WO2024064026A1 - Modulateurs d'akt1 - Google Patents

Modulateurs d'akt1 Download PDF

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Publication number
WO2024064026A1
WO2024064026A1 PCT/US2023/032870 US2023032870W WO2024064026A1 WO 2024064026 A1 WO2024064026 A1 WO 2024064026A1 US 2023032870 W US2023032870 W US 2023032870W WO 2024064026 A1 WO2024064026 A1 WO 2024064026A1
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optionally substituted
pharmaceutically acceptable
solvate
compound
pyridin
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PCT/US2023/032870
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English (en)
Inventor
Michael David Bartberger
Yi Fan
Eric Anthony MURPHY
Xuefeng Zhu
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Alterome Therapeutics, Inc.
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Publication of WO2024064026A1 publication Critical patent/WO2024064026A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • 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

  • AKT1 MODULATORS CROSS REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No.63/376,252 filed September 19, 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.
  • One embodiment provides a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein: Z 1 is N, C-H, or C-R 3 ; Z 2 is N, C-H, or C-R 4 ; Ar is selected from X 1 is N or C-R 7 ; X 2 is N or C-R 7 ; X 3 is N or C-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, optionally substituted carbocyclyl, or optionally substituted heteroaryl; R 3 is selected from optionally substituted C1-C6
  • One embodiment provides a compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: wherein: Z 1 is N, C-H, or C-R 3 ; Z 2 is N, C-H, or C-R 4 ; Ar is selected from X 1 is N or C-R 7 ; X 2 is N or C-R 7 ; X 3 is N or C-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 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; R 5 and R 6 are each independently hydrogen, deuterium, halogen, -
  • R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, or optionally substituted heterocyclyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.
  • One embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: wherein: Z 1 is N, C-H, or C-R 3 ; Z 2 is N, C-H, or C-R 4 ; Ar is selected from X 1 is N or C-R 5 ; X 2 is N or C-R 5 ; X 3 is N or C-R 5 ; 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 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; and each R 5 is independently selected from hydrogen, halogen, -OH, -
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (I) or (II), 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 (II), or pharmaceutically acceptable salt or solvate thereof.
  • Another embodiment provides the method wherein the disease or disorder is cancer.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl).
  • an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl).
  • an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl).
  • an alkyl comprises one to four carbon atoms (e.g., C 1 - 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., C 1 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., C5-C8 alkyl).
  • an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S
  • an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF 3 group.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms.
  • the alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl comprises two to six carbon atoms.
  • an alkynyl comprises two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , - C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is
  • 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, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkylene).
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , - C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is
  • alkenylene or "alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkenylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (e.g., 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., C 2 -C 3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C 2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkenylene).
  • an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O)tR a
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C 5 -C 8 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)tR a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b - OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -
  • 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.
  • “Aralkenyl” 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.
  • alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • "Aralkynyl” refers to a radical of the formula -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.
  • Alkoxy 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. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds).
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.”
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b - N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -O-R c -C(O)N(R b -OR a , -R b
  • Carbocyclylalkyl refers to a radical of the formula –R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkynyl refers to a radical of the formula –R c -carbocyclyl where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula – O-R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems.
  • the heteroatoms in the heterocyclyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocyclyl radical is partially or fully saturated.
  • the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-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 -C(O)OR a , -R b -C(
  • N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- 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) –electron system in accordance with the Hückel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl (benzothion
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , - R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula –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 (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • 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, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions such as iodomethane-d 3 (CD 3 I) are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate.
  • CD3I is illustrated, by way of example only, in the reaction schemes below.
  • Deuterium-transfer reagents such as lithium aluminum deuteride (LiAlD4) are employed to transfer deuterium under reducing conditions to the reaction substrate.
  • LiAlD 4 is illustrated, by way of example only, in the reaction schemes below.
  • Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
  • the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms.
  • the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material. [0060] "Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the AKT1 inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.
  • salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid.
  • Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.
  • the term “subject” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • AKT1 Protein and Function [0066] AKT, also known as protein kinase B (PKB), is a serine/threonine protein kinase with three isoforms, AKT1, AKT2, and AKT3. While the isoforms are encoded by different genes, they are highly homologous at the protein level and share a conserved domain structure comprising an N-terminal pleckstrin homology (PH) domain, a kinase domain, and a C-terminal regulatory domain comprising a hydrophobic moiety, which includes the regulatory serine residue (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).
  • PH N-terminal pleckstrin homology
  • AKT proteins play a crucial role in major cellular functions including cell cycle progression, cell size, regulation of glucose metabolism, transcription, protein synthesis, genome stability, and neovascularization. AKT proteins can block apoptosis by inactivation of pro- apoptotic proteins, and mediate cellular growth factors, promoting cell survival. AKT is a major nucleus of a cell. [0068] 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.
  • PI3K phosphoinositide-3-kinase
  • the AKT cascade can be activated by RTKs and G-protein-compound receptors (GPCRs), along with other signals including integrins, B cell receptors, T cell receptors, and cytokine receptors.
  • GPCRs G-protein-compound receptors
  • AKT1 Mechanism AKT is activated by a second phosphorylation at the regulatory serine residue, Ser473.
  • Known phosphorylating agents of AKT at Ser473 include, but are not limited to PDK-1, integrin-linked kinase (ILK), members of the PI3K-related kinase (PIKK) family, and mammalian target of rapamycin (mTOR) (Nitulescu, G. M.
  • mTOR is a key component in the AKT signaling pathway, which is a downstream member of AKT and important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) to form mTOR complex 2 (mTORC2), which can directly phosphorylate AKT Ser473.
  • RICTOR rapamycin-insensitive companion of mTOR
  • mTORC2 mTOR complex 2
  • AKT can affect cell survival and growth because it can influence the tuberous sclerosis complex (TSC) 1/2 along the mTORC signaling pathway and inhibit pro-apoptotic proteins or signals.
  • AKT is known as a survival kinase and mediates cell survival and proliferation by inhibiting pathways including, but not limited to Bcl2 and MDM2, which promotes apoptosis.
  • Bcl2 and MDM2 promotes apoptosis.
  • Malfunctions of AKT typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270).
  • AKT1 has been found to be involved in invasion and migration of cancerous cells (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). researchers found that silencing the AKT1 isoform can abrogate specific types of cancer cell migration. However, there have been other studies which have demonstrated that activated AKT1 resulted in less metastatic propensity for lung metastatic lesion cells and breast cancer cells.
  • AKT1 has also been identified as a key protein involved in angiogenesis, lung cancer, and tumorigenesis.
  • overexpression of AKT has been correlated to resistance to chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel.
  • chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel.
  • chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel.
  • the AKT1 gene mutation E17K can affect cell growth, proliferation, survival, and migration of breast cancer cells, colorectal cancer cells, and ovarian cancer cells (Chen, Y. et al., Front Cell Dev Biol., 2020; 8: 573599).
  • AKT1 to Phosphatidylinositol-3,4,5-triphosphate (PIP3) lipid ligand, which accelerates transfer of AKT from the cytoplasm to the cell membrane through formation of hydrogen bonds. Transfer of AKT into the cell membrane allows it to be further phosphorylated. Once fully activated, AKT can return to the cytoplasm, or go to the nucleus or other intracellular sites, and phosphorylate other substrate proteins to regulate cell function.
  • PIP3 Phosphatidylinositol-3,4,5-triphosphate
  • a major pathway that activates PI3K-AKT signaling pathway is somatic cell mutations, with the E17K mutation being the highest frequency of AKT1 mutations. It is nearly exclusively present in AKT1.
  • the AKT1(E17K) is a recurrent somatic cell mutation predominantly in breast cancer, ovarian cancer, meningioma, and Proteus syndrome.
  • AKT1(E17K) mutations mediate the PI3K-AKT signaling cascade by expanding PIP lipid specificity, which causes conformational changes. This also enhances subcellular localization to accelerate localization of the PH structural domain to the plasma membrane.
  • the E17K mutation increases PIP3 binding specificity by 7-fold and phosphatidylinositol-(4,5)- bisphosphate (PIP2) by 100-fold.
  • PIP2 phosphatidylinositol-(4,5)- bisphosphate
  • the AKT1(E17K) mutation also causes rapid conformational changes in the AKT1 PH structural domain. The conformational changes to this domain result in a 4.5-fold increase in its membrane localization, which can result in excessive phosphorylation.
  • the AKT1(E17K) mutation can also result in enhanced subcellular localization by increasing the transient expression. [0080] 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 [0081] Most AKT inhibitors targeting the ATP binding site are non-selective against the three isoforms, as well as having poor to no selectivity against other structurally similar kinases. Thus, there remains a need to develop new and novel AKT inhibitors.
