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WO2025230464A1 - Modulateurs de la cétoacide déshydrogénase kinase à chaîne ramifiée et procédés associés - Google Patents

Modulateurs de la cétoacide déshydrogénase kinase à chaîne ramifiée et procédés associés

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Publication number
WO2025230464A1
WO2025230464A1 PCT/SG2025/050234 SG2025050234W WO2025230464A1 WO 2025230464 A1 WO2025230464 A1 WO 2025230464A1 SG 2025050234 W SG2025050234 W SG 2025050234W WO 2025230464 A1 WO2025230464 A1 WO 2025230464A1
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Prior art keywords
optionally substituted
compound
alkyl
heteroaryl
formula
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English (en)
Inventor
Hao Fan
Weiping Han
Qunxiang ONG
Chaitanya K. JALADANKI
Rayakar Achal AJEET
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Agency for Science Technology and Research Singapore
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Agency for Science Technology and Research Singapore
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic 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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates, in general terms, to branched-chain ketoacid dehydrogenase kinase modulators and methods thereof.
  • Branched-chain ketoacid dehydrogenase kinase is an enzyme crucial in regulating branched-chain amino acids (BCAAs) catabolism including leucine, isoleucine, and valine, holds significance in protein synthesis and energy metabolism. Disruptions in BCAA metabolism link to various health conditions, such as metabolic disorders (e.g., obesity, insulin resistance, and type 2 diabetes), neurological disorders, muscle-related issues, and liver disease. In addition to its known role in BCAA catabolism, BCKDK also enhances MEK/ERK signalling, a pivotal pathway driving cell growth and proliferation in cancer.
  • BCAAs branched-chain amino acids
  • BCKDK emerges as a promising target not only for BCAA-related diseases but also for liver cancers.
  • Virtual screening provides a cost-effective and efficient method to identify candidate compounds for subsequent experimental validation, offering a streamlined approach to explore potential interventions targeting BCKDK in the context of both metabolic and cancer-related disorders.
  • BCKDK an unconventional kinase, contains a regulatory domain with an allosteric inhibitory site, binds endogenous ketoleucine.
  • BCKDK inhibitors including (S)-CPP, phenylbutyrate, BT2, aryl-tetrazoles, PF-07238025, PF-07208254 and PF-072476854.
  • Clofibric acid has an undetermined binding location but may bind to this site as well based on structural similarity.
  • Thiamine pyrophosphate has also been described as a BCKDK inhibitor; however, its direct interaction with BCKDK has not been established and is known to be a cofactor.
  • the present disclosure provides a method of treating a disease or condition associated with a dysregulation of a Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK) in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound of Formula (I) or a salt, solvate, stereoisomer or prodrug thereof:
  • Ri and R2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted aryl, optionally substituted heteroaryl; or Ri and R2 are linked to form an optionally substituted cyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
  • R3 is selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, optionally substituted heteroaryl;
  • X2 is selected from N and CR ⁇
  • R4 is selected from optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Xi is selected from N and CRs
  • Rg is selected from optionally substituted alkyl, optionally substituted oxyacyl, optionally substituted acyloxy, optionally substituted aryl, optionally substituted heteroaryl;
  • Rw is selected from optionally substituted aryl, optionally substituted heteroaryl
  • Xs and X7 are independently selected from N and CR11;
  • Xg is selected from N, S and CR11;
  • R11 is independently selected from H, halo, cyano, optionally substituted alkyl; and q is an integer selected from 0 to 4; r is an integer selected from 0 to 2; and t is an integer selected from 0 to 2.
  • the compound of Formula (I) is a compound of Formula (II): wherein Ri and R2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted aryl, optionally substituted heteroaryl; or Ri and R2 are linked to form an optionally substituted cyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
  • R3 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, optionally substituted heteroaryl;
  • R4 is selected from optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Xi is selected from N and CRs
  • Rs is selected from H, halo, cyano, optionally substituted alkyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound of Formula (II) is a compound of Formula (Hi): wherein R9 is selected from optionally substituted alkyl, optionally substituted oxyacyl, optionally substituted acyloxy, optionally substituted aryl, optionally substituted heteroaryl;
  • Rw is selected from optionally substituted aryl, optionally substituted heteroaryl
  • X5 and Xe are independently selected from N and CR11; and q is an integer selected from 0 to 4.
  • the disease or condition associated with a dysregulation of BCKDK is a cancer.
  • the disease or condition associated with a dysregulation of BCKDK is selected from liver cancer, kidney cancer, stomach cancer and colorectal cancer.
  • Ri and R2 are linked to form optionally substituted aryl, or optionally substituted heteroaryl.
  • R3 is selected from H, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroaryl.
  • the compound of Formula (I) is a compound of Formula (lie): wherein Re is selected from halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted heterocyclyl and optionally substituted heteroaryl; or Re is linked with the phenyl moiety to form an optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl; n is an integer selected from 0 to 2; m is an integer selected from 0 to 4.
