl)carbamate (416 mg, 1.94 mmol) in MeCN (10 mL) were added K2CO3 (805 mg, 5.83 mmol) and Nal (58.2 mg, 388 pmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL x 5), dried over Na2SO_i, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 2 ~ 3% MeOH in CH2CI2) to give tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-6]pyri din-3 -yl)benzyl)azepan-3-yl)carbamate (600 mg, yield: 52%) as yellow solid. MS: m/z = 590.4 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-^) 5 8.27 (d, J= 8.4 Hz, 1H), 8.03 (d, J= 7.6 Hz, 2H), 8.00 - 7.96 (m, 2H), 7.51 (d, J= 8.4 Hz, 2H), 7.49 - 7.36 (m, 6H), 7.12 (dd, J= 7.6, 1.6 Hz, 1H), 7.08 (br s, 1H), 6.65 (d, J= 8.4 Hz, 1H), 6.37 (dd, J= 7.6, 4.8 Hz, 1H), 3.74 (s, 2H), 3.60 - 3.53 (m, 1H), 2.82 - 2.77 (m, 1H), 2.66 - 2.61 (m, 1H), 2.56 - 2.52 (m, 2H), 1.80 - 1.72 (m, 1H), 1.66 - 1.61 (m, 2H), 1.56 - 1.46 (m, 3H), 1.33 (s, 9H).
[00380] Step 2: l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-Z>]pyridin-3- yl)benzyl)azepan-3 -amine
[00381] A solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- Z>]pyridin-3-yl)benzyl)azepan-3-yl)carbamate (50 mg, 170 pmol) in HC1 in 1,4-di oxane (4M, 1 mL) was stirred at 25 °C for 1 hr. The mixture was filtered to give l-(4-(2-(2-aminopyri din-3 - yl)-5-phenyl-37/-imidazo[4,5-Z>]pyridin-3-yl)benzyl)azepan-3-amine (Intermediate 38, 83 mg, HC1 salt yield: 93%) as a yellow solid. MS: m/z = 490.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-ds) 8 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.98 (m, 4H), 7.53 - 7.37 (m, 7H), 7.16
- 7.12 (m, 1H), 7.07 (br s, 2H), 6.38 (dd, J= 7.6 , 4.8 Hz, 1H), 3.77 - 3.72 (m, 2H), 3.62 - 3.53 (m, 1H), 2.89 - 2.78 (m, 2H), 2.65 - 2.61 (m, 2H), 2.59 - 2.53 (m, 2H), 1.82 - 1.73 (m, 1H), 1.67
- 1 48 (m, 4H), 1.46 - 1.25 (m, 1H).
[00382] Intermediate 39: 3-(3-(4-(((lS,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)methyl)phenyl)- 5-phenyl-377-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000116_0001
[00383] Step 1 : tert-Butyl (lS,4S)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
[00384] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) in DMF (10 mb) were added DIEA (1.27 mL, 7.28 mmol) and tert-butyl (lS,4S)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (530 mg, 2.67 mmol). The mixture was degassed and purged with N2 three times and stirred at 80 °C for 16 hr under N2. The reaction mixture was diluted with CH2CI2 (80 mL) at 25 °C, washed with brine (50 mL x 3), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 1~4% MeOH in CH2CI2) to give tert-butyl (lS,4S)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.14 g, yield: 75%) as a yellow solid. MS: m/z = 574.4 [M + H]+. XH NMR (400 MHz, Chloroform-^/) 88.12 (d, J= 8.4 Hz, 1H), 8.06 (dd, J= 4.8, 1.6 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.80 (d, J= 8.4 Hz, 1H), 7.50 (d, J= 8.4 Hz, 2H), 7.47 - 7.33 (m, 5H), 7.10 (d, J= 7.6 Hz, 1H), 6.60 (br s, 2H), 6.36 (dd, J= 8.0, 4.8 Hz, 1H), 4.47 - 4.24 (m, 1H), 3.88 - 3.80 (m, 2H), 3.71 - 3.49 (m, 2H), 3.28 - 3.16 (m, 1H), 3.02 - 2.89 (m, 1H), 2.82 - 2.57 (m, 1H), 1.96 - 1.87 (m, 1H), 1.77 - 1.68 (m, 1H), 1.48 (s, 9H).
[00385] Step 2: 3-(3-(4-(((lS,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)methyl)phenyl)-5- phenyl-3//-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine
[00386] To a solution of tert-butyl (lS,4S)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (50 mg, 87.2 pmol) in dioxane (0.5 mL) was added HC1 in 1,4-dioxane (4M, 1 mL). The mixture was degassed and purged with N2 three times and stirred at 25 °C for 2 hr under N2. The reaction mixture was concentrated under reduced pressure. The residue was triturated with 1,4-dioxane (1 mL) at 25 °C for 10 min. 3-(3-(4-(((lS,4S)-2,5-Diazabicyclo[2.2.1]heptan-2- yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 39, 41 mg, HC1 salt, yield: 95%) was obtained as a light-yellow solid. MS: m/z = 474.2 [M + H]+. XHNMR (400 MHz, Dim ethyl sulfoxide-tL) 8 12.43 - 11.57 (m, 1H), 10.39 - 9.51 (m, 2H), 8.55 - 8.39 (m, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.14 (d, J= 5.2 Hz, 1H), 8.11 - 8.01 (m, 3H), 7.94 (d, J = 8.0 Hz, 2H), 7.84 (d, J= 7.2 Hz, 1H), 7.69 (d, J= 8.4 Hz, 2H), 7.54 - 7.40 (m, 3H), 6.91 - 6.87 (m, 1H), 4.68 - 4.40 (m, 4H), 3.99 - 3.94 (m, 1H), 3.80 - 3.75 (m, 2H), 3.42 - 3.40 (m, 1H), 2.60 - 2.52 (m, 1H), 2.20 - 2.06 (m, 1H).
[00387] Intermediate 40: 3-(3-(4-(((lR,4R)-2,5-Diazabicyclo[2.2.1]heptan-2- yl)methyl)phenyl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000117_0001
[00388] Step 1 : tert-Butyl (lR,4R)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
[00389] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) and tert-butyl (lR,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (578 mg, 2.91 mmol) in DMF (15 mL) was added K2CO3 (671 mg, 4.86 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (10 ml) at 25 °C and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SCU, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography ((Eluent of 0-10% MeOH in CH2CI2) to give tert-butyl (lR,4R)-5-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-327-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, yield: 72%) as a yellow solid. MS: m/z = 574.2 [M + H]+.
[00390] Step 2: 3-(3-(4-(((lR,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)methyl)phenyl)-5- phenyl-3//-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine
[00391] To a solution of tert-butyl (lR,4R)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z7- imidazo[4,5-6]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 1.74 mmol) in 1,4-di oxane (2 mL) was added HCl/l,4-dioxane (4M, 10 mL). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane. 3-(3-(4-(((lR,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)methyl)phenyl)-5- phenyl-3//-imidazo[4,5-Z>]pyridin-2-yl)pyridin-2-amine (Intermediate 40, 854 mg, 2HC1 salt, yield: 90%) was obtained as a yellow solid. MS: m/z = 474.2 [M + H]+. 'H NMR (400 MHz, Methanol-^) 6 8.33 (d, J= 8.4 Hz, 1H), 8.06 - 8.00 (m, 6H), 7.88 (dd, J= 7.6, 1.6 Hz, 1H), 7.73 (d, J= 8.4 Hz, 2H), 7.46 - 7.40 (m, 3H), 6.92 (dd, J= 7.6, 6.4 Hz, 1H), 4.84 - 4.81 (m, 1H), 4.75 - 4.65 (m, 2H), 4.14 (d, J = 12.8 Hz, 1H), 3.96 - 3.92 (m, 1H), 3.74 - 3.71 (m, 1H), 3.62 - 3.60 (m, 1H), 3.38 - 3.32 (m, 1H), 2.87 - 2.82 (m, 1H), 2.39 - 2.36 (m, 1H). [00392] Intermediate 41 : 3-(5-Phenyl-3-(4-((piperidin-4-ylamino)methyl)phenyl)-3/7- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
Figure imgf000118_0001
[00393] Step 1 : tert-Butyl 4-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-327-imidazo[4,5-b]pyridin- 3-yl)benzyl)amino)piperidine-l -carboxylate
[00394] To a solution of Intermediate 14 (200 mg, 486 pmol) and tert-butyl 4-aminopiperidine- 1-carboxylate (117 mg, 583 pmol) in DMF (3 mL) were added Nal (7.28 mg, 48.6 pmol) and K2CO3 (134 mg, 971 pmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was poured into H2O (20 mL). The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2CI2 = 0% to 10%), tert-butyl 4-((4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- b]pyri din-3 -yl)benzyl)amino)piperi dine- 1 -carboxylate (90 mg, yield: 26%) was obtained as a light-yellow solid, which was directly used in the next step. MS: m/z = 576.4 [M + H]+.
[00395] Step 2: 3-(5-Phenyl-3-(4-((piperidin-4-ylamino)methyl)phenyl)-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
[00396] A solution of tert-butyl 4-((4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- b]pyri din-3 -yl)benzyl)amino)piperi dine- 1 -carboxylate (90 mg, 156 pmol) in HC1 in 1,4-dioxane (4M, 2 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to give 3-(5- phenyl-3-(4-((piperidin-4-ylamino)methyl)phenyl)-3/7-imidazo[4,5-b]pyridin-2-yl)pyri din-2- amine (Intermediate 41, 80 mg HC1 salt, yield: 100%) as a light-yellow oil. MS: m/z = 476.2 [M + H]+.
[00397] Intermediate 42: 3-(5-Phenyl-3-(4-((piperidin-4-yloxy)methyl)phenyl)-3ZZ- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
Figure imgf000118_0002
[00398] Step 1 : fert-Butyl 4-((4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin- 3-yl)benzyl)oxy)piperidine-l-carboxylate
[00399] To a solution of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (220 mg, 1.1 mmol) in THF (10 mL) at 0 °C was added NaH (58 mg, 1.5 mmol, 60% purity). After addition, the mixture was stirred at 0 °C for 15 min. Intermediate 14 (300 mg, 728 pmol) was added. The resulting mixture was stirred at 65 °C for 16 hr. The reaction mixture was quenched with H2O (20 mL) at 0 °C and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over NaiSO-i, fdtered, and concentrated under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2CI2 = 0% to 7%), Zer/-butyl4-((4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)oxy)piperidine-l-carboxylate (350 mg, yield: 83%) was obtained as a yellow solid. 'H NMR (400 MHz, Chloroform-;/) 8 8.13 (d, J= 8.4 Hz, 1H), 8.03 - 8.00 (m, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.56 (d, J= 8.4 Hz, 2H), 7.48 - 7.37 (m, 6H), 7.11 (dd, J= 8.0, 2.0 Hz, 1H), 6.67 (br s, 2H), 6.41 (dd, J= 7.6, 4.8 Hz, 1H), 4.68 (s, 2H), 3.88 - 3.87 (m, 1H), 3.04 - 3.00 (m, 4H), 1.87 - 1.84 (m, 4H), 1.45 (s, 9H).
[00400] Step 2: 3-(5-Phenyl-3-(4-((piperidin-4-yloxy)methyl)phenyl)-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
[00401] A solution of ter/-butyl4-((4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5- b]pyridin-3-yl)benzyl)oxy)piperidine-l -carboxylate (280 mg, 485 pmol) in 4 M HC1 in 1,4- dioxane (5 mL) was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give 3-(5-phenyl-3-(4-((piperidin-4-yloxy)methyl)phenyl)-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine (Intermediate 42, 200 mg, HC1 salt) as a light-yellow solid, which was used in the next step without further purification. MS: m/z = 477.1 [M + H]+. [00402] Intermediate 43: (J?)-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-327-imidazo[4,5- Z>]pyridin-3-yl)benzyl)piperazin-2-yl)methanol
Figure imgf000119_0001
[00403] Step 1 : Ze/7-Butyl (A)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-(hydroxymethyl)piperazine-l -carboxylate
[00404] To a solution of Intermediate 14 (100 mg, 242 pmol) in DMF (5 mL) were added K2CO3 (100 mg, 728 pmol), Nal (10.9 mg, 72.8 pmol) and Ze/7-butyl (A)-2- (hydroxymethyl)piperazine-l -carboxylate (53 mg, 242 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SC>4, filtered, and concentrated under reduced pressure. After purified by / /i-HPLC (column: Phenomenex C18 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN];B%: 46%-76%,14min), tert-butyl (A)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-3 -yl)benzyl)-2-(hydroxymethyl)piperazine-l -carboxylate (120 mg, yield: 84%) was obtained as a yellow solid. MS: m/z = 592.3 [M + H]+.
[00405] Step 2: (7?)-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-2-yl)methanol
[00406] To a solution of tert-butyl (R)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//- imidazo[4,5-b]pyri din-3 -yl)benzyl)-2-(hydroxymethyl)piperazine-l -carboxylate (40 mg, 67.6 pmol) in 1,4-dioxane (2 mL) was added HCl/l,4-dioxane (4 M). The mixture was stirred at 25 °C for 6 hr. The mixture was filtered and concentrated under reduced pressure. (A)-(4-(4-(2- (2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-/>]pyridin-3-yl)benzyl)piperazin-2-yl)methanol (Intermediate 43, 16 mg, yield: 48%) was obtained as a yellow solid. MS: m/z = 492.3 [M + H]+. 'l l NMR (400 MHz, Methanol-^) 5 8.33 - 8.30 (m, 1H), 8.05 - 7.98 (m, 4H), 7.95 - 7.85 (m, 3H), 7.72 (m, 2H), 7.48 - 7.40 (m, 3H), 6.95 - 6.85 (m, 1H), 4.61 (s, 2H), 3.94 - 3.68 (m, 7H), 3.50 - 3.38 (m, 2H).
[00407] Intermediate 44: (5)-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- i]pyridin-3-yl)benzyl)piperazin-2-yl)methanol
Figure imgf000120_0001
[00408] Step 1 : tert-Butyl (5)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2-(hydroxymethyl)piperazine-l -carboxylate
[00409] To a solution of Intermediate 14 (300 mg, 728 pmol) in DMF (5 mL) were added K2CO3 (302 mg, 2.19 mmol), Nal (32.8 mg, 219 pmol), and tert-butyl (S)-2- (hydroxymethyl)piperazine-l -carboxylate (173 mg, 801 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (EtOAc in petroleum ether = 20-70%) to give tert-butyl (S)- 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z7-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2- (hydroxymethyl)piperazine-l -carboxylate (200 mg, yield: 47%) as a yellow solid. MS: m/z = 592.3 [M + H]+.
[00410] Step 2: (S)-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-2-yl)methanol
[00411] A solution of /erZ-butyl (5)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2-(hydroxymethyl)piperazine-l -carboxylate (200 mg, 338 pmol) in 4 M HC1 in 1,4-di oxane (2 mL) was stirred at 25 °C for 2 hr. The reaction was concentrated under reduced pressure to give a yellow solid (250 mg, HC1 salt). The solid (50 mg, HC1 salt) was diluted with aqueous NaHCCh (10 mL) and extracted with CH2CI2 (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. After purified by /i/'c’/i-TLC (MeOH in CH2Q2 = 10%), (S)-(4-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperazin-2-yl)methanol (Intermediate 44, 20.6 mg, yield: 40%) was obtained as a yellow solid. MS: m/z = 492.2 [M + H]+. 'H NMR (400 MHz, Methanol-^) 3 8.32 (d, J= 8.4 Hz, 1H), 8.06 - 8.00 (m, 4H), 7.91 (d, J = 8.0 Hz, 2H), 7.86 (dd, J= 7.6, 1.2 Hz, 1H), 7.72 (d, J= 8.0 Hz, 2H), 7.47 - 7.40 (m, 3H), 6.94 - 6.86 (m, 1H), 3.92 - 3.86 (m, 2H), 3.81 - 3.64 (m, 5H), 3.60 (s, 2H), 3.43 - 3.34 (m, 2H).
[00412] Intermediate 45: (5)-3-(3-(4-((3-(methylamino)pyrrolidin-l-yl)methyl)phenyl)-5- phenyl-3Z7-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine
Figure imgf000121_0001
[00413] Step I: Zc/Z-Butyl (S)-(l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)(methyl)carbamate
[00414] To a solution of Intermediate 14 (200 mg, 486 pmol) in CH3CN (5 mL) were added zerz-butyl (S)-methyl(pyrrolidin-3-yl)carbamate (97 mg, 486 pmol), Nal (7.28 mg, 48.6 pmol) and K2CO3 (268 mg, 1.94 mmol). The mixture was stirred at 80 °C for 2 hr. The mixture was concentrated under reduced pressure to give tert-butyl (S)-(l-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)(methyl)carbamate (180 mg, yield: 60%) as a yellow solid. MS: m/z = 576.4 [M + H]+. [00415] Step 2: (S)-3-(3-(4-((3-(Methylamino)pyrrolidin-l-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
[00416] To a solution of tert-butyl (S)-(l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3r- imidazo[4,5-b]pyri din-3 -yl)benzyl)pyrrolidin-3-yl)(methyl)carbamate (250 mg, 433 pmol) in CH2CI2 (5 mL) was added TFA (247 mg, 2.17 mmol). The mixture was stirred at 25 °C for 2 hr.
The mixture was duilted with H2O (5 mL). The pH of the mixture was adjusted to about 8 with NaHCCh (aq) and the mixture was extrated with CH2CI2 (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over N 2SO4, filtered and concentrated under reduced pressure. The mixture was purified by /vc/i-TLC (CH2CI2 : MeOH = 10 : 1) to give (S)- 3-(3-(4-((3-(methylamino)pyrrolidin-l-yl)methyl)phenyl)-5-phenyl-3rt-imidazo[4,5-b]pyridin- 2-yl)pyridin-2-amine (Intermediate 45, 200 mg, TFA salt, yield: 81%) as a light-yellow solid. MS: m/z = 476.3 [M + H]+. XHNMR (400 MHz, Methanol-^) 88.19 (d, J= 8.8 Hz, 1H), 8.04 - 8.00 (m, 2H), 7.98 (dd, J= 5.2, 1.6 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.56 (d, J= 8.0 Hz, 2H), 7.47 - 7.40 (m, 4H), 7.38 (d, J= 7.2 Hz, 1H), 7.33 (dd, J = 8.0, 1.6 Hz, 1H), 6.48 (dd, J = 1.6, 4.8 Hz, 1H), 3.84 - 3.72 (m, 2H), 3.70 - 3.64 (m, 1H), 3.01 - 2.98 (m, 1H), 2.90 - 2.84 (m, 1H), 2.64 (s, 3H), 2.50 - 2.44 (m, 1H), 2.38 - 2.28 (m, 1H), 2.23 - 1.96 (m, 1H), 1.94 - 1.83 (m, 1H). [00417] Intermediate 46: 4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-/>]pyridin-3- yl)benzyl)piperazin- 1 -amine
Figure imgf000122_0001
[00418] Step 1 : /c/7-Butyl (4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3 -yl)benzyl)piperazin- 1 -yl)carb amate
[00419] To a solution of Intermediate 14 (300 mg, 728 pmol) and tert-butyl piperazin-1- ylcarbamate (146 mg, 728 pmol) in DMF (3 mL) were added K2CO3 (302 mg, 2.19 mmol) and Nal (32.7 mg, 218 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (10 mL) at 25 °C, diluted with more H2O (30 mL) and extracted with CH2CI2 (30 mL x 2). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (MeOH in DCM = 0% to 10%) to give tert-butyl (4-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3rt-imidazo[4,5-/>]pyridin-3-yl)benzyl)piperazin-l-yl)carbamate (184 mg, yield: 61%) as a yellow solid. MS: m/z = 577.2 [M + H]+. [00420] Step 2: 4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-Z>]pyridin-3- yl)benzyl)piperazin- 1 -amine
[00421] To a solution of te/7-butyl (4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5- Z?]pyridin-3-yl)benzyl)piperazin-l-yl)carbamate (184 mg, 319 pmol) in 1,4-dioxane (1 mL) was added HCl/l,4-di oxane (4 M, 5 mL). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. 4-(4-(2-(2-Aminopyri din-3 -yl)- 5-phenyl-3Z7-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperazin-l-amine (Intermediate 46, 150 mg HC1 salt, yield: 98%) was obtained as a yellow solid. MS: m/z = 477.2 [M + H]+. XH NMR (400 MHz, Methanol-^) 88.33 (d, J= 8.4 Hz, 1H), 8.04 (d, J= 8.4 Hz, 4H), 7.94 - 7.86 (m, 3H), 7.74 (d, J= 7.2 Hz, 2H), 7.48 - 7.39 (m, 3H), 6.94 - 6.87 (m, 1H), 4.56 (s, 2H), 3.77 - 3.68 (m, 2H), 3.54 - 3.47 (m, 4H), 3.28 - 3.21 (m, 2H).
[00422] Intermediate 48: 3-(3-(4-(((3aA,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(l//)- yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-2-yl)pyridin-2-amine
Figure imgf000123_0001
[00423] Step 1 : tert-Butyl (3aA,6aS)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(l//)-carboxylate
[00424] To a solution of Intermediate 14 (4.6 g, 11.2 mmol) and tert-butyl (3aR,6aS)- 2,3,3a,4,6,6a-hexahydro-l//-pyrrolo[3,4-c]pyrrole-5-carboxylate (2.61 g, 12.3 mmol) in DMF (60 mL) were added Nal (502 mg, 3.35 mmol) and K2CO3 (3.09 g, 22.3 mmol) in one portion at 25 °C. The mixture was stirred at 80 °C for 12 hr. The reaction mixture was poured into water (100 mL) at 25 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous NazSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 - 6% MeOH in CH2CI2) to give tert-butyl (3aA,6aS)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//- imidazo[4,5-Z>]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(l//)-carboxylate (3.6 g, yield: 55%) as a yellow solid. MS: m/z = 588.4 [M + H]+. LH NMR (400 MHz, Dimethylsulfoxide-r/r,) 8 8.27 (d, J= 8.4 Hz, 1H), 8.06 - 7.96 (m, 4H), 7.50 - 7.36 (m, 7H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.03 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.65 (s, 2H), 3.51 - 3.41 (m, 2H), 3.17 - 3.10 (m, 2H), 2.76-2.75 (m, 2H), 2.59 - 2.53 (m, 2H), 2.45 - 2.39 (m, 2H), 1.39 (s, 9H). [00425] Step 2: 3-(3-(4-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(17/)-yl)methyl)phenyl)- 5-phenyl-32/-imidazo[4,5-/>]pyridin-2-yl)pyridin-2-amine
[00426] To a solution of tert-butyl (3a7?,6«S)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/- imidazo[4,5-Z>]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(I/7)-carboxylate (50 mg, 85.1 pmol) in 1,4-dioxane (2 mL) was added HCl/l,4-dioxane (4 M, 212 pL). The reaction mixture was stirred at 20 °C for 12 hr. The mixture was quenched with saturation NaHCCh (10 mL) and extracted with CH2Q2 (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous JXfeSCL, filtered and concentrated. 3-(3-(4-(((3o7?,6aS)- Hexahydropyrrolo[3,4-c]pyrrol-2(l/7)-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-/>]pyridin-2- yl)pyridin-2-amine (Intermediate 48, 35.4 mg, yield: 85%) was obtained as an off-white solid. MS: m/z = 488.2 [M + H]+. XHNMR (400 MHz, Dimethylsulfoxide-c/e) 8.27 (d, J= 8.0 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.49 - 7.44 (m, 5H), 7.43 - 7.37 (m, 2H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.04 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.60 (s, 2H), 2.85 - 2.76 (m, 2H), 2.58 - 2.51 (m, 7H), 2.31 - 2.26 (m, 2H).
[00427] Intermediate 49: 3-(3-(4-(l-(4-(Methylamino)piperidin-l-yl)ethyl)phenyl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000124_0001
[00428] Step 1 : 4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3-yl)-?7- methoxy-JV-methy lb enzami de
[00429] To a solution of Intermediate 13 (1 g, 2.37 mmol) in THF (10 mL) were added MeONMe (HC1 salt) (463 mg, 4.75 mmol) and i-PrMgBr (2 M, 5.93 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with saturated solution of NH4CI (10 mL) at 25 °C and extracted with CH2CI2 (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. 4-(2-(2- Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3-yl)-A-methoxy-A-methylbenzamide (1.03 g, yield: 86%) was obtained as a yellow solid. MS: m/z = 451.1.
[00430] Step 2: l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3ff-imidazo[4,5-b]pyridin-3- yl)phenyl)ethan- 1 -one
[00431] To a solution of 4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-3-yl)- A-methoxy-A-methylbenzamide (1.03 g, 2.29 mmol) in THF (10 mb) was added MeMgBr (3 M, 4.57 mL) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was quenched with saturated solution of NH4CI (20 mL) at 25°C and extracted with CH2CI2 (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over NazSC , filtered, and concentrated under reduced pressure. l-(4-(2-(2-Aminopyri din-3 -yl)-5-phenyl-377- imidazo[4,5-b]pyridin-3-yl)phenyl)ethan-l-one (860 mg, yield: 62%) was obtained as a yellow solid. MS: m/z = 406.1.
[00432] Step 3: l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5-b]pyridin-3- yl)phenyl)ethan- 1 -ol
[00433] To a solution of l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5-b]pyridin-3- yl)phenyl)ethan-l-one (860 mg, 2.12 mmol) in THF (10 mL) was added LiAHHL (161 mg, 4.24 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with Na2SC>4. IOH2O (150 mg) at 0 °C, filtered and concentrated under reduced pressure. l-(4- (2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-3-yl)phenyl)ethan-l-ol (850 mg, yield: 98%) was obtained as a yellow solid. MS: m/z = 408.1.
[00434] Step 4: 3-(3-(4-(l-Chloroethyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
[00435] To a solution of l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- yl)phenyl)ethan-l-ol (500 mg, 1.23 mmol) in CH2CI2 (5 mL) was added SOCI2 (438 mg, 3.68 mmol). The mixture was stirred at 40 °C for 1 hr. The reaction was concentrated under reduced pressure. 3-(3-(4-(l-Chloroethyl)phenyl)-5-phenyl-37/-imidazo[4,5-b]pyridin-2-yl)pyri din-2- amine (506 mg, yield: 97%) was obtained as a brown solid. MS: m/z = 426.0 [M + H]+.
[00436] Step 5: Zc/7-Butyl (l-(l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)phenyl)ethyl)piperidin-4-yl)(methyl)carbamate
[00437] To a solution of 3-(3-(4-(l-chloroethyl)phenyl)-5-phenyl-377-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine (400 mg, 939 pmol) and /e/7-butyl methyl(piperidin-4-yl)carbamate (262 mg, 1.22 mmol) in DMF (5 mL) and MeCN (5 mL) was added K2CO3 (649 mg, 4.7 mmol). The mixture was stirred at 50 °C for 16 hr. The reaction mixture was diluted with H2O (5 mL) and extracted with CH2CI2 (20 mL x 2). The combined organic layers were washed with brine (5 mL), dried over ISfeSCh, filtered, and concentrated under reduced pressure. tert-Butyl (l-(l-(4- (2-(2-aminopyridin-3-yl)-5-phenyl-3Zf-imidazo[4,5-b]pyridin-3-yl)phenyl)ethyl)piperidin-4- yl)(methyl)carbamate (500 mg, yield: 88%) was obtained as a brown liquid. MS: m/z = 604.3 [M + H]+.
[00438] Step 6: 3-(3-(4-(l-(4-(Methylamino)piperidin-l-yl)ethyl)phenyl)-5-phenyl-3Zf- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00439] To a solution of tert-butyl (l-(l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5- b]pyridin-3-yl)phenyl)ethyl)piperidin-4-yl)(methyl)carbamate (200 mg, 331 pmol) in 1,4- dioxane (2.0 mL) was added 4M HC1 in 1,4-dioxane (2.0 mL). The mixture was stirred at 25 °C for 0.5 hr. The pH was adjusted to 8 with saturated NaHCCL. The mixture was diluted with H2O (20 mL) and extracted with CH2Q2 (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. 3-(3-(4-(l-(4-(Methylamino)piperidin-l-yl)ethyl)phenyl)-5-phenyl-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine (Intermediate 49, 97.6 mg, yield: 56%) was obtained as a yellow solid. MS: m/z = 504.3. [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-^) 8 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.49 - 7.38 (m, 7H), 7.16 - 7.04 (m, 3H), 6.32 (dd, J= 8.0, 4.8 Hz, 1H), 3.62 - 3.55 (m, 1H), 2.91 - 2.79 (m, 1H), 2.76 - 2.67 (m, 1H), 2.51 - 2.47 (m, 2H), 2.24 (s, 3H), 2.20 - 2.12 (m, 1H), 2.01 - 1.89 (m, 2H), 1.82 - 1.72 (m, 2H), 1.35 (d, J= 6.8 Hz, 3H).
[00440] Intermediate 50: 3-(3-(4-((4-(Ethylamino)piperidin-l-yl)methyl)phenyl)-5-phenyl-377- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
Figure imgf000126_0001
[00441] Step 1 : tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3 /-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)(ethyl)carbamate
[00442] To a solution of Intermediate 14 (235 mg, 569 pmol) in DMF (2 mL) were added K2CO3 (236 mg, 1.71 mmol), Nal (25.6 mg, 171 pmol) and tert-butyl ethyl(piperidin-4- yl)carbamate (130 mg, 569 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was poured into H2O (20 mL). The aqueous phase was extracted with CH2Q2 (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SC>4, filtered and concentrated. tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)(ethyl)carbamate (320 mg, yield: 69%) was obtained as a yellow solid. MS: m/z = 604.2 [M + H]+.
[00443] Step 2: 3-(3-(4-((4-(Ethylamino)piperidin-l-yl)methyl)phenyl)-5-phenyl-3Z7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00444] To a solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)(ethyl)carbamate (320 mg, 530 pmol) in 1,4-dioxane (3.0 mL) was added 4M HC1 in 1,4-dioxane (3.0 mL). The mixture was stirred at 25 °C for 0.5 hr. The mixture was concentrated to give 3-(3-(4-((4-(ethylamino)piperidin-l-yl)methyl)phenyl)-5- phenyl-3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 50, 230 mg HC1 salt) as a yellow solid. MS: m/z = 504.3. [M + H]+. XHNMR (400 MHz, Dimethylsulfoxide-^) 8 8.27 (d, J= 8.0 Hz, 1H), 8.06 - 7.96 (m, 4H), 7.49 - 7.38 (m, 7H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 7.03 (br s, 2H), 6.37 (dd, J= 7.6, 4.8 Hz, 1H), 3.54 (s, 2H), 2.82 - 2.73 (m, 2H), 2.58 - 2.52 (m, 2H), 2.40 - 2.34 (m, 1H), 2.03 - 1.93 (m, 2H), 1.82 - 1.74 (m, 2H), 1.32 - 1.21 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).
[00445] Intermediate 51: 3-(3-(4-((4-(Cyclopropylamino)piperidin-l-yl)methyl)phenyl)-5- phenyl-3Z/-imidazo[4,5-Z>]pyri din-2 -yl)pyridin-2-amine
Figure imgf000127_0001
[00446] Step 1 : Benzyl 4-(cyclopropylamino)piperidine-l-carboxylate
[00447] To a solution of benzyl 4-oxopiperidine-l -carboxylate (500 mg, 2.14 mmol) in CH2CI2 (5 mL) were added cyclopropanamine (184 mg, 3 22 mmol, HC1 salt) and AcOH (193 mg, 3.22 mmol). The mixture was stirred at 25 °C for 1 hr and then NaBH(OAc)3 (681 mg, 3.22 mmol) was added. The resulting mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (10 mL) at 25 °C, diluted with CH2CI2 (10 mL) and extracted with CH2CI2 (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over J feSCU, fdtered, and concentrated under reduced pressure. Benzyl 4-(cyclopropylamino)piperidine-l- carboxylate (580 mg, yield: 93%) was obtained as a yellow oil. MS: m/z = 275.1 [M + H]+. H NMR (400 MHz, Chloroform- ) 5 7.42 - 7.27 (m, 5H), 5.12 (s, 2H), 4.15 - 4.03 (m, 2H), 2.96 - 2.85 (m, 2H), 2.82 - 2.71 (m, 1H), 2.17 - 2.09 (m, 1H), 1.97 - 1.88 (m, 2H), 1.76 - 1.65 (m, 2H), 1.32 - 1.23 (m, 2H), 0.48 - 0.42 (m, 2H), 0.36 - 0.30 (m, 2H).