  • 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 having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein: Z 1 is N, C-H, or C-R 3 ; Z 2 is N, C-H, or C-R 4 ; Ar is selected from X 1 is N or C-R 7 ; X 2 is N or C-R 7 ; X 3 is N or C-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, optionally substituted carbocyclyl, or optionally substituted heteroaryl; R 3 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; R 4 is selected from optionally
  • One embodiment provides a compound having the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: wherein: Z 1 is N, C-H, or C-R 3 ; Z 2 is N, C-H, or C-R 4 ; Ar is selected from X 1 is N or C-R 7 ; X 2 is N or C-R 7 ; X 3 is N or C-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 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; R 5 and R 6 are each independently hydrogen, deuterium, halogen, -
  • R 8 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, and optionally substituted heterocyclyl; m is 0, 1, or 2; n is 1, 2, or 3; and q is 0 or 1.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is N.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is C-H.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is C-R 4 .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted heteroaryl.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridyl.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted aryl.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 5 is hydrogen.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 6 is hydrogen.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 together form an oxo.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 6 is optionally substituted C1-C6 alkyl.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 join together to form a carbocycle or heterocycle.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is -N(R 8 )-.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from: .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from: .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from: .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from: .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from: .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from: .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein L is selected from: .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R 8 is hydrogen or optionally substituted C1-C6 alkyl.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein q is 1.
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Ar is .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein Ar is .
  • Another embodiment provides a compound having the structure of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein X 1 , X 2 , and X 3 are C-H.
  • One embodiment provides a compound having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: wherein: Z 1 is N, C-H, or C-R 3 ; Z 2 is N, C-H, or C-R 4 ; Ar is selected from X 1 is N or C-R 5 ; X 2 is N or C-R 5 ; X 3 is N or C-R 5 ; 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 is selected from optionally substituted C1-C6 alkyl, or optionally substituted aryl; and each R 5 is independently selected from hydrogen, halogen, -OH, -
  • One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein Z 1 is N. [00112] One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is C-H. [00113] One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein Z 2 is C-R 4 . [00114] One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R 1 is optionally substituted heteroaryl.
  • One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted heteroaryl is an optionally substituted pyridyl.
  • One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R 2 is optionally substituted aryl.
  • One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted aryl is an optionally substituted phenyl.
  • One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein .
  • One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein Ar is .
  • One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein .
  • One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein Ar is .
  • One embodiment provides a compound having the structure of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein X 1 , X 2 , and X 3 are C-H.
  • One embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1. Table 1
  • Another embodiment provides an AKT1 inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 2.
  • Table 2
  • compositions [00127]
  • the AKT1 inhibitory compound described herein is administered as a pure chemical.
  • the AKT1 inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising at least one AKT1 inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s)
  • One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition
  • a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), 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 comprising a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the AKT1 inhibitory compound as described by Formula (II), 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.
  • 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
  • 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.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • an appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [00142] 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 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 Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00149] One embodiment provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. [00150] One embodiment provides a pharmaceutical composition comprising a compound of Formula (Ia), 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 (Ia), 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 (Ia), 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 (Ia), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00154] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. [00155] One embodiment provides a pharmaceutical composition comprising a compound of Formula (II), 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 (II), 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 (II), 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 (II), 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. [00159] 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. [00160] 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.
  • 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.
  • AKT1 enzyme comprising contacting the AKT1 enzyme with a compound of Formula (I), (II), 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.
  • Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures.
  • Step 2 tert-Butyl 4-(2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3- yl)benzylcarbamate
  • tert-butyl N-[[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 Na 2 S 2 O 4 (10.1 g, 58.1 mmol).
  • Step 3 3-(3-(4-(Aminomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • tert-butyl N-[[4-[2-(2-amino-3-pyridyl)imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate 350 mg, 840 ⁇ mol
  • 1,4-dioxane 3 mL
  • the crude product was purified by prep-HPLC (Column: Phenomenex luna C18150 x 25 mm x 10 ⁇ m; 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 product (HCl salt).
  • the product was diluted with aqueous NaHCO3 (10 mL) and extracted with DCM (10 mL x 3).
  • Step 2 tert-Butyl N-[[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
  • tert-butyl N-[[4-[(6-chloro-3-nitro-2- pyridyl)amino]phenyl]methyl]carbamate 2.0 g, 5.3 mmol
  • 2-aminopyridine-3-carbaldehyde 0.7 g, 5.8 mmol
  • Na2S2O4 1.8 g, 10.6 mmol
  • Step 3 tert-Butyl N-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]carbamate
  • tert-butyl N-[[4-[2-(2-amino-3-pyridyl)-5-chloro-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]carbamate 500 mg, 1.1 mmol
  • phenylboronic acid 270 mg, 2.2 mmol,
  • the mixture was degassed, purged with N 2 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). The mixture was filtered through celite and extracted with H 2 O (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 to give a residue.
  • Step 4 3-(3-(4-(Aminomethyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine [00182] To a solution of tert-butyl N-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5- b]pyridin-3-yl]phenyl]methyl]carbamate (126 mg, 256 ⁇ mol) in HCl/1,4-dioxane (4 M, 1 mL). The mixture 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 product was purified by prep-HPLC (column: Welch Xtimate C18150 x 25mm x 5 ⁇ m; mobile phase: [water (HCl) - ACN]; B%: 5% - 35%, 8min) to give the desired product (HCl salt).
  • the product was diluted with aqueous NaHCO3 (10 mL) and extracted with DCM (10 mL x 3).
  • Step 2 tert-Butyl 4-[[4-[(3-nitro-6-phenyl-2-pyridyl)amino]phenyl]methyl]piperazine- 1-carboxylate [00187] To a solution of tert-butyl 4-[[4-[(6-chloro-3-nitro-2- pyridyl)amino]phenyl]methyl]piperazine-1-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)Cl2 (327 mg, 0.446 mmol) and K 2 CO 3 (926 mg, 6.7 mmol).
  • 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 [00189] 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-1-carboxylate (900 mg, 1.84 mmol) in DMSO (10 mL) was added Na 2 S 2 O 4 (960 mg, 5.52 mmol) at 15 °C.
  • the mixture was stirred at 100 °C for 20 hr.
  • the reaction mixture was diluted with H 2 O (50 mL) and extracted with DCM (80 mL x 3). The combined organic layers were washed with brine (80 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue.
  • Step 4 3-[5-Phenyl-3-[4-(piperazin-1-ylmethyl)phenyl]imidazo[4,5-b]pyridin-2- yl]pyridin-2-amine [00191] A solution of tert-butyl 4-[[4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methyl]piperazine-1-carboxylate (400 mg, 712 ⁇ mol) in HCl/1,4-dioxane (4M, 8 mL) was stirred at 25 °C for 4 hr.
  • Step 2 tert-butyl (1-(4-((3-nitro-6-phenylpyridin-2-yl)amino)benzyl)piperidin-4- yl)carbamate
  • Step 3 tert-Butyl (1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl) carbamate
  • Step 4 3-(3-(4-((4-Aminopiperidin-1-yl)methyl)phenyl)-5-phenyl-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
  • Step 1 Methyl 4-((6-chloro-3-nitropyridin-2-yl)amino)benzoate [00203] 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.
  • Step 2 Methyl 4-((3-nitro-6-phenylpyridin-2-yl)amino)benzoate [00205] 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 H 2 O (100 mL) were added Pd(dppf)Cl2 (10.7 g, 14.6 mmol) and Cs2CO3 (143 g, 439 mmol).
  • Step 3 Methyl 4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzoate [00207] 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.
  • Step 4 (4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
  • methyl 4-[2-(2-amino-3-pyridyl)-5-phenyl-imidazo[4,5-b]pyridin-3- yl]benzoate (2.5 g, 5.9 mmol) in THF (25 mL) was added LiAlH 4 (450 mg, 11.9 mmol) at 0 °C. After addition, the resulting mixture was stirred at 25 °C for 2 hr.
  • Step 5 3-(3-(4-(Chloromethyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine [00211] 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 CH2Cl2 (25 mL) was added SOCl2 (2.1 g, 17.5 mmol). The mixture was stirred at 40°C for 1 hr. The reaction mixture was filtered.
  • Step 2 2-Hydroxy-4-piperazin-1-yl-benzaldehyde
  • tert-butyl 4-(3-formyl-4-hydroxy-phenyl)piperazine-1-carboxylate 190 mg, 621 ⁇ mol
  • 1,4-dioxane 1,4-dioxane
  • HCl 1,4-dioxane
  • 4M 1,4-dioxane
  • Step 2 2-Hydroxy-5-(piperazin-1-yl)benzaldehyde
  • tert-butyl 4-(3-formyl-4-hydroxy-phenyl)piperazine-1-carboxylate 400 mg, 1.31 mmol
  • 1,4-dioxane 2 mL
  • 4 mL HCl/1,4-dioxane 4 M
  • the mixture was degassed, purged with N2 2.