  • the compound of Formula (I) is a compound of Formula (lid): wherein Re is selected from halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted heterocyclyl and optionally substituted heteroaryl; or Re is linked with the phenyl moiety to form an optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl;
  • L is an acylene linker having 0-5 carbon on either side of the linker; and m is an integer selected from 0 to 4.
  • Rs is selected from halo, alkyl, oxo,
  • Rs is at a para or meta position.
  • R4 is selected from optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted imidazolyl, and optionally substituted tetra hydrofuranyl.
  • the compound of Formula (I) is a compound of Formula (lie):
  • R? is selected from halo, cyano, oxo, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino;
  • Xi is selected from N and C;
  • X3 and X4 are independently CRs or N;
  • Rs is selected from halo, cyano, optionally substituted alkyl; and p is an integer selected from 0 to 4.
  • both X3 and X4 are C, or either one of X3 and X4 is N.
  • R? is selected from halo, cyano, oxo, optionally substituted aryl and optionally substituted heteroaryl.
  • the compound of Formula (I) is a compound of Formula (lif) or Formula (lig) :
  • X5 and X6 are both N.
  • Rg is selected from alkyl, alkyloxyacyl, alkylacyloxy, phenyl.
  • Rio is selected from optionally substituted phenyl and optionally substituted naphthalenyl.
  • the compound of Formula (II) is a compound of Formula (Ilia):
  • R12 is selected from halo, optionally substituted alkyl, optionally substituted alkoxy; and u is an integer selected from 0 to 4.
  • the compound of Formula (II) is a compound of Formula (Ilib): wherein R13 is selected from halo, optionally substituted alkyl, optionally substituted alkoxy; and v is an integer selected from 0 to 4.
  • the present disclosure provides a compound of Formula (lie), (lid) or a salt, solvate, stereoisomer or prodrug thereof: wherein Ri and R2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted aryl, optionally substituted heteroaryl; or Ri and R2 are linked to form an optionally substituted cyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
  • R4 is selected from optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Re is selected from halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted acylamino, optionally substituted aminoacyl, and optionally substituted heteroaryl; or Re is linked with the phenyl moiety to form an optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl;
  • Xi is selected from N and CR4;
  • R4 is selected from optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • L is an acylene linker having 0-5 carbon on either side of the linker; n is an integer selected from 0 to 2; and m is an integer selected from 0 to 4; wherein when meta position.
  • Re is selected from halo, alkyl, oxo,
  • the present disclosure provides a compound of Formula (Hi) or a salt, solvate, stereoisomer or prodrug thereof: wherein R9 is selected from optionally substituted alkyl, optionally substituted oxyacyl, optionally substituted acyloxy, optionally substituted aryl, optionally substituted heteroaryl; Rw is selected from optionally substituted aryl, optionally substituted heteroaryl;
  • Xs and Xe are independently selected from N and CR11; and q is an integer selected from 0 to 4; wherein when Rg is phenyl, Rio is naphthalenyl and q is 1, Rg is substituted at a 5, 6, 7 or 8 position.
  • FIG. 1 Cell proliferation assays of ETBDK8 (Drug 8) and ETBDK9 (Drug 9).
  • A Western blot analysis of BCKDK levels in WT and three knockdown cell lines.
  • B Cell proliferation assays showing that the degree of BCKDK expression is proportional to the IC50 of ETBDK8 and ETBDK9.
  • FIG. 1 Characterization of cell proliferation ETBDK8 and ETBDK9 in liver cancer cell lines.
  • A ETBDK8 and ETBDK9 outperform PF-07208254 in SNU182 cell line.
  • B ETBDK8 and ETBDK9 demonstrate greater potency compared to PF-07208254 in SNU387 and SNU449 cell lines.
  • Figure 5 The predicted docking poses of (A) ETBDK8 and (B) ETBDK9 within the allosteric binding site of BCKDK.
  • FIG. 6 Western blot analysis and Cell proliferation assays of A16 compared to PF- 07209458.
  • A Western blot results show that A16 more effectively inhibits BDK compared to PF-07209458, abrogating BCKDHA phosphorylation at 10 pM and inducing BCKDK degradation at 100 pM.
  • B, C The assays demonstrate the selective inhibitory activity of A16 against liver cancer cell lines (Hep3B, Huh7) while minimally affecting non-cancerous hepatocytes (THLE-2).
  • D Chemical structure of A16.
  • the inventors (i) employed computational tools to identify small molecule inhibitors against BCKDK, (ii) validated the inhibitory effects of selected compounds through in vitro studies, (iii) assessed the impact of BCKDK inhibition on cancer cell viability and metabolic profiles using pertinent cancer models.
  • the inventors have identified two small molecule inhibitors ETBDK8 and ETBDK9 for the Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK), a key enzyme in the regulation of branched-chain amino acid (BCAA) metabolism.
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • the two BCKDK small molecule inhibitors ETBDK8 and ETBDK9 are chemically distinct (Tc ⁇ 0.15) from all 7 known BCKDK inhibitors.