[00448] Step 2: Benzyl 4-((tert-butoxycarbonyl)(cyclopropyl)amino)piperidine-l -carboxylate [00449] To a solution of benzyl 4-(cyclopropylamino)piperidine-l -carboxylate (580 mg, 2.11 mmol) in THF (10 mL) and H2O (5 rnL) were added Na CC (672 mg, 6.34 mmol) and (Boc)2O (554 mg, 2.54 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (5 mL) at 25 °C, diluted with CH2CI2 (10 mL) and extracted with CH2CI2 (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over J feSCU, filtered, and concentrated under reduced pressure. Benzyl 4-((/ert- butoxycarbonyl)(cyclopropyl)amino)piperidine-l -carboxylate (800 mg, yield: 91%) was obtained as a yellow oil. MS: m/z = 397.2 [M + Na]+. 1 H NMR (400 MHz, Chloroform-t/) 8 7.45 - 7.27 (m, 5H), 5.12 (s, 2H), 4.35 - 4.17 (m, 2H), 3.84 - 3.72 (m, 1H), 2.86 - 2.71 (m, 2H), 2.36 - 2.25 (m, 1H), 1.97 - 1.82 (m, 2H), 1.76 - 1.66 (m, 2H), 1.52 (s, 9H), 0.79 - 0.71 (m, 2H), 0.68 - 0.59 (m, 2H).
[00450] Step 3 : tert-Butyl cyclopropyl(piperidin-4-yl)carbamate
[00451] To a solution of benzyl 4-((tert-butoxycarbonyl)(cyclopropyl)amino)piperidine-l - carboxylate (500 mg, 1.34 mmol) in MeOH (10 mL) was added Pd/C (150 mg, 10% purity) under N2 atmosphere. The mixture was purged with H2 three times and stirred at 40 °C under H2 atmosphere (40 Psi) for 16 hr. The mixture was filtered and washed with MeOH (10 mL x 2). The filtrate was concentrated to give tert-butyl cyclopropyl(piperidin-4-yl)carbamate (280 mg, yield: 83%) as a white oil H NMR (400 MHz, Chloroform-< ) 8 3.77 - 3.68 (m, 1H), 3.13 - 3.07 (m, 2H), 2.67 - 2.57 (m, 2H), 2.36 - 2.28 (m, 1H), 1.93 - 1.82 (m, 2H), 1.74 - 1.67 (m, 2H), 1.63 - 1.55 (m, 1H), 1.45 (s, 9H), 0.76 - 0.71 (m, 2H), 0.68 - 0.62 (m, 2H).
[00452] Step 4 : tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin- 3-yl)benzyl)piperidin-4-yl)(cyclopropyl)carbamate
[00453] To a solution of Intermediate 14 (300 mg, 728 pmol) in DMF (10 mL) were added K2CO3 (302 mg, 2.19 mmol), Nal (10.9 mg, 72.8 pmol) and tert-butyl cyclopropyl(piperidin-4- yl)carbamate (350 mg, 1.46 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (10 mL) at 25 °C, diluted with EtOAc (15 mL) and washed with H2O (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. After purified by silica gel flash chromatography ( MeOH in CH2Ch= 1% to 5%), tert-butyl (l-(4-(2-(2-aminopyri din-3- yl)-5-phenyl-3A-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperidin-4-yl)(cyclopropyl)carbamate (400 mg, yield: 83%) was obtained as a yellow solid. MS: m/z = 616.3 [M + H]+.
[00454] Step 5: 3-(3-(4-((4-(Cyclopropylamino)piperidin-l-yl)methyl)phenyl)-5-phenyl-3//- imidazo[4,5-Z>]pyridin-2-yl)pyridin-2-amine
[00455] To a solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-3-yl)benzyl)piperidin-4-yl)(cyclopropyl)carbamate (150 mg, 244 pmol) in CH2CI2 (3 mL) was added TFA (27.8 mg, 244 pmol). The mixture was stirred at 25 °C for 16 hr. The pH of the mixture was adjusted to 8 with saturated NaHCCL The mixture was diluted with CH2O2 (15 mL), extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SCh, filtered and concentrated under reduced pressure, 3-(3-(4-((4- (Cyclopropylamino)piperidin-l-yl)methyl)phenyl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-2- yl)pyridin-2-amine (Intermediate 51, 130 mg, yield: 96%) was obtained as a yellow solid. MS: m/z = 516.3 [M + H]+. XHNMR (400 MHz, Dimethylsulfoxide-tZe) 8 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.49 - 7.42 (m, 6H), 7.41 - 7.38 (m, 1H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.58 (s, 2H), 2.91 - 2.82 (m, 2H), 2.81 - 2.71 (m, 1H), 2.13 - 2.00 (m, 2H), 1.95 - 1.88 (m, 2H), 1.48 - 1.37 (m, 2H), 1.29 - 1.14 (m, 2H), 0.59 - 0.48 (m, 2H), 0.47 - 0.34 (m, 2H).
[00456] Intermediate 52: 4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-/>]pyridin-3- yl)benzyl)-A-methylpiperazin- 1 -amine
Figure imgf000129_0001
[00457] Step 1 : Benzyl 4-((terZ-butoxycarbonyl)amino)piperazine-l -carboxylate
[00458] To a solution of tert-butyl A-piperazin- 1 -yl carbamate (1 g, 4.98 mmol) in DMF (5 mL) were added TEA (1.39 mL, 9.96 mmol) and CbzCl (934 mg, 5.5 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 hr. The mixture was quenched with H2O (35 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NazSCh, filtered and concentrated. After purified by silica gel flash chromatography (EtOAc in petroleum ether = 0% to 60%), benzyl 4-((tert-butoxycarbonyl)amino)piperazine-l - carboxylate (1.2 g, 72% yield) was obtained as an off white solid. MS: m/z = 358.1 [M + 23]+. [00459] Step 2: Benzyl 4-((ter/-butoxycarbonyl)(methyl)amino)piperazine-l -carboxylate [00460] To a mixture of benzyl 4-((tert-butoxycarbonyl)amino)piperazine-l-carboxylate (1.2 g, 3.58 mmol) in THF (10 mb) was added NaH (429 mg, 60% purity) at 0 °C. After stirring at 0 °C for 30 min, CH3I (1.02 g, 7.16 mmol) was added. The resulting mixture was stirred at 25 °C for 5 hr under N2. The reaction was quenched with water (10 mL) at 0 °C and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2 O4, filtered and concentrated. After purified by silica gel flash chromatography (EtOAc in petroleum ether = 0% to 20%), benzyl 4-((ierl- butoxycarbonyl)(methyl)amino)piperazine-l -carboxylate (1.1 g, yield: 88%) was obtained as a colorless oil. MS: m/z = 372.1 [M + 23]+.
[00461] Step 3: tert-Butyl methyl(piperazin-l-yl)carbamate
[00462] To a mixture of benzyl 4-((/er/-butoxycarbonyl )(methyl)amino)piperazine- l - carboxylate (1.1 g, 3.15 mmol) in MeOH (5 mL) was added Pd/C (1.1 g, 10% purity). The mixture was stirred at 25 °C for 12 hr under H2 (50 psi). The mixture was filtered and concentrated to give tert-butyl methyl(piperazin-l-yl)carbamate (670 mg, yield: 99%) as an off- white solid, which was used into the next step without purification. MS: m/z = 160.0 [M - C4H7]+. ’H NMR (400 MHz, Methanol-^) 82.93 - 2.92 (m, 11H), 1.48 (s, 9H).
[00463] Step 4 : tert-Butyl (4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperazin-l-yl)(methyl)carbamate
[00464] To a solution of Intermediate 14 (800 mg, 1.94 mmol) and tert-butyl methyl(piperazin- l-yl)carbamate (460 mg, 2.14 mmol) in DMF (8 mL) were added Nal (58.2 mg, 388 pmol) and K2CO3 (537 mg, 3.88 mmol). The mixture was stirred at 50 °C for 5 hr. The reaction was concentrated, diluted with water (10 mL), and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. After purified by silica gel flash chromatography (CH2CI2 in MeOH = 0% to 2%), tert-butyl (4-(4-(2- (2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperazin-l- yl)(methyl)carbamate (0.35 g, yield: 30%) was obtained as a light yellow solid. MS: m/z = 591.4 [M + 1]+. XHNMR (400 MHz, Dimethylsulfoxide^) 8.27 (d, J = 8.0 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.48 - 7.44 (m, 6H), 7.43 - 7.37 (m, 1H), 7.15 (dd, J= 8.0, 2.0 Hz, 1H), 7.03 (s, 2H), 6.42 - 6.33 (m, 1H), 5.76 - 5.75 (m, 1H), 3.58 (s, 2H), 3.32 - 3.31 (m, 2H), 2.99 - 2.88 (brs, 3H), 2.85 (s, 3H), 2.47 (br s, 3H), 1.41 (s, 9H). [00465] Step 5: 4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- y 1 )benzy I j-A-m ethy I pi perazi n- 1 -amine
[00466] To a solution of te/7-butyl (4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5- />]pyridin-3 -yl)benzyl)piperazin- 1-yl) (methyl) carbamate (347 mg, 587 pmol) in 1,4-dioxane (3 mL) was added HCl/l,4-dioxane (4 M, 147 pL). The mixture was stirred at 25 °C for 5 hr under N2. The mixture was concentrated to give 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377- imidazo[4,5-Z>]pyri din-3 -yl)benzyl)-A-methylpiperazin-l -amine (Intermediate 52, 288 mg, yield: 93.1%, HC1 salt) as a yellow solid, which was used in the next step without further purification. MS: m/z = 491.3 [M + H]+. XH NMR (400 MHz, Dimethylsulfoxide-<76) 11.6 (br s, 1H), 11.2(br s, 2H), 8.59 - 8.43 (m, 2H), 8.39 - 8.37 (m, 1H), 8.15 - 8.09 (m, 1H), 8.08 - 8.07 (m, 3H), 7.89 - 7.87 (m, 1H), 7.92 - 7.87 (m, 2H), 7.83 - 7.67 (m, 2H), 7.56 - 7.38 (m, 4H), 6.95 - 6.88 (m, 1H), 3.71 - 3.41 (m, 10H), 2.68 (br s, 3H).
[00467] Intermediate 53: 2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-azaspiro[3.5]nonan-7-amine
Figure imgf000131_0001
[00468] Step 1 : tert-Butyl (2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2-azaspiro[3.5]nonan-7-yl)carbamate
[00469] To a solution of Intermediate 14 (1.0 g, 2.4 mmol) and tert-butyl (2- azaspiro[3.5]nonan-7-yl)carbamate (642 mg, 2.7 mmol) in DMF (15 mL) were added Nal (36 mg, 243 pmol) and K2CO3 (671 mg, 4.9 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was quenched with H2O (50 mL) at 25 °C and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tert-butyl (2-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3-yl)benzyl)-2-azaspiro[3.5]nonan-7- yl)carbamate (900 mg, yield: 60%) as a yellow solid. MS: m/z = 616.4 [M + H]+. XHNMR (400 MHz, Chloroform- ) 8 8.12 (d, J= 8.4 Hz, 1H), 8.06 (d, J= 5.2 Hz, 1H), 8.02 (d, J= 7.6 Hz, 2H), 7.80 (d, J= 8.4 Hz, 1H), 7.48 - 7.36 (m, 7H), 7.09 (d, J= 8.0 Hz, 1H), 6.59 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 4.46 - 4.29 (m, 1H), 3.77 (s, 2H), 3.49 - 3.34 (m, 1H), 3.26 - 3.01 (m, 4H), 1.99 - 1.92 (m, 2H), 1.91 - 1.84 (m, 2H), 1.59 - 1.52 (m, 2H), 1.44 (s, 9H), 1.21 - 1.09 (m, 2H).
[00470] Step 2: 2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-azaspiro[3.5]nonan-7-amine
[00471] A solution of tert-butyl(2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37T-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-azaspiro[3.5]nonan-7-yl)carbamate (375 mg, 609 pmol ) in HCl in 1,4- dioxane (4M, 5 mL) was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to give 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-azaspiro[3.5]nonan-7-amine (Intermediate 53, 291 mg, HC1 salt, yield: 87%) as a gray solid. MS: m/z = 516.3 [M + H]+. JH NMR (400 MHz, Dimethyl sulfoxide-tfc) 8 8.26 (d, J = 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.49 - 7.44 (m, 2H), 7.43 - 7.37 (m, 5H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.00 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.65 (s, 2H), 3.20 - 3.12 (m, 1H), 2.95 (s, 2H), 2.90 (s, 2H), 1.86 - 1.80 (m, 2H), 1.65 - 1.57 (m, 2H), 1.42 - 1.34 (m, 2H), 1.11 - 0.95 (m, 2H).
[00472] Intermediate 54: 3-(3-(4-((3,9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-5-phenyl- 37/-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
Figure imgf000132_0001
[00473] Step 1 : tert-Butyl 9-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
[00474] To a solution of Intermediate 14 (600 mg, 1.46 mmol), tert-butyl 3,9- diazaspiro[5.5]undecane-3-carboxylate (408 mg, 1.60 mmol) in DMF (5 mL) were added Nal (21.9 mg, 146 pmol) and K2CO3 (403 mg, 2.91 mmol). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was poured into H2O (15 mL), extracted with EtOA (20 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~65% EtOAc in petroleum ether) to give tert-butyl 9-(4-(2-(2-aminopyridin-3-yl)-5-phenyl- 37/-imidazo[4,5-b]pyridin-3-yl)benzyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (450 mg, yield: 49%) as a yellow solid. MS: m/z = 630.5 [M + H]+.
[00475] Step 2: 3-(3-(4-((3,9-Diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-5-phenyl-3J7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine [00476] To a solution of 9-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3 /-imidazo[4,5-b]pyridin-3- yl)benzyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (200 mg, 318 pmol) in 1,4-dioxane (2 m ) was added 4M HC1 in 1,4-dioxane (2 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered. The filter cake was dried to give 3-(3-(4-((3,9- diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5-b]pyri din-2 -yl)pyri din-2- amine (Intermediate 54, 121 mg, HC1 salt, yield: 67%) as a yellow solid. MS: m/z = 530.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/s) 8 10.81 - 10.50 (m, 1H), 8.79 - 8.66 (m, 2H), 8.38 (dd, J= 8.4 Hz, 1H), 8 13 - 8.11 (m, 1H), 8.08 - 8.05 (m, 4H), 7.86 - 7.77 (m, 3H), 7.67 (d, J= 8.0 Hz, 2H), 7.51 - 7.46 (m, 2H), 7.45 - 7.41 (m, 1H), 6.86 - 6.78 (m, 1H), 4.41 ( d, J= 4.4 Hz, 2H), 3.21 - 3.15 (m, 2H), 3.09 - 3.01 (m, 6H), 1.91 - 1.85 (m, 2H), 1.82 - 1.71 (m, 4H), 1.54 - 1.53 (m, 2H).
[00477] Intermediate 55: 3-(3-(4-((4-((Methyl-d3)amino)piperidin-l-yl)methyl)phenyl)-5- phenyl-3H-imidazo[4,5-b]pyri din-2 -yl)pyridin-2-amine
Figure imgf000133_0001
[00478] Step 1 : Benzyl 4-((terZ-butoxycarbonyl)amino)piperidine-l-carboxylate
[00479] To a solution of tertebutyl A-(4-piperidyl)carbamate (12 g, 59.9 mmol) in CH2CI2 (100 mL) were added TEA (18.2 g, 179 mmol), and then CbzCl (11.2 g, 65.9 mmol) was added into the mixture at 0 °C. The mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (Eluent of 10-50% EtOAc in petroleum ether) to give benzyl 4-((tert- butoxycarbonyl)amino)piperidine-l-carboxylate (16 g, yield: 71%) as an off-white solid. 'H NMR (400 MHz, Dimethylsulfoxide-t/g) 8 7.40 - 7.28 (m, 5H), 5.06 (s, 2H), 3.90 (d, J= 13.6 Hz, 2H), 3.50 - 3.34 (m, 2H), 2.89 (s, 2H), 1.71 (d, J= 10.8 Hz, 2H), 1.37 (s, 9H), 1.30 - 1.18 (m, 2H).
[00480] Step 2: Benzyl 4-((ter/-butoxycarbonyl)(methyl-d3)amino)piperidine-l -carboxylate [00481] To a solution of benzyl 4-(te/7-butoxycarbonylamino)piperidine- l -carboxylate (13 g, 38.9 mmol) in THF (200 mL) was added NaH (4.66 g, 117 mmol) at 0 °C. After stirring at 0 °C for 30 min, CD3I (16.5 g, 117 mmol) was added to the mixture The mixture was stirred at 25 °C for 16 hr. The mixture was quenched with NH4CI (aq) (100 mL) at 0 °C. The mixture was duilted with H2O (100 mL) and extrated with CH2Q2 (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over I feSCL, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~20% EtOAc in petroleum ether) to give benzyl 4-((/c/7-butoxycarbonyl)(methyl- t/3)amino)piperidine-l-carboxylate (8.6 g, yield: 56%) as a colorless oil. MS: m/z = 252.3 [M + H - 100]+. (400 MHz, Dimethylsulfoxide-^) 87.42 - 7.28 (m, 5H), 5.07 (s, 2H), 4.14 - 3.89 (m, 3H), 2.82 (s, 2H), 1.58 - 1.48 (m, 4H), 1.39 (s, 9H).
[00482] Step 3 : ZcrZ-Butyl (methyl-d3)(piperidin-4-yl)carbamate
[00483] To a solution of benzyl 4-[/c77-butoxycarbonyl(trideuteriomethyl)amino]piperidine- l - carboxylate (8.6 g, 24.5 mmol) in MeOH (90 mL) was added Pd/C (900 mg, 24.5 mmol). The mixture was stirred at 25 °C for 16 hr under H2 (15 psi). The mixture was filtered, and the filter cake was washed by MeOH (30 mL). The filtrate was concentrated under reduced pressure to give a zc/'Z-butyl (methyl-6?3)(piperidin-4-yl)carbamate (5 g, yield: 80%) as a colorless oil. MS: m/z = 218.3 [M + H]+. XHNMR (400 MHz, Dimethylsulfoxide-zfc) 83.93 - 3.62 (m, 1H), 3.26 - 3.16 (m, 1H), 2.95 (d, J= 12.0 Hz, 2H), 2.47 - 2.38 (m, 2H), 1.54 - 1.42 (m, 4H), 1.39 (s, 9H).
[00484] Step 4: zcz'Z-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)(methyl-d3)carbamate
[00485] To a solution of Intermediate 14 (1 g, 2.43 mmol) in DMF (10 mL) were added tert- butyl (methyl-6/3)(piperidin-4-yl)carbamate (527 mg, 2.43 mmol), Nal (182 mg, 1.21 mmol) and K2CO3 (1.0 g, 7.28 mmol). The mixture was stirred at 80 °C for 18 hr. The reaction mixture was added H2O (20 mL) and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~6% MeOH in CH2CI2) to give Zez7-butyl (l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)(methyl-<i3)carbamate (750 mg, yield: 49%) as a yellow solid. MS: m/z = 593.3 [M + H]+.
[00486] Step 5: 3-(3-(4-((4-((Methyl-d3)amino)piperidin-l-yl)methyl)phenyl)-5-phenyl-3H- imidazo[4,5-b]pyri din-2 -yl)pyri din-2 -amine
[00487] To a solution of Zcz'Z-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)(methyl-d3)carbamate (430 mg, 725 pmol) in CH2CI2 (5 mL) was added TFA (165 mg, 1.45 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was diluted with H2O (10 mL). The pH of the mixture was adjusted to about 8 by NaHCCh (aq.). The mixture was extracted with CH2CI2 (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SC>4, filtered, and concentrated under reduced pressure. After purified by >rep-TLC (CH2CI2: MeOH = 5: 1), 3-(3-(4-((4-((methyl- t/3)amino)piperidin-l-yl)methyl)phenyl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-2-yl)pyridin-2- amine (Intermediate 55, 350 mg crude, yield: 50%) was obtained as a light-yellow solid. MS: m/z = 493.3 [M + H]+. 'H NMR (400 MHz, Methanol-^) 88.19 (d, J = 8.4 Hz, 1H), 8.03 (d, J= 7.2 Hz, 2H), 7.98 (dd, J= 4.8, 1.6 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 8.4 Hz, 2H), 7.47 - 7 35 (m, 5H), 7.32 (dd, J= 7.6, 1.6 Hz, 1H), 6 47 (dd, J= 7.6, 4.8 Hz, 1H), 3.65 (s, 2H), 3.08 - 3.03 (m, 2H), 3.02 - 2.95 (m, 1H), 2.21 - 2.15 (m, 2H), 2.08 - 2.05 (m, 2H), 1.67 - 1.61 (m, 2H).
[00488] Intermediate 56: 3-(3-(4-((2,8-Diazaspiro[4.5]decan-2-yl)methyl)phenyl)-5-phenyl- 3rt-imidazo[4,5-A]pyridin-2-yl)pyridin-2-amine
Figure imgf000135_0001
[00489] Step 1: Zcrt-Butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3rt-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate
[00490] To a solution of Intermediate 14 (1.5 g, 3.6 mmol) and tert-butyl 2,8- diazaspiro[4.5]decane-8-carboxylate (1.0 g, 4.4 mmol) in DMF (10 mL) were added Nal (273 mg, 1.8 mmol) and K2CO3 (1.0 g, 7.0 mmol). The mixture was stirred at 80 °C for 1 hr. After cooling to 20°C, the reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-85% EtOAc in petroleum ether) to give tert-butyl 2-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3rt-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,8-diazaspiro[4.5]decane- 8-carboxylate (720 mg, yield: 34%) as a yellow solid. MS: m/z = 616.4 [M + H]+
[00491] Step 2: 3-(3-(4-((2,8-Diazaspiro[4.5]decan-2-yl)methyl)phenyl)-5-phenyl-3rt- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00492] A solution of tert-butyl 2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (720 mg, 1.2 mmol) in HC1 in 1,4-dioxane (4 M, 5 mL) was stirred at 25 °C for 0.5 hr. The mixture was concentrated and washed with CH2CI2 (3 mL), then concentrated to dryness under reduced pressure. 3-(3-(4- ((2, 8-Diazaspiro[4.5 ]decan-2-yl)methyl)phenyl)-5 -phenyl-3Z/-imidazo [4, 5 - ] py ri di n-2- yl)pyridin-2-amine (Intermediate 56, 600 mg, HC1 salt, yield: 91%) was obtained as a yellow solid. MS: m/z = 516.3 [M + H]+. 'H NMR (400 MHz, Methanol-^) 3 8.33 (d, J= 8.8 Hz, 1H), 8.10 - 8.01 (m, 4H), 7.96 - 7.87 (m, 3H), 7.72 (d, J= 8.0 Hz, 2H), 7.49 - 7.40 (m, 3H), 6.96 - 6.87 (m, 1H), 4.67 - 4.54 (m, 2H), 3.75 - 3.65 (m, 2H), 3 51 (d, J= 10.0 Hz, 1H), 3.35 (s, 2H), 3.32 - 3.20 (m, 3H), 2.32 - 2.23 (m, 1H), 2.15 - 2.05 (m, 2H), 2.04 - 1.96 (m, 3H).
[00493] Example 1: 3-(4-(4-(2-(2-Aminopyri din-3 -yl)-37/-imidazo[4,5-b]pyri din-3 - yl)benzyl)piperazin- 1 -yl)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000136_0001
[00494] To a solution of Intermediate 2 (200 mg, 519 pmol) in MeOH (4 mL) were added TEA (2.5 mmol) and 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (88.5 mg, 623 pmol). The reaction mixture stirred at 25 °C for 16 hr. The mixture was then filtered and the collected solid residue was washed with MeOH (10 mL x 2) and dried in vacuo to give 3-(4-(4-(2-(2-aminopyridin-3- yl)-3Zf-imidazo[4,5-b]pyri din-3 -yl)benzyl)piperazin-l-yl)-4-methoxy cy cl obut-3-ene-l, 2-dione (Example 1, 150 mg, yield: 54%) as a light-yellow solid. MS: m/z = 496.2 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide-<A) 88.33 (dd, J= 4.8, 1.2 Hz, 1H), 8.20 (dd, J= 8.0, 1.6 Hz, 1H), 7.98 (dd, J= 4.8, 1.6 Hz, 1H), 7.46 (d, J= 8.0 Hz, 2H), 7.43 - 7.36 (m, 3H), 7.16 (dd, J =
7.6, 1.6 Hz, 1H), 6.99 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 4.30 (s, 3H), 3.86 - 3.76 (m, 2H), 3.62 (s, 2H), 3.60 - 3.45 (m, 2H), 2.57 - 2.51 (m, 4H).
[00495] Example 2: 3-((4-(2-(2-Aminopyridin-3-yl)-3Z7-imidazo[4,5-b]pyridin-3- yl)benzyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000136_0002
[00496] Following the general procedure of Example 1, the reaction of Intermediate 1 (200 mg, 632 pmol) with 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (108 mg, 759 pmol) was carried out. After prep-TLC (CH2Q2 : MeOH = 10 : 1), 3-((4-(2-(2-aminopyridin-3-yl)-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)amino)-4-methoxycy cl obut-3-ene-l, 2-dione (Example 2, 50 mg, yield: 11%, 1:1 mixture of tautomers) was obtained as an off-white solid. MS: m/z = 427.0 [M + H]+. 'H NMR (400 MHz, Dim ethyl sulfoxide-cL) 3 9.35 - 9.28 (m, 0.5H), 9.18 - 9.05 (m, 0.5H), 8. 1 (dd, <7= 4.8, 1.2 Hz, 1H), 8.20 (dd, J = 8.0, 1.2 Hz, 1H), 7.99 (dd, = 4.8, 1.6 Hz, 1H), 7.47 - 7.41 (m, 4H), 7.39 (dd, J = 8.0, 4.8 Hz, 1H), 7.22 (dd, J= 7.6, 1.6 Hz, 1H), 6.92 (br s, 2H), 6.40 (dd, J= 7.6, 4.8 Hz, 1H), 4.77 (d, J= 5.6 Hz, 1H), 4.55 (d, J= 6.0 Hz, 1H), 4.30 (s, 3H).
[00497] Example 3: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000137_0001
[00498] Following the general procedure of Example 1, the reaction of Intermediate 3 (200 mg, 500 pmol) with 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (85.4 mg, 600 pmol) was carried out and 3-((l-(4-(2-(2-aminopyridin-3-yl)-3Z/-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione (Example 3, 120 mg, yield: 44%, 6:4 mixture of tautomers) was obtained as an orange solid. MS: m/z = 510.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/g) 58.86 (d, J= 8.4 Hz, 0.6H), 8.65 (d, J= 8.4 Hz, 0.4H), 8.33 (dd, J= 4.8, 1.6 Hz, 1H), 8.20 (dd, J= 8.0, 1.2 Hz, 1H), 7.99 (dd, J= 4.8, 1.6 Hz, 1H), 7.48 - 7.30 (m, 5H), 7.16 (dd, J= 7.7, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.37 (t, J= 6.0 Hz, 1H), 4.31 - 4.27 (m, 3H), 3.87 - 3.78 (m, 0.4H), 3.54 (s, 2H), 3.42 - 3.38 (m, 0.6H), 2.86 - 2.77 (m, 2H), 2.07 - 1.94 (m, 2H), 1.86 - 1.78 (m, 2H), 1.62 - 1.50 (m, 2H).
[00499] Example 4: 3-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Zf-imidazo[4,5-b]pyridin-3- yl)benzyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000137_0002
[00500] Following the general procedure of Example 1, the reaction of Intermediate 4 (200 mg, 510 pmol) with 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (86.9 mg, 612 pmol) was carried out. After prep-TLC (CH2Q2 : MeOH = 10 : 1), 3-((4-(2-(2-aminopyridin-3-yl)-5-phenyl-3 /- imidazo[4,5-b]pyridin-3-yl)benzyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione (Example 4, 13.0 mg, yield: 4.6%, 1 : 1 mixture of tautomers) was obtained as a brown solid. MS: m/z =
503.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/e) 89.37 - 9.27 (m, 0.5H), 9.17 - 9.06 (m, 0.5H), 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.51 - 7.38 (m, 7H), 7.21 (d, J= 7.6 Hz, 1H), 6.92 (br s, 2H), 6.42 (dd, J= 7.6, 4.8 Hz, 1H), 4.85 - 4.76 (m, 1H), 4.62 - 4.54 (m, 1H), 4.30 (s, 3H). [00501] Example 5: 3-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z7-imidazo[4,5-b]pyridin-3- yl)benzyl)amino)-4-hydroxycyclobut-3-ene-l, 2-dione
Figure imgf000138_0001
[00502] To a solution of Example 4 (200 mg, 398 pmol) in EtOH (4 mL) at 0 °C was added NaOH (79.5 mg, 1.99 mmol) in H2O (2 mL) dropwise. The reaction mixture was stirred at 25 °C for 16 hr. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25mm 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 26% - 56%, 8 min) to give 3-((4-(2-(2-aminopyridin-3-yl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-3-yl)benzyl)amino)-4-hydroxycyclobut-3-ene- 1,2-dione (Example 5, 30 mg, yield: 15%, mixture of tautomers) as a white solid. MS: m/z = 489.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tZe) 8 8.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.93 - 7.82 (m, 1H), 7.51 - 7.43 (m, 6H), 7.42 - 7.36 (m, 1H), 7.22 (dd, J= 7.6, 2.0 Hz, 1H), 7.08 (s, 0.5H), 6.98 (br s, 2H), 6.94 (s, 0.5H), 6.43 (dd, J= 7.6, 4.8 Hz, 1H), 4.71 (d, J= 6.4 Hz, 2H).
[00503] Example 6: JV-(3-(2-(2-Aminopyridin-3-yl)-3-(4-(((2-methoxy-3,4-dioxocyclobut-l-en- l-yl)amino)methyl)phenyl)-3//-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
Figure imgf000138_0002
[00504] Following the general procedure of Example 1, the reaction of Intermediate 5 (170 mg, 378 pmol) with 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (64.5 mg, 454 pmol) was carried out.
A-(3-(2-(2-aminopyridin-3-yl)-3-(4-(((2-methoxy-3,4-dioxocyclobut-l-en-l- yl)amino)methyl)phenyl)-3//-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide (Example 6, 150 mg, yield: 67%, 1 : 1 mixture of tautomers) was obtained as a brown solid. MS: m/z = 560.1 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide-^) 8 10.06 (s, 1H), 9.38 - 9.30 (m, 0.5H), 9.19 - 9.06 (m, 0.5H), 8.28 (d, J= 8.4 Hz, 1H), 8.12 (d, J= 12.0 Hz, 1H), 8.00 (dd, J= 4.8, 2.0 Hz, 1H), 7.85 (d, J= 8.4 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.54 - 7.45 (m, 4H), 7.38 (dd, J= 7.6, 7.6 Hz, 1H), 7.21 (d, ./= 7,6 Hz, 1H), 6.88 (br s, 2H), 6.41 (dd, J = 7.6, 4.8 Hz, 1H), 4.80 (d, J= 5.6 Hz, 1H), 4.70 (d, J= 6.0 Hz, 1H), 4.30 (s, 3H), 2.05 (s, 3H).
[00505] Example 7: JV-(3-(2-(2-Aminopyridin-3-yl)-3-(4-((4-(2-methoxy-3,4-dioxocyclobut-l- en-l-yl)piperazin-l-yl)methyl)phenyl)-3/7-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
Figure imgf000139_0001
[00506] Following the general procedure of Example 1, the reaction of Intermediate 6 (160 mg, 309 pmol) with 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (52.6 mg, 370 pmol) was carried out. N-(3 -(2-(2-aminopyri din-3 -y 1 )- 3 -(4-((4-(2-methoxy-3 ,4-dioxocy clobut- 1 -en- 1 -yl)piperazin- 1 - yl)methyl)phenyl)-3//-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide (Example 7, 110 mg, yield: 53%) was obtained as a brown solid. MS: m/z = 629.1 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide-t/s) 8 10.04 (s, 1H), 8.27 (d, J= 8.4 Hz, 1H), 8.20 (s, 1H), 7.99 (dd, J= 4.8, 1.6 Hz, 1H), 7.87 (d, J= 8.4 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.51 - 7.44 (m, 4H), 7.38 (dd, J= 8.0, 8.0 Hz, 1H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 6.98 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 4.30 (s, 3H), 3.86 - 3.77 (m, 2H), 3.63 (s, 2H), 3.59 - 3.52 (m, 2H), 2.58 - 2.54 (m, 4H), 2.05 (s, 3H).