  • the reaction mixture was filtered and the filtered cake was concentrated under reduced pressure to give 2- hydroxy-5-(piperazin-1-yl)benzaldehyde (Intermediate 7, 320 mg, HCl salt).
  • Step 1 Benzyl 4-(cyclopropylamino)piperidine-1-carboxylate
  • benzyl 4-oxopiperidine-1-carboxylate 500 mg, 2.14 mmol
  • CH2Cl2 5 mL
  • cyclopropanamine 184 mg, 3.22 mmol, HCl salt
  • 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.
  • Step 2 Benzyl 4-((tert-butoxycarbonyl)(cyclopropyl)amino)piperidine-1-carboxylate
  • benzyl 4-(cyclopropylamino)piperidine-1-carboxylate 580 mg, 2.11 mmol
  • H2O 5 mL
  • Na2CO3 672 mg, 6.34 mmol
  • Boc 2O
  • Step 3 tert-Butyl cyclopropyl(piperidin-4-yl)carbamate
  • benzyl 4-((tert-butoxycarbonyl)(cyclopropyl)amino)piperidine-1- carboxylate 500 mg, 1.34 mmol
  • MeOH MeOH
  • Pd/C 150 mg, 10% purity
  • the mixture was purged with H 2 three times and stirred at 40 °C under H 2 atmosphere (40 Psi) for 16 hr.
  • the mixture was filtered and washed with MeOH (10 mL x 2).
  • Step 4 tert-Butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)(cyclopropyl)carbamate
  • K 2 CO 3 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 H 2 O (20 mL x 3).
  • Step 5 3-(3-(4-((4-(Cyclopropylamino)piperidin-1-yl)methyl)phenyl)-5-phenyl-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b CH 2 Cl 2 (3 of the mixture was adjusted to 8 with saturated NaHCO 3 .
  • the mixture was diluted with CH 2 Cl 2 (15 mL), extracted with CH 2 Cl 2 (20 mL x 3).
  • Step 2 3-(3-(4-((4-(Ethylamino)piperidin-1-yl)methyl)phenyl)-5-phenyl-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine [00237] To a solution of tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)(ethyl)carbamate (320 mg, 530 ⁇ mol) in 1,4-dioxane (3.0 mL) was added 4M HCl in 1,4-dioxane (3.0 mL).
  • Step 1 tert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(2-oxo-1,2-dihydropyridin-3-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carboxylate
  • 2CO3 470 mg, 1.44 mmol
  • Pd(dppf)Cl2 70.4 mg, 2O (1 mL) was degassed and purged with N 2 three times.
  • the mixture was stirred at 80 °C for 16 hr under N 2 atmosphere.
  • the reaction mixture was filtered at 25°C, diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 2 3-(2-(2-Aminopyridin-3-yl)-3-(4-(piperazin-1-ylmethyl)phenyl)-3H- imidazo[4,5-b]pyridin-5-yl)pyridin-2(1H)-one
  • tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(2-oxo-1,2-dihydropyridin- 3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carboxylate 200 mg, 346 ⁇ mol
  • Step 1 (4-((3-Nitropyridin-2-yl)amino)phenyl)methanol [00247] To a solution of (4-aminophenyl)methanol (10 g, 81.2 mmol) in 1,4-dioxane (150 mL) were added DIEA (31.5 g, 244 mmol) and 2-chloro-3-nitro-pyridine (15.5 g, 97.4 mmol). The mixture was stirred at 100 °C for 16 hr.
  • Step 2 (4-(2-(2-Aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)methanol
  • 4-((3-nitropyridin-2-yl)amino)phenyl)methanol 10 g, 40.8mmol
  • Na 2 S 2 O 4 21.3 g, 122 mmol
  • 2-aminopyridine-3-carbaldehyde 5.98 g, 48.9 mmol
  • Step 3 3-(3-(4-(Chloromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine [00251] To a solution of (4-(2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol (1.0 g, 3.15 mmol) in CH 2 Cl 2 (10 mL) was added SOCl 2 (3.3 g, 27.6 mmol). The mixture was stirred at 40 °C for 1 hr.
  • Step 2 2-Fluoro-6-hydroxy-4-(piperazin-1-yl)benzaldehyde
  • HCl 1,4-dioxane (4 M, 231 pressure
  • 2-fluoro-6-hydroxy-4-(piperazin-1-yl)benzaldehyde (Intermediate 15, 200 mg, crude, HCl salt) as a yellow solid which was used in the next step.
  • Step 2 2-Hydroxy-4-(piperazin-1-yl)-5-vinylbenzaldehyde
  • HCl 1,4-dioxane (4 M, 90.2 pressure
  • MS: m/z 233.1 [M + H] + .
  • Step 2 3-(5-(3,6-Dihydro-2H-pyran-4-yl)-3-(4-(piperazin-1-ylmethyl)phenyl)-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine [00276] To a solution of tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(3,6-dihydro-2H-pyran-4- yl)-3H-imidazo[4,5-b 25 °C for 3 hr. The mixture was filtrated and concentrated.
  • Step 2 Methyl 4-(2-(2-aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5-b]pyridin-3- yl)benzoate
  • a mixture of methyl 4-((6-morpholino-3-nitropyridin-2-yl)amino)benzoate (2.94 g, 8.20 mmol), 2-aminonicotinaldehyde (1.10 g, 9.02 mmol), and Na2S2O4 (5.71 g, 32.8 mmol) in DMSO (30 mL) was stirred at 100 °C for 16 hr. The reaction mixture was cooled to room temperature and the pH was adjusted to about 9 with sat.
  • Step 3 (4-(2-(2-Aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
  • Step 4 3-(3-(4-(Chloromethyl)phenyl)-5-morpholino-3H-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • Step 4 3-(3-(4-(Chloromethyl)phenyl)-5-morpholino-3H-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • Step 2 tert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carboxylate
  • 2-aminonicotinaldehyde 9 mg, 794 ⁇ mol
  • Na 2 S 2 O 4 542 mg, 2.65 mmol
  • Step 3 3-(5-Morpholino-3-(4-(piperazin-1-ylmethyl)phenyl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
  • tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-morpholino-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carboxylate 270 mg, 473 ⁇ mol
  • the mixture was stirred at 100 °C for 16 hr under N2 atmosphere.
  • the reaction mixture was filtered at 25°C, diluted with H 2 O (20 mL), and extracted with CH 2 Cl 2 (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 2 3-(2-(2-Aminopyridin-3-yl)-3-(4-(piperazin-1-ylmethyl)phenyl)-3H- imidazo[4,5-b]pyridin-5-yl)benzonitrile
  • tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(3-cyanophenyl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carboxylate 240 mg, 409 ⁇ mol
  • 1,4-dioxane for 16 hr.
  • the reaction mixture was filtered.
  • the mixture was stirred at 120 °C for 16 hr under N2 atmosphere.
  • the reaction mixture was filtered at 25 °C, diluted with H 2 O (20 mL), and extracted with CH 2 Cl 2 (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 2 2-(2-(2-Aminopyridin-3-yl)-3-(4-(piperazin-1-ylmethyl)phenyl)-3H- imidazo[4,5-b]pyridin-5-yl)benzonitrile
  • tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(2-cyanophenyl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carboxylate 400 mg, 682 ⁇ mol
  • the reaction mixture was filtered.
  • Step 2 tert-Butyl 4-((3-methoxy-4-vinylphenyl)amino)piperidine-1-carboxylate [00317] To a solution of tert-butyl 4-((4-bromo-3-methoxyphenyl)amino)piperidine-1- carboxylate (500 mg, 1.3 mmol) and Pd(dppf)Cl2 (95 mg, ) in toluene (10 mL) was added tributyl(vinyl)stannane (2.03 g, 6.4 mmol).
  • Step 3 tert-Butyl 4-((4-formyl-3-methoxyphenyl)amino)piperidine-1-carboxylate [00319] To a solution of tert-butyl 4-((3-methoxy-4-vinylphenyl)amino)piperidine-1- carboxylate (800 mg, 2.41 mmol) and K 2 O S O 4 (26.6 mg, ) in THF (9 mL) and H 2 O (3 mL) was added NaIO4 (1.54 g, 7.22 mmol). The mixture was stirred at 25 °C for 1 hr.
  • Step 4 2-Methoxy-4-(piperidin-4-ylamino)benzaldehyde
  • tert-butyl 4-((4-formyl-3-methoxyphenyl)amino)piperidine-1- 1,4-dioxane 2 mL
  • 4M HCl 4M HCl in 1,4-dioxane (2 mL)
  • the reaction mixture was concentrated under reduced pressure to give 2-methoxy-4-(piperidin-4-ylamino)benzaldehyde (Intermediate 30, 30 mg, HCl salt) was obtained as a yellow solid.