  • ETBDK8 and ETBDK9 outperform BT2 and PF- 07208254 in liver cancer cell lines, and show no significant toxic effects in epithelial liver cell line.
  • ETBDK8 has an IC50 for Hep3B: 4.13 pM, and IC50 for Hep3B KD: 17.67 pM.
  • ETBDK9 has an IC50 for Hep3B: 8.88 pM, and IC50 for Hep3B KD: 69.49 pM.
  • a new target like BCKDK signifies an opportunity to address unmet medical needs, potentially targeting specific cancer types more effectively.
  • This specific allosteric inhibition allows for tailored treatments with reduced off-target effects.
  • the corresponding inhibitor by selectively modulating the identified target, can disrupt cancer cell proliferation and survival pathways. This targeted approach may enhance treatment efficacy while minimizing adverse effects on healthy tissues.
  • the discovery of inhibitor for new target like BCKDK opens avenues for innovative combination therapies, overcoming resistance mechanisms. The potential commercial impact is substantial, attracting pharmaceutical interest in developing novel drugs and reinforcing the ongoing pursuit of more effective and targeted cancer treatments.
  • the present disclosure pertains to compounds and their various forms, including ionic forms, tautomers, isomers, polymorphs, pseudopolymorphs, amorphous forms. solvates, co-crystals, chelates, esters, prodrugs, and protected forms.
  • the disclosure also encompasses methods of utilizing these compounds for various purposes. It should be noted that terms like "crystalline form,” “polymorph,” can be used interchangeably to include all crystalline and amorphous forms, such as polymorphs, pseudopolymorphs, solvates (including hydrates), co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is specified.
  • the compounds and their subgroups include polymorphs, solvates, co-crystals, isomers, tautomers, and/or oxides. In other embodiments, they may include polymorphs, solvates, and/or co-crystals.
  • Alkyl refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, /so-propyl, n-butyl, isobutyl, n-hexyl, and the like. When specifying an alkyl residue with a particular number of carbons, it is understood to encompass all possible straight and branched chain versions with that number of carbons. For example, “propyl” includes both n-propyl and isopropyl; while “butyl” includes n-butyl, sec-butyl, isobutyl and t-butyl.
  • Alkoxy refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo.
  • Aryl refers to an unsaturated aromatic carbocyclic group having a single ring (eg. phenyl) or multiple condensed rings (eg. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms.
  • aryl groups include phenyl, naphthyl and the like.
  • Aryl groups can be monocyclic or polycyclic (such as bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group can be aromatic (e.g., naphthyl).
  • polycyclic aryl groups may include a non-aromatic ring (e.g., cycloalkyl, heterocycloalkyl, cycloalkenyl) fused to an aromatic ring provided that the connection to the parent structure occurs via an atom in the aromatic ring.
  • a non-aromatic ring e.g., cycloalkyl, heterocycloalkyl, cycloalkenyl
  • a l,2,3,4-tetrahydronaphthalen-5-yl group, bound to the parent structure via an aromatic carbon atom is considered an aryl group
  • 1,2, 3, 4- tetrahydronaphthalen-l-yl bound to the parent structure via a nonaromatic carbon atom, is not considered an aryl group.
  • Heteroaryl refers to a monovalent aromatic heterocyclic group which fulfils the Hiickel criteria for aromaticity (ie. contains 4n + 2 n electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium and nitrogen).
  • Such heteroaryl groups can have a single ring (eg. pyridyl, pyrrolyl or N- oxides thereof or furyl) or multiple condensed rings (eg. indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl).
  • heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiophene, benzo[b]thiophene, triazole, imidazopyridine,
  • Acyl refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxyacyl refers to groups HOC(O)-, alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl-OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Amino refers to the group -NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Aminoacyl refers to the group -C(O)NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl. aryl, heteroaryl and heterocyclyl is as described herein.
  • Acylamino refers to the group -NR"C(O)R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Acyloxy refers to the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)O-heteroaryl, and -C(O)O-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Cycloalkyl refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 11 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, indanyl, 1,2,3,4-tetrahydronapthalenyl and the like.
  • Fused, spiro, bridged and caged ring groups e.g., norbornane, bicyclo[4.3.0]nonane
  • one ring may be aromatic, provided that the connection to the parent structure is through a non-aromatic carbon.
  • Heterocyclyl refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen. It will be understood that where, for instance, R2 or R' is an optionally substituted heterocyclyl which has one or more ring heteroatoms, the heterocyclyl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.
  • heterocyclyl and heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline.
  • phthalimide 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiazolidine, thiophene, benzo[b]th iophene, morpholino, piperidinyl, pyrrolidine, tetra hydrofuranyl, triazole, and the like.
  • C1-4 alkyl When a range of values is specified, for example C1-4 alkyl, it encompasses each value within the range, as well as, all possible intervening ranges.
  • C1-4 alkyl this includes Ci, C2, C3, C4, C1-4, C2-4, C3-4, C1-3, C2-3, and C1-2 alkyl.