[00507] Example 8: JV-(3-(2-(2-Aminopyridin-3-yl)-3-(4-((4-((2-methoxy-3,4-dioxocyclobut-l- en-l-yl)amino)piperidin-l-yl)methyl)phenyl)-3//-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide
Figure imgf000139_0002
[00508] Following the general procedure of Example 1, the reaction of Intermediate 12 (200 mg, 375 pmol) with 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (64.0 mg, 450 pmol) was carried out. After prep-HPLC(column: Waters Xbridge C18 150 x 25mm x 10 pm, mobile phase: [water (NH3H2O) - ACN]; B%: 10%-30%, 6min) and prep-TLC (CH2C12 : MeOH = 10 : 1), N- (3-(2-(2-aminopyridin-3-yl)-3-(4-((4-((2-methoxy-3,4-dioxocyclobut-l-en-l-yl)amino)piperidin- l-yl)methyl)phenyl)-377-imidazo[4,5-b]pyridin-5-yl)phenyl)acetamide (Example 8, 10 mg, yield: 4.0%, 1 : 1 mixture of tautomers) was obtained as a yellow solid. MS: m/z = 643.1 [M + H]+. 'HNMR (400 MHz, Chloroform-tT) 88.13 - 8.03 (m, 3H), 7.77 (d, J= 8.4 Hz, 1H), 7.72 (d, J= 7.6 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.50 - 7.33 (m, 5H), 7.05 (d, J= 7.2 Hz, 1H), 6.61 (br s, 2H), 6.52 (br s, 1H), 6.34 (dd, J= 7.6, 4.8 Hz, 1H), 4.43 - 4.33 (m, 3H), 3.57 (s, 3H), 2.93 - 2.84 (m, 2H), 2.24 - 2.17 (m, 2H), 2.14 (s, 3H), 1.99 - 1.94 (m, 2H), 1.70 - 1.58 (m, 2H).
[00509] Example 9: 3-(4-(4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000140_0001
[00510] Following the general procedure of Example 1, the reaction of Intermediate 8 (200 mg, 433 pmol) with 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (73.9 mg, 520 pmol) was carried out. 3-(4-(4-(2-(2-aminopyridin-3-yl)-6-phenyl-3/7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazin-l- yl)-4-m ethoxy cyclobut-3-ene- 1,2-dione (Example 9, 165 mg, yield: 61%) was obtained as a yellow solid. MS: m/z = 572.1 [M + H]+. LH NMR (400 MHz, Dimethylsulfoxide-<A) 3 8.63 (d, J= 1.8 Hz, 1H), 8.47 (d, J= 1.8 Hz, 1H), 8.02 - 7.98 (m, 1H), 7.84 - 7.77 (m, 2H), 7.55 - 7.46 (m, 4H), 7.45 - 7.39 (m, 3H), 7.21 - 7.17 (m, 1H), 7.04 (br s, 2H), 6.40 (dd, J= 7.6, 4.8 Hz, 1H), 4.30 (s, 3H), 3.88 - 3.74 (m, 2H), 3.63 (s, 2H), 3.58 - 3.50 (m, 2H), 2.57 - 2.53 (m, 4H).
[00511] Example 10: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-6-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
Figure imgf000140_0002
[00512] Following the general procedure of Example 1, the reaction of Intermediate 9 (200 mg, 420 pmol) with 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (71.7 mg, 504 pmol) was carried out. 3-((l-(4-(2-(2-aminopyridin-3-yl)-6-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperi din-4- yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione (Example 10, 50 mg, yield: 19.5%, 1 :1 mixture of tautomers) was obtained as a yellow solid. MS: m/z = 586.3 [M + H]+. 1 H NMR (400 MHz, Chloroform-t/) 8 8.62 (d, J= 2.0 Hz, 1H), 8.27 (d, J= 2.0 Hz, 1H), 8.06 (dd, J= 4.8, 1.6 Hz, 1H), 7.64 (d, J= 7.2 Hz, 2H), 7.53 - 7.48 (m, 4H), 7.44 - 7.35 (m, 3H), 7.09 (dd, J= 7.6, 1.2 Hz, 1H), 6.66 (br s, 2H), 6.50 - 6.38 (m, 1H), 6.35 (dd, J= 7.6, 4.8 Hz, 1H), 4.42 (s, 3H), 3.61 (s, 2H), 3.60 - 3.51 (m, 1H), 2.95 - 2.85 (m, 2H), 2.26 - 2.17 (m, 2H), 2.03 - 1.93 (m, 2H), 1.73 - 1.61 (m, 2H). [00513] Example 11 : 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-isopropoxycy cl obut-3-ene- 1,2-dione
Figure imgf000141_0001
[00514] To a solution of Intermediate 11 (100 mg, 210 pmol) and TEA (1.05 mmol) in MeOH (4 mL) was added 3, 4-diisopropoxycyclobut-3-ene-l, 2-dione (50 mg, 252 pmol). The reaction mixture stirred at 25 °C for 16 hr. The mixture was concentrated under reduced pressure and purified by prep-TLC (MeOH : CH2CI2 = 1 : 10) to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-32/-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)-4-isopropoxycyclobut-3- ene-1, 2-dione (Example 11, 18.9 mg, yield: 14%, 1 :1 mixture of tautomers) as a light-yellow powder. MS: m/z = 614.2 [M + H]+. 'H NMR (400 MHz, Dim ethyl sulfoxide-cL) 8 8.86 (d, J = 8.0 Hz, 0.5H), 8.65 (d, J= 8.0 Hz, 0.5H), 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.49 - 7.43 (m, 6H), 7.42 - 7.37 (m, 1H), 7.15 (d, J= 8.0 Hz, 1H), 7.03 (br s, 2H), 6.41 - 6.35 (m, 1H), 5.29 - 5.19 (m, 1H), 3.89 - 3.79 (m, 0.5H), 3.57 (s, 2H), 3.48 - 3.41 (m, 0.5H), 2.90-2.80 (m, 2H), 2.10-1.98 (m, 2H), 1.86-1.75 (m, 2H), 1.63 - 1.54 (m, 2H), 1.38 (t, J= 5.6 Hz, 6H).
[00515] Example 12: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-ethoxycyclobut-3-ene-l, 2-dione
Figure imgf000141_0002
[00516] Following the general procedure for Example 11, the reaction of Intermediate 11 (100 mg, 210 pmol) with 3, 4-di ethoxy cyclobut-3-ene- 1,2-dione (42.9 mg, 252 pmol) was carried. After prep-TLC (MeOH : CH2Q2 = 1 : 10), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/f- imidazo[4,5-b]pyri din-3 -yl)benzyl)piperidin-4-yl)amino)-4-ethoxycyclobut-3-ene- 1,2-dione (Example 12, 11.3 mg, yield: 8.8%, 1 : 1 mixture of tautomers) was obtained as a light-yellow powder. MS: m/z = 600.3 [M + H]+. XH NMR (400 MHz, Dimethyl sulfoxide-^) 8 8.87 (d, J = 8.0 Hz, 0.5H), 8.66 (d, J= 8.4 Hz, 0.5H), 8.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.49 - 7.43 (m, 6H), 7.42 - 7.37 (m, 1H), 7.17 - 7.12 (m, 1H), 7.03 (br s, 2H), 6.41 - 6.34 (m, 1H), 4.66 (q, J= 7.2 Hz, 2H), 3.89 - 3.76 (m, 0.5H), 3.57 (s, 2H), 3.43 - 3.41 (m, 0.5H), 2.90 - 2.78 (m,
2H), 2.11 - 1.95 (m, 2H), 1.89 - 1.75 (m, 2H), 1.63 - 1.53 (m, 2H), 1.36 (t, J = 7.2 Hz, 3H).
[00517] Example 13: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(methoxy-d3)cyclobut-3-ene- 1,2-dione
Figure imgf000142_0001
[00518] Following the general procedure for Example 11, the reaction of Intermediate 11 (100 mg, 210 pmol) with 3, 4-bis(tri deuteri omethoxy)cyclobut-3-ene- 1,2-dione (46.7 mg, 315 pmol) was carried out. After prep-TLC (MeOH: CH2Q2 = 1 : 10), 3-((l-(4-(2-(2-aminopyridin-3-yl)- 5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)-4-(methoxy-d3)cyclobut- 3-ene-l, 2-dione (Example 13, 17.3 mg, yield: 13%, 1 :1 mixture of tautomers) was obtained as a light-yellow solid. MS: m/z = 589.3 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxi de-ds) 6 8.86 (d, J= 8.4 Hz, 0.5H), 8.65 (d, J = 7.6 Hz, 0.5H), 8.26 (d, J = 8.0 Hz, 1H), 8.04 - 7.96 (m, 4H), 7.48 - 7.42 (m, 6H), 7.41 - 7.37 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.02 (br s, 2H), 6.38 -
6.37 (m, 1H), 3.89 - 3.76 (m, 0.5H), 3.57 (s, 2H), 3.17 (d, .7 = 4,8 Hz, 0.5H), 2.88 - 2.77 (m, 2H),
2.06 - 2 03 (m, 2H), 1.88 - 1.71 (m, 2H), 1.63 - 1.54 (m, 2H)
[00519] Example 14: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(cyclopentyloxy)cyclobut-3-ene-l, 2-dione
Figure imgf000142_0002
[00520] Following the general procedure for Example 11, the reaction of Intermediate 11 (100 mg, 210 pmol) with 3, 4-bis(cyclopentoxy)cyclobut-3-ene-l, 2-dione (63.1 mg, 252 pmol) was carried out. After silica gel flash chromatography (Eluent of 0~7% EtOAc in petroleum ether), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperi din-4- yl)amino)-4-(cyclopentyloxy)cyclobut-3-ene-l, 2-dione (Example 14, 40.7 mg, yield: 30%, 1: 1 mixture of tautomers) was obtained as a light-yellow powder. MS: m/z = 640.4 [M + H]+. ’H NMR (400 MHz, Dimethylsulfoxide- e) 3 8.87 (d, J= 8.0 Hz, 0.5H), 8.60 (d, J= 8.0 Hz, 0.5H), 8.27 (d, J= 8.4 Hz, 1H), 8.09 - 7.93 (m, 4H), 7.53 - 7.42 (m, 6H), 7.42 - 7.36 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.03 (br s, 2H), 6.44 - 6.31 (m, 1H), 5.57 - 5.43 (m, 1H), 3.91 - 3.77 (m, 0.5H), 3.57 (s, 2H), 3.43 - 3.39 (m, 0.5H), 2.93 - 2.80 (m, 2H), 2.63 - 2.52 (m, 2H), 2.07 - 1.98 (m, 2H), 1.87 - 1.79 (m, 4H), 1.73 - 1.55 (m, 6H).
[00521] Example 15: 2-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-3-(cyclopentyloxy)-4-thioxocyclobut-2-en-l-one
Figure imgf000143_0001
[00522] Following the general procedure for Example 11, the reaction of Intermediate 11 (100 mg, 210 pmol) with 2,3-bis(cyclopentyloxy)-4-thioxocyclobut-2-enone (138 mg, 630 pmol) was carried out. After prep-TLC (MeOH: CH2CI2 = 1 : 10), 2-((l-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)-3-(cyclopentyloxy)-4- thioxocyclobut-2-en-l-one (Example 15, 22.2 mg, yield: 16%, 1 :1 mixture of tautomers) was obtained as a yellow solid. MS: m/z = 656.4 [M + H]+. LH NMR (400 MHz, Dimethylsulfoxide-t/g) 89.83 (d, J= 8.0 Hz, 0.5H), 9.48 (d, J= 8.0 Hz, 0.5H), 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.49 - 7.44 (m, 6H), 7.41 - 7.37 (m, 1H), 7.18 - 7.14 (m, 1H), 7.03 (br s, 2H), 6.40 - 6.35 (m, 1.5H), 6.30 - 6.26 (m, 0.5H), 3.90 - 3.77 (m, 0.5H), 3.58 (s, 2H), 3.51 - 3.47 (m, 0.5H), 2.89 - 2.84 (m, 2H), 2.07 - 1.95 (m, 4H), 1.90 - 1.84 (m, 4H), 1.73 - 1.62 (m, 6H).
[00523] Example 16: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(cyclopentyloxy)cyclobut-3-ene-l,2-dithione
Figure imgf000143_0002
[00524] Following the general procedure for Example 11, the reaction of Intermediate 11 (100 mg, 210 pmol) with 3,4-bis(cyclopentyloxy)cyclobut-3-ene-l,2-dithione (178 mg, 630 pmol) was carried out. After silica gel flash chromatography (Eluent of 0~6% EtOAc in petroleum ether), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(cyclopentyloxy)cyclobut-3-ene-l,2-dithione (Example 16, 11.5 mg, yield: 8.1%, 6:4 mixture of tautomers) was obtained as a yellow solid. MS: m/z = 672.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/s) 3 9.85 (d, J= 8.0 Hz, 0.6H), 9.75 (d, J= 7.6 Hz, 0.4H), 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.49 - 7.44 (m, 5H), 7.42 - 7.37 (m, 1H), 7.19 - 7.12 (m, 1H), 7.03 (br s, 2H), 6.48 - 6.29 (m, 2H), 4.88 - 4.60 (m, 0.4H), 3.58 (s, 2H), 3.46 - 3.38 (m, 0.6H), 2.96 - 2.83 (m, 2H), 2.04 - 1.94 (m, 6H), 1.90 - 1.84 (m, 2H), 1.77 - 1 63 (m, 6H).
[00525] Example 17: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000144_0001
[00526] Following the general procedure for Example 11, the reaction of Intermediate 11 (250 mg, 526 pmol) with 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (89.6 mg, 631 pmol) was carried out. The mixture was filtered and the collected solid was washed with MeOH (10 mL x 2) to give 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione (Intermediate 17, 84.4 mg, 27% yield, 1 : 1 mixture of tautomers) ) as a brown solid. MS: m/z = 586.2 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide-6 ) 8 8.86 (d, J= 8.0 Hz, 0.5H), 8.65 (d, J= 8.0 Hz, 1H), 8.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.48 - 7.31 (m, 7H), 7.15 (dd, J = 1.6, 1.2 Hz, 1H). 7.04 (s, 2H), 6.39 - 6.36 (m, 1H), 4.29 (s, 3H), 3.84 - 3.78 (m, 0.5H), 3.57 (s, 2H), 3.45 - 3.40 (m, 0.5H), 2.84 (br d, J= 10.8 Hz, 2H), 2.02 - 2.00 (m, 2H), 1.84 - 1.81 (m, 2H), 1.62 - 1.56 (m, 2H).
[00527] Example 18: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-hydroxycyclobut-3-ene-l, 2-dione
Figure imgf000144_0002
[00528] To a solution of Example 17 (100 mg, 170 pmol) in EtOH (1 mL) was added NaOH (20.5 mg, 512 pmol) in 0.5 mL H2O at 0 °C. The mixture was stirred at 25 °C for 16 hr. The reaction was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25 mm 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 7% - 37%, 8 min) to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)-4-hydroxycyclobut-3-ene- 1,2-dione (Example 18, 40 mg, yield: 39%) as a light-yellow solid. MS: m/z = 572.2 [M + H]+. 'H NMR (400 MHz, Methanol-^) 6 8.21 (d, J= 8.4 Hz, 1H), 8.04 - 7.99 (m, 3H), 7.95 (d, J= 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.62 (d, J= 8.4 Hz, 2H), 7.44 - 7.35 (m, 4H), 6.52 (dd, J= 7.6, 4.8 Hz, 1H), 4.29 (s, 2H), 4.09 - 4.02 (m, 1H), 3.51 - 3.41 (m, 2H), 3.10 - 2.94 (m, 2H), 2.22 - 2.15 (m, 2H), 1.99 - 1.86 (m, 2H).
[00529] Example 19: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(dimethylamino)cyclobut-3-ene- 1,2-dione
Figure imgf000145_0001
[00530] To a solution of Example 17 (50 mg, 85.4 pmol) in DMSO (0.15 m ) was added N- methylmethanamine (2 M in THF, 650 pL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep- HPLC (column: Waters xbridge 150 x 25 mm 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 29% - 59%, 8 min) to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-3 -yl)benzyl)piperidin-4-yl)amino)-4-(dimethylamino)cy cl obut-3-ene- 1,2- dione (Example 19, 20 mg, yield: 39%) as an off-white solid. MS: m/z = 599.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/e 8 8.27 (d, J= 8.4 Hz, 1H), 8.07 - 7.95 (m, 4H), 7.55- 7.41 (m, 8H), 7.14 (dd, J= 8.0, 1.6 Hz, 1H), 7.04 (br s, 2H), 6.38 (dd, J= 8.0, 5.2 Hz, 1H), 4.15 - 4.02 (m, 1H), 3.59 (s, 2H), 3.16 (s, 6H), 2.91 - 2.84 (m, 2H), 2.07 - 1.99 (m, 2H), 1.87 - 1.79 (m, 2H), 1.71 - 1.59 (m, 2H).
[00531] Example 20: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z7-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(methylamino)cyclobut-3-ene-l, 2-dione
Figure imgf000145_0002
[00532] To a solution of Example 17 (50 mg, 85.4 pmol) in MeOH (0.5 mL) and CHCI3 (0.5 mL) was added MeNH2 (1.0 mL, 30% purity in ethanol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 pm; mobile phase: [water (HC1)- ACN]; B%: 2% - 32%, 11 min) to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-3 -yl)benzyl)piperidin-4-yl)amino)-4-(methylamino)cy cl obut-3-ene- 1,2- dione (Example 20, 3HC1 salt, 20 mg, yield: 40%, 1:1 mixture of tautomers) as a yellow solid. MS: m/z = 584.9 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-^ 8 10.89 (br s, 1H), 9.19 - 8.36 (m, 3H), 8.35 - 8.20 (m, 1H), 8.17 - 8.04 (m, 4H), 7.97 - 7.76 (m, 4H), 7.71 - 7.66 (m, 2H), 7.53 - 7 39 (m, 3H), 6.90 (dd, J =7.2, 6.4 Hz, 1H), 4.44 (d, J= 4.8 Hz, 0.5H), 4.38 (d, J= 4.2 Hz, 1.5H), 4.29 - 4.20 (m, 0.5H), 4.13 - 3.97 (m, 1.5H), 3.41 - 3.38 (m, 1H), 3.19 - 3.03 (m, 5H), 2.23 - 2.09 (m, 2H), 2.05 - 1.87 (m, 2H).
[00533] Example 21 : 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000146_0001
[00534] To a solution of Intermediate 10 (200 mg, 433 pmol) in MeOH (4 mL) were added TEA (2.15 mmol) and dimethoxy cy cl obut-3-ene- 1,2-dione (73.9 mg, 520 pmol). The reaction mixture was stirred at 25 °C for 16 hr. The mixture was filtered. The collected solid residue was washed with MeOH (10 mL x 2) and dried in vacuo to give 3-(4-(4-(2-(2-aminopyridin-3- yl)-5-phenyl-3/f-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazin-l-yl)-4-m ethoxy cy cl obut-3-ene- 1, 2-dione (Example 21, 90 mg, yield: 34%) as a brown solid. MS: m/z = 572.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- g) 88.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7 52 - 7.45 (m, 6H), 7.42 - 7.38 (m, 1H), 7.16 (dd, J= 8.0, 2.0 Hz, 1H), 7.02 (br s, 2H), 6.39 (dd, J = 7.6, 4.8 Hz, 1H), 4.30 (s, 3H), 3.85 - 3.77 (m, 2H), 3.64 (s, 2H), 3.58 - 3.53 (m, 2H), 2.59 - 2.53 (m, 4H).
[00535] Example 22: 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-hydroxycyclobut-3-ene- 1,2-dione
Figure imgf000146_0002
[00536] To a solution of Example 21 (200 mg, 350 pmol) in EtOH (4 mL) at 0 °C was added NaOH (42 mg, 1.05 mmol) in H2O (0.8 mL) dropwise. The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters xbridge 150 x 25 mm 10 pm; mobile phase: [water( NH4HCO3) - ACN]; B%: 17% - 47%, 8 min) to give 3-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-3 -yl)benzyl)piperazin- 1 -yl)-4-hydroxycy cl obut-3-ene- 1,2-dione (Example 22, 15 mg, yield: 7.6%) as a light-yellow solid. MS: m/z = 558.0 [M + H]+. XHNMR (400 MHz, Methanol-^) 3 8.20 (d, J= 8.4 Hz, 1H), 8.05 - 8.01 (m, 2H), 7.99 (dd, J= 5..2, 2.0 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.51 - 7.33 (m, 6H), 6.50 (dd, J= 7.6, 4.8 Hz, 1H), 4.00 - 3.88 (m, 4H), 3.85 (s, 2H), 2.88 - 2.72 (m, 4H).
[00537] Example 23: 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-(methoxy-d3)cyclobut-3-ene-l, 2-dione
Figure imgf000147_0001
[00538] Following the general procedure of Example 21, the reaction of Intermediate 10 (200 mg, 433 pmol) with 3, 4-bis(tri deuteri omethoxy)cyclobut-3-ene- 1,2-dione (96.3 mg, 650 pmol) in DCM (4 mL) was carried out. After silica gel flash chromatography (Eluent of 0~5% MeOH in CH2CI2), 3-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-(methoxy-d3)cyclobut-3-ene-l, 2-dione (Example 23, 70 mg, yield: 27%) was obtained as a yellow solid. MS: m/z = 575.4 [M + H]+. XH NMR (400 MHz, Dimethylsulfoxide- e) 8 8.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.51 - 7.44 (m, 6H), 7.42- 7.33 (m, 1H), 7.15 (dd, J = 7.6, 2.0 Hz, 1H), 7.01 (br s, 2H), 6.39 (dd, J= 8.0, 4.8 Hz, 1H), 3.85 - 3 77 (m, 2H), 3.64 (s, 2H), 3.58 - 3.51 (m, 2H), 2 57 - 2.53 (m, 4H).
[00539] Example 24: 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-ethoxycy cl obut-3-ene- 1,2-dione
Figure imgf000147_0002
[00540] Following the general procedure of Example 21, the reaction of Intermediate 10 (180 mg, 390 pmol) with 3, 4-diethoxycyclobut-3-ene- 1,2-dione (79.6 mg, 468 pmol) was carried out. 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazin-l- yl)-4-ethoxycyclobut-3-ene-l, 2-dione (Example 24, 152 mg, yield: 62%) was obtained as a brown solid. MS: m/z = 586.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/g) 3 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.53 - 7.37 (m, 7H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 4.66 (q, J= 7.2 Hz, 2H), 3.88 - 3.75 (m, 2H), 3.64 (s, 2H), 3.60 - 3.53 (m, 2H), 2.56 - 2.54 (m, 2H), 2.52 - 2.51 (m, 2H), 1.37 (t, J= 7.2 Hz, 3H).
[00541] Example 25: 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin- 1 -yl)-4-isopropoxycyclobut-3 -ene- 1 ,2-dione
Figure imgf000148_0001
[00542] Following the general procedure of Example 21, the reaction of Intermediate 10 (180 mg, 390 pmol) with 3, 4-diisopropoxycyclobut-3-ene-l, 2-dione (92.8 mg, 468 pmol) was carried out. 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyri din-3 - yl)benzyl)piperazin-l-yl)-4-isopropoxycy cl obut-3 -ene- 1,2-dione (Example 25, 135 mg, yield: 55%) was obtained as a brown solid. MS: m/z = 600.3 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide- s) 8 8.27 (d, J= 8.4 Hz, 1H), 8.07 - 7.94 (m, 4H), 7.53 - 7.34 (m, 7H), 7.16 (dd, <7= 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.39 (dd, J= 7.6, 4 8 Hz, 1H), 5.25 (m, 1H), 4.16 - 4.06 (m, 2H), 3.86 - 3.75 (m, 2H), 3.64 (s, 2H), 2.58 - 2.52 (m, 4H), 1.37 (d, J= 6.4 Hz, 6H). [00543] Example 26: 3-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin- 1 -yl)-4-(cyclopentyloxy)cyclobut-3-ene- 1 ,2-dione
Figure imgf000148_0002
[00544] Following the general procedure of Example 21, the reaction of Intermediate 10 (180 mg, 390 pmol) with 3, 4-bis(cyclopentyloxy)cyclobut-3-ene-l, 2-dione (117 mg, 468 pmol) was carried out. 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-l-yl)-4-(cyclopentyloxy)cyclobut-3-ene-l, 2-dione (Example 26, 52.0 mg, yield: 20%) was obtained as a brown solid. MS: m/z = 626.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- s) 8 8.27 (d, J= 8.4 Hz, 1H), 8.06 - 7.96 (m, 4H), 7.51 - 7.37 (m, 7H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 5.53 - 5.44 (m, 1H), 3.88 - 3.72 (m, 2H), 3.65 (s, 2H), 3.59 - 3.50 (m, 2H), 2.58 - 2.53 (m, 4H), 1.94 - 1.80 (m, 4H), 1.72 - 1.57 (m, 4H).
[00545] Example 27: 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
Figure imgf000149_0001
[00546] Step 1 : 3-[3-[4-[[4-(methylamino)-l-piperidyl]methyl]phenyl]-5-phenyl-imidazo[4,5- b]pyridin-2-yl]pyridin-2-amine
[00547] To a solution of Intermediate 14 (300 mg, 0.73 mmol) and Ze/7-butyl A-methyl-/V-(4- piperidyl)carbamate (312 mg, 1.46 mmol) in DMF (2 mL) were added Nal (18.2 mg, 0.073 mmol) and K2CO3 (336 mg, 2.43 mmol). The mixture was stirred at 80 °C for 2 hr. After cooling to 20 °C, the reaction mixture was poured into H2O (3 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~7% MeOH in CH2Q2) to give tert-butyl A-[l-[[4-[2-(2-amino-3- pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]-4-piperidyl]-A-methyl-carbamate (220 mg, yield: 51%,) as a yellow solid. MS: m/z = 590.3 [M + H]+.
[00548] Step 2: 3-(3-(4-((4-(Methylamino)piperidin-l-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00549] To a solution of tert-butyl Ar-[l-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]-4-piperidyl]-A-methyl-carbamate (200 mg, 0.339 mmol) in CH2CI2 (2 mL) was added TFA (38.7 mg, 0.339 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated to give a residue (185 mg TFA salt, yield: 93%). The crude (50 mg) was diluted with aqueous NaHCCh (10 mL) and extracted with CH2CI2 (10 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated. The residue was purified by prep-TLC (CH2CI2: MeOH = 10: 1) to give 3-[3-[4-[[4-(methylamino)- l-piperidyl]methyl]phenyl]-5-phenyl-imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine as an off- white solid. MS: m/z = 490.2 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-^) 8 8.27 (d, J = 8.4 Hz, 1H), 8.07 - 7.94 (m, 4H), 7.53 - 7.43 (m, 6H), 7.41 -7.39 (m, 1H), 7.16 (dd, J= 7.8, 1.2 Hz, 1H), 7.02 (br s, 2H), 6.37 (dd, J= 7.4, 4.8 Hz, 1H), 3.55 (s, 2H), 3.47-3.37 (m, 1H), 2.80 (br d, J= 12.0 Hz, 2H), 2.31 (s, 3H), 2.01 (dd, J= 11.4, 9.8 Hz, 2H), 1.85 - 1.77 (m, 2H), 1.36 - 1.22 (m, 2H).
[00550] Step 3: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
[00551] To a solution of 3-[3-[4-[[4-(methylamino)-l-piperidyl]methyl]phenyl]-5-phenyl- imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (50 mg, 0.102 mmol) and TEA (51.7 mg, 0.511 mmol) in MeOH (2 mL) was added 3, 4-dimethoxycy cl obut-3-ene- 1,2-dione (17.4 mg, 0.123 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated and purified by prep-TLC (DCM: MeOH = 10 : 1) to give 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5- phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)(methyl)amino)-4- methoxycy cl obut-3-ene- 1,2-dione (Example 27, 10.5 mg, yield: 17%, mixture of tautomers) as an off-white solid. MS: m/z = 600.3 [M + H]+. 'H NMR (400 MHz, Dim ethyl sulfoxide-cA) 8 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.93 (m, 4H), 7.50 - 7.43 (m, 6H), 7.41 - 7.36 (m, 1H), 7.14 (dd, J= 7.2, 1.4 Hz, 1H), 7.02 (br s, 2H), 6.43 - 6.33 (m, 1H), 4.34 - 4.28 (m, 3H), 3.72 - 2.61 (m, 1H), 3.59 (s, 2H), 3.22 (s, 2H), 3.03 (s, 1H), 2.93 (br d, J= 10.4 Hz, 2H), 2.07 - 1.99 (m, 2H), 1.92 - 1.80 (m, 2H), 1.73 - 1.62 (m, 2H).
[00552] Example 28: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzoyl)piperidin-4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000150_0001
[00553] Step 1 : 4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3ff-imidazo[4,5-b]pyridin-3-yl)benzoic acid [00554] To a solution of Intermediate 13 (500 mg, 1.2 mmol) in H2O (1 mL) and THF (2 mL) was added LiOH JLO (56.8 mg, 2.4 mmol). The mixture was stirred at 25 °C for 16 hr . The reaction mixture was fdtered. The filter liquor was concentrated to dryness to give 4-[2-(2- amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]benzoic acid (485 mg Li salt, yield: 99%) as a yellow solid, which was directly used to next step without further purification. MS: m/z = 408.1 [M + H]+.
[00555] Step 2: tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3 /-imidazo[4,5-b]pyridin- 3-yl)benzoyl)piperidin-4-yl)carbamate
[00556] To a solution of 4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]benzoic acid (500 mg, 1.2 mmol), in DMF (5 mL) was added tert-butyl N-(4- piperidyl)carbamate (368.7 mg, 1.8 mmol), DIEA (793 mg, 6.2 mmol) and HATU (700 mg, 1.8 mmol). The resulting mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with CH2CI2 (10 mL), the organic phase was separated and washed with H2O (10 mL x 2) and brine (10 mL x 2), dried over NaiSCL, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel flash chromatography (Eluent of 0~5% MeOH in CH2CI2) to give tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3rt-imidazo[4,5- b]pyridin-3-yl)benzoyl)piperidin-4-yl)carbamate (645 mg, yield: 89%) as a yellow solid. MS: m/z = 590.3 [M + H]+.
[00557] Step 3: (4-Aminopiperidin-l-yl)(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyri din-3 -yl)phenyl)m ethanone
[00558] To a solution of tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzoyl)piperidin-4-yl)carbamate (500 mg, 0.848 mmol) in 1,4-dioxane (5 mL) was added 4M HC1 in 1,4-dioxane (1.0 mL) at 15°C. The mixture was stirred at 25°C for 16 hr. The reaction mixture was filtered. The filter cake was concentrated to dryness. The crude product was triturated with 1,4-dioxane at 25°C for 30 min to give (4-aminopiperidin-l-yl)(4-(2- (2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3-yl)phenyl)methanone (410 mg HC1 salt, yield: 92%) as a yellow solid. MS: m/z = 490.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/g) 8 8.28 (d, J= 8.4 Hz, 1H), 8.07 - 7.99 (m, 4H), 7.60 - 7.52 (m, 4H), 7.50 - 7.44 (m, 2H), 7.42 - 7.38 (m, 1H), 7.22 (dd, J= 7.6, 1.6 Hz, 1H), 6.95 (br s, 2H), 6.43 (dd, J= 7.6, 4.8 Hz, 1H), 4 45 - 4.03 (m, 1H), 3.63 - 3.48 (m, 1H), 3.16 - 2.94 (m, 2H), 2.88 - 2.79 (m, 1H), 1.84 - 1.56 (m, 4H).