  • Step 1 tert-Butyl 4-(3-bromo-2-methoxybenzamido)piperidine-1-carboxylate [00326] To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (2 g, 9.99 mmol) in DMF (10 mL) were added 3-bromo-2-methoxybenzoic acid (2.31 g, 9.99 mmol), HATU (5.70 g, 14.9 mmol) and DIEA (3.87 g, 29.9 mmol).
  • Step 3 tert-Butyl 4-(3-formyl-2-methoxybenzamido)piperidine-1-carboxylate
  • tert-butyl 4-(2-methoxy-3-vinylbenzamido)piperidine-1-carboxylate 1.2 g, 3.33 mmol
  • H2O 5 mL
  • K2OsO4.2H2O 123 mg, 333 4 (2.14 g, 9.99 mmol
  • Step 4 3-Formyl-2-methoxy-N-(piperidin-4-yl)benzamide
  • tert-butyl 4-(3-formyl-2-methoxybenzamido)piperidine-1-carboxylate 1.1 g, 3.04 mmol
  • CH2Cl2 tert-butyl 4-(3-formyl-2-methoxybenzamido)piperidine-1-carboxylate
  • the mixture was filtered and the filter cake was concentrated under reduced pressure to give 3-formyl-2-methoxy-N-(piperidin-4-yl)benzamide (Intermediate 32, 600 mg, yield: 67%) as a yellow solid.
  • MS: m/z 263.1 [M + H] + .
  • Step 2 3-(3-(4-((4-Aminopiperidin-1-yl)methyl)phenyl)-5-morpholino-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
  • reaction mixture was diluted with H2O (200 mL) and extracted with CH 2 Cl 2 (50 mL x 3). The pH of aqueous phase was adjusted to about 8 ⁇ 9 with sat. Na 2 CO 3 (100 mL). The mixture was extracted with EtOAc (50 mL x 6), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 (4-((3-Nitro-5-phenylpyridin-2-yl)amino)phenyl)methanol
  • Step 3 (4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
  • [4-[(3-nitro-5-phenyl-2-pyridyl)amino]phenyl]methanol 15 g, 46.7 mmol
  • Na2S2O4 16 g, 93 mmol
  • 2-aminopyridine-3- carbaldehyde (6.8 g, 56 mmol). The mixture was stirred at 100 °C for 12 hr.
  • Step 4 3-(3-(4-(Chloromethyl)phenyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • [4-[2-(2-amino-3-pyridyl)-6-phenyl-imidazo[4,5-b]pyridin-3- yl]phenyl]methanol 500 mg, 1.3 mmol
  • SOCl 2 771 mg, 6.5 mmol
  • Step 2 3-(3-(4-((4-(Methylamino)piperidin-1-yl)methyl)phenyl)-5-phenyl-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • Step 2 3-(3-(4-((4-(Methylamino)piperidin-1-yl)methyl)phenyl)-5-phenyl-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • Step 2 2-Hydroxy-5-(methyl(piperidin-4-yl)amino)benzaldehyde
  • tert-butyl 4-((3-formyl-4-hydroxyphenyl)(methyl)amino)piperidine-1- carboxylate 150 mg, ) in CH 2 Cl 2 (2 mL
  • 4M HCl 1,4-dioxane(1.68 mL)
  • pressure to give 2-hydroxy-5-(methyl(piperidin-4-yl)amino)benzaldehyde (Intermediate 39, 102 mg, HCl salt) as an off white solid, which was used in the next step without further purification.
  • Step 1 tert-Butyl 2-(4-formyl-3-hydroxyphenyl)-2,7-diazaspiro[3.5]nonane-7- carboxylate [00381] To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (200 mg, 1.43 mmol) and 4-fluoro-2-hydroxybenzaldehyde (323 mg, 1.43 mmol) in DMSO (2 mL) was added DIEA (553 mg, 4.28 mmol).
  • Step 2 2-Hydroxy-4-(2,7-diazaspiro[3.5]nonan-2-yl)benzaldehyde
  • tert-butyl 2-(4-formyl-3-hydroxyphenyl)-2,7-diazaspiro[3.5]nonane-7- carboxylate 200 mg, 577 mol
  • 1,4-dioxane 2 mL
  • HCl 1,4-dioxane
  • Step 2 2-Hydroxy-5-(2,7-diazaspiro[4.4]nonan-2-yl)benzaldehyde
  • tert-butyl 7-(3-formyl-4-hydroxy-phenyl)-2,7-diazaspiro[4.4]nonane-2- 2Cl2 (2 mL) was added 4M HCl in EtOAc (2 mL). The mixture was stirred at 25 °C for 1hr.
  • Step 2 2-Hydroxy-5-(2,6-diazaspiro[3.3]heptan-2-yl)benzaldehyde
  • TFA 1.8 g, 13.5 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 CH 2 Cl 2 (20 mL x 3). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 2 (R)-3-(3-(4-((2,7-Diazaspiro[4.4]nonan-2-yl)methyl)phenyl)-5-phenyl-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • R tert-butyl
  • Step 2 1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)azepan-4-amine
  • Step 2 tert-Butyl 4-(2-formyl-3-methoxyphenoxy)piperidine-1-carboxylate
  • tert-butyl 4-(2-bromo-3-methoxyphenoxy)piperidine-1-carboxylate 1 2 2.
  • the reaction mixture was diluted with NH 4 Cl (30 mL) and extracted with EtOAc (50 mL x 3).
  • the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 3 2-Methoxy-6-(piperidin-4-yloxy)benzaldehyde
  • HCl 1,4-dioxane (4 M, 0.5 mL).
  • the reaction mixture concentrated under reduced pressure to give 2-methoxy-6-(piperidin-4-yloxy)benzaldehyde (Intermediate 87, 160 mg, HCl salt, yield: 99%) as an off white solid which was used directly for next step.
  • Step 1 tert-Butyl (S)-(1-(4-nitrophenyl)ethyl)carbamate
  • Step 2 tert-Butyl (S)-(1-(4-aminophenyl)ethyl)carbamate
  • Step 3 tert-Butyl (S)-(1-(4-((6-chloro-3-nitropyridin-2- yl)amino)phenyl)ethyl)carbamate
  • Step 4 tert-Butyl (S)-(1-(4-((3-nitro-6-phenylpyridin-2- yl)amino)phenyl)ethyl)carbamate
  • a mixture of tert-butyl (S)-(1-(4-((6-chloro-3-nitropyridin-2- yl)amino)phenyl)ethyl)carbamate (6.1 g, 14.0 mmol), phenylboronic acid (2.04 g, 16.8 mmol), Pd(dppf)Cl2 (1.02 g, 1.40 mmol), Cs2CO3 (13.7 g, 42.0 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) was degassed and purged with N2 hr under N 2 atmosphere.
  • Step 5 tert-Butyl (S)-(1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)ethyl)carbamate
  • tert-butyl (S)-(1-(4-((3-nitro-6-phenylpyridin-2- yl)amino)phenyl)ethyl)carbamate (4.34 g, 9.99 mmol)
  • 2-aminonicotinaldehyde (1.46 g, 11.9 mmol) in DMSO (40 mL) was added Na 2 S 2 O 4 (3.48 g, 19.9 mmol).
  • Step 6 (S)-3-(3-(4-(1-Aminoethyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • (S)-(1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)ethyl)carbamate 1.3 g, 2.57 mmol) in CH2Cl2 (10 mL) was added HCl in was concentrated under reduced pressure to give (S)-3-(3-(4-(1-aminoethyl)phenyl)-5-phenyl- 3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 94, 1.2 g, HCl salt, yield: 83
  • Step 2 3-(5-(2-Fluorophenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine hydrochloride
  • tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(2-fluorophenyl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carboxylate 500 mg, 863 ⁇ mol
  • 1,4-dioxane 5 mL
  • HCl/1,4-dioxane 4M, 5 mL
  • Step 2 3-(5-(4-Fluorophenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine hydrochloride [00511] To a solution of tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(4-fluorophenyl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carboxylate (500 mg, 863 ⁇ mol) in 1,4-dioxane (5 mL) was added HCl/1,4-dioxane (4 M, 5 mL).
  • Step 2 Methyl 4-(2-(2-aminopyridin-3-yl)-5-(2-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzoate
  • methyl 4-((6-(2-chlorophenyl)-3-nitropyridin-2-yl)amino)benzoate 1.5 g, 3.91 mmol
  • 2-aminonicotinaldehyde 525 mg, 4.30 mmol
  • the mixture was stirred at 100 °C for 12 hr.