  • a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkyl, alkoxy, alkenyl, alken
  • “Isomer” includes especially optical isomers (for example essentially pure enantiomers, essentially pure diastereomers, and mixtures thereof) as well as conformation isomers (i.e. isomers that differ only in their angles of at least one chemical bond), position isomers (particularly tautomers), and geometric isomers (e.g. cis-trans isomers).
  • optical isomers for example essentially pure enantiomers, essentially pure diastereomers, and mixtures thereof
  • conformation isomers i.e. isomers that differ only in their angles of at least one chemical bond
  • position isomers particularly tautomers
  • geometric isomers e.g. cis-trans isomers
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • the invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • "Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer.
  • the compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer.
  • the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • Jacques et al. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).
  • the present disclosure provides a compound of Formula (I) or a salt, solvate, stereoisomer or prodrug thereof: wherein Ri and R2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted aryl, optionally substituted heteroaryl; or Ri and R2 are linked to form an optionally substituted cyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
  • R3 is selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, optionally substituted heteroaryl;
  • X2 is selected from N and CP ;
  • R4 is selected from optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Xi is selected from N and CRs
  • Rs is selected from H, halo, cyano, optionally substituted alkyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • At least one of Xi and X2 is N. In some embodiments, X2 is N and Xi is CRs. In some embodiments, both Xi and X2 are N.
  • the present disclosure provides a compound of Formula (li) or a salt, solvate, stereoisomer or prodrug thereof: wherein Ri and 2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted aryl, optionally substituted heteroaryl; or Ri and R2 are linked to form an optionally substituted cyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
  • R3 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, optionally substituted heteroaryl;
  • R4 is selected from optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Xi is selected from N and CRs
  • Rs is selected from H, halo, cyano, optionally substituted alkyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • Compounds of Formula (I) are inhibitors which lack a carboxylate moiety or their bioisosteres. They also show no significant toxic effects in epithelial liver cell line. These compounds show 80% or better performance with respect to ETBDK8 and ETBDK9.
  • Xi is N. In some embodiments, Xi is N and X2 is CR4.
  • Ri and R2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, Ri and R2 are independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, Ri and R2 are independently selected from hydrogen, halo, and optionally substituted alkyl. In some embodiments, Ri and R2 are independently selected from hydrogen, halo, and optionally substituted alkyl. C1-C6
  • Ri and R2 are linked to form optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, Ri and R2 are linked to form optionally substituted aryl.
  • the compound of Formula (I) is a compound of Formula (lia): wherein R' is selected from halo, oxo, cyano, optionally substituted alkyl, and optionally substituted alkoxy; and a is an integer selected from 0 to 4.
  • Ri and R2 are linked to form optionally substituted heteroaryl.
  • the compound of Formula (I) is a compound of Formula (lb):
  • R 3 is selected from H, optionally substituted arylalkyl, optionally substituted aryl, optionally substituted heteroaryl. In some embodiments, R 3 is selected from optionally substituted aryl(Ci-C4)alkyl, optionally substituted aryl, optionally substituted heteroaryl. In some embodiments, R 3 is selected from optionally substituted phenylmethyl, optionally substituted phenyl, and optionally substituted 3,4-dihydro-2H- isoquinolin-l-onyl.
  • Rs is selected from optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted fused phenylpiperidonyl, optionally substituted benzimidazolyl, and optionally substituted furanyl.
  • the optionally subsituted Rs is selected from In some embodiments, the optional substituent on Rs is selected from halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted heterocyclyl and optionally substituted heteroaryl.
  • the optional substituent on Rs is selected from halo, oxo, optionally substituted C1-C5 alkyl, optionally substituted Ci- Cs alkoxy, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted heterocyclyl and optionally substituted heteroaryl.
  • the optional substituent on R3 is selected from halo, oxo, C1-C5 alkyl, C1-C5 alkoxy, trifluoromethyl,
  • the compound of Formula (I) is a compound of Formula (lie): wherein R6 is selected from halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted heterocyclyl and optionally substituted heteroaryl; or R6 is linked with the phenyl moiety to form an optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl; n is an integer selected from 0 to 2; m is an integer selected from 0 to 4.
  • the compound of Formula (I) is a compound of Formula (lid): wherein Rs is selected from halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted heterocyclyl and optionally substituted heteroaryl; or Rs is linked with the phenyl moiety to form an optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl;
  • L is an acylene linker having 0-5 carbon on either side of the acylene moiety; and m is an integer selected from 0 to 4.
  • Rs is selected from halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aminoacylalkyl, optionally substituted acylaminoalkyl, and optionally substituted heteroaryl.
  • Rs is selected from halo, oxo, optionally substituted Ci-Cs alkyl, optionally substituted Ci-Cs alkoxy, optionally substituted aminoacyl(Ci-Cs)alkyl, optionally substituted acylamino(Ci-Cs)alkyl, and optionally substituted heteroaryl.
  • Rs is linked with the phenyl moiety to form an optionally subsituted heterocyclyl.
  • optionally substituted 3,4-dihydro-2H-isoquinolin- 1-only may be formed.