[00559] Step 4: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3rt-imidazo[4,5-b]pyridin-3- yl)benzoyl)piperidin-4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione [00560] To a solution of (4-amino-l-piperidyl)-[4-[2-(2-amino-3-pyridyl)-5-phenyl- imidazo[4,5-b]pyridin-3-yl]phenyl]methanone (100 mg, 0.204 mmol) and TEA (103 mg, 1.0 mmol) in MeOH (1 mL) was added 3, 4-dimethoxycy cl obut-3-ene- 1,2-dione (34.8 mg, 0.245 mmol). The reaction mixture stirred at 25 °C for 16 hr. The reaction mixture was filtered. The collected solid was washed with MeOH (2 mL x 2) and dried in vacuo to give 3-((l-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzoyl)piperidin-4-yl)amino)-4- methoxy cy cl obut-3-ene- 1,2-dione (Example 28, 41.2 mg, yield: 32%, 1 : 1 mixture of tautomers) as a white solid. MS: m/z = 600.3 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide-t/e) 8 8.92 (br d, J= 6.8 Hz, 0.5H), 8.71 (br d, J= 7.6 Hz, 0.5H), 8.29 (d, J= 8.4 Hz, 1H), 8.09 - 7.97 (m, 4H), 7.58 - 7.61 (m, 3H), 7.51 - 7.44 (m, 2H), 7.43 - 7.37 (m, 1H), 7.22 (d, J= 7.2 Hz, 1H), 6.94 (br s, 2H), 6.44 (dd, J= 7.6, 4.2 Hz, 1H), 4.55 - 4.34 (m, 1H), 4.30 (s, 3H), 4.33 - 4.27 (m, 3H), 4.22 - 3.96 (m, 1H), 3.74 - 3.59 (m, 1H), 3.25 - 3.08 (m, 2H), 3.07 - 2.95 (m, 1H), 2.01 - 1.84 (m, 2H), 1.60 - 1.45 (m, 2H).
[00561] Example 29: (S)-3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-3-yl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000152_0001
[00562] Step 1 : (S)-to7-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-3-yl)carbamate
[00563] To a solution of Intermediate 14 (800 mg, 1.9 mmol) in ACN (6 mL) were added tert- butyl A-[(3 )-3-piperidyl]carbamate (427 mg, 2.1 mmol), Nal (29.1 mg, 0.194 mmol) and K2CO3 (1.1 g, 7.8 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-50% EtOAc in petroleum ether) to give (S)-ferz-butyl (l-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-3-yl)carbamate (400 mg, yield: 29%) as a brown solid. MS: m/z = 576.2 [M + H]+. [00564] Step 2: (S)-3-(3-(4-((3-Aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
[00565] To a solution of tert-butyl A-[(35)-l-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]-3-piperidyl]carbamate (27 mg, 0.0469 mmol) in CH2CI2 (1 mL) was added TFA (10.7 mg, 0.0938 mmol). The mixture was stirred at 25 °C for 0.5 hr. The mixture was concentrated under reduced pressure to give a crude (26 mg TFA salt, yield: 100%). The crude was purified by re/?-HPLC (column: Welch Xtimate C18 150*25mm*5pm; mobile phase: [water (HCl)-ACN]; B%: 5%-35%,8min) to give (5)-3-(3-(4-((3-aminopiperidin-l- yl)methyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (5.3 mg HC1 salt) as a light-yellow lyophilized powder. MS: m/z = 476.2 [M + H]+. 1H NMR (400 MHz, Methanol-^) 88.32 (d, J= 8.4 Hz, 1H), 8.10 - 7.98 (m, 4H), 7.94 (d, J= 8.4 Hz, 2H), 7.89 (dd, J= 7.6, 1.2 Hz, 1H), 7.74 (d, J= 8.4 Hz, 2H), 7.49 - 7.34 (m, 3H), 6.93 (dd, J= 7.6, 6.4 Hz, 1H), 4.62 (s, 2H), 3.89 - 3.56 (m, 3H), 3.28 - 3.12 (m, 2H), 2.26 - 1.99 (m, 3H), 1.90 - 1.66 (m, 1H)
[00566] Step 3: (S)-3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperi din-3 -yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
[00567] To a solution of 3-[3-[4-[[(3S)-3-amino-l-piperidyl]methyl]phenyl]-5-phenyl- imidazo[4,5-b]pyridin-2-yl]pyridin-2 -amine (50 mg, 0.105 mmol) in MeOH (2 mL) were added 3, 4-dimethoxycy cl obut-3-ene- 1,2-dione (17.9 mg, 0.126 mmol) and TEA (53.2 mg, 0.525 mmol). The mixture was stirred at 25 °C for 2 hr. The mixture was filtered and the filter cake was concentrated under reduced pressure to give the (S)-3-((l-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3H-imidazo[4,5-b]pyri din-3-yl)benzyl)piperidin-3-yl)amino)-4-m ethoxy cyclobut-3-ene- 1, 2-dione (Example 29, 10.4 mg, yield: 16%, 3:2 mixture of tautomers) as a light-yellow solid. MS: m/z = 586.3 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide- <&) 88.82 (d, J = 8.0 Hz, 0.6H), 8.62 (d, J= 8.0 Hz, 0.4H), 8.27 (d, J= 8.4 Hz, 1H), 8.02 (d, J= 8.0 Hz, 2H), 8.00 - 7.96 (m, 2H), 7.50 - 7.43 (m, 6H), 7.41 - 7.36 (m, 1H), 7.14 (d, J= 7.6 Hz, 1H), 7.03 (br s, 2H), 6.39 - 6.27 (m, 1H), 4.27 (s, 1.2H), 4.20 (s, 1.8H), 4.07 - 3.97 (m, 0.4H), 3.68 - 3.54 (m, 2.6H), 2.91 - 2.85 (m, 1H), 2.72 - 2.66 (m, 1H), 2.03 - 1.92 (m, 2H), 1.90 - 1.84 (m, 1H), 1.76 - 1.68 (m, 1H), 1.55 - 1.45 (m, 1H), 1.37 - 1.27 (m, 1H).
[00568] Example 30: (S)-3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyri din-3 -yl)benzyl)pyrrolidin-3-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000154_0001
[00569] Following the general procedure of Example 29, the reaction was carried out using the corresponding starting material. (S)-3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377- imidazo[4,5-b]pyri din-3 -yl)benzyl)pyrrolidin-3-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione (Example 30) was obtained as a light-yellow solid. MS: m/z = 572.4 [M + H]+. 1 H NMR (400 MHz, Methanol- d4) 88. 19 (d, J= 8.5 Hz, 1H), 8.05 - 8.01 (m, 2H), 7.98 (dd, J= 4.8, 2.0 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.47 - 7.27 (m, 6H), 6.47 (dd, J= 7.6, 4.8, Hz, 1H), 4.36 (s, 3H), 3.78 - 3.72 (m, 1H), 3.35 (s, 2H), 2.92 - 2.81 (m, 2H), 2.68 - 2.56 (m, 2H), 2.40 - 2.28 (m, 1H), 1.90 - 1.80 (m, 1H).
[00570] Example 31 : 3-(9-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,9-diazaspiro[5.5]undecan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000154_0002
[00571] Step 1 : Zc/7-Butyl 9-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-
3-yl)benzyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate [00572] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) in DMF (10 mL) were added K2CO3 (671 mg, 4.86 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate (679 mg, 2.67 mmol). The mixture was stirred at 25 °C for 48 hr. The reaction mixture was diluted with H2O (10 mL) at 25 °C and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na SO-i. filtered, and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography (Eluent of 1~4% MeOH in CH2CI2) to give tert-butyl 9-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,9-diazaspiro[5.5]undecane-2-carboxylat (612 mg, yield: 40%) as a yellow solid. MS: m/z = 630.5 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-^) 88.26 (d, J= 8.4 Hz, 1H), 8.06 - 7.94 (m, 4H), 7.48 - 7.33 (m, 7H), 7.14 (dd, J= 7.6, 1.6 Hz, 1H), 7.05 (br s, 2H), 6.35 (dd, J= 7.2, 5.2 Hz, 1H), 3.62 - 3.55 (m, 2H), 3.27 (s, 2H), 3.22 - 3.15 (m, 2H), 2.49 - 2.44 (m, 2H), 2.35 - 2.22 (m, 2H), 1.38 - 1.34 (m, 8H), 1.38 (s, 9H).
[00573] Step 2: 3-(3-(4-(2,9-Diazaspiro[5.5]undecan-9-ylmethyl)phenyl)-5-phenyl-37T- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00574] A solution of tert-butyl 9-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin- 3-yl]phenyl]methyl]-2,9-diazaspiro[5.5]undecane-2-carboxylate (630 mg, 1.0 mmol) in HCl/1,4- dioxane (4M, 6 mL) was stirred at 25 °C for 1 hr. The reaction was concentrated under reduced pressure to give 3-(3-(4-(2,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)-5-phenyl-37T- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine (540 mg, HC1 salt) as a yellow solid. MS: m/z = 530.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-d ) 8 11.24 - 10.95 (m, 1H), 9.45 - 8.99 (m, 2H), 8.52 (br s, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.16 (d, J= 6.0 Hz, 1H), 8.12 - 8.02 (m, 3H), 7.91 - 7.81 (m, 3H), 7.73 - 7.62 (m, 2H), 7.52 - 7.40 (m, 3H), 6.93 - 6.84 (m, 1H), 4.41 (d, J= 5.2 Hz, 2H), 3.21 - 3.09 (m, 5H), 2.99 - 2.90 (m, 2H), 2.87 - 2.75 (m, 1H), 2.13 - 2.09 (m, 1H), 2.00 - 1.88 (m, 1H), 1.86 - 1.73 (m, 2H), 1.72 - 1.56 (m, 3H), 1.45 - 1.40 (m, 1H).
[00575] Step 3: 3-(9-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,9-diazaspiro[5.5]undecan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
[00576] To a solution of 3-(3-(4-(2,9-diazaspiro[5.5]undecan-9-ylmethyl)phenyl)-5-phenyl-3//- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine (50 mg, 94.4 pmol) in MeOH (1 mL) were added TEA (47.8 mg, 472 pmol) and 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (16.1 mg, 113 pmol). The reaction mixture stirred at 25 °C for 16 hr. The mixture was fdtered and the collected solid residue was washed with MeOH (10 mL x 2) and dried in vacuo to give 3-(9-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,9- diazaspiro[5.5]undecan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 31, 20.1 mg, yield: 32%) as a brown solid. MS: m/z = 640.5 [M + H]+. LH NMR (400 MHz, Dimethylsulfoxide-<A) 38.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.48 - 7.36 (m, 7H), 7.15 (d, J= 7.6 Hz, 1H), 7.04 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 4.30 (s, 3H), 3.76 - 3.70 (m, 1H), 3.66 - 3.61 (m, 1H), 3.59 - 3.54 (m, 2H), 3.49 - 3.44 (m, 1H), 3.31 - 3.23 (m, 1H), 2.42 - 2.28 (m, 4H), 1.66 - 1.58 (m, 2H), 1.53 - 1.41 (m, 6H).
[00577] Example 32: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3Z7-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
Figure imgf000156_0001
[00578] Step 1 : (4-((5-Bromo-3-nitropyridin-2-yl)amino)phenyl)methanol
[00579] To a solution of 5-bromo-2-chloro-3-nitro-pyridine (10 g, 42 mmol) and (4- aminophenyl)methanol (5.2 g, 42 mmol) in DMSO (100 mL) was added DIEA (16.3 g, 126 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SC>4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (Eluent of 10-50% EtOAc in petroleum ether) to give (4-((5-bromo-3-nitropyridin-2-yl)amino)phenyl)methanol (6.28 g, yield: 46%) as a red solid. MS: m/z = 324.0, 325.0 [M + H]+. 'H NMR (400 MHz, Chloroform-d-) 8 10.05 (br s, 1H), 8.65 (d, J= 2.4 Hz, 1H), 8.50 (d, J= 2.4 Hz, 1H), 7.59 (d, J= 8.4 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 4.71 (s, 2H).
[00580] Step 2: (4-((3-Nitro-5-phenylpyridin-2-yl)amino)phenyl)methanol [00581] A mixture of [4-[(5-bromo-3-nitro-2-pyridyl)amino]phenyl]methanol (5.4 g, 16.7 mmol), phenylboronic acid (6.1 g, 50 mmol), K2CO3 (4.62 g, 33.44 mmol), and Pd(dppf)C12 (1.22 g, 1.67 mmol) in 1,4-dioxane (60 mL) and H2O (12 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 8 hr under N2 atmosphere. The reaction mixture was poured into H2O (100 mL) and extracted with CH2CI2 (100 mL x 3) The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (Eluent of 0-50% EtOAc in petroleum ether) to give [4-[(3-nitro-5-phenyl-2-pyridyl)amino]phenyl]methanol (4 6 g, yield: 86%) as a red solid. MS : m/z = 322.1 [M + H]+. 1 H NMR (400 MHz, Chloroform-;/) 3 10.15 (s, 1H), 8.78 - 8.72 (m, 2H), 8.25 (d, J = 8.0 Hz 1H), 7.70 - 7.65 (m, 2H), 7.59 - 7.56 (m, 2H), 7.51 - 7.49 (m, 2H), 7.44 - 7.41 (m, 2H), 4.72 (s, 2H).
[00582] Step 3: (4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3B-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
[00583] To a solution of [4-[(3-nitro-5-phenyl-2-pyridyl)amino]phenyl]methanol (15 g, 46.7 mmol) in DMSO (600 mL) were added Na2S2C>4 (16 g, 93 mmol) and 2-aminopyridine-3- carbaldehyde (6.8 g, 56 mmol). The mixture was stirred at 100°C for 12 hr. After cooling to 25° C, the reaction mixture was diluted with H2O (200 mL) and extracted with CH2CI2 (200ml x 3). The combined organic layers were washed with brine (200ml x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-100% EtOAc in petroleum ether) to give [4-[2-(2-amino-3- pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]methanol (5.15 g crude, yield: 28%) as a yellow solid. MS: m/z = 394.0 [M + H]+.
[00584] Step 4: 3-(3-(4-(Chloromethyl)phenyl)-6-phenyl-3Z/-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
[00585] To a solution of [4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methanol (500 mg, 1.3 mmol) in CH2CI2 (10 mL) was added SOCI2 (771 mg, 6.5 mmol). The mixture was stirred at 40°C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-100% EtOAc in petroleum ether) to give 3-[3-[4-(chloromethyl)phenyl]-6-phenyl- imidazo[4,5-b]pyridin-2-yl]pyridin-2-amine (267 mg, yield: 51%) as a yellow solid. MS: m/z = 411.8 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-^) 3 8.63 (d, J= 2.0 Hz, 1H), 8.47 (d, J= 2.0 Hz, 1H), 8.01 (dd, J = 8.8, 3.2 Hz, 1H), 7.79 (d, J= 7.2 Hz, 2H), 7.61 (d, J= 8.4 Hz, 2H), 7.55 - 7.47 (m, 4H), 7.45 - 7.40 (m, 1H), 7.25 (dd, J= 7.6, 1.8 Hz, 1H), 6.96 (br s, 2H), 6.44 (dd, J= 7.6, 4.8 Hz, 1H), 4.86 (s, 2H). [00586] Step 5 : tert-Butyl (l-(4-(2-(2-aminopyri din-3 -yl)-6-phenyl-37/-imidazo[4, 5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)(methyl)carbamate
[00587] To a solution of 3-[3-[4-(chloromethyl)phenyl]-6-phenyl-imidazo[4,5-b]pyridin-2- yl]pyridin-2-amine (130 mg, 0.315 mmol) and tert-butyl A-methyl-A-(4-piperidyl)carbamate (81 mg, 0 378 mmol) in DMF (2 mL) were added Nal (57 mg, 378 mmol) and K2CO3 (130 mg, 946 mmol). The mixture was stirred at 80 °C for 8 hr. After cooling to 20°C, the reaction mixture was poured into H2O (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure The residue was purified by silica gel flash chromatography (Eluent of 0-100% EtOAc in petroleum ether) to give tert-butyl (l-(4-(2-(2-aminopyridin-3-yl)-6-phenyl-377-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)carbamate (54 mg, yield: 29%) as a yellow solid. MS: m/z = 590.5 [M + H]+.
[00588] Step 6: 3-(3-(4-((4-(Methylamino)piperidin-l-yl)methyl)phenyl)-6-phenyl-377- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00589] To a solution of tert-butyl A-[l-[[4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]-4-piperidyl]-A-methyl-carbamate (60 mg, 0.101 mmol) in 1 mL CH2CI2 was added TFA (36 mg, 0.303 mmol). The mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure to give a crude product (55 mg TFA salt, yield: 90%). The crude was triturated with EtOAc (2 mL) at 25 °C for 5 min to give 3-[3-[4-[[4- (methylamino)-l-piperidyl]methyl]phenyl]-6-phenyl-imidazo[4,5-b]pyridin-2-yl]pyri din-2- amine (16.6 mg) as a yellow solid. MS: m/z = 490.2 [M + H]+. XH NMR (400 MHz, Dimethylsulfoxide-rfc) 8 8.63 (d, J= 2.0 Hz, 1H), 8.47 (d, J= 2.0 Hz, 1H), 8.01 (dd, J= 4.8, 1.6 Hz, 1H), 7.79 (d, J= 7.2 Hz, 2H), 7.59 - 7.50 (m, 2H), 7.49 - 7.35 (m, 5H), 7.20 (dd, J= 7.6, 1.6 Hz, 1H), 7.05 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.57 (s, 2H), ), 2.96 - 1.84 (m, 3H), 2.54 (s, 3H), 2.06 - 1.90 (m, 4H), 1.57 - 1.44 (m, 2H).
[00590] Step 7: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
[00591] To a solution of 3-(3-(4-((4-(methylamino)piperidin-l-yl)methyl)phenyl)-6-phenyl- 3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (30 mg, 0.061 mmol) and 3,4- dimethoxycyclobut-3-ene- 1,2-dione (10 mg, 73 pmol) in MeOH (2 mL) was added TEA (2.5 mmol). The reaction mixture stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure and purified by prep-TLC (DCM : MeOH 10 : 1 ) to give 3-((l-(4-(2-(2- Aminopyridin-3-yl)-6-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)(methyl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione (Example 32, 12 mg, yield: 31%) as a yellow solid. MS: m/z = 600.4 [M + H]+. XHNMR (400 MHz, Methanol-d4) 8 8.59 (d, J= 2.0 Hz, 1H), 8.38 (d, J= 2.0 Hz, 1H), 7.98 (dd, J= 5.2, 1.8 Hz, 1H), 7.72 (d, J= 8.0 Hz 2H), 7.58 - 7.48 (m, 5H), 7.43 - 7.36 (m, 2H), 7.29 - 7.34 (m, 1H), 6.50 - 6.44 (m, 1H), 3.72 - 3.63 (m, 1H), 3.35(s, 3H), 3.30 (s, 3H), 3.12 (s, 2H), 3.09 - 2.99 (m, 2H), 2.23 - 2.09 (m, 2H), 2.01 - 1.93 (m, 2H), 1.79 - 1.73 (m, 2H).
[00592] Example 33: A-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)-3 -((2 -m ethoxy-3, 4-dioxocy cl obut-l-en-l-yl)amino)benzamide
Figure imgf000159_0001
[00593] Step 1 : Zc/7-Butyl (3-((4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin- 3-yl)benzyl)carbamoyl)phenyl)carbamate
[00594] A mixture of Intermediate 4 (500 mg, 1.27 mmol), 3-((tert- butoxycarbonyl)amino)benzoic acid (332 mg, 1.40 mmol) , EDCI (366 mg, 1.91 mmol) , HOBt (258 mg, 1.91 mmol) and DIEA (659 mg, 5.10 mmol) in DMF (5 mb) was degassed and purged with N2 three times. The mixture was stirred at 25 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched with H2O (10 mL) at 25 °C and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 5-25% EtOAc in petroleum ether) to give /c/7-butyl (3-((4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)carbamoyl)phenyl)carbamate (600 mg, yield: 77%) as an off-white solid. MS: m/z = 612.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-^) 8 9.49 (br s, 1H), 9.06 (t, J= 6.0 Hz, 1H), 8.25 (d, J= 8.4 Hz, 1H), 8.06 - 7.95 (m, 4H), 7.58 - 7.42 (m, 8H), 7.41 - 7.32 (m, 2H), 7.22 (dd, J= 7.6, 2.0 Hz, 1H), 6.94 (br s, 2H), 6.42 (dd, J= 7.6, 4.8 Hz, 1H), 4.58 (d, J= 6.0 Hz, 2H), 1.48 (s, 9H). [00595] Step 2: 3-Amino-A-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)benzamide
[00596] A solution of Zert-butyl A-[3-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methylcarbamoyl]phenyl]carbamate (200 mg, 0.327 mmol) in HCl/1,4- di oxane (1 mL) was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to give a crude product (150 mg HC1 salt, yield: 84%). The crude was triturated with MeOH (10 mL x 2 ) and filtrated to give 3-amino-A-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-3-yl)benzyl)benzamide (60 mg) as a yellow solid. MS: m/z = 512.3 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.34 (d, J= 8.8 Hz, 1H), 8.09 - 7.91 (m, 7H), 7.73 - 7.54 (m, 6H), 7.41 - 7.31 (m, 3H), 6.88 (dd, J= 7.6, 7.2 Hz, 1H), 4.75 (s, 2H).
[00597] Step 3: A-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-3-((2-m ethoxy-3, 4-dioxocy cl obut-l-en-l-yl)amino)benzamide
[00598] To a solution of 3-amino-A-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyri din-3 -yl)benzyl)benzamide (50 mg, 97.7 pmol) in MeOH (2 mL) were added TEA (0.3 mmol) and 3, 4-dimethoxycy cl obut-3-ene- 1,2-dione (16.7 mg, 117 pmol). The reaction mixture stirred at 25 °C for 16 hr. The mixture was filtered and the collected solid was washed with MeOH (10 mL x 2) and dried in vacuo to give A-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z7- imidazo[4,5-b]pyri din-3 -yl)benzyl)-3-((2-methoxy-3, 4-dioxocy cl obut-l-en-1- yl)amino)benzamide (Example 33, 8.0 mg, yield: 12%) as a brown solid. MS: m/z = 622.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tfc) 8 10.90 (br s, 1H), 9.13 (t, J= 6.0 Hz, 1H), 8.26 (d, J= 8.4 Hz, 1H), 8.04 - 7.95 (m, 4H), 7.87 (s, 1H), 7.67 (d, J= 7.2 Hz, 1H), 7.53 - 7.36 (m, 9H), 7.22 (dd, J= 7.6, 2.0 Hz, 1H), 6.93 (br s, 2H), 6.42 (dd, J= 7.6, 4.8 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H), 4.36 (s, 3H).
[00599] Example 34: (7?)-3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-3-yl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000161_0001
[00600] Step 1 : (7?)-tert-Butyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-3-yl)carbamate
[00601] To a solution of Intermediate 14 (50 mg, 0.121 mmol) in DMF (0.5 mL) were added terLbutyl /V-[(37?)-3-piperidyl]carbamate (26.7 mg, 0.133 mmol), Nal (2 mg, 0.0121 mmol) and K2CO3 (33.5 mg, 0.242 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was diluted with H2O (5 mL) and filtered to give (7?)-te/7-butyl (l-(4-(2-(2-aminopyridin-3-yl)- 5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-3-yl)carbamate (60 mg, yield: 85%) as a yellow solid, which was used in the next step without further purification. MS: m/z = 576.4 [M + H]+.
[00602] Step 2: (7?)-3-(3-(4-((3-Aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-37T- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00603] To a solution of (A)-terLbutyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377- imidazo[4,5-b]pyri din-3 -yl)benzyl)piperi din-3 -yl)carbamate (60 mg, 0.104 mmol) in CH2CI2 (2 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 20 °C for 2 hr. The reaction mixture was quenched with saturated NaHCCh (5 mL) and extracted with CH2O2 (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (CH2CI2: MeOH = 10: 1) to give (7?)-3-(3-(4-((3-aminopiperidin-l-yl)methyl)phenyl)-5-phenyl- 3//-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (6.0 mg, yield: 11.5%) as a light-yellow powder. MS: m/z = 476.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- de) 3 8.27 (d, J = 8.0 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.50 - 7.44 (m, 6H), 7.42 - 7.38 (m, 1H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.62 - 3.52 (m, 2H), 2.90 - 2.85 (m, 1H), 2.79 - 2.74 (m, 1H), 2.62 - 2.59 (m, 1H), 2.09 - 2.00 (m, 1H), 1.95 - 1.87 (m, 1H), 1.80 - 1.74 (m, 1H), 1.70 - 1.64 (m, 1H), 1.53 - 1.45 (m, 1H), 1.26 - 1.21 (m, 1H) [00604] Step 3: (7?)-3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperi din-3 -yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
[00605] To a solution of (A)-3-(3-(4-((3-aminopiperidin-l-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (100 mg, 0.21 mmol) and 3,4-dimethoxycyclobut- 3-ene-l, 2-dione (35.8 mg, 0.252 mmol) in MeOH (1 mL) was added TEA (106 mg, 1 05 mmol).
The mixture was stirred at 20 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (CH2Q2: MeOH = 10: 1) to give (R)- 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperi din-3- yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione (Example 34, 9.2 mg, yield: 7.3%, 3:2 mixture of tautomers) as a light-yellow powder. MS: m/z = 586.3 [M + H]+. LH NMR (400 MHz, Dimethylsulfoxide- d6 5 8.82 (d, J= 8.4 Hz, 0.6H), 8.63 (d, J= 8.0 Hz, 0.4H), 8.27 (d, J= 8.4 Hz, 1H), 8.06 - 7.95 (m, 4H), 7.52 - 7.36 (m, 7H), 7.14 (d, J= 7.6 Hz, 1H), 7.03 (br s, 2H), 6.38 - 6.29 (m, 1H), 4.27 (s, 1.2H), 4.20 (s, 1.8H), 4.16 - 3.97 (m, 1H), 3.64 - 3.58 (m, 2H), 3.17 (d, J = 4.8 Hz, 1H), 2.91 - 2.84 (m, 1H), 2.72 - 2.67 (m, 1H), 2.03 - 1.98 (m, 2H), 1.90 - 1.83 (m, 1H), 1.75 - 1.66 (m, 1H), 1.54 - 1.46 (m, 1H), 1.36 - 1.29 (m, 1H).
[00606] Example 35: 3-((7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-7-azaspiro[3.5]nonan-2-yl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000162_0001
[00607] Step 1 : /c/'Z-Butyl (7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin- 3-yl)benzyl)-7-azaspiro[3.5]nonan-2-yl)carbamate
[00608] To a solution of Intermediate 14 (1 g, 2.43 mmol) and fert-butyl 7-azaspiro[3.5]nonan- 2-ylcarbamate (700 mg, 2.92 mmol) in ACN (20 mL) were added Nal (36.4 mg, 0.243 mmol) and K2CO3 (671 mg, 4.86 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was concentrated to give a residue. The residue was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2Q2) to give Zc/7-butyl (7-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-32/-imidazo[4,5-b]pyridin-3-yl)benzyl)-7-azaspiro[3.5]nonan-2- yl)carbamate (480 mg, yield: 32%,) as a light-yellow solid, which was used directly in the next step without further purification. MS: m/z = 616.1 [M + H]+.
[00609] Step 2: 7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- yl)benzyl)-7-azaspiro[3.5]nonan-2-amine
[00610] A solution of te/7-butyl A-[7-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-yl]carbamate (450 mg, 0.731 mmol) in HCl/l,4-dioxane (4M, 6 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenom enex Cl 8 150 x 25 mm x 10pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 28% - 58%, 8 min) to give 7-[[4-[2-(2- amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]-7-azaspiro[3.5]nonan-2- amine (370 mg, yield: 91%) as a light-yellow oil. MS: m/z = 516.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-cfc) 5 8.27 (d, J= 8.0 Hz, 1H), 8.06 - 7.95 (m, 4H), 7.55 - 7.35 (m, 7H), 7.15 (d, J = 7.2 Hz, 1H), 7.01 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 3.71 - 3.58 (m, 1H), 3.52 (s, 2H), 2.41 - 2.20 (m, 4H), 2.14 - 2.05 (m, 2H), 1.90 - 1.80 (m, 2H), 1.67 - 1.53 (m, 4H). [00611] Step 3: 3-((7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-7-azaspiro[3.5]nonan-2-yl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
[00612] To a solution of 7-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-amine (100 mg, 0.181 mmol), 3,4- dimethoxycyclobut-3-ene- 1,2-dione (30.9 mg, 0.217 mmol) in MeOH (2 mL) was added TEA (91.6 mg, 0.906 mmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated to give a residue. The residue was purified by prep-TLC (CH2Q2 : MeOH = 10 : 1) to give 3-((7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-7- azaspiro[3.5]nonan-2-yl)amino)-4-methoxycyclobut-3-ene-l, 2-dione (Example 35, 11.2 mg, yield: 10%, 1 : 1 mixture of tautomers) as a light-yellow solid. MS: m/z = 626.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tL) 8 9.18 - 8.79 (m, 1H), 8.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.48 - 7.39 (m, 7H), 7.6 (dd, J= 7.6, 1.6 Hz, 1H), 7.03 (s, 2H), 6.37 (dd, J= 7.6, 4.8 Hz, 1H), 4.53 - 4.39 (m, 0.5H), 4.29 (s, 3H), 4.10 - 4.03 (m, 0.5H), 3.52 (s, 2H), 2.38 - 2.22 (m, 4H), 2.21 - 2.13 (m, 2H), 1.85 - 1.77 (m, 2H), 1.55 (br s, 4H).
[00613] Example 36: (S)-3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyri din-3 -yl)benzyl)-2-methylpiperazin-l-yl)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000164_0001
[00614] Step 1 : (S)-fert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-methylpiperazine-l -carboxylate
[00615] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) and (S)-teH-butyl 2- methylpiperazine-1 -carboxylate (583 mg, 2.91 mmol) in DMF (10 mb) was added K2CO3 (671 mg, 4.86 mmol). The mixture was stirred at 25 °C for 24 hr. The reaction mixture was diluted with H2O (10 mb) at 25°C and extracted with CH2CI2 (20 mb x 3). The combined organic layers were washed with (15 mb), dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-60% EtOAc in petroleum ether) to give GS')-/ -butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyri din-3 -yl)benzyl)-2-methylpiperazine-l -carboxylate (550 mg, yield: 35%) as a yellow solid, which was used in the next step without further purification. MS: m/z = 576.1 [M + H]+.
[00616] Step 2: (S)-3-(3-(4-((3-Methylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00617] A solution of (5)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2 -m ethylpiperazine- 1 -carboxylate (500 mg, 0.869 mmol) in HCl/l,4-di oxane (4M, 5 mb) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane. The crude product was triturated with MeOH (2mL) at 25 °C for 0.5 hr to give ( )-3-(3-(4-((3-methylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (350 mg, yield: 82%) as a yellow solid. MS: m/z = 476.2 [M + H]+. 'H NMR (400 MHz, Methanol^) 3 8.32 (d, J= 8.4 Hz, 1H), 8.07 - 7.99 (m, 4H), 7.94 - 7.84 (m, 3H), 7.73 (d, J= 8.4 Hz, 2H), 7.50 - 7.37 (m, 3H), 6.96 - 6.88 (m, 1H), 4.57 (s, 1H), 4.60 - 4.53 (s, 2H), 3.94 - 3.83 (m, 1H), 3.81 - 3.69 (m, 3H), 3.68 - 3.56 (m, 1H), 3.54 - 3.41 (m, 1H), 3.39 - 3.31 (m, 1H), 1.45 (d, J= 6.8 Hz, 3H) [00618] Step 3: (S)-3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-methylpiperazin-l-yl)-4-methoxycyclobut-3-ene-l, 2-dione
[00619] To a solution of (S)-3-(3-(4-((3-methylpiperazin-l-yl)methyl)phenyl)-5-phenyl-3J7- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine (50 mg, 0.105 mmol) and 3,4-dimethoxycyclobut- 3-ene-l, 2-dione (18 mg, 0.126 mmol) in MeOH (1 mL) was added TEA (53 mg, 0.526 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was filtered and concentrated to give (5)- 3-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)-2- methylpiperazin-l-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 36, 9.1 mg, yield: 15%) as a yellow solid. MS: m/z = 586.4 [M + H]+. JH NMR (400 MHz, Dimethylsulfoxide-t/g) 8 8.27 (d, J= 8.4 Hz, 1H), 8.10 - 7.90 (m, 4H), 7.53 - 7.44 (m, 6H), 7.42 - 7.37 (m, 1H), 7.16 (dd, 7.6, 1.8 Hz, 1H), 7.02 (br s, 2H), 6.39 (dd, J= 7.8, 4.8 Hz, 1H), 4.06 (s, 3H), 4.15 - 4.02 (m, 1H), 3.73 - 3.49 (m, 4H), 3.61 - 3.49 (m, 2H), 2.96 - 2.83 (m, 1H), 2.73 - 2.65 (m, 1H), 2.36 - 2.29 (m, 1H), 2.26 - 2.13 (m, 1H), 1.36 (d, J= 6.8 Hz, 3H).