  • Step 3 (4-(2-(2-Aminopyridin-3-yl)-5-(2-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
  • Step 3 (4-(2-(2-Aminopyridin-3-yl)-5-(2-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
  • Step 4 3-(3-(4-(Chloromethyl)phenyl)-5-(2-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • 4-(2-(2-aminopyridin-3-yl)-5-(2-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)methanol 700 mg, 1.64 mmol
  • SOCl 2 (1.17 g, 9.82 mmol
  • Step 1 Methyl 4-((6-(4-chlorophenyl)-3-nitropyridin-2-yl)amino)benzoate
  • Step 2 Methyl 4-(2-(2-aminopyridin-3-yl)-5-(4-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzoate [00525] To a solution of methyl 4-((6-(4-chlorophenyl)-3-nitropyridin-2-yl)amino)benzoate (5 g, 13.0 mmol) and 2-aminonicotinaldehyde (1.75 g, 14.3 mmol) in DMSO (150 mL) was added Na 2 S 2 O 4 (9.07 g, 52.1 mmol). The mixture was stirred at 100 °C for 16 hr.
  • Step 3 (4-(2-(2-Aminopyridin-3-yl)-5-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3- yl)phenyl)methanol
  • 4-(2-(2-aminopyridin-3-yl)-5-(4-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzoate (2.3 g, 5.05 mmol) in THF (30 mL) was added LiAlH 4 (2.5 M, 2.42 mL) at 0 °C. The mixture was stirred at 25°C for 2 hr.
  • Step 4 3-(3-(4-(Chloromethyl)phenyl)-5-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2- yl)pyridin-2-amine
  • [00529] To a solution of (4-(2-(2-aminopyridin-3-yl)-5-(4-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)methanol (1.85 g, 4.32 mmol) in CH 2 Cl 2 (40 mL) was added SOCl 2 (1.54 g, 13.0 mmol) at 0 °C. The mixture was stirred at 40 °C for 3 hr.
  • Step 1 tert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(4-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carboxylate [00532] To a solution of Intermediate 98 (1 g, 2.24 mmol), tert-butyl piperazine-1-carboxylate 2CO3 (929 mg, 6.72 mmol).
  • Step 2 3-(5-(4-Chlorophenyl)-3-(4-(piperazin-1-ylmethyl)phenyl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine
  • [00534] To a solution of tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(4-chlorophenyl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carboxylate (550 mg, 923 ⁇ mol) in 1,4-dioxane for 1 hr.
  • Step 1 tert-Butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(cyclohex-1-en-1-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carboxylate [00537] 2 O (1 2CO3 (159 mg, 1.15 mmol) and Pd(dppf)Cl2 2.
  • Step 2 3-(5-(Cyclohex-1-en-1-yl)-3-(4-(piperazin-1-ylmethyl)phenyl)-3H-imidazo[4,5- b]pyridin-2-yl)pyridin-2-amine [00539] To a solution of tert-butyl 4-(4-(2-(2-aminopyridin-3-yl)-5-(cyclohex-1-en-1-yl)-3H- imidazo[4,5-b for 3 hr. The mixture was filtrated and concentrated.
  • Step 2 2-Hydroxy-4-(4,7-diazaspiro[2.5]octan-4-yl)benzaldehyde
  • Step 2 2-Hydroxy-4-(4,7-diazaspiro[2.5]octan-4-yl)benzaldehyde
  • Example 1 N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-4-formyl-3-hydroxybenzamide
  • HATU 2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl
  • DIPEA 329 mg, 2.55 mmol
  • Example 2 N-(4-(2-(2-Aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-3- formyl-4-hydroxybenzamide [00550] Following the general procedure of Example 1, the reaction of Intermediate 1 (150 mg, 478 ⁇ mol) with 3-formyl-4-hydroxy-benzoic acid (94.5 mg, 567 ⁇ mol) was carried out.
  • Example 3 N-(4-(2-(2-Aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-4- formyl-3-hydroxybenzamide [00552] Following the general procedure of Example 1, the reaction of Intermediate 1 (150 mg, 478 ⁇ mol) with 4-formyl-3-hydroxybenzoic acid (94.5 mg, 567 ⁇ mol) was carried out.
  • Example 4 N-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-3-formyl-4-hydroxybenzamide
  • EDCI 73 mg, 382 ⁇ mol
  • HOBt 52 mg, 382 ⁇ mol
  • DIEA 132 mg, 1.02 mmol
  • Example 5 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00556] Following the general procedure of Example 4, the reaction of Intermediate 3 (150 mg, 325 ⁇ mol) with 3-formyl-4-hydroxy-benzoic acid (59 mg, 357 ⁇ mol) was carried out.
  • Example 6 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde
  • Step 6 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde
  • Example 7 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)-3-formyl-4-hydroxybenzamide [00560] Following the general procedure of Example 4, the reaction of Intermediate 4 (150 mg, 315 ⁇ mol) with 3-formyl-4-hydroxy-benzoic acid (59 mg, 357 ⁇ mol) was carried out.
  • Example 8 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)-4-formyl-3-hydroxybenzamide [00562] Following the general procedure of Example 4, the reaction of Intermediate 4 (150 mg, 315 ⁇ mol) with 4-formyl-3-hydroxy-benzoic acid (58 mg, 347 ⁇ mol) was carried out.
  • Example 9 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-1-yl)-2-hydroxybenzaldehyde
  • DIEA 169 ⁇ L, 971 ⁇ mol
  • Intermediate 6 59 mg, 243 ⁇ mol
  • Example 10 5-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-1-yl)-2-hydroxybenzaldehyde
  • DIEA 0.51 mL, 2.91 mmol
  • Intermediate 7 (194 mg, 801 ⁇ mol)
  • the mixture was degassed and purged with N 2 2 .
  • the reaction mixture was quenched with H2 2Cl2 (10 mL x 3).
  • Example 12 N-(1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)-N-cyclopropyl-3-formyl-4-hydroxybenzamide [00570] The mixture was filtered and concentrated under reduced pressure.
  • Example 13 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)-N-ethyl-3-formyl-4-hydroxybenzamide [00572] hr. The mixture was filtered and concentrated under reduced pressure.
  • Example 14 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(2-oxo-1,2-dihydropyridin-3-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde
  • Example 15 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(2-oxo-1,2-dihydropyridin-3-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde
  • Example 16 4-(4-(4-(2-(2-Aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-1-yl)-2-hydroxybenzaldehyde
  • 2CO3 370 mg, 2.7 mmol. The mixture was stirred at 80 °C for 2 hr. The mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (30 mL ⁇ 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Example 17 4-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)(methyl)amino)-2-hydroxybenzaldehyde [00580]
  • Step 1 3-(3-(4-(((4-Bromo-3-methoxyphenyl)(methyl)amino)methyl)phenyl)-5-phenyl- 3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine [00581] 2CO3 The mixture was stirred at 25 °C for 16 hr.
  • Step 2 3-(3-(4-(((3-Methoxy-4-vinylphenyl)(methyl)amino)methyl)phenyl)-5-phenyl- 3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • 3-(3-(4-(((4-bromo-3-methoxyphenyl)(methyl)amino)methyl)phenyl)- 5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine 100 mg, ) and 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (130 mg, ) in DMF (2 mL) were added Cs2CO3 (165 mg, 507 mol) and Pd(dppf)Cl2 (12.4 mg, ).
  • the mixture was degassed, purged with N 2 three times and stirred at 100 °C for 16 hr under N 2 atmosphere.
  • the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 3 4-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)(methyl)amino)-2-methoxybenzaldehyde
  • the mixture was stirred at 25 °C for 1 hr.
  • the reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 4 4-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)(methyl)amino)-2-hydroxybenzaldehyde
  • the mixture was degassed, purged with N2 three times, and stirred at 25 °C for 16 hr under N 2 atmosphere.
  • the reaction mixture was alkalized with aqueous NaHCO 3 to pH around 9 and extracted with CH 2 Cl 2 (20 mL x 2).
  • the combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Example 18 5-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)(methyl)amino)-2-hydroxybenzaldehyde [00589] Following the general procedures described in Example 17, the reactions were carried out using Intermediate 5.
  • Example 20 N-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-3-formyl-2-hydroxybenzamide [00593] Step 1: N-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-3-bromo-2-methoxybenzamide [00594] To a solution of Intermediate 2 (1.0 g, 2.6 mmol) and 3-bromo-2-methoxybenzoic acid (880 mg, 4 mmol) in DMF (10 mL) were added DIEA (1.7 g, 13 mmol) and HATU (2.9 g, 7.6 mmol).
  • Step 2 N-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-methoxy-3-vinylbenzamide
  • a mixture of N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-3-bromo-2-methoxybenzamide 1.2 g, 2 mmol
  • 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane 610 mg, 4 mmol
  • KOAc 389 mg, 4 mmol
  • Pd(dppf)Cl 2 and H2O 3 mL) in 1,4-dioxane (12 mL) was degassed and purged with N2 three times.