  • Rs is selected from halo, alkyl, oxo, In some embodiments, Re is at a para position. In some embodiments, Re is at a meta position.
  • n is an integer selected from 0 to 1.
  • L is selected from
  • m is an integer selected from 0 to 3. In some embodiments, m is an integer selected from 0 to 2. In some embodiments, m is an integer selected from 0 to 1.
  • R4 is selected from optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, R4 is selected from optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, and optionally substituted tetra hydrofuranyl.
  • the optional substituent on R4 is selected from halo, cyano, oxo, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, and optionally substituted acylamino. In some embodiments, the optional substituent on R4 is selected from halo, optionally substituted alkyl,C o1-pCti6onally substituted imidazolyl.
  • Rs is selected from H, halo, cyano, optionally substituted alkyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, Rs is selected from optionally substituted alkyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, Rs is optionally substituted alkyl. In some embodiments, Rs is optionally substituted C1- aCl6kyl.
  • the compound of Formula (I) is a compound of Formula (lie) :
  • R? is selected from halo, cyano, oxo, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino;
  • X3 and X4 are independently CR8 or N;
  • Rs is selected from halo, cyano, optionally substituted alkyl; and p is an integer selected from 0 to 4.
  • halophenyl ring compounds demonstrate better activity than five-membered ring such as imidazole, pyridyl, and pyrimidyl analogs.
  • the optional substituent on R7 is selected from halo, cyano, oxo, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, and optionally substituted acylamino.
  • R? is selected from halo, cyano, oxo, optionally substituted aryl and optionally substituted heteroaryl.
  • the optional substituent on R7 is selected from halo, optionally substitutedC1-C6 alkyl, optionally substituted imidazolyl.
  • both X3 and X4 are C, or either one of X3 and X4 is N.
  • p is an integer selected from 0 to 3. In some embodiments, p is an integer selected from 0 to 2. In some embodiments, p is an integer selected from 0 to 1.
  • the compound of Formula (I) is a compound of Formula (Ilf): In some embodiments, the compound of Formula (I) is a compound of Formula (lig): (lig).
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and at least one of a carrier, diluent and excipient.
  • the compound is a compound of Formula (I) or a salt, solvate, stereoisomer or prodrug thereof: wherein Ri and R2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted aryl, optionally substituted heteroaryl; or Ri and R2 are linked to form an optionally substituted cyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
  • R3 is selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, optionally substituted heteroaryl;
  • X2 is selected from N and CR
  • R4 is selected from optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • X1 is selected from N and CR5;
  • R5 is selected from H, halo, cyano, optionally substituted alkyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and wherein at least one of Xi and X2 is N.
  • the compound is a compound of Formula (Hi) or a salt, solvate, stereoisomer or prodrug thereof: wherein Ri and R2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted aryl, optionally substituted heteroaryl; or Ri and R2 are linked to form an optionally substituted cyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
  • R3 is selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, optionally substituted heteroaryl;
  • Xi is selected from N and CRs;
  • Rs is selected from H, halo, cyano, optionally substituted alkyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound of Formula (I) is selected from:
  • the compound of Formula (I) is selected from:
  • the present disclosure also provides a compound of Formula (II) or a salt, solvate, stereoisomer or prodrug thereof: wherein Rg is selected from optionally substituted alkyl, optionally substituted oxyacyl, optionally substituted acyloxy, optionally substituted aryl, optionally substituted heteroaryl;
  • Rw is selected from optionally substituted aryl, optionally substituted heteroaryl;
  • X5 and X e are independently selected from N and CR11;
  • X6 is selected from N, S and CR11;
  • Rn is selected from H, halo, cyano, optionally substituted alkyl; and q is an integer selected from 0 to 4; r is an integer selected from 0 to 2; and t is an integer selected from 0 to 2.
  • the present disclosure also provides a compound of Formula (Hi) or a salt, solvate, stereoisomer or prodrug thereof: wherein Rg is selected from optionally substituted alkyl, optionally substituted oxyacyl, optionally substituted acyloxy, optionally substituted aryl, optionally substituted heteroaryl;
  • R10 is selected from optionally substituted aryl, optionally substituted heteroaryl
  • X5 and Xs are independently selected from N and CR11; and q is an integer selected from 0 to 4.
  • Compounds of Formula (II) are inhibitors which lack a carboxylate moiety or their bioisosteres. They also show no significant toxic effects in epithelial liver cell line. These compounds show 80% or better performance with respect to ETBDK8 and ETBDK9.
  • Rg is selected from optionally substituted alkyl, optionally C1-C6 substituted C1-C a6lkyloxyacyl, optionally substituted alkylacyloCx1y-,C6 optionally substituted aryl, optionally substituted 5 or 6 membered heteroaryl.
  • the optionally substituted 5 or 6 membered heteroaryl may be fused to the naphthalene ring.
  • Rg is selected from alkyl, tCri1f-lCuo6romethyl, alkyloxyacyl, Ci-CC1s-C6 alkylacyloxy, phenyl, and fused pyrrolyl.