[00620] Example 37: 3-(7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-4,7-diazaspiro[2.5]octan-4-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000165_0001
[00621] Step 1 : tert-Butyl 7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3f/-imidazo[4,5-b]pyridin- 3-yl)benzyl)-4,7-diazaspiro[2.5]octane-4-carboxylate
[00622] To a solution of Intermediate 14 (1.0 g, 2.43 mmol) and tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate (618 mg, 2 91 mmol) in DMF (10 mL) was added K2CO3 (671 mg, 4.86 mmol). The mixture was stirred at 25 °C for 24 hr. The reaction mixture was diluted with H2O (10 mL) at 25°C and extracted with CH2Q2 (20 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-60% EtOAc in petroleum ether) to give tert-butyl 7-[[4-[2-(2-amino-3-pyridyl)-5-phenyl- imidazo[4,5-b]pyridin-3-yl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-4-carboxylate (610 mg, yield: 38%) as a yellow solid, which was used in the next step without further purification. MS: m/z = 588.1 [M + H]+.
[00623] Step 2: 3-(3-(4-(4,7-Diazaspiro[2.5]octan-7-ylmethyl)phenyl)-5-phenyl-3/f- imidazo[4,5-b]pyridin-2-yl)pyridin-2 -amine
[00624] To a solution of tert-butyl 7-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]-4,7-diazaspiro[2.5]octane-4-carboxylate (500 mg, 0.851 mmol) in 1,4-dioxane (3 mL) was added HCl/l,4-dioxane (4M, 5 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove 1,4- dioxane. The crude was dissolved in H2O (5 mL) and extracted with CH2CI2 (5 mL x 3). The aqueous phase was added NaHCO, and extracted with CH2Q2 (5 mL x 3), filtered and concentrated to give 3-[3-[4-(4,7-diazaspiro[2.5]octan-7-ylmethyl)phenyl]-5-phenyl- imidazo[4,5-b]pyridin-2-yl]pyridin-2 -amine (350 mg, yield: 81%) as a yellow solid. MS: m/z = 488.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-fifc) 3 8.26 (d, J= 8.4 Hz, 1H), 8.09 - 7.92 (m, 4H), 7.56 - 7.33 (m, 7H), 7.14 (dd, J= 7.8, 1.8 Hz, 1H), 7.05 (br s, 2H), 6.34 (dd, J = 7.6, 4.8 Hz, 1H), 3.52 (s, 2H), 2.76 (t, J= 4.8 Hz, 2H), 2.44 - 2.32 (m, 2H), 2.18 (s, 2H), 0.47 - 0.38 (m, 2H), 0.35 - 0.25 (m, 2H).
[00625] Step 3: 3-(7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-4,7-diazaspiro[2.5]octan-4-yl)-4-methoxycyclobut-3-ene-l, 2-dione
[00626] To a solution of 3-[3-[4-(4,7-diazaspiro[2.5]octan-7-ylmethyl)phenyl]-5-phenyl- imidazo[4,5-b]pyridin-2-yl]pyridin-2 -amine (50 mg, 0.103 mmol) and 3,4-dimethoxycyclobut- 3-ene-l, 2-dione (17.5 mg, 0.123 mmol) in MeOH (1 mL) was added TEA (52 mg, 0.513 mmol). The mixture was stirred at 25 °C for 1 hr. The mixture was filtered and concentrated to give 3- (7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-4,7- diazaspiro[2.5]octan-4-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 37, 30 mg, yield: 49%) as a yellow solid. MS: m/z = 598.4 [M + H]+. XHNMR (400 MHz, Dimethylsulfoxide-t/e) 8 8.26 (d, J= 8.4 Hz, 1H), 8.09 - 7.92 (m, 4H), 7.56 - 7.33 (m, 7H), 7.14 (dd, J= 8.0, 2.0 Hz, 1H), 7.05 (br s, 2H), 6.34 (dd, J= 7.6, 4.8 Hz, 1H), 4.32 (s, 3H), 3.62 (s, 2H), 2.74 - 2.56 (m, 4H), 2.40 (s, 2H), 1.13 - 0.97 (m, 2H), 0.76 - 0 69 (m, 2H).
[00627] Example 38: 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)- 1 ,4-diazepan- 1 -yl)-4-methoxy cy clobut-3 -ene- 1 ,2-dione
Figure imgf000167_0001
[00628] Step 1 : tert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3 -yl)benzyl)- 1 ,4-diazepane- 1 -carboxylate
[00629] To a solution of Intermediate 14 (1 g, 2.43 mmol), tert-butyl 1,4-diazepane-l- carboxylate (584 mg, 2.92 mmol) in ACN (20 mL) were added Nal (36.4 mg, 243 pmol) and K2CO3 (671 mg, 4.86 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was concentrated. The residue was purified by silica gel flash chromatography (Eluent of 0-10% MeOH in CH2CI2) to give tert-butyl 4-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]-l,4-diazepane-l -carboxylate (520 mg, yield: 33%) as a lightyellow solid, which was used in the next step without further purification. MS: m/z = 576.4 [M + H]+.
[00630] Step 2: 3-(3-(4-((l,4-Diazepan-l-yl)methyl)phenyl)-5-phenyl-3//-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
[00631] A solution of tert-butyl 4-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin- 3-yl]phenyl]methyl]-l,4-diazepane-l-carboxylate (520 mg, 0.903 mmol) in HCl/l,4-dioxane (4M, 10 mL) was stirred at 25 C for 1 hr. The reaction mixture was concentrated to give a crude product (310 mg HC1 salt, yield: 67%). The crude (100 mg) was purified by prep-HPLC (column: Phenomenex C18 150 x 25mm x 10pm; mobile phase: [water (NH4HCO3)-ACN]; B%: 28% - 58%, 8 min) to give 3-[3-[4-(l,4-diazepan-l-ylmethyl)phenyl]-5-phenyl-imidazo[4,5- b]pyridin-2-yl]pyridin-2-amine (9 mg) as light-yellow solid. MS: m/z = 476.3 [M + H]+. ’H NMR (400 MHz, Dimethylsulfoxide- g) 8 8.4 (d, J= 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.52 - 7.39 (m, 7H), 7.14 (dd, J= 7.6, 1.8 Hz, 1H), 7.05 (br s, 2H), 6.39 - 6.34 (m, 1H), 3.72 (s, 2H), 2.82 (t, J= 6.4 Hz, 2H), 2.78 - 2.74 (m, 2H), 2.67 (t, J= 6.4 Hz, 2H), 2.66 - 2.57 (m, 2H), 1.78 - 1.64 (m, 2H). [00632] Step 3: 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)- 1 ,4-diazepan- 1 -yl)-4-methoxy cy clobut-3 -ene- 1 ,2-dione
[00633] To a solution of 3-[3-[4-(l,4-diazepan-l-ylmethyl)phenyl]-5-phenyl-imidazo[4,5- b]pyridin-2-yl]pyridin-2-amine (100 mg HC1 salt, 195 pmol) and 3,4-dimethoxycyclobut-3-ene- 1, 2-dione (33.3 mg, 234 pmol) in MeOH (2 mb) was added TEA (98.8 mg, 976 pmol). The mixture was stirred at 25 C for 2 hr. The reaction mixture was concentrated. The residue was purified by prep-TLC (CH2CI2: MeOH = 10 : 1) to give 3-(4-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3/f-imidazo[4,5-b]pyridin-3-yl)benzyl)-l,4-diazepan-l-yl)-4-methoxycyclobut-3-ene- 1, 2-dione (Example 38, 19.1 mg, yield: 16%) as a light yellow solid. MS: m/z = 586.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-^) 5 8.28 (d, J= 8.4 Hz, 1H), 7.98 (m, 4H), 7.56 - 7.36 (m, 7H), 7.14 (dd, J= 7.6, 1.6 Hz, 1H), 7.04 (br s, 2H), 6.44 - 6.33 (m, 1H), 4.29 (s, 3H), 3.90 - 3.85 (m, 2H), 3.76 (d, J= 6.4 Hz, 2H), 3.68 - 3.57 (m, 2H), 2.76 (dd, J= 9.6, 5.2 Hz, 2H), 2.70 - 2.66 (m, 2H), 1.89 - 1.78 (m, 2H).
[00634] Example 39: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(ethylthio)cy clobut-3 -ene- 1,2-dione
Figure imgf000168_0001
[00635] To a solution of Example 17 (200 mg, 0.341 mmol) in CH2CI2 (1 m ) were added TEA (104 mg, 1.02 mmol) and ethanethiol (2.23 g, 35.9 mmol). The mixture was stirred at 25 °C for 24 hr. The reaction was concentrated under reduced pressure to give a residue. The crude product was purified by silica gel flash chromatography (Eluent of 50-80% EtOAc in petroleum ether) to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3 -yl)benzyl)piperidin-4-yl)amino)-4-(ethylthio)cyclobut-3 -ene- 1,2-dione (Example 39, 39.4 mg, yield: 12%) as a yellow solid. MS: m/z = 616.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/g) 8 9.27 (d, J= 8.4 Hz, 0.5H), 8.86 (d, J= 8.4 Hz, 0.5H), 8.27 (d, J= 8.4 Hz, 1H), 8.07 - 7.92 (m, 4H), 7.50 - 7.36 (m, 7H), 7.15 (d, J= 7.6 Hz, 1H), 7.04 (br s, 2H), 6.41
- 6.35 (m, 1H), 3.58 (s, 2H), 3.45 - 3.33 (m, 3H), 2.93 - 2.82 (m, 2H), 2.10 - 1.99 (m, 2H), 1.90 - 1.81 (m, 2H), 1.69 - 1.54 (m, 2H), 1.36 (t, J = 7.2 Hz, 3H).
[00636] Example 40: 3-(6-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-ethoxycyclobut-3-ene- 1,2-dione
Figure imgf000169_0001
[00637] To a solution of Intermediate 15 (100 mg, 211 pmol) in MeOH (2 mL) were added TEA (64 mg, 633 pmol) and 3, 4-diethoxycyclobut-3-ene-l, 2-dione (36 mg, 211 pmol). The reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched with saturated NaHCCh (aq) (10 mL) at 25 °C and extracted with CH2CI2 (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over ISfeSCL, filtered, and concentrated under reduced pressure. After purified by silica gel flash chromatography ( MeOH in CH2C12= 0% to 8%), 3-(6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-ethoxycyclobut-3-ene-l, 2-dione (Example 40, 42.9 mg, yield: 33%) was obtained as a yellow solid. MS: m/z = 598.3 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.19 (d, J= 8.4 Hz, 1H), 8.03 (d, J= 7.2 Hz, 2H), 7.98 (dd, J= 5.2, 1.6 Hz, 1H), 7.94 (d, J= 8.8 Hz, 1H), 7.49 - 7.35 (m, 7H), 7.32 (dd, J= 7.6, 2.0 Hz, 1H), 6.48 (dd, J = 7.6, 5.2 Hz, 1H), 4.65 (q, J= 7.2 Hz, 2H), 4.60 - 4.51 (m, 4H), 3.71 (s, 2H), 3.52 (s, 4H), 1.42 (t, J = 7.2 Hz, 3H).
[00638] Example 41 : 3-(6-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-methoxycy cl obut-3-ene-l, 2-dione
Figure imgf000169_0002
[00639] To a solution of Intermediate 15 (50 mg, 105 pmol) in MeOH (2 mL) were added TEA (23.5 mg, 232 pmol) and 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (15 mg, 105 pmol). The reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched with NaHCOs (aq) (10 mL) at 25 °C and extracted with CH2CI2 (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 - 8% MeOH in CH2CI2) to give 3-(6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-methoxycyclobut-3-ene- 1,2-dione (Example 41, 14.3 mg, yield: 22%) as a yellow solid. MS: m/z = 584.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-cZe) 5 8.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.49 - 7.38 (m, 7H), 7.18 - 7.11 (m, 1H), 6.99 (br s, 2H), 6.44 - 6.36 (m, 1H), 4.57 - 4.38 (m, 4H), 4.28 - 4.18 (m, 3H), 3.61 (s, 2H), 3.40 - 3.37 (m, 4H).
[00640] Example 42: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,6-diazaspiro[3.4]octan-6-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000170_0001
[00641] To a solution of Intermediate 16 (100 mg, 205 pmol) in MeOH (2 mb) were added TEA (45 mg, 451 pmol) and 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (29 mg, 205 pmol). The reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched with NaHCCh (aq) (10 mb) at 25 °C and extracted with CH2CI2 (50 mb x 2). The combined organic layers were washed with brine (50 mL), dried over ISfeSCh, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 - 8% MeOH in CH2CI2) to give 3-(2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyri din-3 -yl)benzyl)-2, 6-diazaspiro[3.4]octan-6-yl)-4-methoxycy cl obut-3-ene-l, 2-dione (Example 42, 12.9 mg, yield: 10%) as a yellow solid. MS: m/z = 598.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-cL) 8 8.27 (d, J= 8.4 Hz, 1H), 8.07 - 7.94 (m, 4H), 7.51 - 7.37 (m, 7H), 7.16 (dd, J = 8.0, 2.0 Hz, 1H), 6.99 (br s, 2H), 6.40 (dd, J= 8.0, 5.2 Hz, 1H), 4.29 - 4.25 (m, 3H), 3.85 - 3.68 (m, 4H), 3.23 - 3.17 (m, 4H), 2.14 - 2.06 (m, 2H), 1.26 - 1.22 (m, 2H). [00642] Example 43 : A-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)-3 -((2 -hydroxy-3 ,4-di oxocyclob ut- 1 -en- 1 -yl)amino)benzamide
Figure imgf000170_0002
[00643] To solution of Example 33 (150 mg, 241 pmol) in THF (1 mL) and H2O (1 mL) was added K2CO3 (100 mg, 724 pmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was diluted with CH2CI2 (20 mL) and washed with water (20 ml x 2) and brine (20 ml x 2). The organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. After purified by /vcyi-HPLC (column: Welch Xtimate Cis 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 10% - 40%, 10 min), A-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-327-imidazo[4,5-b]pyridin-3-yl)benzyl)-3-((2-hydroxy-3,4-dioxocyclobut-l-en-l- yl)amino)benzamide (Example 43, 23.4 mg, yield: 15%) was obtained as a yellow solid. MS: m/z = 608.3. [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-afc) 8 9.41 (s, 1H), 8.93 (t, J = 6.0 Hz, 1H), 8.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.94 (m, 6H), 7.51 - 7.37 (m, 7H), 7.31 - 7.26 (m, 2H), 7.22 (dd, J= 7.6, 1.6 Hz, 1H), 6.95 (br s, 2H), 6.43 (dd, J= 7.6, 4.8 Hz, 1H), 4.58 (d, J = 5.6 Hz, 2H).
[00644] Example 44 and 45: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- Z>]pyri din-3 -yl)benzyl)piperidin-4-yl)amino)-4-mercaptocy cl obut-3-ene- 1,2-dione and 3-((l-(4- (2-(2-aminopyridin-3-yl)-5-phenyl-3.H-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperi din-4- yl)amino)-4-(methylthio)cyclobut-3-ene- 1,2-dione
Figure imgf000171_0001
[00645] Step 1 : 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-mercaptocyclobut-3-ene-l, 2-dione
[00646] To a solution of Example 17 (100 mg, 171 pmol) in EtOH (2 mb) was added NaSH (28.7 mg, 512 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction was concentrated under reduced pressure. After purified by prep-HPLC (column: Phenom enex Cl 8 150 x 25mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 20% - 50%, 14 min), 3- ((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-A]pyridin-3-yl)benzyl)piperidin-4- yl)amino)-4-mercaptocy cl obut-3-ene- 1,2-dione (Example 44, 6.7 mg, yield: 6.5%) was obtained as a yellow lyophilized powder. MS: m/z = 588.2 [M + H]+. 'H NMR (400 MHz, Methanol-^) 88.22 (d, J= 8.4 Hz, 1H), 8.06 - 7.98 (m, 3H), 7.95 (d, J= 8.4 Hz, 1H), 7.67 (d, ~ 8.0 Hz, 2H), 7.62 (d, J= 8.0 Hz, 2H), 7.47 - 7.36 (m, 4H), 6.52 (dd, J= 7.6, 4.8 Hz, 1H), 4.59 - 4.53 (m, 1H), 4.31 - 4.17 (m, 2H), 3.50 - 3.38 (m, 2H), 3.12 - 2.93 (m, 2H), 2.32 - 2.15 (m, 2H), 2.01 - 1.79 (m, 2H).
[00647] Step 2: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-4-(methylthio)cyclobut-3-ene- 1,2-dione
[00648] To a solution of Example 44 (150 mg, 255 pmol) in EtOH (2 mb) was added CH3I (72.5 mg, 510 pmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The mixture was filtrated and washed with MeOH (10 mL x 2). The filtrate was concentrated under reduced pressure. After purified by p/e/i-HPLC (column: Waters xbridge 150 x 25mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 38% - 68%, 8 min), 3-((l-(4-(2-(2-aminopyridin-3-yl)- 5-phenyl-3//-imidazo[4,5-/>]pyridin-3-yl)benzyl)piperidin-4-yl)amino)-4-(methylthio)cyclobut- 3-ene-l, 2-dione (Example 45, 15.5 mg, yield: 10%, 1 :1 mixture of tautomers) was obtained as a yellow lyophilized powder. MS: m/z = 602.4 [M + H]+. XH NMR (400 MHz, Dimethylsulfoxide-de) 89.25 (d, J= 8.0 Hz, 0.5H), 8.85 (d, J= 8.0 Hz, 0.5H), 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.50 - 7.43 (m, 6H), 7.42 - 7.37 (m, 1H), 7.16 - 7.13 (m, 1H), 7.03 (br s, 2H), 6.40 - 6.35 (m, 1H), 3.93 - 3.87 (m, 0.5H), 3.59 (s, 2H), 3.43 - 3.36 (m, 0.5H), 2.94 - 2.87 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.06 - 1.95 (m, 2H), 1.87 - 1.82 (m, 2H), 1.69 - 1.55 (m, 2H).
[00649] Example 46 and 47: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyri din-3 -yl)benzyl)piperidin-4-yl)(methyl)amino)-4-mercaptocy cl obut-3-ene- 1,2-dione and 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperidin-4- yl)(methyl)amino)-4-(methylthio)cy cl obut-3-ene- 1,2-dione
Figure imgf000172_0001
[00650] Step 1 : 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-mercaptocyclobut-3-ene-l, 2-dione
[00651] To a solution of Example 27 (130 mg, 217 pmol) in EtOH (1 mb) was added NaSH (36.5 mg, 650 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction was concentrated under reduced pressure. After purified by /w/i-HPLC (column: Waters xbridge 150 x 25mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 23% - 53%, 8 min), 3- ((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperi din-4- yl)(methyl)amino)-4-mercaptocyclobut-3-ene-l, 2-dione (Example 46, 35.3 mg, yield: 27%) was obtained as a yellow solid. MS: m/z = 602.5 [M + H]+. LH NMR (400 MHz, Methanol-4/7) 88.22 (d, J= 8.0 Hz, 1H), 8.04 - 8.02 (m, 2H), 7.96 (d, J= 8.4 Hz, 1H), 7.68 (d, J= 7.2 Hz, 2H), 7.60 (d, J= 7.2 Hz, 2H), 7.46 - 7.35 (m, 5H), 6.58 - 6.50 (m, 1H), 4.66 - 4.56 (m, 2H), 4.28 - 4.21 (m, 1H), 3.75 - 3.54 (m, 2H), 3.48 - 3.36 (m, 3H), 3.10 - 2.88 (m, 2H), 2.21 - 2.01 (m, 4H).
[00652] Step 2: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-(methylthio)cy cl obut-3-ene-l, 2-dione [00653] To a solution of Example 46 (80 mg, 133 pmol) in EtOH (1 mL) was added CH3I (56.6 mg, 399 pmol) at 0 °C. The mixture was stirred at 25 °C for 2 hr. The reaction was concentrated under reduced pressure. After purified by / /i-HPLC (column: Waters xbridge 150 x 25mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 42% - 72%, 8 min), 3- ((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperi din-4- yl)(methyl)amino)-4-(methylthio)cy cl obut-3-ene- 1,2-dione (Example 47, 5.7 mg, yield: 6.6%) was obtained as a yellow solid. MS: m/z = 616.4 [M + H]+. 1 H NMR (400 MHz, Mcthanol-<A) 8 8.20 (d, J= 8.8 Hz, 1H), 8.04 (d, J= 7.2 Hz, 2H), 7.98 - 7.97 (m, 1H), 7.96 - 7 93 (m, 1H), 7.54 (d, J= 8.0 Hz, 2H), 7.46 - 7.41 (m, 4H), 7.40 - 7.37 (m, 1H), 7.34 - 7.31 (m, 1H), 6.53 - 6.46 (m, 1H), 4.61 - 4.57 (m, 1H), 3.68 - 3.64 (m, 2H), 3.34 (s, 3H), 3.10 - 3.04 (m, 2H), 2.92 - 2.88 (m, 3H), 2.22 - 2.15 (m, 2H), 2.05 - 1.98 (m, 2H), 1.85 - 1.75 (m, 2H).
[00654] Example 48: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(2-hydroxyethyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000173_0001
[00655] Step 1 : Benzyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(2-hydroxyethyl)carbamate)
[00656] To a solution of Intermediate 14 (1.0 g, 2.43 mmol), Intermediate 17 (676 mg HC1 salt, 2.15 mmol), and K2CO3 (1.0 g, 7.28 mmol) in DMF (10 mL) was added Nal (36 mg, 242 pmol). The mixture was stirred at 80 °C for 5 hr. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, fdtered, and concentrated under reduced pressure. After purified by silica gel flash chromatography (Eluent of 0 ~ 9% MeOH in CH2CI2), benzyl (l-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)(2- hydroxyethyl)carbamate (500 mg, yield: 27%) was obtained as a yellow solid. MS: m/z = 654.2 [M + H]+.
[00657] Step 2: 2-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)ethanol
[00658] A mixture of benzyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)(2 -hydroxy ethyl)carbamate (220 mg, 336 pmol) and Pd/C (30 mg, 10% purity) in MeOH (5 mL) was degassed and purged with Hz three times. The mixture was stirred at 40 °C for 6 hr under Hz atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. After purified by prep-WC (CHzClz in MeOH = 10%), 2-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)ethanol (11.4 mg, yield: 6%) was obtained as a light yellow solid. MS: m/z = 534.3 [M + H]+. XHNMR (400 MHz, Methanol-^) 8 8.18 (d, J= 8.4 Hz, 1H), 8.05 - 8.01 (m, 2H), 7.98 (dd, J= 4.8, 1.6 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.45 - 7.35 (m, 5H), 7.31 (dd, J= 7.6, 1.6 Hz, 1H), 6.46 (dd, J= 7.6, 4.8 Hz, 1H), 3.69 - 3.65 (m, 2H), 3.61 (s, 2H), 3.01 - 2.91 (m, 2H), 2.78 (t, J= 5.6 Hz, 2H), 2.63 - 2.55 (m, 1H), 2.17 - 2.09 (m, 2H), 1.98 - 1.89 (m, 2H), 1.54 - 1.44 (m, 2H).
[00659] Step 3: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(2-hydroxyethyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
[00660] To a solution of 2-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)amino)ethanol (85 mg, 140 pmol) in MeOH (1 mL) were added TEA (17 mg, 168 pmol) and 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (20 mg, 140 pmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure. After purified by prep-TLC (CHzClz in MeOH = 10%), 3-((l-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-327-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)(2- hydroxyethyl)amino)-4-m ethoxy cy cl obut-3-ene-l, 2-dione (Example 48, 30 mg, yield: 31%) was obtained as a yellow solid. MS: m/z = 630.3 [M + H]+. LH NMR (400 MHz, Methanol-<4) 8 8.19 (d, J= 8.4 Hz, 1H), 8.05 - 8.01 (m, 2H), 7.98 (dd, J= 4.8, 1.6 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.47 - 7.31 (m, 6H), 6.53 - 6.45 (m, 1H), 4.38 - 4.36 (m, 3H), 3.85 - 3.78 (m, 1H), 3.76 - 3.61 (m, 5H), 3.60 - 3.55 (m, 1H), 3.06 - 3.01 (m, 2H), 2.22 - 2.12 (m, 2H), 2.05 - 1 95 (m, 2H), 1.90 - 1.78 (m, 2H).
[00661] Example 49: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-/>]pyridin-3- yl)benzyl)piperidin-4-yl)(methyl)amino)-4-(ethylthio)cy cl obut-3-ene- 1,2-dione
Figure imgf000175_0001
[00662] To a solution of Example 27 (200 mg, 334 pmol) in CH2CI2 (5 mL) were added TEA (169 mg, 1.67 mmol) and EtSH (2.56 g, 41.2 mmol). The resulting mixture was stirred at 25 °C for 24 hr. The reaction mixture was quenched with H2O (5 mL) at 0 °C, diluted with CH2CI2 (10 mL) and extracted with CH2CI2 (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over JSfeSCL, filtered, and concentrated under reduced pressure. After purified by prep-HPLC (column: Waters xbridge 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 44% - 74%, 14 min), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperidin-4-yl)(methyl)amino)-4-(ethylthio)cyclobut-3-ene- 1,2-dione (Example 49, 24.8 mg, yield: 11%) was obtained as a light-yellow lyophilized powder. MS: m/z = 630.3 [M + H]+. XHNMR (400 MHz, Dimethylsulfoxide-t/g) 3 8.27 (d, J = 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.51 - 7.44 (m, 6H), 7.42 - 7.37 (m, 1H), 7.18 - 7.13 (m, 1H), 7.03 (br s, 2H), 6.42 - 6.36 (m, 1H), 4.44 - 4.28 (m, 0.5H), 3.70 - 3.63 (m, 0.5H), 3.60 (s, 2H), 3.45 - 3.39 (m, 2H), 3.25 (s, 1.5H), 3.13 (s, 1.5H), 2.95 (t, J= 10.8 Hz, 2H), 2.09 - 2.01 (m, 2H),
1.96 - 1.84 (m, 2H), 1.76 - 1.67 (m, 2H), 1.35 (t, J= 7.6 Hz, 3H).
[00663] Example 50: (A)-3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000175_0002
[00664] To a solution of Intermediate 18 (150 mg, 324 pmol) in MeOH (1 mL) were added 3,4- dimethoxycyclobut-3-ene- 1,2-dione (55.4 mg, 389 pmol) and TEA (164 mg, 1.62 mmol). The mixture was stirred at 20 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-H LC (column: Phenomenex C18 150 * 25mm * 10 um; mobile phase: [water (NH4HCO3) - ACN]; B%: 35%-65%, 14 min) and then purified by prep-TLC (CH2Q2 : MeOH = 10 : 1). (A)-3-((l-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)amino)-4-methoxycyclobut-3- ene-1, 2-dione (Example 50, 17.9 mg, yield: 32%) was obtained as a yellow solid. MS: m/z = 572.2 [M + H]+. 'H NMR (400 MHz, Methanol- d4) 8 8.19 (d, J= 8.8 Hz, 1H), 8.00 (d, J= 7.2 Hz, 2H), 7.98 (dd, J= 5.2, 2.0 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.47 - 7.28 (m, 6H), 6.46 (d, J= 7.6, 4.8 Hz, 1H), 4.36 (s, 3H), 3.77 - 3.73 (m, 1H), 3.33 - 3.32 (m, 2H), 2.92 - 2.80 (m, 2H), 2.70 - 2.56 (m, 2H), 2.42 - 2.30 (m, 1H), 1.90 - 1.78 (m, 1H).
[00665] Example 51 : 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- yl)benzyl)azeti din-3 -yl)amino)-4-methoxycy cl obut-3-ene-l, 2-dione
Figure imgf000176_0001
[00666] To a solution of Intermediate 19 (150 mg, 335 pmol) in MeOH (1 mL) were added TEA (169 mg, 1.68 mmol) and 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (57.1 mg, 402 pmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0~6% MeOH in CH2CI2) and then purified again by prep-TLC (CH2CI2: MeOH = 10: 1). 3-((l-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)azetidin-3-yl)amino)-4- methoxycy cl obut-3-ene- 1,2-dione (Example 51, 15.3 mg, yield: 8.0%, 1 :1 mixture of tautomers) was obtained as a light-yellow solid. MS: m/z = 558.3 [M + H]+. 'H NMR (400 MHz, Methanol- d4) 8 8.19 (d, J= 8.4 Hz, 1H), 8.03 (d, J= 7.2 Hz, 2H), 7.98 (dd, J= 5.2, 1.6 Hz, 1H), 7.96 - 7.93 (m, 1H), 7.52 - 7.35 (m, 8H), 6.55 - 6.46 (m, 1H), 4.58 (s, 1.5H), 4.38 (s, 1.5H), 3.80 - 3.76 (m, 1H), 3.77 - 3.65 (m, 2H), 3.35 (s, 2H), 3.28 - 3.12 (m, 2H).
[00667] Example 52: 3-((2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-azaspiro[4.5]decan-8-yl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
Figure imgf000176_0002
[00668] To a solution of Intermediate 20 (100 mg, 189 pmol) in MeOH (2 mL) were added 3,4- dimethoxycyclobut-3-ene- 1,2-dione (26.8 mg, 189 pmol) and TEA (42 mg, 415 pmol). The reaction mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure. The residue was purified by /?re/?-TLC (CH2CI2 : MeOH = 10 : 1) to give 3-((2-(4-(2- (2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3-yl)benzyl)-2-azaspiro[4.5]decan- 8-yl)amino)-4-methoxycyclobut-3-ene- 1,2-dione (Example 52, 20.5 mg, yield: 17%, 1 : 1 mixture of tautomers) as a light-yellow solid. MS: m/z = 640.4 [M + H]+. 'H NMR (400 MHz, Methanol-^) 38.19 (d, J= 8.4 Hz, 1H), 8.03 (d, J= 7.2 Hz, 2H), 7.98 (dd, J= 4.8, 1.6 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.57 - 7.52 (m, 2H), 7.46 - 7.43 (m, 2H), 7.43 - 7.31 (m, 4H), 6.50 - 6.44 (m, 1H), 4.38 - 4.29 (m, 3H), 3.92 - 3.85 (m, 0.5H), 3.78 - 3.68 (m, 2H), 3.53 - 3 48 (m, 0.5H), 2.76 - 2.68 (m, 2H), 2.58 - 2.46 (m, 2H), 1.86-1.84 (m, 2H), 1.80 - 1.68 (m, 4H), 1.54 - 1.42 (m, 4H).
[00669] Example 53: 3-(7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000177_0001
[00670] To a solution of Intermediate 21 (100 mg, 199 pmol) and 3,4-dimethoxycyclobut-3- ene- 1,2-dione (34 mg, 239 pmol) in MeOH (2 mL) was added TEA (101 mg, 997 pmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated. The residue was purified by prep-TLC (CH2Q2 : MeOH = 10 : 1) to give 3-(7-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-4- methoxycy cl obut-3-ene- 1,2-dione (Example 53, 12.7 mg, yield: 9.9%) as a light-yellow solid. MS: m/z = 612.3 [M + H]+. 'H NMR (400 MHz, Dimethyl sulfoxide-^) 8 8.28 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.86 - 7.63 (m, 1H), 7.51 - 7.38 (m, 6H), 7.16 (dd, J= 7.2, 2 Hz, 1H), 7.04 - 6.96 (m, 2H), 6.46 - 6.33 (m, 1H), 4.29 (s, 2H), 4.21 (s, 3H), 4.17 - 4.03 (m, 4H), 3.58 - 3.49 (m, 4H), 1.92 - 1.77 (m, 4H).