  • Step 3 N-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-3-formyl-2-methoxybenzamide
  • N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-methoxy-3-vinylbenzamide 4 (581 mg, 2.7 mmol) and K2OsO4.2H2 2O (2 mL). The mixture was stirred at 25 °C for 2 hr.
  • Step 4 N-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-3-formyl-2-hydroxybenzamide
  • BBr 3 542 mg, 2 mmol
  • Example 21 N-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-2-formyl-3-hydroxybenzamide
  • the reactions were carried out using Intermediate 2.
  • After purified by prep-TLC (SiO2, CH2Cl2 : MeOH 15 : 1), N-(4-(2- (2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)-2-formyl-3- hydroxybenzamide (Example 21) was obtained as an off white solid.
  • Example 22 2-Amino-N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-5-formyl-4-hydroxybenzamide
  • Step 1 2-Amino-N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-5-bromo-4-methoxybenzamide
  • HATU 291 mg, 764 mol
  • DIEA 329 mg, 2.55 mmol
  • the mixture was stirred at 25 °C for 16 hr.
  • the reaction mixture was diluted with H 2 O (10 mL) and extracted with CH 2 Cl 2 (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 2 2-Amino-N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-4-methoxy-5-vinylbenzamide
  • 2-amino-N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-5-bromo-4-methoxybenzamide 360 mg, 581 mol
  • Pd(dba)2 (16.7 mg, ) in toluene (5 mL) was added tributyl(vinyl)stannane (780 mg, 2.46 mmol).
  • the mixture was degassed and purged with N 2 three times and stirred at 110 °C for 16 hr under N 2 atmosphere.
  • the reaction mixture was quenched with aqueous KF (10 mL) at 25 °C, diluted with H2O (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 3 2-Amino-N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-5-formyl-4-methoxybenzamide
  • Step 4 2-Amino-N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-5-formyl-4-hydroxybenzamide [00611] To a solution of 2-amino-N-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-5-formyl-4-methoxybenzamide ( ) in CH 2 Cl 2 (10 mL) was added BBr3 at 0 °C.
  • the mixture degassed, purged with N2 three times, and stirred at 25 °C for 16 hr under N2 atmosphere.
  • the reaction mixture was alkalized with aqueous NaHCO 3 to pH around 9 and extracted with CH 2 Cl 2 (20 mL x 2).
  • the combined organic layers were washed with brine (20 mL x 2), dried over Na 2 SO 4 , filtered, and 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-1-yl)-2-hydroxybenzaldehyde [00613]
  • Step 1 3-(3-(4-((4-(3-Bromo-2-methoxyphenyl)piperazin-1-yl)methyl)phenyl)-5-phenyl- 3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • the mixture was stirred at 25 °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 (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 3-(3-(4-((4-(2-Methoxy-3-vinylphenyl)piperazin-1-yl)methyl)phenyl)-5-phenyl- 3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • a mixture of 3-(3-(4-((4-(3-bromo-2-methoxyphenyl)piperazin-1-yl)methyl)phenyl)-5- phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine 230 mg, 356 mol
  • 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (65.7 mg, 427 mol)
  • Pd(dppf)Cl 2 26 mg, 35.6 mol
  • Cs2CO3 34.8 mg, 1.07 mmol) in 1,4-dioxane (5 mL) and H2O
  • the mixture was stirred at 100 °C for 16 hr under N2 atmosphere.
  • the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 3 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-1-yl)-2-methoxybenzaldehyde
  • 4-(4-(4-(2-methoxy-3-vinylphenyl)piperazin-1-yl)methyl)phenyl)-5- phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine 150 mg, 253 mol
  • THF 3-(4-(4-((4-(2-methoxy-3-vinylphenyl)piperazin-1-yl)methyl)phenyl)-5- phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
  • NaIO 4 (162 mg, 756 mol
  • K 2 O S O 4 9.31 mg, 25.3 mol
  • the mixture was stirred at 0 °C for 2 hr.
  • the reaction mixture was quenched with Na2SO3 (5 mL) and NaHCO 3 (5 mL) at 0 °C.
  • the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 4 3-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-1-yl)-2-hydroxybenzaldehyde
  • BBr 3 To a solution of 3-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 2Cl2 (5 mL) was added BBr 3 The reaction mixture was quenched with H 2 O (30 mL) at 25°C, diluted with NaHCO 3 (20 mL), and extracted with EtOAc (3 ⁇ 30 mL).
  • Example 24 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-1-yl)-2-fluoro-6-hydroxybenzaldehyde
  • 2CO3 (231 mg, purified by prep-HPLC (column: [water (NH 4 HCO 3 ) - ACN]; B%: 52% - 82%, 18 min)
  • 27.4 mg, yield: 13.4% was obtained as a light yellow solid.
  • Example 25 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-1-yl)-5-fluoro-2-hydroxybenzaldehyde [00624] 2CO 3 (231 After purified by prep-HPLC (column: [water (NH4HCO3) - ACN]; B%: 51% - 81%, 18 min), 4- (4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazin-1-yl)- 5-fluoro-2-hydroxybenzaldehyde (Example 25, 16 mg, yield: 7.9% for two steps) was obtained as a yellow solid.
  • Example 28 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperazin-1-yl)-2-hydroxy-5-vinylbenzaldehyde
  • 2CO3 167 mg, 1.21 purified by prep-HPLC (column: [water (NH4HCO3) - ACN]; B%: 62% - 92%, 10 min)
  • 4-(4-(4- (2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazin-1-yl)-2- hydroxy-5-vinylbenzaldehyde Example 28, 8.9 mg, yield: 5.9% for two steps was obtained as a yellow solid.
  • Example 29 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(3,6-dihydro-2H-pyran-4-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde
  • 2 Cl 2 0.5 mL were added H2O (10 mL) and extracted with CH2Cl2 (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • Example 30 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(3,6-dihydro-2H-pyran-4-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00634] Following the general procedures described in Example 29, the reactions was carried out using Intermediate 20.
  • Example 31 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazin-1-yl)-2-hydroxybenzaldehyde
  • 2CO3 (246 mg, 1.78 mmol). 2O (1 mL), filtered, and concentrated under reduced pressure.
  • Example 32 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde
  • Example 33 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00640] Following the general procedures described in Example 32, the reaction was carried out using Intermediate 22.
  • Example 34 3-(2-(2-Aminopyridin-3-yl)-3-(4-((4-(3-formyl-4- hydroxybenzoyl)piperazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzonitrile [00642] reaction mixture was filtered and concentrated under reduced pressure.
  • Example 35 3-(2-(2-Aminopyridin-3-yl)-3-(4-((4-(4-formyl-3- hydroxybenzoyl)piperazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzonitrile [00644] Following the general procedures described in Example 34, the reaction was carried out using corresponding starting material 4-formyl-3-hydroxybenzoic acid.
  • Example 36 2-(2-(2-Aminopyridin-3-yl)-3-(4-((4-(3-formyl-4- hydroxybenzoyl)piperazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzonitrile [00646] To a solution of Intermediate 24 (50 mg, 103 ⁇ mol) and 3-formyl-4-hydroxybenzoic acid (17 mg, 103 ⁇ mol) in DMF (1 mL) were added EDCI (30 mg, 154 ⁇ mol), DIEA (66 mg, 514 ⁇ mol) and HOBt (21 mg, 154 ⁇ mol).
  • Example 37 2-(2-(2-Aminopyridin-3-yl)-3-(4-((4-(4-formyl-3- hydroxybenzoyl)piperazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzonitrile [00648] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 24.
  • Example 38 4-(2-(2-Aminopyridin-3-yl)-3-(4-((4-(3-formyl-4- hydroxybenzoyl)piperazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzonitrile [00650] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 25.
  • Example 39 4-(2-(2-Aminopyridin-3-yl)-3-(4-((4-(4-formyl-3- hydroxybenzoyl)piperazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzonitrile [00652] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 25.
  • Example 40 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(3-fluorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00654] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 26.
  • Example 41 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(3-fluorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00656] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 26.
  • Example 42 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(3-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00658] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 27.
  • Example 43 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(3-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00660] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 27.
  • Example 44 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(1-methyl-6-oxo-1,6-dihydropyridin- 3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde
  • DIEA 7.4 mg, 548 mol
  • HATU 7.6 mg, 201 mol
  • 3-formyl-4-hydroxybenzoic acid quenched with H2O (10 mL) at 0 °C and extracted with CH2Cl2 (10 mL x 3).
  • Example 45 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(6-oxo-1,6-dihydropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00664] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 29.
  • Example 46 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(6-oxo-1,6-dihydropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00666] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 29.
  • Example 47 4-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-2-hydroxybenzaldehyde [00668]
  • Step 1 4-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-2-methoxybenzaldehyde [00669] 2CO 3
  • the reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL x 2).