  • Rio is selected from optionally substituted aryl. In some embodiments, Rio is selected from optionally substituted phenyl and optionally substituted naphthalenyl. In some embodiments, Rio is selected from optionally substituted phenyl. In some embodiments, Rio is selected from optionally substituted pyrazolyl, optionally substituted triazolyl, optionally substituted tetrazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, and optionally substituted pyrimidinyl.
  • the optional substituent on Rio is selected from halo, optionally substituted alkyl, and optionally substituted alkoxy.
  • the optional substituent on Rw is selected from halo, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.
  • At least one of X5 and X6 is N. In some embodiments, X5 and X6 are both N.
  • q is an integer selected from 0 to 3. In some embodiments, q is an integer selected from 0 to 2. In some embodiments, q is an integer selected from 0 to 1.
  • the compound of Formula (II) is a compound of Formula (Ilia): wherein R12 is selected from halo, optionally substituted alkyl, optionally substituted alkoxy; and u is an integer selected from 0 to 4.
  • naphthalene moiety performs better than a phenyl moiety as the molecule's hydrophobicity is enhanced, allowing this group to interact more effectively with the hydrophobic region of the binding site.
  • the optional substituent on R12 is selected from halo, optionally substituted alkyl, and optionally substituted alkoxy. In some embodiments, the optional substituent on R12 is selected from halo, optionally substituted C1-C6 alkyl, and optionally substitutedC1-C6 alkoxy.
  • u is an integer selected from 0 to 3. In some embodiments, u is an integer selected from 0 to 2. In some embodiments, u is an integer selected from 0 to 1.
  • the compound of Formula (II) is a compound of Formula (Ilib):
  • R13 is selected from halo, optionally substituted alkyl, optionally substituted alkoxy; and v is an integer selected from 0 to 4.
  • the optional substituent on R13 is selected from halo, optionally substituted alkyl, and optionally substituted alkoxy. In some embodiments, the optional substituent on R13 is selected from halo, optionally substituted C1-C6 alkyl, and optionally substituted C1- aCl6koxy.
  • v is an integer selected from 0 to 3. In some embodiments, v is an integer selected from 0 to 2. In some embodiments, v is an integer selected from 0 to 1.
  • the compound is a compound of Formula (Ilii) or a salt, solvate, stereoisomer or prodrug thereof: wherein R9 is selected from optionally substituted alkyl, optionally substituted oxyacyl, optionally substituted acyloxy, optionally substituted aryl, optionally substituted heteroaryl;
  • Rio is selected from optionally substituted aryl, optionally substituted heteroaryl
  • X7 are independently selected from N and CR11;
  • Rn is selected from H, halo, cyano, optionally substituted alkyl; and q is an integer selected from 0 to 4; r is an integer selected from 0; and t is an integer selected from 0 to 1. Accordingly, the structure may be represented as follows:
  • the compound of Formula (II) is selected from:
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), (II), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and at least one of a carrier, diluent and excipient.
  • the present disclosure provides a method of treating a disease or condition associated with a dysregulation of a Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK) in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound of Formula (I) as disclosed herein, or a salt, solvate, stereoisomer or prodrug thereof.
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • the present disclosure also provides a compound of Formula (I) for use in treating a disease or condition associated with a dysregulation of a Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK).
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • the present disclosure also provides a use of a compound of Formula (I) in the manufacture of a medicament for the treatment of a disease or condition associated with a dysregulation of a Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK).
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • the present disclosure provides a method of treating a disease or condition associated with a dysregulation of a Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK) in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound of Formula (II) as disclosed herein or a salt, solvate, stereoisomer or prodrug thereof.
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • the present disclosure also provides a compound of Formula (II) for use in treating a disease or condition associated with a dysregulation of a Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK).
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • the present disclosure also provides a use of a compound of Formula (II) in the manufacture of a medicament for the treatment of a disease or condition associated with a dysregulation of a Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK).
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • the disease or condition associated with a dysregulation of BCKDK is a cancer.
  • the disease or condition associated with a dysregulation of BCKDK is selected from liver cancer, kidney cancer, stomach cancer and colorectal cancer.
  • the top metabolic pathway being perturbed is the downregulation of BCAA catabolism.
  • the downregulation of BCAA catabolism is also present in other cancers.
  • the compound of the invention can be administered to a subject as a pharmaceutically acceptable salt thereof.
  • Suitable pharmaceutically acceptable salts include, but are not limited to salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
  • the present invention includes within its scope cationic salts eg sodium or potassium salts, or alkyl esters (eg methyl, ethyl) of the phosphate group.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • prodrug any compound that is a prodrug of the compound of formula (I) or (II) is also within the scope and spirit of the invention.
  • the compound of the invention can be administered to a subject in the form of a pharmaceutically acceptable pro-drug.
  • pro-drug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compound of the invention. Such derivatives would readily occur to those skilled in the art.