[00671] Example 54: 3-(8-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,8-diazaspiro[4.5]decan-2-yl)-4-methoxycyclobut-3-ene- 1,2-dione
Figure imgf000177_0002
[00672] To a solution of Intermediate 22 (100 mg, 194 pmol) and TEA (98 mg, 970 pmol) in MeOH (2 mL) was added 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (33 mg, 233 pmol). The mixture was stirred at 25 °C for 2 hr. The residue was purified by prep-TLC (CH2Q2 : MeOH = 10 1) to give 3-(8-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,8-diazaspiro[4.5]decan-2-yl)-4-methoxycyclobut-3-ene- 1,2-dione (Example 54, 10.0 mg, yield: 8%) as a yellow solid. MS: m/z = 626.4 [M + H]+. 1HNMR (400 MHz, Methanol- d4) 8 8.19 (d, J= 8 4 Hz, 1H), 8.06 - 8.01 (m, 2H), 7.98 (dd, J= 5.2, 1.6 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 8.4 Hz, 2H), 7.46 - 7 30 (m, 6H), 6.51 - 6.43 (m, 1H), 4.34 (s, 3H), 3.88 (t, J= 7.2 Hz, 1H), 3.72 (t, J= 7.2 Hz, 1H), 3.69 - 3.67 (m, 1H), 3.65 (s, 2H), 3.51 - 3.47 (m, 1H), 2.66 - 2.56 (m, 2H), 2.48 - 2.38 (m, 2H), 1.91 - 1.84 (m, 2H), 1.75 - 1.67 (m, 4H).
[00673] Example 55: 3-(6-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,6-diazaspiro[3.4]octan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000178_0001
[00674] To a solution of Intermediate 23 (80 mg, 164 pmol) and 3,4-dimethoxycyclobut-3-ene- 1, 2-dione (28 mg, 197 pmol) in MeOH (2 mL) was added TEA (49.8 mg, 492 pmol). The mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure. After purified by prep-TLC (MeOH in CH2CI2 = 10%), 3-(6-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-b]pyridin-3-yl)benzyl)-2,6-diazaspiro[3.4]octan-2-yl)-4-methoxycyclobut-3-ene- 1, 2-dione (Example 55, 7.7 mg, yield: 8%) was obtained as a yellow solid. MS: m/z = 598.3 [M + H]+. 'H NMR (400 MHz, Methanol-A) 8 8.22 - 8.13 (m, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.99 - 7.91 (m, 2H), 7.55 - 7.50 (m, 2H), 7.45 - 7.29 (m, 6H), 6.52 - 6.44 (m, 1H), 4.42 - 4.34 (m, 3H), 4.28 (s, 2H), 3.73 (s, 2H), 3.37 - 3.32 (m, 2H), 2.89 (s, 2H), 2.72 - 2.66 (m, 2H), 2.23 - 2.18 (m, 2H).
[00675] Example 56: 3-(7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- >]pyridin-3- yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000178_0002
[00676] To a solution of Intermediate 24 (200 mg, 399 pmol,) and 3,4-dimethoxycyclobut-3- ene- 1,2-dione (68 mg, 478 pmol) in MeOH (1 mL) was added TEA (40 mg, 399 pmol). The mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0-80% EtOAc in petroleum ether), 3-(7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5-6]pyridin-3-yl)benzyl)-2,7- diazaspiro[4.4]nonan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 56, 26.2 mg, yield: 10%) was obtained as a yellow solid. MS: m/z = 612.3 [M + H]+. 1H NMR (400 MHz, Dimethylsulfoxide-dfi) 8 8.26 (d, J= 8.4 Hz, 1H), 8.08 - 7.94 (m, 4H), 7.51 - 7.37 (m, 7H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.36 (dd, J= 12, 4.8 Hz, 1H), 4.26 (s, 3H), 3.96 - 3.90 (m, 1H), 3.73 - 3.69 (m, 2H), 3.60 - 3.55 (m, 1H), 3.48 - 3.42 (m, 1H), 2.67 - 2.65 (m, 1H), 2.58 - 2.56 (m, 1H), 2.45 - 2.41 (m, 1H), 2.32 - 2.30 (m, 1H), 1.98 - 1.88 (m, 2H), 1.84 - 1.75 (m, 2H).
[00677] Example 57: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,8-diazaspiro[4.5]decan-8-yl)-4-methoxycyclobut-3-ene- 1,2-dione
Figure imgf000179_0001
[00678] To a solution of Intermediate 56 (100 mg, 186 pmol) and 3,4-dimethoxycyclobut-3-ene- 1, 2-dione (32 mg, 223 pmol) in MeOH (1 mL) was added TEA (19 mg, 186 pmol). The mixture was stirred at 25 °C for 2 hr. The mixture was fdtered, washed with MeOH (3 mL), and concentrated under reduced pressure to give 3-(2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,8-diazaspiro[4.5]decan-8-yl)-4-methoxycyclobut-3-ene- 1,2-dione (Example 57, 14.1 mg, yield: 12%) as a yellow solid. MS: m/z = 626.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tfk) 8 8.27 (d, J = 8.4 Hz, 1H), 8.08 - 7.96 (m, 4H), 7.51 - 7.41 (m, 6H), 7.41 - 7.34 (m, 1H), 7.17 (dd, 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.38 (dd, J = 1.6, 4.8 Hz, 1H), 4.29 (s, 3H), 3.83 - 3.77 (m, 1H), 3.74 - 3.68 (m, 1H), 3.66 (s, 2H), 3.51 - 3.43 (m, 2H), 3.17 (s, 2H), 2.60 - 2.56 (m, 2H), 2.45 - 2.43 (m, 1H), 1.69 - 1.59 (m, 4H).
[00679] Example 58: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3 /-imidazo[4,5- >]pyridin-3- yl)benzyl)-2,7-diazaspiro[4.5]decan-7-yl)-4-methoxycyclobut-3-ene- 1,2-dione
Figure imgf000180_0001
[00680] To a solution of Intermediate 25 (160 mg, 319 pmol) and 3,4-dimethoxycyclobut-3-ene-
1, 2-dione (55 mg, 383 pmol) in MeOH (1 mL) was added TEA (33 mg, 319 pmol). The mixture was stirred at 25 °C for 2 hr. The mixture was filtered, washed with MeOH (3 mL), and concentrated under reduced pressure to give 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377- imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.5]decan-7-yl)-4-methoxycyclobut-3-ene-
1, 2-dione (Example 58, 17.5 mg, yield: 9%) as a yellow solid. MS: m/z = 626.4 [M + H]+. 'H NMR (400 MHz, Dim ethyl sulfoxide-cL) 5 8.27 (d, J = 8.4 Hz, 1H), 8.07 - 7.91 (m, 4H), 7.54 - 7.44 (m, 5H), 7.43 - 7.35 (m, 2H), 7.14 (t, J= 5.6 Hz, 1H), 7.05 (br s, 1H), 7.01 (br s, 1H), 6.40 -
6.30 (m, 1H), 4.30 (s, 1.5H), 4.24 (s, 1.5H), 3.91 - 3.77 (m, 1H), 3.75 - 3.71 (m, 2H), 3.61 - 3.46
(m, 3H), 3.32 - 3.29 (m, 1H), 3.25 - 3.14 (m, 1H), 2.75 - 2.68 (m, 1H), 2.62 - 2.54 (m, 1H), 2.46 -
2.42 (m, 1H), 2.25 - 2.16 (m, 1H), 1.65 - 1.55 (m, 4H).
[00681] Example 59: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3- yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-ethoxycyclobut-3-ene- 1,2-dione
Figure imgf000180_0002
[00682] To a solution of Intermediate 26 (100 mg, 199 pmol) and 3,4-diethoxycyclobut-3-ene-
1, 2-dione (40.7 mg, 239 pmol) in MeOH (2 mL) was added TEA (101 mg, 997 pmol). The mixture was stirred at 25 °C for 14 hr. The mixture was filtrated. The solid was collected, washed with MeOH (10 mL x 2), and dried under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2C12 = 1% to 5%), 3-(2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7- imidazo[4,5-6]pyridin-3-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-ethoxycyclobut-3-ene- 1,2- dione (Example 59, 15.6 mg, yield: 14%) was obtained as a yellow solid. MS: m/z = 626.3 [M + H]+. XH NMR (400 MHz, Methanol-^) 8 8.16 (d, J= 8.4 Hz, 1H), 8.04 - 8.00 (m, 2H), 7.97 (dd, J= 5.2, 1.6 Hz, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.45 - 7.33 (m, 5H), 7.29 (dd, J= 7.6, 2.0 Hz, 1H), 6.45 (dd, J= 8.0, 5.2 Hz, 1H), 4.71 (q, J= 7.2 Hz, 2H), 3.83 - 3.78 (m, 2H), 3.77 (s, 2H), 3.59 - 3.54 (m, 2H), 3.23 - 3.18 (m, 4H), 1.93 - 1.84 (m, 4H), 1.43 (t, J = 7.2 Hz, 3H).
[00683] Example 60: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-Z>]pyridin-3- yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000181_0001
[00684] To a solution of Intermediate 26 (80 mg, 159 pmol) in MeOH (1 mL) were added TEA (81 mg, 797 pmol) and 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (27 mg, 191 pmol). The reaction mixture was stirred at 25 °C for 16 hr. The mixture was filtered, washed with MeOH (2 mL x 2) and dried under reduced pressure. 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 60, 24 mg, yield: 24%) was obtained as a yellow solid. MS: m/z = 612.4 [M + H]+. 'H NMR (400 MHz, Di methyl sulfoxide-^) 8 8.26 (d, J = 8.0 Hz, 1H), 8.03 - 7.95 (m, 4H), 7.49 - 7.39 (m, 7H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 6.96 (br s, 2H), 6.40 (dd, J= 7.6, 4.8 Hz, 1H), 4.29 (s, 3H), 3.74 - 3.69 (m, 2H), 3.66 (s, 2H), 3.53 - 3.50 (m, 2H), 3.05 (s, 4H), 1.84 - 1.77 (m, 4H).
[00685] Example 61: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- >]pyridin-3- yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-(ethylthio)cyclobut-3-ene- 1,2-dione
Figure imgf000181_0002
[00686] To a solution of Example 60 (130 mg, 213 pmol) in CH2CI2 (2 mL) were added TEA (108 mg, 1.06 mmol) and EtSH (1.95 g, 31.4 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (10 mL) at 25°C, extracted with CH2CI2 (15 mL), washed with H2O (20 mL x 3) and brine (20 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. After purified by /i/e/i-HPLC (column: Phenomenex C18 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 47% - 77%, over 16 min) and prep-TLC (MeOH in CH2CI2 = 10%), 3-(2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- Z>]pyridin-3-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-(ethylthio)cyclobut-3-ene- 1,2-dione (Example 61, 2.2 mg, yield: 1.6%) was obtained as a light-yellow solid. MS: m/z = 642.4 [M + H]+. XH NMR (400 MHz, Methanol-^) 8 8.19 (d, J= 8.4 Hz, 1H), 8.06 - 8.01 (m, 2H), 7.98 (dd, J= 5.2, 2.0 Hz, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.52 - 7.37 (m, 7H), 7.33 (dd, J= 8.0, 2.0 Hz, 1H), 6.48 (dd, J= 7.6, 4.8 Hz, 1H), 3.95 - 3.89 (m, 2H), 3.81 (s, 2H), 3.67 - 3.63 (m, 2H), 3.47 (q, J = 7.2 Hz, 2H), 3.27 - 3.25 (m, 4H), 1.98 - 1.91 (m, 4H), 1.43 (t, J= 7.2 Hz, 3H)
[00687] Example 62: (R)-3-(7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000182_0001
[00688] To a solution of Intermediate 27 (70 mg, 140 pmol) in MeOH (1 mL) were added TEA (71 mg, 698 pmol) and 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (24 mg, 167 pmol). The reaction mixture was stirred at 25 °C for 16 hr and then was filtered. The collected solid was washed with MeOH (2 mL x 2) and dried under reduced pressure to give (R)-3-(7-(4-(2-(2-aminopyridin-3-yl)- 5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)-4- methoxycy cl obut-3-ene- 1,2-dione (Example 62, 18.2 mg, yield: 21%) as a yellow solid. MS: m/z = 612.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-tfe) 8 8.27 (d, J= 8.0 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.50 - 7.43 (m, 6H), 7.41 - 7.37 (m, 1H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 7.02 (br s, 2H), 6.36 (dd, J= 7.6, 4.8 Hz, 1H), 4.26 (s, 3H), 3.71 - 3.67 (m, 2H), 3.61 - 3.51 (m, 2H), 3.48 - 3.40 (m, 2H), 2.69 - 2.65 (m, 1H), 2.57 - 2.54 (m, 2H), 2.45 - 2.40 (m, 1H), 1.99 - 1.89 (m, 2H), 1.85 - 1.76 (m, 2H).
[00689] Example 63: 3-(5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- >]pyridin-3- yl)benzyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000182_0002
[00690] To a solution of Intermediate 28 (70 mg, 144 pmol) in MeOH (1 mL) were added TEA (73 mg, 718 pmol) and 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (25 mg, 172 pmol). The reaction mixture stirred at 25 °C for 16 hr. The mixture was fdtered. The collected solid residue was washed with MeOH (2 mL x 2) and dried under reduced pressure. 3-(5-(4-(2-(2-Aminopyridin- 3-yl)-5-phenyl-3J/-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-4- methoxy cy cl obut-3-ene- 1,2-dione (Example 63, 29.1 mg, yield: 33%) was obtained as a white solid. MS: m/z = 598.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-^) 5 8.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.53 - 7.50 (m, 2H), 7.49 - 7.43 (m, 4H), 7.42 - 7.37 (m, 1H), 7.17 - 7.14 (m, 1H), 7.01 (br s, 2H), 6.42 - 6.37 (m, 1H), 4.44 - 4.34 (m, 1H), 4.30 - 4.26 (m, 3H), 4.17 - 3.99 (m, 1H), 3.89 - 3.83 (m, 2H), 3.67 - 3.58 (m, 1H), 3.01 - 2.96 (m, 2H), 2.93 - 2.88 (m, 1H), 2.11 - 2.03 (m, 1H), 1.95 - 1.84 (m, 2H), 1.76 - 1.68 (m, 1H).
[00691] Example 64: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3- yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-(methylthio)cyclobut-3-ene- 1,2-dione
Figure imgf000183_0001
[00692] Step 1: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3- yl)benzyl)-2,7-diazaspiro [3.5 ]nonan-7-yl)-4-mercaptocy clobut-3 -ene- 1 ,2-dione
[00693] To a solution of Example 60 (120 mg, 196 pmol) in EtOH (1 mL) was added sulfanylsodium (55 mg, 980 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was quenched with H2O (10 mL) at 25 °C, diluted with CH2CI2 (15 mL), washed with H2O (20 mL x 3) and brine (20 mL), dried over JSfeSCL, filtered and concentrated under reduced pressure. 3-(2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-3-yl)benzyl)- 2, 7-diazaspiro[3.5]nonan-7-yl)-4-mercaptocyclobut-3-ene-l, 2-dione (120 mg, yield: 55%) was obtained as a yellow solid. MS: m/z = 614.2 [M + H]+.
[00694] Step 2: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3- yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-(methylthio)cyclobut-3-ene- 1,2-dione
[00695] To a solution of 3-(2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5-Z>]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-mercaptocyclobut-3-ene-l, 2-dione (120 mg, 196 pmol) in EtOH (4 mL) was added CH3I (83.5 mg, 589 pmol). The mixture was stirred at 25 °C for 2 hr. The reaction was concentrated under reduced pressure. After purified by /vtyi-HPLC (column: Waters xbridge 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 37% - 67%, over 14 min), 3-(2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-(methylthio)cyclobut-3-ene- 1,2-dione (Example 64, 6.6 mg, yield: 4.8%) was obtained as a yellow solid. MS: m/z = 628.4 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.19 (d, J= 8.4 Hz, 1H), 8.05 - 8.01 (m, 2H), 7.98 (dd, J = 4.8, 1.6 Hz, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.54 - 7.46 (m, 4H), 7.45 - 7.36 (m, 3H), 7.34 (dd, J= 8.0, 1.6 Hz, 1H), 6.48 (dd, J= 7.6, 5.2 Hz, 1H), 3.94 - 3.89 (m, 2H), 3.83 (s, 2H), 3.65 - 3 60 (m, 2H), 3.29 - 3.28 (m, 4H), 2.90 (s, 3H), 1.99 - 1.91 (m, 4H).
[00696] Example 65: 3-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- >]pyridin-3- yl)benzyl)-2,6-diazaspiro[3.5]nonan-6-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000184_0001
[00697] To a solution of 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (27.2 mg, 191 pmol) and Intermediate 29 (80.0 mg, 159 pmol) in MeOH (2 mL) was added TEA (80.7 mg, 797 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction was fdtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 - 10% MeOH in CH2Q2) to give 3-(2-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,6-diazaspiro[3.5]nonan-6-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 65, 36 mg, yield: 37%) as a yellow solid. MS: m/z = 612.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-cA) 8 8.31 - 8.28 (m, 1H), 8.02 - 7.98 (m, 4H), 7.51 - 7.30 (m, 7H), 7.15 (dd, .7 = 7.6, 1.6 Hz, 1H), 6.99 (br s, 2H), 6.41 - 6.36 (m, 1H), 4.35 - 4.30 (m, 1.5H), 4.31 - 4.20 (m, 1.5H), 3.92 - 3.88 (m, 1H), 3.75 - 3.65 (m, 4H), 3.43 - 3.40 (m, 1H), 3.10 - 3.00 (m, 2H), 2.95 - 2.85 (m, 2H), 1.80 - 1.70 (m, 2H), 1.60 - 1.50 (m, 2H).
[00698] Example 66: (S)-3-(7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000184_0002
[00699] To a solution of Intermediate 30 (50 mg, 99.6 pmol) and 3,4-dimethoxycyclobut-3- ene-1, 2-dione (17.0 mg, 119 pmol) in MeOH (1 mL) was added TEA (50.4 mg, 498 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 0 - 10% MeOH in CH2CI2) to give (S)-3-(7-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 66, 29.3 mg, yield: 48%) as a yellow solid. MS: m/z = 612.2 [M + H]+. 'H NMR (400 MHz, Methanol -d/) 8 8.19 (d, J= 8.4 Hz, 1H), 8.05 - 8.02 (m, 2H), 7.97 (dd, J= 4.8, 1.6 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 8.4 Hz, 1H), 7.46 - 7.30 (m, 6H), 6.45 (dd, J= 7.2, 4.8 Hz,lH), 4.32 (s, 3H), 3.89 - 3.61 (m, 6H), 2.85 - 2.65 (m, 3H), 2.55 (d, ./ - 9.6 Hz, 1H), 2.01 - 1.89 (m, 4H).
[00700] Example 67: (A)-3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyri din-3 -yl)benzyl)-2-methylpiperazin-l-yl)-4-methoxycy cl obut-3-ene- 1,2-dione
Figure imgf000185_0001
[00701] To a solution of Intermediate 31 (55 mg, 116 pmol) in MeOH (1 mL) were added TEA (58.5 mg, 578 pmol) and 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (19.7 mg, 139 pmol). The reaction mixture stirred at 25 °C for 16 hr. Then the mixture was filtered. The collected solid residue was washed with MeOH (2 mL x 2) and dried in vacuum to give (7?)-3-(4-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3-yl)benzyl)-2-methylpiperazin-l-yl)-4- methoxycy cl obut-3-ene- 1,2-dione (Example 67, 25.5 mg, yield: 37%) as a brown solid. MS: m/z = 586.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-^) 8 8.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.98 (m, 4H), 7.51 - 7.44 (m, 6H), 7.41 - 7.38 (m, 1H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.02 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 4.67 - 4.58 (m, 0.5H), 4.30 (s, 3H), 4 29 - 4.17 (m, 1H), 4.08 - 3.98 (m, 0.5H), 3.67 (d, J= 13.6 Hz, 1H), 3.55 (d, J= 13.6 Hz, 1H), 3.47 - 3.42 (m, 1H), 2.93 - 2.90 (m, 1H), 2.69 - 2.66 (m, 1H), 2.35 - 2.30 (m, 1H), 2.26 - 2.18 (m, 1H), 1.36 (d, J= 6.8 Hz, 3H).
[00702] Example 68: 3-((2S,6A)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,6-dimethylpiperazin-l-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000186_0001
[00703] To a solution of Intermediate 32 (80 mg, 163 pmol), 3, 4-dimethoxycy cl obut-3-ene- 1,2- dione (27.9 mg, 196 pmol) in MeOH (1 mb) was added TEA (82.7 mg, 817 pmol). The mixture was stirred at 25 °C for 2 hr. The mixture was filtered and concentrated to give 3-((25,6A)-4-(4- (2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,6- dimethylpiperazin-l-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 68, 12.8 mg, yield: 13%) as yellow solid. MS: m/z = 600.2 [M + H]+. LH NMR (400 MHz, Di methyl sulfoxide-^) 8 8.27 (d, J= 8.4 Hz, 1H), 7.98 - 8.05 (m, 4H), 7.56 (d, J= 8.4 Hz, 2H), 7.43 - 7.49 (m, 4H), 7.37 - 7.42 (m, 1H), 7.17 (dd, J= 7.6, 2.0 Hz, 1H), 7.04 (br s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 4.31 (s, 3H), 3.63 (s, 2H), 3.34 - 3.40 (m, 2H), 2.72 - 2.74 (m, 2H), 2.34 - 2.38 (m, 2H), 1.38 (d, J = 7.2 Hz, 6H).
[00704] Example 69: 3-((27?,6A)-4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-
Z>]pyridin-3-yl)benzyl)-2,6-dimethylpiperazin-l-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000186_0002
[00705] To a solution of Intermediate 33 (66 mg, 135 pmol) and TEA (68.2 mg, 674 pmol) in MeOH (2 mL) was added 3, 4-dimethoxycy cl obut-3-ene- 1,2-dione (23 mg, 162 pmol). The mixture was stirred at 25 °C for 16 hr. The mixture was concentrated and purified by silica gel flash chromatography (Eluent of 0 ~ 8% MeOH in CH2CI2) to give 3-((2A,6A)-4-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,6-dimethylpiperazin-l- yl)-4-m ethoxy cyclobut-3-ene- 1,2-dione (Example 69, 44.6 mg, yield: 54%) as a yellow solid. MS: m/z = 600.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- e) 88.27 (d, J= 8.4 Hz, 1H), 8.10 - 7.94 (m, 4H), 7.54 - 7.37 (m, 7H), 7.17 (dd, J= 7.6, 1.6 Hz, 1H), 7.03 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 4.34 (s, 3H), 4.30 - 4.18 (m, 2H), 3.67 (d, J= 13.6 Hz, 1H), 3.56 (d, J = 13.6 Hz, 1H), 2.68 - 2.63 (m, 2H), 2.36-2.30 (m, 2H), 1.35 (d, J= 6.4 Hz, 6H). [00706] Example 70: 3-((2S,6S)-4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-
Z>]pyridin-3-yl)benzyl)-2,6-dimethylpiperazin-l-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000187_0001
[00707] To a solution of Intermediate 34 (80 mg, 163 pmol) in MeOH (1 mL) were added TEA (82.7 mg, 817 pmol) and 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (27.9 mg, 196 pmol). The reaction mixture stirred at 25 °C for 16 hr. The reaction mixture was filtrated, washed with MeOH (10 ml x 2), concentrated under reduced pressure. After purified by silica gel flash chromatography (Eluent of 0-5% MeOH in CH2CI2), 3-((25,6S)-4-(4-(2-(2-aminopyridin-3-yl)- 5-phenyl-377-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2,6-dimethylpiperazin-l-yl)-4- methoxycy cl obut-3-ene- 1,2-dione (Example 70, 5.5 mg, yield: 5.4%) was obtained as a yellow solid. MS: m/z = 600.3 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.19 (d, J = 8.8 Hz, 1H), 8.05 - 8.01 (m, 2H), 7.98 (dd, J= 4.8, 1.6 Hz, 1H), 7.94 (d, .7= 8.4 Hz, 1H), 7.54 (d, .7= 8.0 Hz, 2H), 7.47 - 7.35 (m, 5H), 7.32 (dd, J = 1.6, 1.6 Hz, 1H), 6.47 (dd, J = 1.6, 5.2 Hz, 1H), 4.41 (s, 3H), 4.40 - 4.32 (m, 2H), 3.68 (d, J= 13.6 Hz, 1H), 3.68 (d, J= 13.6 Hz, 1H), 2.67 (dd, J= 11.6, 3.2 Hz, 2H), 2.43 - 2.35 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H).
[00708] Example 71 : 3-(8-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)-3, 8-diazabicyclo[3.2. l]octan-3-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000187_0002
[00709] To a solution of 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (32.0 mg, 225 pmol) and Intermediate 35 (100 mg, 205 pmol) in MeOH (2 mL) was added TEA (103 mg, 1.03 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hr. The reaction was filtered and concentrated under reduced pressure. After purified by /?rep-HPLC(column: Waters xbridge 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; B%: 40% - 70%, 10 min), 3-(8-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-/>]pyridin-3-yl)benzyl)-3,8- diazabicyclo[3.2. l]octan-3-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 71, 16 mg, yield: 13%) was obtained as a light yellow solid. MS: m/z = 598.3 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide-de) 8 8.26 (d, J= 8.4 Hz, 1H), 8.05 - 7.98 (m, 4H), 7.56 (d, J= 8.0 Hz, 2H), 7.50 - 7.36 (m, 6H), 7.17 (dd, J= 7.6, 1.6 Hz, 1H), 6.99 (d, J= 4.4 Hz, 1H), 6.40 (dd, J= 7.6, 4.0 Hz, 1H), 4.29 (s, 3H), 4.13 - 4.06 (m, 1H), 3.64 (s, 2H), 3.55 - 3.45 (m, 3H), 3.30 - 3.28 (m, 2H), 2.10 - 2.05 (m, 2H), 1.65 - 1.60 (m, 2H).
[00710] Example 72: 3-(3-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-3- yl)benzyl)-3,8-diazabicyclo[3.2. l]octan-8-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000188_0001
[00711] To a solution of Intermediate 36 (100 mg, 205 pmol) and 3,4-dimethoxycyclobut-3- ene-1, 2-dione (32.1 mg, 226 pmol) in MeOH (2 mL) was added TEA (104 mg, 1.03 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure. After purified by /?re/»-TLC (CH2CI2: MeOH = 10: 1), 3- (3-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-3,8- diazabicyclo[3 2. l]octan-8-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 72, 292 mg, yield: 24%) was obtained as a light yellow solid. MS: m/z = 598.3 [M + H]+. 'H NMR (400 MHz, Dim ethyl sulfoxide-cL) 5 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.98 (m, 4H), 7.50 - 7.36 (m, 7H), 7.13 (dd, J= 7.6, 1.6 Hz, 1H), 7.03 (s, 2H), 6.36 (dd, J= 7.6, 4.0 Hz, 1H), 4.65 - 4.55 (m, 1H), 4.31 (s, 3H), 4.25 - 4.17 (m, 1H), 3.61 (s, 2H), 2.80 - 2.75 (m, 2H), 2.35 - 2.30 (m, 2H), 1.99 - 1.87 (m, 4H).
[00712] Example 73: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)azepan-4-yl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione
Figure imgf000188_0002
[00713] To a solution of Intermediate 37 (60 mg, 114 pmol) and TEA (57.7 mg, 570 pmol) in MeOH (1 mL) was added 3, 4-dimethoxycy cl obut-3-ene- 1,2-dione (19.5 mg, 136.9 pmol). The mixture was stirred at 25 °C for 16 hr. The mixture was concentrated to give a residue. The residue was purified by silica gel flash chromatography (Eluent of 0 ~ 10% MeOH in CH2Q2) to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5-Z>]pyridin-3-yl)benzyl)azepan- 4-yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione (Example 73, 18.5 mg, yield: 26%, 6:4 mixture of tautomers) as a yellow solid. MS: m/z = 600.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- e) 88.86 (d, J= 7.2 Hz, 0.6H), 8.63 (m, J= 7.2 Hz, 0.4H), 8.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.52 - 7.35 (m, 7H), 7.15 (d, J= 7.2 Hz, 1H), 7.04 (br s, 2H), 6.37 (dd, J= 7.6, 4.8 Hz, 1H), 4.28 (s, 3H), 3.86 - 3 73 (m, 1H), 3.70 (s, 2H), 2.71 - 2.58 (m, 4H), I.94 . 1.84 (m, 2H), 1.76 - 1.71 (m, 2H), 1.64 - 1.49 (m, 2H).
[00714] Example 74: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)azepan-3-yl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione
Figure imgf000189_0001
[00715] To a solution of Intermediate 38 (80.0 mg, 164 pmol) and TEA (83.0 mg, 570 pmol) in MeOH (1 m ) was added 3, 4-dimethoxycy cl obut-3-ene- 1,2-dione (23.2 mg, 164 pmol). The mixture was stirred at 25 °C for 16 hr. The mixture was concentrated and purified by silica gel flash chromatography (Eluent of 2 ~ 3% MeOH in CH2CI2), to give 3-((l-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-/>]pyridin-3-yl)benzyl)azepan-3-yl)amino)-4- methoxy cyclobut-3-ene- 1,2-dione (Example 74, 17.2 mg, yield: 16%, 6:4 mixture of tautomers) as a yellow solid. MS: m/z = 600.3 [M + H]+. 1 H NMR (400 MHz, Dimethyl sulfoxide-^) 8 8.75 (d, J= 8.0 Hz, 0.6H), 8.56 (d, J= 8.0 Hz, 0.4H), 8.26 (d, J= 8.4 Hz, 1H), 8.04 - 7.96 (m, 4H), 7.52 (d, J= 8.4 Hz, 2H), 7.48 - 7.42 (m, 4H), 7.41 - 7.37 (m, 1H), 7.11 (dd, J= 7.6, 2.0 Hz, 1H), 7.04 (br s, 2H), 6.35 - 6.29 (m, 1H), 4.25 - 4.19 (m, 3H), 4.18 - 4.14 (m, 0.4H), 3.746 (s, 2H), 3.75 - 3.71 (m, 0.6H), 2.93 - 2.84 (m, 1H), 2.71 - 2.62 (m, 3H), 1.96 - 1.83 (m, 1H), 1.73 - 1.63 (m, 3H), 1.58 - 1.47 (m, 2H).
[00716] Example 75: 3-((lS,4S)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5- b]pyri din-3 -yl)benzyl)-2, 5-diazabicyclo[2.2. l]heptan-2-yl)-4-m ethoxy cyclobut-3-ene-l, 2-dione
Figure imgf000190_0001
[00717] To a solution of Intermediate 39 (150 mg, 317 pmol) and 3,4-dimethoxycyclobut-3- ene-1, 2-dione (45 mg, 317 pmol) in MeOH (1 mL) was added TEA (132 pL, 950 pmol). The mixture was degassed and purged with N2 three times and stirred at 25 °C for 16 hr under N2. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by /'cyi-TLC (CH2C2 : MeOH = 10 : 1) to give 3-((lS,4S)-5-(4-(2-(2-aminopyridin-3- yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4- methoxy cy cl obut-3-ene- 1,2-dione (Example 75, 41 mg, yield: 22%) as a yellow solid. MS: m/z = 584.2 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.19 (d, J= 8.4 Hz, 1H), 8.03 (d, J= 7.2 Hz, 2H), 7.98 (dd, J= 5.2, 1.6 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.57 (d, J= 8.4 Hz, 2H), 7.47 - 7.36 (m, 5H), 7.33 (d, J= 7.6 Hz, 1H), 6.48 (dd, J= 7.2, 4.8 Hz, 1H), 4.41 - 4.34 (m, 3H), 4.13 - 3.94 (m, 1H), 3.94 - 3.77 (m, 3H), 3.76 - 3.70 (m, 1H), 3.69 - 3.55 (m, 1H), 3.03 - 2.93 (m, 1H), 2.83 - 2.75 (m, 1H), 2.18 - 2.07 (m, 1H), 1.93 - 1.83 (m, 1H).