  • Step 2 4-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-2-hydroxybenzaldehyde [00671] To a solution of 4-((1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)amino)-2-methoxybenzaldehyde ( ) in CH2Cl2 (10 mL) was added BBr3 (446 mg, 7.42 mmol) at 0 °C.
  • the mixture was degassed and purged with N 2 three times and stirred at 25 °C for 16 hr under N 2 atmosphere.
  • the reaction mixture was alkalized with aqueous NaHCO3 to pH to around 9 and extracted with CH2Cl2 (20 mL x 2).
  • the combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Example 48 5-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)amino)-2-hydroxybenzaldehyde [00673] Following the general procedures described in Example 47, the reaction was carried out using Intermediate 5 and Intermediate 31.
  • Example 49 N-(1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)-3-formyl-2-hydroxybenzamide [00675] Following the general procedures described in Example 47, the reaction was carried out using Intermediate 5 and Intermediate 32.
  • Example 50 3-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)amino)-2-hydroxybenzaldehyde [00677] Following the general procedures described in Example 47, the reaction was carried out using Intermediate 5 and Intermediate 33.
  • Example 51 2-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)amino)-6-hydroxybenzaldehyde [00679] Following the general procedures described in Example 47, the reaction was carried out using Intermediate 5 and Intermediate 34.
  • Example 52 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)-3-formyl-4-hydroxybenzamide [00681] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 35.
  • Example 53 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)-4-formyl-3-hydroxybenzamide [00683] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 35.
  • Example 54 4-(4-(4-(2-(2-Aminopyridin-3-yl)-6-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazin-1-yl)-2-hydroxybenzaldehyde
  • 2CO3 201 mg, 1.5 mmol. The mixture was stirred at 80 °C for 2 hr. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (60 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Example 55 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)-3-formyl-4-hydroxy-N-methylbenzamide [00687] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 37.
  • Example 56 4-((1R,4R)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-2-hydroxybenzaldehyde [00689] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 38.
  • Example 57 4-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)(methyl)amino)-2-hydroxybenzaldehyde [00691] Following the general procedures described in Example 54, the reaction was carried out using Intermediate 5 and Intermediate 39.
  • Example 58 (R)-N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-3-yl)-3-formyl-4-hydroxybenzamide [00693] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 40.
  • Example 59 (R)-N-(1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)-3-formyl-4-hydroxybenzamide [00695] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 41.
  • Example 60 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)piperidin-4-yl)-4-formyl-3-hydroxy-N-methylbenzamide [00697] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 37.
  • Example 61 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)azetidin-3-yl)-3-formyl-4-hydroxybenzamide [00699] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 42.
  • Example 62 5-(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-carbonyl)-2-hydroxybenzaldehyde [00701] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 43.
  • Example 63 (R)-N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-3-yl)-4-formyl-3-hydroxybenzamide [00703] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 40.
  • Example 64 (R)-N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)pyrrolidin-3-yl)-4-formyl-3-hydroxybenzamide [00705] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 41.
  • Example 65 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)azetidin-3-yl)-4-formyl-3-hydroxybenzamide [00707] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 42.
  • Example 66 4-(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-carbonyl)-2-hydroxybenzaldehyde [00709] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 43.
  • Example 67 5-(7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-hydroxybenzaldehyde [00711] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 44.
  • Example 68 N-(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)-3-formyl-4-hydroxybenzamide [00713] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 45.
  • Example 69 N-(2-(4-(2-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)-3-formyl-4-hydroxybenzamide [00715] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 46.
  • Example 70 N-(2-(4-(2-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)-4-formyl-3-hydroxybenzamide [00717] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 46.
  • Example 71 4-(7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-2-hydroxybenzaldehyde [00719] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 44.
  • Example 72 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-1,4-diazepane-1-carbonyl)-2-hydroxybenzaldehyde [00721] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 47.
  • Example 73 4-(7-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-hydroxybenzaldehyde [00723] 2CO3 (151 mg, 1.09 mmol) and NaI (5.46 mg, The reaction mixture was filtered and concentrated under reduced pressure.
  • Example 74 5-(8-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decane-2-carbonyl)-2-hydroxybenzaldehyde [00725] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 49.
  • Example 75 4-(8-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decane-2-carbonyl)-2-hydroxybenzaldehyde [00727] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 49.
  • Example 76 4-(8-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-hydroxybenzaldehyde [00729] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 50.
  • Example 77 5-(9-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-2-hydroxybenzaldehyde [00731] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 51.
  • Example 78 4-(9-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-hydroxybenzaldehyde [00733] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 52.
  • Example 79 4-(6-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-hydroxybenzaldehyde [00735] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 53.
  • Example 80 5-(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-carbonyl)-2-hydroxybenzaldehyde [00737] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 54.
  • Example 81 4-(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-carbonyl)-2-hydroxybenzaldehyde [00739] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 54.
  • Example 82 4-(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)-2-hydroxybenzaldehyde [00741] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 55.
  • Example 83 5-(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)-2-hydroxybenzaldehyde [00743] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 56.
  • Example 84 5-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-2-hydroxybenzaldehyde [00745] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 57.
  • Example 85 4-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-hydroxybenzaldehyde [00747] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 58.
  • Example 86 5-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[4.5]decane-7-carbonyl)-2-hydroxybenzaldehyde [00749] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 59.
  • Example 87 4-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[4.5]decane-7-carbonyl)-2-hydroxybenzaldehyde [00751] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 59.
  • Example 88 4-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[4.5]decan-7-yl)-2-hydroxybenzaldehyde [00753] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 60.
  • Example 89 4-(6-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-hydroxybenzaldehyde [00755] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 61.
  • Example 90 4-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-2-hydroxybenzaldehyde [00757] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 57.
  • Example 91 5-(6-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-hydroxybenzaldehyde [00759] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 62.
  • Example 92 5-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)-2-hydroxybenzaldehyde [00761] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 63.
  • Example 93 4-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.4]octane-6-carbonyl)-2-hydroxybenzaldehyde [00763] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 63.
  • Example 94 4-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.4]octan-6-yl)-2-hydroxybenzaldehyde [00765] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 64.
  • Example 95 5-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-2-hydroxybenzaldehyde [00767] Following the general procedures described in Example 44, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 65.
  • Example 96 4-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-2-hydroxybenzaldehyde [00769] Following the general procedures described in Example 44, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 65.
  • Example 97 4-(2-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-hydroxybenzaldehyde [00771] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 66.
  • Example 98 (R)-5-(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-carbonyl)-2-hydroxybenzaldehyde [00773] Following the general procedures described in Example 44, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 67.
  • Example 99 (R)-4-(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-carbonyl)-2-hydroxybenzaldehyde [00775] Following the general procedures described in Example 44, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 67.
  • Example 100 (R)-4-(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)-2-hydroxybenzaldehyde [00777] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 68.
  • Example 101 (S)-5-(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-carbonyl)-2-hydroxybenzaldehyde [00779] Following the general procedures described in Example 44, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 69.
  • Example 102 (S)-4-(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-carbonyl)-2-hydroxybenzaldehyde [00781] Following the general procedures described in Example 44, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 69.
  • Example 103 (S)-4-(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)-2-hydroxybenzaldehyde [00783] stirred at 80 °C for 1 hr. The mixture was concentrated under reduced pressure.
  • Example 104 (R)-4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-methylpiperazin-1-yl)-2-hydroxybenzaldehyde [00785] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 71.
  • Example 105 (S)-5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-methylpiperazine-1-carbonyl)-2-hydroxybenzaldehyde [00787] Following the general procedures described in Example 44, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 72.
  • Example 106 (S)-4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-methylpiperazine-1-carbonyl)-2-hydroxybenzaldehyde [00789] Following the general procedures described in Example 44, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 72.
  • Example 107 (S)-4-(4-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2-methylpiperazin-1-yl)-2-hydroxybenzaldehyde [00791] Following the general procedures described in Example 103, the reaction was carried out using Intermediate 5 and Intermediate 73.
  • Example 108 4-(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)-2-hydroxybenzaldehyde [00793] Following the general procedures described in Example 103, the reaction was carried out using Intermediate 5 and Intermediate 101.
  • Example 109 4-(3-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-2-hydroxybenzaldehyde [00795] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 74.
  • Example 110 5-(3-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-2-hydroxybenzaldehyde [00797] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 74.
  • Example 111 4-(3-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-hydroxybenzaldehyde [00799] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 75.
  • Example 112 5-(8-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-2-hydroxybenzaldehyde [00801] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 76.
  • Example 113 4-(8-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-2-hydroxybenzaldehyde [00803] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 76.
  • Example 114 4-(8-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-hydroxybenzaldehyde [00805] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 77.
  • Example 115 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)azepan-4-yl)-3-formyl-4-hydroxybenzamide [00807] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 78.
  • Example 116 N-(1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)azepan-4-yl)-4-formyl-3-hydroxybenzamide [00809] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 78.