  • Other texts which generally describe prodrugs (and the preparation thereof) include: Design of Prodrugs, 1985, H. Bundgaard (Elsevier); The Practice of Medicinal Chemistry, 1996, Camille G. Wermuth et al., Chapter 31 (Academic Press); and A Textbook of Drug Design and Development, 1991, Bundgaard et al., Chapter 5, (Harwood Academic Publishers).
  • the compound of the invention may be in crystalline form either as the free compound or as a solvate (e.g. hydrate) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
  • the compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the patient in a therapeutically effective amount.
  • a therapeutically effective amount is intended to include at least partially attaining the desired effect, or delaying the onset of, or inhibiting the progression of, or halting or reversing altogether the onset or progression of macular degeneration.
  • the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages may lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
  • Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the severity of the condition as well as the general age, health and weight of the patient to be treated.
  • the compound of the invention may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition.
  • the formulation of such compositions is well known to those skilled in the art.
  • the composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.
  • compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the compound may be injected directly to the eye, and in particular the vitreous of the eye.
  • the compound, composition or combination of the invention can be administered to the vitreous of the eye using any intravitreal or transscleral administration technique.
  • the compound, composition or combination can be administered to the vitreous of the eye by intravitreal injection.
  • Intravitreal injection typically involves administering a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug in a total amount between 0.1 ng to 10 mg per dose.
  • Injectables for such use can be prepared in conventional forms, either as a liquid solution or suspension or in a solid form suitable for preparation as a solution or suspension in a liquid prior to injection, or as an emulsion.
  • Carriers can include, for example, water, saline (e.g., normal saline (NS), phosphate-buffered saline (PBS), balanced saline solution (BSS)), sodium lactate Ringer's solution, dextrose, glycerol, ethanol, and the like; and if desired, minor amounts of auxiliary substances, such as wetting or emulsifying agents, buffers, and the like can be added.
  • saline e.g., normal saline (NS), phosphate-buffered saline (PBS), balanced saline solution (BSS)
  • NS normal saline
  • PBS phosphate-buffered saline
  • BSS balanced saline solution
  • Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by using surfactants.
  • the compound, composition or combination can be dissolved in a pharmaceutically effective carrier and be injected into the vitreous of the eye with a fine gauge hollow bore needle (e.g., 30 gauge, 1/2 or 3/8 inch needle) using a temporal approach (e.g., about 3 to about 4 mm posterior to the limbus for human eye to avoid damaging the lens).
  • solutions or suspensions of the compound, composition or combinations of the invention may be formulated as eye drops, or as a membranous ocular patch, which is applied directly to the surface of the eye.
  • Topical application typically involves administering the compound of the invention in an amount between 0.1 ng and 10 mg.
  • the compound of the invention may also be suitable for intravenous administration.
  • a compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate or prodrug thereof may be administered intravenously at a dose of up to 16 mg/m 2 .
  • the compound or composition of the invention may also be suitable for oral administration and may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • the compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate or prodrug is orally administerable.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • a binder e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • the compound or composition of the invention may be suitable for topical administration in the mouth including lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compound or composition of the invention may be suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like.
  • Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Transdermal patches may also be used to administer the compounds of the invention.
  • the compound or composition of the invention may be suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the compound, composition or combination isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compound or composition may be presented in unitdose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage composition are those containing a daily dose or unit, daily subdose, as herein above described, or an appropriate fraction thereof, of the active ingredient.
  • composition or combination of this invention may include other agents conventional in the art having regard to the type of composition or combination in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
  • suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
  • Suitable disintegrating agents include cornstarch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable flavouring agents include peppermint oil, oil of Wintergreen, cherry, orange or raspberry flavouring.
  • Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters. waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • the present disclosure relates to small molecule inhibitors targeting the Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK), a key enzyme in the regulation of branched- chain amino acid (BCAA) metabolism.
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • BCAA branched- chain amino acid
  • Experimental validation revealed micromolar potency of two compounds ETBDK8 and ETBDK9, confirming their inhibitory effects on BCKDK.
  • the machine learning (ML) model recently developed in house was used to screen ⁇ 10 million small molecules in ZINC20 database that are available for purchase. The topranked 10,000 compounds were then further studied through molecular docking analysis against the homology model of human BCKDK.
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • the molecular docking analysis was performed using the Glide modules within the Schrodinger software suite, against the homology model of human Branched-Chain Ketoacid Dehydrogenase Kinase (BCKDK).
  • BCKDK Branched-Chain Ketoacid Dehydrogenase Kinase
  • the protein structure was prepared by adding hydrogen atoms.
  • the database of top-ranked 10,000 compounds from Machine learning based virtual screening was prepared and optimized using LigPrep module, 9 to generate all possible ionization states at pH 7.0 ⁇ 2.0 and generating multiple conformations for each compound.
  • a receptor grid box was generated around the allosteric site of BCKDK where the tetrazole derivative binds in the 8EGQ structure using the Receptor Grid Generation tool in Glide.
  • the grid box dimensions were set to encompass the entire active site with a sufficient margin for accurate docking.
  • the receptor grid was designed to allow flexibility in ligand positioning during the molecular docking simulations.