[00718] Example 76: 3-((lR,4R)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-
Z?]pyri din-3 -yl)benzyl)-2, 5-diazabicyclo[2.2. l]heptan-2-yl)-4-m ethoxy cyclobut-3-ene-l, 2-dione
Figure imgf000190_0002
[00719] To a solution of Intermediate 40 (50 mg, 105 pmol) and 3,4-dimethoxycyclobut-3-ene- 1, 2-dione (18.0 mg, 126 pmol) in MeOH (1 m ) was added TEA (53.4 mg, 528 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction was filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Eluent of 2 ~ 3% MeOH in CH2CI2) to give 3-((lR,4R)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-
Z>]pyri din-3 -yl)benzyl)-2, 5-diazabicyclo[2.2. l]heptan-2-yl)-4-m ethoxy cyclobut-3-ene-l, 2-dione (Example 76, 16.1 mg, yield: 26%) as a yellow solid. MS: m/z = 584.3 [M + H]+. 'HNMR (400 MHz, Methanol-^) 8 8.19 (d, J= 8.4 Hz, 1H), 8.03 (d, J= 7.2 Hz, 2H), 7.98 (dd, J= 5.2, 2.0 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.56 (d, J= 8.4 Hz, 2H), 7.45 - 7.41 (m, 4H), 7.39 - 7.37 (m, 1H), 7.33 - 7.31 (m, 1H), 6.48 (dd, J= 7.6, 5.2 Hz, 1H), 4.60 (s, 2H), 4.39 - 4.35 (m, 3H), 3.92 - 3.84 (m, 2H), 3.71 - 3.65 (m, 2H), 2.96 (d, J= 10.0 Hz, 1H), 2.81 - 2.77 (m, 1H), 2.13 - 2.11 (m, 1H), 1.89 - 1.85 (m, 1H).
[00720] Example 77: 3-(4-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)amino)piperidin- 1 -yl)-4-methoxy cyclob ut-3-ene- 1 ,2-dione
Figure imgf000191_0001
[00721] To a solution of Intermediate 41 (80 mg, 156 pmol) and 3,4-dimethoxycyclobut-3-ene- 1, 2-dione (26.6 mg, 187 pmol) in MeOH (2 m ) was added TEA (79.1 mg, 781 pmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. After purified by p/ p-HPLC (column: Waters xbridge 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 30% - 60% B over 14 min), 3-(4-((4-(2-(2- aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)amino)piperidin-l-yl)-4- methoxy cyclobut-3-ene- 1,2-dione (Example 77, 8 mg, yield: 8.5%) was obtained as a lightyellow solid. MS: m/z = 586.2 [M + H]+. XHNMR (400 MHz, Methanol-^) 5 8.19 (d, J= 8.4 Hz, 1H), 8.04 - 7.92 (m, 4H), 7.58 (d, J= 8.4 Hz, 2H), 7.48 - 7.34 (m, 6H), 6.48 (dd, J= 7.6, 5.2 Hz, 1H), 4.58 - 4.54 (m, 1H), 4.38 (s, 3H), 4.09 - 4.00 (m, 1H), 3.94 (s, 2H), 2.97 - 2.83 (m, 1H), 2.15 - 2 04 (m, 2H), 1.69 - 1.46 (m, 4H).
[00722] Example 78: 3-(4-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)oxy)piperidin-l-yl)-4-methoxycy cl obut-3-ene-l, 2-dione
Figure imgf000191_0002
[00723] To a solution of Intermediate 42 (200 mg, 420 pmol) and 3,4-dimethoxycyclobut-3- ene-1, 2-dione (72 mg, 504 pmol) in MeOH (5 mL) was added TEA (85 mg, 839 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. After purified by p/'cyi-TLC (MeOH in CH2Q2 = 10%), 3-(4-((4-(2-(2-aminopyridin- 3-yl)-5-phenyl-3/f-imidazo[4,5-b]pyridin-3-yl)benzyl)oxy)piperidin-l-yl)-4-methoxycyclobut- 3-ene-l, 2-dione (Example 78, 10.1 mg, yield: 4%) was obtained as a light-yellow solid. MS: m/z = 587.1 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/e) 8 8.21 - 8.17 (m, 1H), 8.04 (d, J= 7.6 Hz, 2H), 7.99 (dd, J= 5.2, 1.6 Hz, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.57 (d, J= 8.4 Hz, 2H), 7.48 - 7.40 (m, 4H), 7.39 - 7.33 (m, 2H), 6.49 (dd, J= 7.6, 4.8 Hz, 1H), 4.70 (s, 2H), 4.15 - 4.01 (m, 1H), 3.89 - 3.78 (m, 3H), 3.66 - 3.52 (m, 2H), 2.05 - 2.02 (m, 2H), 1.92 - 1.78 (m, 2H), 1.34 - 1.32 (m, 2H).
[00724] Example 79: (/?)-3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-(hydroxymethyl)piperazin-l-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000192_0001
[00725] To a solution of Intermediate 43 (70 mg, 142 pmol) and 3,4-dimethoxycyclobut-3-ene- 1, 2-dione (22.3 mg, 157 pmol) in MeOH (2 mL) was added TEA (72.0 mg, 712 pmol). The mixture was stirred at 25 °C for 16 hr. The mixture filtered and concentrated under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2CI2 = 0 - 10%), (R)- 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3-yl)benzyl)-2- (hydroxymethyl)piperazin-l-yl)-4-methoxycyclobut-3-ene- 1,2-dione (Example 79, 25 mg, yield: 29%) was obtained as a yellow solid. MS: m/z = 602.2 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-ds) 8 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.98 (m, 4H), 7.50 - 7.36 (m, 7H), 7.16 (dd, J= 7.6, 1.6 Hz, 1H), 7.03 (s, 2H), 6.38 (dd, J= 7.6, 4.0 Hz, 1H), 5.00 - 4.92 (m, 1H), 4 50 - 4.40 (m, 1H), 4.29 (s, 3H), 4.10 (m, 1H), 4.00 - 3.84 (m, 2H), 3.65 - 3.53 (m, 3H), 2.92 - 2.80 (m, 2H), 2.33 - 2.20 (m, 2H).
[00726] Example 80: (S)-3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-
Z>]pyridin-3-yl)benzyl)-2-(hydroxymethyl)piperazin-l-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000192_0002
Intermediate 44 Example 80 [00727] To a solution of Intermediate 44 (50 mg, 102 pmol) in MeOH (1 mL) were added TEA (51.5 mg, 509 pmol) and 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (17.3 mg, 122 pmol). The reaction mixture was stirred at 25 °C for 16 hr. The mixture was filtered. The collected solid was washed with MeOH (2 mL x 2) to give (5)-3-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37T- imidazo[4,5-6]pyri din-3 -yl)benzyl)-2-(hydroxymethyl)piperazin-l-yl)-4-m ethoxy cy cl obut-3- ene-1, 2-dione (Example 80, 19.5 mg, yield: 31%) as a light yellow solid. MS: m/z = 602.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-t/s) 8 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.98 (m, 4H), 7.50 - 7 44 (m, 6H), 7.42 - 7.37 (m, 1H), 7.16 (dd, J= 7.6, 2.0 Hz, 1H), 7.03 (s, 2H), 6.40 (dd, J = 7.6, 4.8 Hz, 1H), 5.02 - 4.86 (m, 1H), 4.48 - 4.41 (m, 0.5H), 4.30 (s, 3H), 4.01 - 3.87 (m, 1.5H), 3.66 - 3.61 (m, 1H), 3.56 - 3.52 (m, 2H), 3.36 - 3.34 (m, 2H), 2.92 - 2.82 (m, 2H), 2.32 - 2.20 (m, 2H).
[00728] Example 81 : (5)-3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)(methyl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione
Figure imgf000193_0001
[00729] To a solution of Intermediate 45 (50 mg, 105 pmol) in MeOH (2 mL) were added 3,4- dimethoxycyclobut-3-ene- 1,2-dione (14.9 mg, 105 pmol) and TEA (23.4 mg, 231 pmol). The reaction mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure. The residue was purified by /v'c/i-TLC (CH2CI2 : MeOH = 10 : 1) to give (S)-3-((l-(4- (2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)pyrrolidin-3- yl)(methyl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione (Example 81, 7.1 mg, yield: 11%) as a light-yellow solid. MS: m/z = 586.3 [M + H]+. LH NMR (400 MHz, Methanol-^) 88.18 (d, J = 8.4 Hz, 1H), 8.05 - 8.00 (m, 2H), 7.97 (dd, J= 4.8, 1.6 Hz, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 8.4 Hz, 2H), 7.45 - 7.35 (m, 5H), 7.31 (dd, J= 7.6, 2.0 Hz, 1H), 6.46 (dd, J= 7.6, 5.2 Hz, 1H), 4.35 (s, 3H), 3.83 - 3.76 (m, 1H), 3.34 (br s, 3H), 3.19 (s, 2H), 3.01 - 2.94 (m, 1H), 2.89 - 2.86 (m, 1H), 2.66 - 2.57 (m, 1H), 2.49 - 2.39 (m, 1H), 2.26 - 2.16 (m, 1H), 2.05 - 1.99 (m, 1H).
[00730] Example 82: 6-(l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- >]pyridin-3- yl)benzyl)pyrrolidin-3-yl)-2-oxa-6-azabi cyclo[5.2.0]non-l(7)-ene-8, 9-dione
Figure imgf000194_0001
[00731] Step 1 : ZcvZ-Butyl 3 -((3 -hydroxypropyl)amino)pyrrolidine-l -carboxylate
[00732] To a solution of ZcvZ-butyl 3-oxopyrrolidine-l-carboxylate (20 g, 108 mmol) and 3- aminopropan-l-ol (16.2 g, 215 mmol) in CH2CI2 (200 mL) was added AcOH (6.48 g, 108 mmol). The resulting mixture was degassed and purged with N2 three times. NaBH(OAc)3 was added (45.7 g, 216 mmol). The mixture was stirred at 25 °C for 12 hr. The pH of the reaction mixture was adjusted to 9 - 10 with saturated aqueous NaOH. The mixture was extracted with CH2CI2 (200 mL x 2). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. Z rz-Butyl 3-((3- hydroxypropyl)amino)pyrrolidine-l-carboxylate (23 g, yield: 87%) was obtained as a black brown oil, which was used in the next step without further purification. 'H NMR (400 MHz, Chloroform-rZ) 8 3.87 - 3.73 (m, 2H), 3.61 - 3.52 (m, 1H), 3.50 - 3.25 (m, 3H), 3.21 - 3.01 (m, 1H), 2.96 - 2.80 (m, 2H), 2.55 - 2.46 (m, 2H), 2.13 - 1.98 (m, 1H), 1.80 - 1.63 (m, 3H), 1.46 (s, 9H).
[00733] Step 2 : Zez7-Butyl 3-(((benzyloxy)carbonyl)(3-hydroxypropyl)amino)pyrrolidine-l- carboxylate
[00734] To a solution of tert-butyl 3-((3-hydroxypropyl)amino)pyrrolidine-l-carboxylate (5.0 g, 20.5 mmol) in CH2CI2 (50 mL) at 0 °C were added TEA (4.14 g, 40.9 mmol) and CbzCl (3.84 g, 22.5 mmol). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO i, filtered and concentrated under reduced pressure. Zc/'Z-Butyl 3-(((benzyloxy)carbonyl)(3-hydroxypropyl)amino)pyrrolidine-l- carboxylate (7.7 g, crude) was obtained as a black brown oil.
[00735] Step 3: Benzyl (3-hydroxypropyl)(pyrrolidin-3-yl)carbamate
[00736] To a solution of zc/'Z-butyl 3-(((benzyloxy)carbonyl)(3- hydroxypropyl)amino)pyrrolidine-l-carboxylate (7.7 g, 16.3 mmol,) in CH2CI2 (20 mL) was added HC1 in 1,4-di oxane (4 M, 4.07 mL). The mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure to give benzyl (3-hydroxypropyl)(pyrrolidin- 3-yl)carbamate (4.5 g, HC1 salt) as black brown oil.
[00737] Step 4: Benzyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- >]pyridin-3- yl)benzyl)pyrrolidin-3-yl)(3-hydroxypropyl)carbamate
[00738] To a solution of Intermediate 14 (500 mg, 1.21 mmol) and benzyl (3- hydroxypropyl)(pyrrolidin-3-yl)carbamate (459 mg, 1.46 mmol, HC1 salt) in DMF (10 mL) were added Nal (18.2 mg, 121 mol) and K2CO3 (839 mg, 6.07 mmol). The mixture was stirred at 25 °C for 3 hr. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, fdtered, and concentrated under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2CI2 = 0% to 8%), benzyl (l-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-327-imidazo[4,5-/>]pyridin-3-yl)benzyl)pyrrolidin-3-yl)(3-hydroxypropyl)carbamate (230 mg, yield: 24%) was obtained as a yellow oil. MS: m/z = 654.5 [M + H]+.
[00739] Step 5: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-3- yl)benzyl)pyrrolidin-3-yl)amino)propan-l-ol
[00740] A mixture of benzyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5- Z>]pyridin-3-yl)benzyl)pyrrolidin-3-yl)(3-hydroxypropyl)carbamate (230 mg, 292 pmol) and Pd(OH)2 (30 mg, 20% purity) in MeOH (2 mL) was degassed and purged with H2 three times. The mixture was stirred at 40 °C for 6 hr under H2 (30 Psi) atmosphere. The mixture was filtered and concentrated under reduced pressure to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3Z/-imidazo[4,5-Z>]pyridin-3-yl)benzyl)pyrrolidin-3-yl)amino)propan-l-ol (108 mg) as a yellow oil. MS: m/z = 520.2 [M + H]+.
[00741] Step 6: 6-(l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5-Z>]pyridin-3- yl)benzyl)pyrrolidin-3-yl)-2-oxa-6-azabi cyclo[5.2.0]non-l(7)-ene-8, 9-dione
[00742] To a solution of 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin- 3-yl)benzyl)pyrrolidin-3-yl)amino)propan-l-ol (100 mg, 129 pmol) and TEA (26.1 mg, 258 pmol) in MeOH (5 mL) was added 3 ,4-dimethoxycyclobut-3-ene- 1,2-dione (23.8 mg, 168 pmol). The mixture was stirred at 25 °C for 12 hr. The mixture was concentrated under reduced pressure. After purified by prep-HPLC (column: [water (NH4HCO3) - ACN]; B%: 35% - 65%, 18 min), 6-(l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3- yl)benzyl)pyrrolidin-3-yl)-2-oxa-6-azabicyclo[5.2.0]non-l(7)-ene-8, 9-dione (Example 82, 16 mg, yield: 10%) was obtained as a light-yellow solid. MS: m/z = 598.2 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.20 (d, J= 8.4 Hz, 1H), 8.06 - 8.01 (m, 2H), 7.98 (dd, J= 52, 1.6 Hz, 1H), 7.94 (d, J= 8.8 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.47 - 7.32 (m, 6H), 6.48 (dd, J= 7.6, 5.2 Hz, 1H), 5.44 - 5.32 (m, 1H), 4.52 - 4.42 (m, 2H), 3.80 - 3.67 (m, 4H), 3.05 - 2.88 (m, 2H), 2.68 - 2.58 (m, 1H), 2.46 - 2.36 (m, 1H), 2.35 - 2.26 (m, 1H), 2.25 - 2.18 (m, 2H), 2.10 - 2.02 (m, 1H).
[00743] Example 83: 3-((4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-/>]pyridin-3- yl)benzyl)piperazin-l-yl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000196_0001
[00744] To a solution of Intermediate 46 (100 mg, 209 pmol) and 3,4-dimethoxycyclobut-3- ene-1, 2-dione (35.8 mg, 252 pmol) in MeOH (2 mL) was added TEA (106 mg, 1.05 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction was filtered and concentrated under reduced pressure. 3 -((4-(4-(2-(2-Aminopyri din-3 -y l)-5 -phenyl-327-imidazo [4, 5 -Z>]pyri din-3 - yl)benzyl)piperazin-l-yl)amino)-4-methoxycyclobut-3-ene-l, 2-dione (Example 83, 52.4 mg, yield: 42%) was obtained as a yellow solid. MS: m/z = 587.4 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-dfi) 89.96 (br s, 1H), 8.27 (d, J= 8.4 Hz, 1H), 8 05 - 7.97 (m, 4H), 7.49 - 7.43 (m, 6H), 7.42 - 7.37 (m, 1H), 7.15 (dd, J= 8.0, 1.6 Hz, 1H), 7.01 (s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 4.31 - 4.25 (m, 3H), 3.59 (s, 2H), 3.27 - 3.20 (m, 3H), 3.17 (m, 1H), 2.90 - 2.83 (m, 4H).
[00745] Example 84: 6-(l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin-3- yl)benzyl)piperidin-4-yl)-2-oxa-6-azabicyclo[5.2.0]non-l(7)-ene-8, 9-dione
Figure imgf000197_0001
[00746] Step 1 : tert-Butyl 4-(((benzyloxy)carbonyl)(3-hydroxypropyl)amino)piperidine-l- carboxylate)
[00747] A mixture of tert-butyl 4-((3-hydroxypropyl)amino)piperidine-l-carboxylate (5 g, 19.3 mmol), TEA (3.92 g, 38.7 mmol) in CH2CI2 (100 m ) was added CbzCl (3.63 g, 21.2 mmol). The mixture was stirred at 25 °C for 16 hr under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) at 10 °C and extracted with CH2CI2 (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure, tert-butyl 4-(((benzyloxy)carbonyl)(3- hydroxypropyl)amino)piperidine-l -carboxylate (6 g, yield: 80%) was obtained as a light-yellow oil. H NMR. (400 MHz, Chloroform - d) 8 7.38 - 7.31 (m, 5H), 5.17 - 5.12 (m, 2H), 4.26 - 4.13 (m, 2H), 4.05 - 3.76 (m, 1H), 3.62 - 3.52 (m, 2H), 3.46 - 3.19 (m, 2H), 2.77 - 2.63 (m, 2H), 1.71 - 1.63 (m, 6H), 1.44 (s, 9H).
[00748] Step 2: Benzyl (3-hydroxypropyl)(piperidin-4-yl)carbamate)
[00749] A mixture of tert-butyl 4-(((benzyloxy)carbonyl)(3-hydroxypropyl)amino)piperidine- 1 -carboxylate (2 g, 5.10 mmol) in HCl/l,4-dioxane (4 M, 13.1 mL) was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give benzyl (3- hydroxypropyl)(piperidin-4-yl)carbamate (1.5 g, HC1 salt) as a light-yellow oil, which was used directly in the next step.
[00750] Step 3: Benzyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-3- yl)benzyl)piperidin-4-yl)(3-hydroxypropyl)carbamate)
[00751] A mixture of Intermediate 14 (1 g, 2.43 mmol) and benzyl (3- hydroxypropyl)(piperidin-4-yl)carbamate (1.09 g, 2.67 mmol) in DMF (10 mL) were added K2CO3 (1.68 g, 12.1 mmol) and Nal (181 mg, 1.21 mmol). The mixture was stirred at 80 °C for 5 hr under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with CH2CI2 (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na?SO4, filtered, and concentrated under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2Ch= 0% to 15%), benzyl (l-(4-(2-(2-aminopyridin-3-yl)- 5-phenyl-3/f-imidazo[4,5-/>]pyridin-3-yl)benzyl)piperidin-4-yl)(3-hydroxypropyl)carbamate (250 mg, yield: 13%) was obtained as a yellow solid. MS: m/z = 668.2 [M + H]+. XH NMR (400 MHz, Chloroform-t?) 8 8.13 (d, J= 8.4 Hz, 1H), 8.06 (dd, J= 4.8, 1.2 Hz, 1H), 8.02 (d, J= 7.2 Hz, 2H), 7.80 (d, J= 8.4 Hz, 1H), 747 - 7.33 (m, 10H), 7.09 (dd, J= 8.0, 1.6 Hz, 1H), 6.59 (br s, 2H), 6.40 - 6.31 (m, 1H), 5.18 (s, 2H), 4.02 - 3.77 (m, 1H), 3.60 (s, 2H), 3.52 - 3.30 (m, 2H), 3.09 - 2.95 (m, 2H), 2.23 - 2.06 (m, 2H), 1.94 - 1.84 (m, 2H), 1.80 - 1.65 (m, 6H).
[00752] Step 4: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3- yl)benzyl)piperidin-4-yl)amino)propan-l-ol)
[00753] A mixture of benzyl (l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5- Z>]pyridin-3-yl)benzyl)piperidin-4-yl)(3-hydroxypropyl)carbamate (250 mg, 374 pmol), Pd(OH)2/C (50 mg, 20% purity) in MeOH (5 mL) was degassed and purged with H2 three times. The mixture was stirred at 40 °C for 6 hr under H2 atmosphere (30 Psi). The reaction mixture was filtered and washed with CH2CI2 (100 mL), concentrated under reduced pressure. After purified by /v'cp-TLC (MeOH in CH2Q2 = 10%), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl- 3//-imidazo[4,5-6]pyridin-3-yl)benzyl)piperidin-4-yl)amino)propan-l-ol (75 mg, yield: 36%) was obtained as a light-yellow solid. MS: m/z = 534.3 [M + H]+. 'H NMR (400 MHz, Methanal-^) 8 8.19 (d, J= 8.4 Hz, 1H), 8.05 - 8.01 (m, 2H), 7.97 (dd, J= 5.2, 2.0 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.46 - 7.37 (m, 5H), 7.31 (dd, J= 7.6, 2.0 Hz, 1H), 6.46 (dd, J= 7.6, 5.2 Hz, 1H), 3.70 - 3.65 (m, 2H), 3.64 (s, 2H), 3.04 - 2.96 (m, 4H), 2.93 - 2.85 (m, 1H), 2.20 - 2.10 (m, 2H), 2.30 - 1.80 (m, 2H), 1.85 - 1.79 (m, 2H), 1.64 - 1.55 (m, 2H).
[00754] Step 5: 6-(l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3- yl)benzyl)piperidin-4-yl)-2-oxa-6-azabicyclo[5.2.0]non-l(7)-ene-8, 9-dione)
[00755] A mixture of 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-3- yl)benzyl)piperidin-4-yl)amino)propan-l-ol (60 mg, 112 pmol), TEA (34.1 mg, 337 pmol) and 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (17.5 mg, 123 pmol) in MeOH (1 mL) was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. The residue was washed with MeOH (10 mL) and filtered. The filtrate was concentrated and purified by p/'cyi-TLC (MeOH in CH2Q2 = 10%) to give 6-(l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377- imidazo[4,5-6]pyridin-3-yl)benzyl)piperidin-4-yl)-2-oxa-6-azabicyclo[5.2.0]non-l(7)-ene-8,9- dione (Example 84, 9.2 mg, yield: 12%) as a white solid. MS: m/z = 612.3 [M + H]+. 'H NMR (400 MHz, Acetonitrile - d3) 8 8.17 (d, J= 8.4 Hz, 1H), 8.02 (d, J= 6.4 Hz, 2H), 7.90 (d, J= 8.8 Hz, 1H), 7.52 - 7.39 (m, 8H), 7.15 (d, J= 7.6 Hz, 1H), 6.58 (br s, 2H), 6.38 (dd, J= 7.6, 5.2 Hz, 1H), 4.45 - 4.40 (m, 3H), 3.62 (s, 2H), 3.52 - 3.48 (m, 2H), 3.05 - 2.95 (m, 2H), 1.80 - 1.70 (m, 2H), 1.30 - 1.20 (m, 4H), 0.90 - 0.83 (m, 2H).
[00756] Example 85: 6-(l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)-2-thia-6-azabicyclo[5.2.0]non-l(7)-ene-8, 9-dione
Figure imgf000199_0001
[00757] Step 1 : S-(3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)propyl)ethanethioate
[00758] To a solution of Intermediate 11 (500 mg, 1.05 mmol) and S-(3- bromopropyl)ethanethioate (186 mg, 946 pmol) in CH3CN (10 mL) were added K2CO3 (581 mg, 4.21 mmol) and Nal (31.5 mg, 210 pmol). The mixture was stirred at 80 °C for 5 hr. The reaction mixture was filtered and concentrated under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2Q2 = 5% to 7%), -(3-((l-(4-(2-(2-aminopyri din-3 -yl)- 5-phenyl-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)propyl)ethanethioate (120 mg, yield: 16%) was obtained as a yellow solid. MS: m/z = 592.3 [M + H]+.
[00759] Step 2: 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)propane-l-thiol
[00760] To a solution of S-(3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)propyl)ethanethioate (120 mg, 202 pmol) in MeOH (5 mL) was added HC1 (12 M, 50.7 pL). The mixture was stirred at 60 °C for 16 hr. The reaction mixture was quenched with saturated Na2CO3 (5 mL), diluted with H2O (5 mL), and extracted with CH2CI2 (20 mL x 3). The combined organic layers were washed with brine (20 mb), dried over N 2SC>4, filtered and concentrated under reduced pressure to give 3-((l-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperi din-4- yl)amino)propane-l -thiol (100 mg crude) as a yellow solid, which was used directly in the next step. MS: m/z = 550.3 [M + H]+.
[00761] Step 3: 6-(l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)-2-thia-6-azabicyclo[5.2.0]non-l(7)-ene-8, 9-dione
[00762] To a solution of 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)amino)propane-l-thiol (100 mg, 181 pmol) and 3,4- dimethoxycyclobut-3-ene- 1,2-dione (25.8 mg, 181 pmol) in MeOH (1 mL) was added TEA (55.2 mg, 545 pmol). The mixture was stirred at 20 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2CI2 = 0% to 7%), and then purified by prep-HPLC (column: Waters xbridge 150 x 25 mm 10 um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 39% - 69% B over 10 min), 6-(l-(4- (2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)-2-thia- 6-azabicyclo[5.2 0]non-l(7)-ene-8, 9-dione (Example 85, 4.2 mg, yield: 3.3%) was obtained as a light-yellow solid. MS: m/z = 628.5 [M + H]+. LH NMR (400 MHz, Methanol -c/ ) 8 8.20 (d, J = 8.4 Hz, 1H), 8.05 - 8.02 (m, 2H), 7.99 (dd, J = 5.2, 2.0 Hz, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 8.4 Hz, 2H), 7.48 - 7.39 (m, 5H), 7.32 (dd, J= 7.6, 1.6 Hz, 1H), 6.50 (dd, J= 7.6, 5.2 Hz, 1H), 3.68 (s, 2H), 3.63 - 3.60 (m, 2H), 3.50 - 3.47 (m, 1H), 3.15 - 3.12 (m, 2H), 3.10 - 3.05 (m, 2H), 2.36 - 2.31 (m, 2H), 2.25 - 2.20 (m, 2H), 1.89 - 1.82 (m, 4H).
[00763] Example 86: 3-((3aA,6aS)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(l//)-yl)-4-methoxycyclobut-3-ene-l,2- dione
Figure imgf000200_0001
[00764] To a mixture of Intermediate 48 (200 mg, 382 pmol, HC1) and TEA (116 mg, 1.14 mmol) in MeOH (1.5 mL) was added 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (60.0 mg, 420 pmol) at 0 °C, the mixture was stirred at 25 °C for 16 hr under N2. The reaction mixture was concentrated and purified by silica gel flash chromatography (MeOH in DCM = 0% to 6%) to give 3-((3aR,6aS)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-Z>]pyridin-3- yl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(17/)-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 86, 160 mg, yield 70%) as a yellow solid. MS: m/z = 620.1 [M + Na]+. 'H NMR (400 MHz, Dimethylsulfoxide-c/e) 3 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.49 - 7.36 (m, 7H), 7.16 (dd, J= 8.0, 2.0 Hz, 1H), 7.02 (s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 4.26 (s, 3H), 3.92 - 3.80 (m, 1H), 3.76 - 3.59 (m, 4H), 3.44 - 3.38 (m, 3H), 2.91 - 2.82 (m, 2H), 2.48 - 2.42 (m, 2H).
[00765] Example 87: 3-((3aR,6aS)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(l//)-yl)-4-(methylthio)cyclobut-3-ene- 1,2-dione
Figure imgf000201_0001
[00766] To a solution of Example 86 (60 mg, 100 pmol) in EtOH (2 mL) was added NaSH (33.8 mg, 602 pmol) at 20 °C. The reaction mixture was stirred at 20 °C for 12 hr. Then CH3I (21.4 mg, 151 pmol) was added at 20 °C. The reaction mixture was stirred at 20 °C for 2 hr and concentrated under reduced pressure at 30 °C. The residue was purified by p/cyi-HPLC (column: Welch Xtimate C18 150 x 30 mm x 5 pm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 60% - 90% B over 7 min) to give 3-((3aR,6aS)-5-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-Z>]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4- c]pyrrol-2(l/7)-yl)-4-(methylthio)cyclobut-3-ene-l, 2-dione (Example 87, 6.7 mg, yield: 11%) as a gray solid. MS: m/z = 614.2 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide-ifc) 8.27 (d, J = 8.8 Hz, 1H), 8.06 - 7.96 (m, 4H), 7.49 - 7.37 (m, 7H), 7.18 - 7.13 (m, 1H), 7.02 (s, 2H), 6.39 (dd, J= 8.0, 4.8 Hz, 1H), 3.96 - 3.83 (m, 2H), 3.78 - 3.72 (m, 1H), 3.70 - 3.57 (m, 2H), 3.54 - 3.48 (m, 1H), 3.40 - 3.35 (m, 2H), 3.33 - 3.30 (m, 2H), 2.92 - 2.85 (m, 2H), 2.80 (s, 3H).
[00767] Example 88: 3-((3aR,6aS)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-
Z>]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(l/7)-yl)-4-(ethylthio)cyclobut-3-ene-l,2- dione
Figure imgf000202_0001
[00768] To a solution of Example 86 (150 mg, 251 pmol) in CH2CI2 (5 mL) were added TEA (127 mg, 1.25 mmol) and EtSH (1.97 g, 31.7 mmol). The mixture was stirred at 20 °C for 12 hr. The reaction mixture was quenched with H2O (lOmL) at 0 °C and extracted with CH2CI2 (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. After purified by p/up-HPLC (column: Phenomenex Cl 8 80 x 40 mm x 3 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 60% - 90% B over 8 min), 3-((3rzA,6aS)-5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//- imidazo[4,5-Z>]pyri din-3 -yl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(l//)-yl)-4- (ethylthio)cyclobut-3-ene- 1,2-dione (Example 88, 20.7 mg, yield: 13%) was obtained as a yellow solid. MS: m/z = 628.3 [M + H]+. JH NMR (400 MHz, Dimethylsulfoxide-t/e) 8.27 (d, J = 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.49 - 7.37 (m, 7H), 7.15 (dd, J= 7.6, 2.0 Hz, 1H), 7.03 (s, 2H), 6.39 (dd, J= 7.6, 4.8 Hz, 1H), 3.97 - 3.82 (m, 2H), 3.78 - 3.72 (m, 1H), 3.70 - 3.57 (m, 2H), 3.54 - 3.48 (m, 1H), 3.42 - 3.35 (m, 2H), 3.33 - 3.28 (m, 1H), 2.89 (br s, 2H), 2.57 - 2.52 (m, 3H), 1.32 (t, J= 7.6 Hz, 3H).
[00769] Example 89: (S)-7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)-5,5a,6,7,8,9-hexahydro-4//-cyclobuta[b]pyrazino[l,2-d][l,4]oxazepine-l,2-dione
Figure imgf000202_0002
[00770] Step 1 : fert-Butyl (l-(4-((6-morpholino-3-nitropyri din-2 -yl)amino)benzyl)piperidin-4- yl)carbamate
[00771] To a solution of Intermediate 14 (200 mg, 485 pmol) in DMF (3 mL) were added tert- butyl (S)-2-(2-hydroxyethyl)piperazine-l -carboxylate (123 mg, 534 pmol), Nal (14.5 mg, 97.1 pmol) and K2CO3 (268 mg, 1.94 mmol). The mixture was stirred at 80 °C for 1.5 hr. The reaction mixture was diluted with H2O (20 mL) and fdtered. The filter cake was concentrated under reduced pressure. After purified by silica gel flash chromatography (MeOH in CH2Q2 = 0% to 3%), zc/ -butyl (S)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-(2-hydroxyethyl)piperazine-l -carboxylate (130 mg, yield: 34%) was obtained as a yellow solid. MS: m/z = 606.4 [M + H]+. JH NMR (400 MHz, Chloroform-t/) 8 8.13 (d, J= 8.4 Hz, 1H), 8.06 (dd, J= 4.8, 1.2 Hz, 1H), 8.01 (d, J = 7.2 Hz, 2H), 7.81 (d, J= 8.4 Hz, 1H), 7.50 - 7.37 (m, 7H), 7.12 (dd, J= 7.6, 1.2 Hz, 1H), 6.73 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 3.93 - 3.84 (m, 1H), 3.68 - 3.56 (m, 3H), 3.47 - 3.33 (m, 1H), 3.12 - 3.04 (m, 1H), 2.87 - 2.79 (m, 1H), 2.80 - 2.70 (m, 1H), 2.37 - 2.22 (m, 2H), 2.16 - 2.10 (m, 1H), 1.93 - 1.79 (m, 2H), 1.48 (s, 9H).