  • Example 117 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)azepan-3-yl)-3-formyl-4-hydroxybenzamide [00811] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 79.
  • Example 118 N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)azepan-3-yl)-4-formyl-3-hydroxybenzamide [00813] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 79.
  • Example 119 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-1,4-diazepane-1-carbonyl)-2-hydroxybenzaldehyde [00815] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 47.
  • Example 120 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-1,4-diazepan-1-yl)-2-hydroxybenzaldehyde [00817] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 81.
  • Example 121 5-((1S,4S)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-2-hydroxybenzaldehyde [00819] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 82.
  • Example 122 4-((1S,4S)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-2-hydroxybenzaldehyde [00821] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 82.
  • Example 123 4-((1S,4S)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-hydroxybenzaldehyde [00823] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 83.
  • Example 124 4-((1R,4R)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-hydroxybenzaldehyde [00825] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 84.
  • Example 125 4-(5-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-2-hydroxybenzaldehyde [00827] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 85.
  • Example 126 5-(5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-2,5-diazabicyclo[2.2.2]octane-2-carbonyl)-2-hydroxybenzaldehyde [00829] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 85.
  • Example 127 4-(5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-hydroxybenzaldehyde [00831] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 5 and Intermediate 86.
  • Example 128 2-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)oxy)-6-hydroxybenzaldehyde [00833] Step 1: 2-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)oxy)-6-methoxybenzaldehyde [00834] HCl salt 2 CO 3 (419 mg, for 2 hr under N2.
  • Step 2 2-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)piperidin-4-yl)oxy)-6-hydroxybenzaldehyde
  • BBr 3 3 (30 mL)
  • H 2 O 20 mL
  • CH2Cl2 30 mL x 3
  • Example 129 4-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)oxy)-2-hydroxybenzaldehyde [00838] Following the general procedures described in Example 128, the reactions were carried out using Intermediate 5 and Intermediate 88.
  • Example 130 5-((1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperidin-4-yl)oxy)-2-hydroxybenzaldehyde [00840] Following the general procedures described in Example 128, the reactions were carried out using Intermediate 5 and Intermediate 89.
  • Example 131 5-((3aR,6aS)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2-hydroxybenzaldehyde [00842] Following the general procedures described in Example 44, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 90.
  • Example 132 4-((3aR,6aS)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2-hydroxybenzaldehyde [00844] Following the general procedures described in Example 44, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 90.
  • Example 133 4-((3aR,6aS)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-hydroxybenzaldehyde [00846] 2. The mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated.
  • Example 134 5-((3aR,6aS)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-hydroxybenzaldehyde [00848] Following the general procedures described in Example 133, the reaction was carried out using Intermediate 5 and Intermediate 92.
  • Example 135 5-((3aS,6aS)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2-hydroxybenzaldehyde [00850] Following the general procedures described in Example 44, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 93.
  • Example 136 4-((3aS,6aS)-5-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2- hydroxybenzaldehyde
  • the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 93.
  • Example 137 2-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)oxy)-6-hydroxybenzaldehyde [00854] 2CO3 (712 mg, 2.19 mmol). The mixture was stirred at 30 °C for 3 hr. The reaction mixture was filtered and concentrated under reduced pressure.
  • Example 138 4-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)oxy)-2-hydroxybenzaldehyde [00856] 2CO3 (237 and concentrated under reduced pressure.
  • Example 139 5-((4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3- yl)benzyl)oxy)-2-hydroxybenzaldehyde [00858] To a solution of Intermediate 5 (500 mg, 1.21 mmol), 2,5-dihydroxybenzaldehyde 2CO 3 (1.19 g, 3.64 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure.
  • Example 140 (S)-N-(1-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)phenyl)ethyl)-3-formyl-4-hydroxybenzamide [00860] in CH2Cl2 NaHCO 3 (20 mL) and extracted with CH 2 Cl 2 (50 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Example 141 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(2-fluorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00862] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 95.
  • Example 142 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(2-fluorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00864] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 95.
  • Example 143 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(4-fluorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00866] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 96.
  • Example 144 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(4-fluorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00868] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 96.
  • Example 145 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(2-chlorophenyl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazin-1-yl)-2-hydroxybenzaldehyde [00870] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 6 and Intermediate 97.
  • Example 146 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(4-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazin-1-yl)-2-hydroxybenzaldehyde [00872] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 6 and Intermediate 98.
  • Example 147 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(4-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00874] Following the general procedures described in Example 36, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 99.
  • Example 148 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(4-chlorophenyl)-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00876] Following the general procedures described in Example 36, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 99.
  • Example 149 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(4-chlorophenyl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazin-1-yl)-2-hydroxybenzaldehyde [00878] Following the general procedures described in Example 73, the reaction was carried out using Intermediate 98 and Intermediate 7.
  • Example 150 5-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(cyclohex-1-en-1-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00880] Following the general procedures described in Example 44, the reaction was carried out using 3-formyl-4-hydroxybenzoic acid and Intermediate 100.
  • Example 151 4-(4-(4-(2-(2-Aminopyridin-3-yl)-5-(cyclohex-1-en-1-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperazine-1-carbonyl)-2-hydroxybenzaldehyde [00882] Following the general procedures described in Example 44, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 100.
  • Example 152 4-(9-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5- b]pyridin-3-yl)benzyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-2-hydroxybenzaldehyde [00884] Following the general procedures described in Example 44, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 51.
  • Example 153 4-(6-(4-(2-(2-Aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin- 3-yl)benzyl)-2,6-diazaspiro[3.4]octane-2-carbonyl)-2-hydroxybenzaldehyde [00886] Following the general procedures described in Example 44, the reaction was carried out using 4-formyl-3-hydroxybenzoic acid and Intermediate 102.
  • NanoBRET Target Engagement (TE) Assay 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.
  • NanoBRET assay procedure was used to interrogate the compounds against the full length AKT E17K per manufacturers suggestions. Briefly, HEK-293 cells (ATCC Cat # CRL-1573) were used for transfection purposes using FuGENE HD Transfection Reagent (Promega Cat # E2311). All cells were evaluated for viability prior to transfection and optimization of the transfection was done prior to experimentation. Greater than 95% viability was used for all experiments. Following transfection, cells were washed and resuspended in Opti-MEM. NanoBRET assays were performed in white, 384-well plates (Corning) at a density of 2x10 5 cells/well. All example compounds were prepared as concentrated stock solutions in DMSO (Sigma-Aldrich).
  • Example compounds are dissolved in DMSO to make 10 mM stock solution.
  • Example compounds were transferred as 40uL of 10 mM stock solution to a 384 pp-plate (LABCYTE, PP-0200) and 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
  • specific probe NaBRET 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).

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Abstract

L'invention concerne des inhibiteurs d'AKT1, des compositions pharmaceutiques contenant les composés inhibiteurs, et des procédés d'utilisation des composés inhibiteurs d'AKT1 pour le traitement d'une maladie.
PCT/US2023/032870 2022-09-19 2023-09-15 Modulateurs d'akt1 WO2024064026A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011082098A1 (fr) * 2009-12-30 2011-07-07 The Rockefeller University Inhibiteurs de lysine et arginine méthyltransférase pour le traitement du cancer
WO2011082270A2 (fr) * 2009-12-30 2011-07-07 Arqule. Inc. Composés imidazopyridinyl-aminopyridine substitués
WO2014165815A2 (fr) * 2013-04-04 2014-10-09 University Of Maryland, Baltimore Composés non-stéroïdiens et stéroïdiens puissants en termes de régulation à la baisse du récepteur des androgènes et d'activité contre le cancer de la prostate
WO2023168291A1 (fr) * 2022-03-02 2023-09-07 Terremoto Biosciences, Inc. Modificateurs covalents de akt1 et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011082098A1 (fr) * 2009-12-30 2011-07-07 The Rockefeller University Inhibiteurs de lysine et arginine méthyltransférase pour le traitement du cancer
WO2011082270A2 (fr) * 2009-12-30 2011-07-07 Arqule. Inc. Composés imidazopyridinyl-aminopyridine substitués
WO2014165815A2 (fr) * 2013-04-04 2014-10-09 University Of Maryland, Baltimore Composés non-stéroïdiens et stéroïdiens puissants en termes de régulation à la baisse du récepteur des androgènes et d'activité contre le cancer de la prostate
WO2023168291A1 (fr) * 2022-03-02 2023-09-07 Terremoto Biosciences, Inc. Modificateurs covalents de akt1 et leurs utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ASHWELL, M. A. ET AL.: "Discovery and Optimization of a Series of 3-(3-Phenyl-3H- imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: Orally Bioavailable, Selective, and Potent ATP-independent Akt Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 11, 2012, pages 5291 - 5310, XP055076710, DOI: 10.1021/jm300276x *

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