  • the prepared compound database was docked into the allosteric site of BCKDK using the Glide Standard Precision (SP) docking method.
  • SP Glide Standard Precision
  • the docking results were analyzed, and compounds were ranked based on their Glide Score values, reflecting the predicted binding affinities.
  • the top 100 compounds were visually inspected and shortlisted 14 compounds for further experimental investigation.
  • Knockdown cell line #64 has the highest level of BCKDK expression among the knockdown cell lines, followed by #26 and #82, which shows almost complete knockdown of BCKDK.
  • Figure IB cell proliferation assays showed that the degree of BCKDK expression is proportional to the IC50 of the two hits we discovered, indicating that these hits act mostly by targeting BCKDK.
  • THLE-2 cell line which is an epithelial liver cell line commonly used for comparison with liver cancer cell lines.
  • Figure 3 shows that both hits do not cause significant toxic effects on THLE-2 cell line.
  • ETBDK8 and ETBDK9 exhibit distinct scaffolds with a Tanimoto coefficient (Tc) of 0.11, indicating their substantial dissimilarity between them.
  • Tc Tanimoto coefficient
  • the two hits differ significantly (Tc ⁇ 0.15) from known BCKDK inhibitors also such as (S)- CPP, phenylbutyrate, BT2, aryl-tetrazoles, PF-07238025, PF-07208254, and PF- 07247685.
  • the known BCKDK inhibitors feature a carboxylic acid group (found in (S)- CPP, phenylbutyrate, BT2, PF-07238025, PF-07208254, and PF-07247685) or its bioisoster tetrazole (as in aryl-tetrazoles).
  • the newly identified two hits lack any acidic functional groups.
  • the known inhibitors showcase distinct structural motifs, such as thiophene/benzothiophene (BT2, PF-07208254), thiazole (PF- 07238025, PF-07247685), or an aryl tetrazole ring.
  • ETBDK8 has a novel scaffold composed of a pyridine (Rl), imidazole (R2), aryl (R3), and benzimidazole (R4) rings.
  • ETBDK9 features a naphthalene group (Rl) linked to a piperazine sulphonyl group, quinoxaline, and aryl ring. This structural comparative analysis underscores the unique structural features of ETBDK8 and ETBDK9, setting them apart from the established hits in terms of both scaffold and functional groups.
  • the compound ETBDK8 and ETBDK9 bind to allosteric binding site of BCKDK ( Figure 5).
  • the nitrogen atom of pyridine ring (Rl) of BCKDK8 formed a hydrogen bond interaction with R197, and additionally, pyridine ring is nestled between H162 and Y129, forming a sandwich-like structure through pi-pi stacking interactions with both residues, imidazole (R2) ring is positioned within the hydrophobic pocket, formed by residues 1102, L136, V155, L158, L159 and 1200.
  • the phenyl ring (R3) formed cation-Pi interaction with R197 and concurrently established hydrophobic interactions with L159.
  • the Benzimidazole ring (R4) formed a cation-pi interactions with both R197 and R201. Additionally, R4 also interacted with L198 and Y376.
  • the naphthalene ring (Rl') interacts with H162 and Y129, through a parallel displaced pi-pi stacking interactions with both residues. Additionally, Rl' is occupied the hydrophobic pocket, formed by residues 1102, L136, V155, L158, L159 and 1200.
  • the quinoxaline ring (R2') formed a cation-pi interactions with R201.
  • the phenyl ring (R3 1 ) formed cation-Pi interaction with R197 and concurrently hydrophobically interacted with L164 and Y376.
  • ETBDK8 analogues All- A26
  • 5 ETBDK9 analogues B11-B15
  • A16 demonstrated the most potent activity, with an ICso of 0.38 pM on Hep3B cells significantly lower than that of ETBDK8 (4.13 pM). Additionally, its ICso on Hep3B BCKDK KD cells was 10 times higher, indicating target specificity.
  • A16 also exhibited efficacy against other liver cancer cell lines, such as Huh7, while minimally affecting THLE-2, a non-cancerous hepatocyte cell line.
  • imidazole derivatives are synthesized in good yields through the reaction of commercially accessible guanidine with a-halo ketones in DMF or MeCN.
  • the benzimidazole ring is synthesized through the condensation of o-diaminobenzenes with carboxylic acids or their derivatives. This process involves heating the reagents together in the presence of concentrated hydrochloric acid (Philips reaction).
  • the sulfonamide can be synthesized by the reaction of amine with sulfonyl chloride with good yields
  • Aryl amination can be achieved using a copper catalyst. This reaction involves the combination of an amine with an aryl chloride in the presence of both a copper catalyst and a base, often yielding satisfactory yields.

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Abstract

La présente divulgation concerne des modulateurs de la cétoacide déshydrogénase kinase à chaîne ramifiée et des procédés associés.
PCT/SG2025/050234 2024-04-29 2025-04-01 Modulateurs de la cétoacide déshydrogénase kinase à chaîne ramifiée et procédés associés Pending WO2025230464A1 (fr)

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