[00772] Step 2: (S)-2-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-2-yl)ethan- 1 -ol
[00773] To a solution of terLbutyl (S)-4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-(2 -hydroxy ethyl)piperazine-l -carboxylate (130 mg, 214 ol,) in CH2CI2 (2 mL) was added HCl/l,4-dioxane (4 M, 0.5 mL). The mixture was stirred at 20 °C for 0.2 hr. The reaction mixture was concentrated under reduced pressure to give (S)-2-(4-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazin-2-yl)ethan-l-ol (120 mg, HC1 salt) as a yellow solid, which was used directly in the next step. MS: m/z = 506.3 [M + H]+.
[00774] Step 3: (S)-7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)-5,5a,6,7,8,9-hexahydro-4/7-cyclobuta[b]pyrazino[l,2-d][l,4]oxazepine-l,2-dione
[00775] To a solution of (S)-2-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazin-2-yl)ethan-l-ol (100 mg, 161 pmol) in MeOH (3 mL) were added 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (22.9 mg, 161 pmol) and TEA (81.6 mg, 806 pmol). The mixture was stirred at 60 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. After purified by prep-HP C (column: Waters xbridge 150 x25 mm 10 um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 35% - 65% B over 10 min), (S)-7-(4-(2-(2- aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3-yl)benzyl)-5,5a,6,7,8,9-hexahydro- 47/-cyclobuta[b]pyrazino[l,2-d][l,4]oxazepine-l, 2-dione (Example 89, 15.8 mg, yield: 16%) was obtained as a light-yellow powder. MS: m/z = 584.3 [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide- e) 8 8.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.52 - 7.45 (m, 6H), 7.42 - 7.38 (m, 1H), 7.16 (dd, = 7.6, 1.6 Hz, 1H), 7.01 (br s, 2H), 6.40 (dd, J= 7.6, 4.4 Hz, 1H), 4.64 - 4 56 (m, 1H), 4.50 - 4.42 (m, 1H), 4.38 - 4.31 (m, 1H), 3.69 - 3.61 (m, 2H), 3.58 - 3.50 (m, 1H), 3.28 - 3.23 (m, 1H), 2.93 - 2.82 (m, 2H), 2.26 - 2.19 (m, 1H), 2.14 - 1.97 (m, 3H).
[00776] Example 90: 3-((l-(l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- b]pyridin-3-yl)phenyl)ethyl)piperi din-4-yl)(methyl)amino)-4-methoxycy cl obut-3-ene-l, 2-dione
Figure imgf000204_0001
[00777] To a solution of Intermediate 49 (80 mg, 159 pmol) and 3,4-dimethoxycyclobut-3-ene- 1, 2-dione (27.1 mg, 191 pmol) in MeOH (2 mL) was added TEA (80.4 mg, 794 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was filtrated. The solid was collected, washed with MeOH (10 mL x 2), and dried under reduced pressure. 3-((l-(l-(4-(2-(2- Aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5-b]pyridin-3-yl)phenyl)ethyl)piperi din-4- yl)(methyl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione (Example 90, 33.3 mg, yield: 34%) was obtained as a yellow solid. MS: m/z = 614.3. [M + H]+. ’H NMR (400 MHz, Dimethylsulfoxide-tfc) 8 8.27 (d, J= 8.4 Hz, 1H), 8.05 - 7.96 (m, 4H), 7.52 - 7.39 (m, 7H), 7.15 - 7.01 (m, 3H), 6.44 - 6.27 (m, 1H), 4.33 - 4.24 (m, 3H), 4.19 - 4.11 (m, 0.5H), 3.76 - 3.65 (m, 1H), 3.59 - 3.51 (m, 0.5H), 3.19 (s, 1H), 3.02 (s, 3H), 2.93 - 2.85 (m, 1H), 2.00 - 1.64 (m, 6H), 1.42 - 1.32 (m, 3H).
[00778] Example 91 : 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-methoxycyclobut-3-ene- 1,2-dione
Figure imgf000204_0002
[00779] To a solution of Intermediate 50 (50 mg, 99.3 pmol) and 3,4-dimethoxycyclobut-3-ene- 1, 2-dione (16.9 mg, 119 pmol) in MeOH (2 mL) was added TEA (50.2 mg, 496 pmol). The resulting mixture was stirred at 25 °C for 16 hr. The reaction mixture was filtrated. The solid was collected, washed with MeOH (10 mL x 2), dried under reduced pressure. After triturated with MeOH (20 mL), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione (Example 91, 16.5 mg, yield: 26%) was obtained as a yellow solid. MS: m/z = 614.4. [M + H]+. 'H NMR (400 MHz, Dimethylsulfoxide-c/e) 8 8.27 (d, J= 8.4 Hz, 1H), 8 06 - 7.97 (m, 4H), 7.49 - 7.43 (m, 6H), 7.42 - 7.38 (m, 1H), 7.17 - 7.12 (m, 1H), 7.02 (br s, 2H), 6.42 - 6.35 (m, 1H), 4.33 - 4.29 (m, 3H), 4.20 - 4.14 (m, 0.5H), 3.65 - 3.63 (m, 0.5H), 3.61 - 3.58 (m, 2H), 3.45 - 3.34 (m, 2H), 2.97 - 2.91 (m, 2H), 2.09 - 2.00 (m, 2H), 1.93 - 1.82 (m, 2H), 1.77 - 1.69 (m, 2H), 1.16 (t, = 6.8 Hz, 3H).
[00780] Example 92: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-(methylthio)cy cl obut-3-ene-l, 2-dione
Figure imgf000205_0001
[00781] Step 1 : 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-mercaptocyclobut-3-ene-l, 2-dione
[00782] To a solution of Example 91 (100 mg, 163 pmol) in EtOH (5 mL) was added NaHS (45.7 mg, 815 pmol). The mixture was stirred at 25 °C for 24 hr. The reaction was concentrated under reduced pressure to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyri din-3 -yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-mercaptocy cl obut-3-ene- 1,2-dione (100 mg, crude) as a yellow solid. MS: m/z = 616.3. [M + H]+.
[00783] Step 2: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-(methylthio)cy cl obut-3-ene-l, 2-dione
[00784] To a solution of 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-mercaptocyclobut-3-ene-l, 2-dione (100 mg, 163 pmol) in EtOH (5 mL) was added CH3I (69.4 mg, 489 pmol). The mixture was stirred at 25 °C for 16 hr. The reaction was concentrated under reduced pressure. After purified by /v'cyi-HPLC (column: Waters xbridge 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 49% - 79%, over 4 min), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-(methylthio)cy cl obut-3-ene- 1,2-dione (Example 92, 6.5 mg, yield: 6.2%) was obtained as a yellow solid. MS: m/z = 630.4. [M + H]+. 'H NMR (400 MHz, Dim ethyl sulfoxidc-cL) 8 8.28 (d, J= 8.4 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.51
- 7 44 (m, 6H), 7.43 - 7.39 (m, 1H), 7.18 - 7.12 (m, 1H), 7.03 (br s, 2H), 6.43 - 6.34 (m, 1H), 4.40 - 4.30 (m, 0.5H), 3.67 - 3.65 (m, 0.5H), 3.60 (s, 2H), 3.51 - 3.35 (m, 2H), 2.99 - 2.93 (m, 2H), 2.89 - 2.85 (m, 3H), 2.08 - 2.02 (m, 2H), 1.91 - 1.74 (m, 4H), 1.25 - 1.19 (m, 3H).
[00785] Example 93: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-(ethylthio)cy cl obut-3-ene-l, 2-dione
Figure imgf000206_0001
[00786] To a solution of Example 92 (100 mg, 163 pmol) in CH2O2 (2 mL) were added TEA (82.4 mg, 815 pmol) and ethanethiol (1.19 g, 19.2 mmol). The mixture was stirred at 25 °C for 24 hr. The reaction mixture was quenched with H2O (5 mL) at 0 °C, diluted with H2O (10 mL) and extracted with CH2CI2 (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure. After purified by /VC/J-HPLC (column: Waters xbridge 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 44% - 74%, over 14 min), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3Z7-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)(ethyl)amino)-4-
(ethylthio)cy cl obut-3-ene- 1,2-dione (Example 93, 5.6 mg, yield: 5.2%) was obtained as a yellow solid. MS: m/z = 644.5. [M + H]+. H NMR (400 MHz, Dimethylsulfoxide-cL) 8 8.27 (d, J= 8.0 Hz, 1H), 8.05 - 7.97 (m, 4H), 7.50 - 7.43 (m, 6H), 7.42 - 7.38 (m, 1H), 7.17 - 7.12 (m, 1H), 7.02 (br s, 2H), 6.44 - 6.31 (m, 1H), 4.35 - 4.29 (m, 0.5H), 3.68 - 3.66 (m, 0.5H), 3.60 (s, 2H), 3.45 - 3.41 (m, 2H), 2.97 - 2.91 (m, 2H), 2.52 - 2.51 (m, 2H), 2.07 - 2.01 (m, 2H), 1.90 - 1.72 (m, 4H), 1.36 - 1.30 (m, 3H), 1.24 - 1.18 (m, 3H).
[00787] Example 94: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-/>]pyridin-3- yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)-4-m ethoxy cyclobut-3-ene- 1,2-dione
Figure imgf000207_0001
[00788] To a solution of Intermediate 51 (180 mg, 349 pmol) and 3,4-dimethoxycyclobut-3- ene-1, 2-dione (59.5 mg, 419 pmol) in MeOH (1 mL) was added TEA (106 mg, 1.05 mmol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was filtrated. The solid was collected, washed with MeOH (10 mL x 2), dried under reduced pressure. After triturated with MeOH (20 mL), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3/f-imidazo[4,5- >]pyridin-3- yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)-4-m ethoxy cyclobut-3-ene- 1,2-dione (Example 94, 224 mg, yield: 92%) was obtained as a brown solid. MS: m/z = 626.3 [M + H]+. 'HNMR (400 MHz, Dimethylsulfoxide-c/e) 5 8.27 (d, J= 8.4 Hz, 1H), 8 04 - 7.97 (m, 4H), 7.50 - 7.44 (m, 6H), 7.42 - 7.37 (m, 1H), 7.15 (dd, J= 7.6, 1.6 Hz, 1H), 7.03 (br s, 2H), 6.38 (dd, J= 7.6, 4.8 Hz, 1H), 4.30 (s, 3H), 3.59 (s, 2H), 3.29 - 3.28 (m, 1H), 2.96 - 2.90 (m, 2H), 2.87 - 2.81 (m, 1H), 2.05 - 1.98 (m, 4H), 1.84 - 1.74 (m, 2H), 0.82 - 0.76 (m, 4H).
[00789] Example 95: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-/>]pyridin-3- yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)-4-(methylthio)cy cl obut-3-ene-l, 2-dione
Figure imgf000207_0002
[00790] Step 1: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3 /-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(cy cl opropyl)amino)-4-mercaptocy cl obut-3-ene- 1,2-dione
[00791] To a solution of Example 94 (100 mg, 160 pmol) in EtOH (5 mL) was added NaHS (44.8 mg, 799 pmol). The mixture was stirred at 25 °C for 14 hr. The reaction was concentrated under reduced pressure to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- Z>]pyridin-3-yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)-4-mercaptocy cl obut-3-ene-l, 2-dione (100 mg, yield: 95%) as a yellow solid. MS: m/z = 628.2 [M + H]+.
[00792] Step 2: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin-3- yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)-4-(methylthio)cy cl obut-3-ene-l, 2-dione [00793] To a solution of 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin- 3 -yl)benzyl)piperidin-4-yl)(cy cl opropyl)amino)-4-mercaptocy cl obut-3-ene- 1,2-dione (100 mg, 160 pmol) in EtOH (5 mL) was added CH3I (68.1 mg, 479 pmol). The mixture was stirred at 0 °C for 4 hr. The reaction was concentrated under reduced pressure. After purified by prep- HPLC (column: Waters xbridge 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 50% - 80%, 10 min), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//- imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)-4-(methylthio)cyclobut- 3-ene-l, 2-dione (Example 95, 29.5 mg, yield: 28%) was obtained as a yellow solid. MS: m/z = 642.4 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.19 (d, J= 8.4 Hz, 1H), 8.06 - 8.02 (m, 2H), 7.98 (dd, J= 5.2, 2.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.56 - 7.52 (m, 2H), 7.47 - 7.35 (m, 5H), 7.32 (dd, J= 7.6, 1.6 Hz, 1H), 6.49 (dd, J= 7.6, 5.2 Hz, 1H), 3.66 (s, 2H), 3.35 - 3.33 (m, 1H), 3.10 - 3.03 (m, 2H), 3.01 - 2.91 (m, 1H), 2.88 (s, 3H), 2.23 - 2.15 (m, 4H), 1.95 - 1.84 (m, 2H), 1.00 - 0.93 (m, 4H).
[00794] Example 96: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5-/>]pyridin-3- yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)-4-(ethylthio)cy cl obut-3-ene-l, 2-dione
Figure imgf000208_0001
[00795] To a solution of Example 94 (100 mg, 160 pmol) in CH2O2 (5 mL) were added TEA (80.9 mg, 799 pmol) and ethanethiol (1.65 g, 26.6 mmol). The mixture was stirred at 25 °C for 24 hr. The reaction mixture was quenched with H2O (5 mL) at 25 °C, diluted with CH2CI2 (10 mL) and extracted with CH2Q2 (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. After purified by rep-HPLC (column: Waters xbridge 150 x 25 mm x 10 pm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 55% - 85%, 10 min), 3-((l-(4-(2-(2-aminopyridin-3-yl)-5- phenyl-3Z/-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperidin-4-yl)(cyclopropyl)amino)-4- (ethylthio)cy cl obut-3-ene- 1,2-dione (Example 96, 15.7 mg, yield: 14%) was obtained as a yellow solid. MS: m/z = 656.3 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.19 (dd, J= 8.4, 0.8 Hz, 1H), 8.06 - 8.01 (m, 2H), 7.98 (dd, J= 4.8, 2.8 Hz, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.54 (d, J=1.6 Hz, 2H), 7.47 - 7.30 (m, 6H), 6.49 (dd, J= 8.0, 5.2 Hz, 1H), 3.66 (s, 2H), 3.47 (q, J = 7.2 Hz, 2H), 3.36 - 3.33 (m, 1H), 3.10 - 2.93 (m, 3H), 2.23 - 2.15 (m, 4H), 1.95 - 1.83 (m, 2H), 1.41 (t, J= 7.6 Hz, 3H), 1.02 - 0.94 (m, 4H).
[00796] Example 97: 3-((4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-37/-imidazo[4,5-Z>]pyridin-3- yl)benzyl)piperazin-l-yl)(methyl)amino)-4-(ethylthio)cyclobut-3-ene-l, 2-dione
Figure imgf000209_0001
[00797] Step 1 : 3-((4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin-3- yl)benzyl)piperazin-l-yl)(methyl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
[00798] To a mixture of Intermediate 52 (150 mg, 95.0 pmol, HC1 salt) and TEA (84 mg, 860 pmol) in MeOH (3 mL) was added 3, 4-dimethoxycyclobut-3-ene- 1,2-dione (44 mg, 312 pmol) at 0 °C. The mixture was stirred at 20 °C for 12 hr under N2. The reaction mixture was concentrated. After purified by silica gel flash chromatography (MeOH in CH2CI2 = 0% to 6%), 3-((4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3J7-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperazin-l- yl)(methyl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione (120 mg, yield: 70%) was obtained as a yellow solid. MS: m/z = 601.3 [M + H]+.
[00799] Step 2: 3-((4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-6]pyridin-3- yl)benzyl)piperazin-l-yl)(methyl)amino)-4-(ethylthio)cyclobut-3-ene-l, 2-dione
[00800] To a solution of 3-((4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin- 3 -yl)benzyl)piperazin- l-yl)(methyl)amino)-4-m ethoxy cy cl obut-3-ene- 1,2-dione (120 mg, 200 pmol) in CH2Q2 (5 mL) were added TEA (101 mg, 999 pmol) and ethanethiol (1.49 g, 24.0 mmol). The mixture was stirred at 20 °C for 12 hr. The reaction mixture was quenched with H2O (10 mL) at 0 °C and extracted with CH2CI2 (15 mL x 2) The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. After purified by prep-HPLC (column: Boston Prime C18 150 x 30 mm x 5 pm; mobile phase: [water (NH3H2O + NH4HCO3) - ACN]; gradient: 60% - 90% B over 7 min), 3-((4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-Z>]pyridin-3-yl)benzyl)piperazin-l- yl)(methyl)amino)-4-(ethylthio)cyclobut-3-ene-l, 2-dione (Example 97, 31.7 mg, yield: 25 %) was obtained as an off white solid. MS : m/z = 631.1 [M + H]+. 1 H NMR (400 MHz, Dimethylsulfoxide-rfc) 8 8.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.99 (m, 4H), 7.51 - 7.39 (m, 7H), 7.15 (d, J= 6.0 Hz, 1H), 7.03 (s, 2H), 6.38 (dd, J= 8.0, 5.2 Hz, 1H), 3.61 (s, 2H), 3.69 - 3.25 (m, 5H), 3.01 - 2.96 (m, 2H), 2.84 - 2.81 (m, 4H), 2.37 - 2.32 (m, 2H), 1.35 (t, J= 12 Hz, 3H).
[00801] Example 98: 3-((2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-azaspiro[3.5]nonan-7-yl)amino)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000210_0001
[00802] To a solution of Intermediate 53 (100 mg, 181 pmol) and 3,4-dimethoxycyclobut-3- ene-1, 2-dione (39 mg, 272 pmol) in MeOH (3 mL) was added TEA (37 mg, 362 pmol). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (CH2Q2 : MeOH = 10 : 1) to give 3-((2-(4-(2- (2-aminopyridin-3-yl)-5-phenyl-3/7-imidazo[4,5-b]pyridin-3-yl)benzyl)-2-azaspiro[3.5]nonan-7- yl)amino)-4-methoxycy cl obut-3-ene- 1,2-dione (Example 98, 10.9 mg, yield: 9.6%, 1:1 mixture of tautomers) as a light-yellow solid. MS: m/z = 626.4 [M + H]+. 'H NMR (400 MHz, Methanol -d4) 8 8.18 (d, J = 8.4 Hz, 1H), 8.04 - 8.01 (m, 2H), 7.98 (dd, J= 4.8, 1.6 Hz, 1H), 7.93 (d, <7= 8.4 Hz, 1H), 7.50 - 7.39 (m, 7H), 7.31 (dd, .7= 7.6, 1.6 Hz, 1H), 6.46 (dd, J = 7.6, 5.2 Hz, 1H), 4.38- 4.34 (m, 3H), 3.88 - 3.82 (m, 0.5H), 3.77 (s, 2H), 3.53 - 3.47 (m, 0.5H), 3.19 (s, 2H), 3.12 (s, 2H), 2.04 - 1.98 (m, 2H), 1.90 - 1.84 (m, 2H), 1.59 - 1.50 (m, 2H), 1.45 - 1.38 (m, 2H).
[00803] Example 99: 3-(9-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5-b]pyridin-3- yl)benzyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000210_0002
[00804] To a solution of 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (30.1 mg, 212 pmol) in MeOH (2 mL) were added TEA (35.8 mg, 353 pmol) and Intermediate 54 (100 mg, 177 pmol). The mixture was stirred at 25 °C for 1 hr. The mixture was added H2O (5 mL) and extracted with EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with MeOH (5 mL) at 25 °C for 30 min. 3-(9-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-377-imidazo[4,5- b]pyridin-3-yl)benzyl)-3,9-diazaspiro[5.5]undecan-3-yl)-4-methoxycyclobut-3-ene-l, 2-dione (Example 99, 44.0 mg, yield: 39%) was obtained as a yellow solid. MS: m/z = 640.4 [M + H]+. 'H NMR (400 MHz, Methanol-^) 8 8.20 (d, J= 8.4 Hz, 1H), 8.03 (d, J= 7.2 Hz, 2H), 7.99 (dd, J = 4.8, 1.6 Hz, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.56 (d, J= 8.0 Hz, 2H), 7.50 - 7.33 (m, 6H), 6.47 (dd, J= 7.2, 4.8 Hz, 1H), 4.37 (s, 3H), 3.93 - 3 85 (m, 2H), 3.74 (s, 2H), 3.66 - 3.59 (m, 2H), 2.83 - 2.41 (m, 4H), 1.66 - 1.53 (m, 8H).
[00805] Example 100: 3-((l-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3//-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)(methyl-6/3)amino)-4-methoxycyclobut-3-ene-l, 2-dione
Figure imgf000211_0001
[00806] To a solution of Intermediate 55 (100 mg, 165 pmol) in MeOH (2 mL) were added TEA (50 mg, 494 pmol) and 3, 4-dimethoxycyclobut-3-ene-l, 2-dione (23 mg, 165 pmol). The mixture was stirred at 25 °C for 16 hr. The mixture was filtered and the filter cake was dried under reduced pressure to give 3-((l-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3Z/-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)(methyl-< 3)amino)-4-methoxycy cl obut-3-ene-l, 2-dione (Example 100, 45.7 mg, yield: 44%) as a light-yellow solid. MS: m/z = 603.4 [M + H]+, 'H NMR (400 MHz, Dimethylsulfoxide-tfc) 88.27 (d, J= 8.4 Hz, 1H), 8.04 - 7.97 (m, 4H), 7.52 - 7.44 (m, 6H), 7.41 - 7.37 (m, 1H), 7.15 (d, J= 7.2 Hz, 1H), 7.02 (br s, 2H), 6.42 - 6.33 (m, 1H), 4.34 . 4.24 (m, 4H), 3.60 (s, 2H), 2.98 - 2.87 (m, 2H), 2.07 - 1.96 (m, 2H), 1.91 - 1.79 (m, 2H), 1.73 - 1.61 (m, 2H). n. Biological Evaluation
Example 1: NanoBRET Target Engagement (TE) Assay
[00807] NanoBRET is a highly specific and validated cell-based technique for assessing target engagement (Vasta et al., 2018, Cell Chem Biol. 25(2):206-214). The NanoBRET™ Target Engagement (TE) Intracellular Kinase Assays are based on the NanoBRET™ System (Promega Corporation), an energy transfer technique designed to measure molecular proximity in living cells. The NanoBRET™ TE Assays measure the apparent affinity of test compounds by competitive displacement of the NanoBRET™ tracer compound, which is a cell permeable molecule engineered to be reversibly bound to a NanoLuc® luciferase-kinase fusion expressed in cells. For compound screening, when a test compound binds to the selected kinase, the BRET signal is attenuated. For kinase inhibitors in particular, intracellular target selectivity is fundamental to pharmacological mechanism and allows the proteins of interest to be in the correct cellular confirmation. Although non-cell-based techniques have been developed to measure kinase binding or enzymatic inhibition with accuracy and precision, such approaches can fail to accurately predict engagement of the full-length target protein in the more complex and biologically relevant cellular context (Knight and Shokat, 2005, Chem. Biol. 12, 621-637; Smyth and Collins, 2009, J. Chem. Biol. 2, 131-1 1). The NanoBRET assay procedure was used to interrogate the compounds against the full length AKT E17K per manufacturers suggestions. Briefly, HEK-293 cells (ATCC Cat # CRL-1573) were used for transfection purposes using FuGENE HD Transfection Reagent (Promega Cat # E2311). All cells were evaluated for viability prior to transfection and optimization of the transfection was done prior to experimentation. Greater than 95% viability was used for all experiments. Following transfection, cells were washed and resuspended in Opti-MEM. NanoBRET assays were performed in white, 384-well plates (Corning) at a density of 2xl05 cells/well. All example compounds were prepared as concentrated stock solutions in DMSO (Sigma-Aldrich). Compounds are dissolved in DMSO to make 10 mM stock solution. Example compounds were transferred as 40uL of 10 mM stock solution to a 384 pp-plate (LABCYTE, PP-0200) and diluted in 3-fold, 10-point dilution via transferring 12 pL compound into 24 pL DMSO by Apricot liquid handler. A Labcyte ECHO 550 compound dispenser was used to facilitate compound transfer directly to cells. Cells were equilibrated for 2 hr with energy transfer probes and example compound prior to BRET measurements. The AKTE17K (Promega Cat # NV2421) as well as specific probe (NanoBRET tracer, Promega Cat # N264B) was prepared at a concentration of 20X in tracer dilution buffer (12.5 mM HEPES, 31.25% PEG-400, pH 7.5). For target engagement analysis, the energy transfer probes were added to the cells at concentrations optimized for the target in question (AKT E17K). Following compound incubation, NanoBRET NanoGio Substrate (Promega Cat # N157D) and Extracellular Nanoluc Inhibitor (Promega Cat # N235C) was added according to the manufacturer’s recommended protocol, and luminescence was measured on Envision Reader (Perkin Elmer) Multimode Luminometer equipped with 450nmBPfilter (donor)and 600nmLPfilter (acceptor), using 0.5 s integration time. Milli-BRET units (mBU) are calculated by multiplying the raw BRET values by 1000. Apparent tracer affinity values (EC50) were determined using the sigmoidal doseresponse (variable slope). Competitive displacement data were then plotted and data were fit to determine the EC50 value for each example compound. Table 3 provides the assay results for select examples. Activity is defined as for EC50 greater 600 nanomolar; “++” for EC50 between 60-600 nanomolar; “+++” for EC50 between 15-60 nanomolar; and “++++”, for EC50 less than 15 nanomolar.
Table 3
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
HI. Preparation of Pharmaceutical Dosage Forms
[00808] Example 1 : Oral capsule
[00809] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
[00810] Example : Solution for injection
[00811] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg- eq/mL.
[00812] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS What is claimed is:
1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000220_0001
wherein:
G is O or CR4R5;
Z1 is N, C-H, or C-R9;
Z2 is N, C-H, or C-R3;
X1 is O or S;
X2 is O or S;
X3 is a bond, O, S, N-R7;
R1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl;
R4 and R5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R4 and R5 together form an oxo; or R4 and R5 join together to form a carbocycle or heterocycle;
R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R6 is absent and X3 and L join together to form a heterocycle;
R7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R6 and R7 join together to form a heterocycle;
L is selected from -N(R8)-, or a divalent radical selected from:
Figure imgf000220_0002
Figure imgf000221_0001
Figure imgf000222_0001
wherein the asterisk (*) indicates the bond to the squaric acid group;
R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R8 and R6 join to form a ring; or optionally R8 and R7 join to form a ring;
R9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
2. A compound having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000222_0002
wherein:
G is O or CR4R5;
Z1 is N, C-H, or C-R9;
Z2 is N, C-H, or C-R3;
X1 is O or S;
X2 is O or S;
X3 is a bond, O, S, N-R7;
R1 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R2 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; R4 and R5 are each independently hydrogen, halogen, -OH, or optionally substituted Cl- C6 alkyl; or R4 and R5 together form an oxo; or R4 and R5 join together to form a carbocycle or heterocycle;
R6 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or R6 is absent and X3 and L join together to form a heterocycle;
R7 is selected from hydrogen, -OH, -NH2, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally, R6 and R7 join together to form a heterocycle;
L is selected from -N(R8)-, or a divalent radical selected from:
Figure imgf000223_0001
Figure imgf000224_0001
wherein the asterisk (*) indicates the bond to the squaric acid group;
R8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; or optionally R8 and R6 join to form a ring; or optionally R8 and R7 join to form a ring;
R9 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; m is 0, 1 or 2; and n is 1-4.
3. The compound of claim 1 or 2, or pharmaceutically acceptable salt or solvate thereof, wherein G is O.
4. The compound of claim 1 or 2, or pharmaceutically acceptable salt or solvate thereof, wherein G is CR4R5.
5. The compound of any one of claims 1-4, or pharmaceutically acceptable salt or solvate thereof, wherein Z1 is N.
6. The compound of any one of claims 1-4, or pharmaceutically acceptable salt or solvate thereof, wherein Z2 is C-H.
7. The compound of any one of claims 1-4, or pharmaceutically acceptable salt or solvate thereof, wherein Z2 is C-R3.
8. The compound of any one of claims 1-7, or pharmaceutically acceptable salt or solvate thereof, wherein X1 is O.
9. The compound of any one of claims 1-7, or pharmaceutically acceptable salt or solvate thereof, wherein X2 is O.
10. The compound of any one of claims 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein X3 is a bond.
11. The compound of any one of claims 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein X3 is O.
12. The compound of any one of claims 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein X3 is S.
13. The compound of any one of claims 1-9, or pharmaceutically acceptable salt or solvate thereof, wherein X3 is N-R7.
14. The compound of any one of claims 1-13, or pharmaceutically acceptable salt or solvate thereof, wherein R1 is optionally substituted heteroaryl.
15. The compound of claim 14, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridyl.
16. The compound of any one of claims 1-15, or pharmaceutically acceptable salt or solvate thereof, wherein R2 is optionally substituted aryl.
17. The compound of claim 14, or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl.
18. The compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.
19. The compound of any one of claims 1-18, or pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen.
20. The compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 together form an oxo.
21. The compound of any one of claims 1-20, or pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen.
22. The compound of any one of claims 1-20, or pharmaceutically acceptable salt or solvate thereof, wherein R6is optionally substituted C1-C6 alkyl.
23. The compound of any one of claims 1-20, or pharmaceutically acceptable salt or solvate thereof, wherein R6 is optionally substituted C3-C7 cycloalkyl.
24. The compound of any one of claims 1-20, or pharmaceutically acceptable salt or solvate thereof, wherein R6 is optionally substituted heterocyclyl.
25. The compound of any one of claims 1-20, or pharmaceutically acceptable salt or solvate thereof, wherein R6 is absent and X3 and L join together to form a heterocycle.
26. The compound of any one of claims 1-25, or pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, or optionally substituted C1-C6 alkyl.
27. The compound of any one of claims 1-25, or pharmaceutically acceptable salt or solvate thereof, wherein R6 and R7 join together to form a heterocycle.
28. The compound of any one of claims 1-27, or pharmaceutically acceptable salt or solvate thereof, wherein L is -N(R8)-.
29. The compound of any one of claims 1-27, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000226_0001
30. The compound of any one of claims 1-27, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000226_0002
31. The compound of any one of claims 1-27, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000226_0003
32. The compound of any one of claims 1-27, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000226_0004
33. The compound of any one of claims 1-27, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000226_0005
34. The compound of any one of claims 1-27, or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from:
Figure imgf000227_0001
35. The compound of any one of claims 1-34, or pharmaceutically acceptable salt or solvate thereof, wherein R8 is hydrogen or optionally substituted C1-C6 alkyl.
36. A compound, or pharmaceutically acceptable salt or solvate thereof, as described in Table 1.
37. A compound, or pharmaceutically acceptable salt or solvate thereof, as described in Table 2.
38. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in any one of claims 1-35 and a pharmaceutically acceptable excipient.
39. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-35, and a pharmaceutically acceptable carrier.
40. A compound of any one of claims 1-35, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
41. A compound of any one of claims 1-35, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
42. Use of a compound of any one of claims 1-35, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
43. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1-35, or pharmaceutically acceptable salt or solvate thereof.
44. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-35, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
45. A method of inhibiting a AKT1 enzyme comprising contacting the enzyme with a compound of any one of claims 1-35, wherein the AKT1 enzyme is contacted in an in vitro setting.
46. A method of inhibiting a AKT1 enzyme comprising contacting the enzyme with a compound of any one of claims 1-35, wherein the AKT1 enzyme is contacted in an in vivo setting.
PCT/US2023/032104 2022-09-08 2023-09-06 Akt1 modulators WO2024054512A1 (en)

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Citations (4)

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US20040014756A1 (en) * 2002-03-21 2004-01-22 Michaelides Michael R Thiopyrimidine and isothiazolopyrimidine kinase inhibitors
WO2006036395A2 (en) * 2004-08-23 2006-04-06 Merck & Co., Inc. Inhibitors of akt activity
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US20070037796A1 (en) * 2003-11-25 2007-02-15 Barda David A 7-Phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (proteinkinase b)
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