Glucose uptake inhibitors
Inventors
Olszewski, Kellen L. • Kim, Ji-In • Poyurovsky, Masha V. • Liu, Kevin G. • Barsotti, Anthony • Morris, Koi
Assignees
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Publication Number
US-10988484-B2
Publication Date
2021-04-27
Expiration Date
Abstract
Provided herein are compounds that modulate glucose uptake activity and are useful for treating cancer, autoimmune diseases, inflammation, infectious diseases, and metabolic diseases. In certain embodiments, the compounds modulate glucose uptake activity by modulating cellular components, including, but not limited to those related to glycolysis and the known transporters/co-transporters of glucose such as GLUT1 and other GLUT family members/alternative hexose transporters. In certain embodiments, the compounds have the structure of formula I: wherein the variables have the values disclosed herein.
Core Innovation
The invention relates to a compound having the formula I, or a pharmaceutically acceptable salt thereof, defined by a structural framework that includes Ring B and Ring C and multiple substitution selections. Ring B is a five- or six-membered ring containing 1 or 2 heteroatoms selected from N, O and S, while Ring C is a five- or six-membered aryl or heteroaryl ring containing from 0 to 2 heteroatoms selected from N, O and S. The structure includes substituent selection rules for R1 and R2, with R3 and R4 as H and n and m each selected from 0, 1, or 2.
D is selected from O(CH2)yC(=O)NR5R6, OC(=O)(CH2)yNR5R6, O(CH2)yNR5R6, NHC(=O)(CH2)yNR5R6, NHC(=O)(CH2)yR7, and NH(CH2)yNR5R6, where y is selected from 1, 2, or 3. R5 and R6 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C1-C6 alkyl)-O(C1-C6 alkyl), aryl, aralkyl, heteroaryl, and C3-C6 cycloalkyl, and may together with the nitrogen form a 5- to 6-membered heterocyclic ring having up to 3 heteroatoms selected from N, O, and S.
R7 is selected from aryl, heteroaryl, and a heterocyclic group. The disclosure provides representative chemical structures across heteroaromatic fused ring cores with phenoxyacetyl or amide-linked side chains, including variants with different ring systems and chlorine substitution, and also describes a specific sub-structure B selection where X is O or S and R11 is H or C1-C6 alkyl.
Claims Coverage
The claim coverage centers on one independent compound claim defining formula I and four merged inventive features: ring composition, linker D selection, optional heterocycle formation from R5 and R6 with R7 selection, and a specific Ring B sub-structure refinement. Dependent claims also define a formula IIIa compound, a pharmaceutical composition, and a method of inhibiting tumor growth or metastasis.
Compound of formula I with defined ring composition
A compound having the formula I, or a pharmaceutically acceptable salt thereof, wherein Ring B is a five- or six-membered ring containing 1 or 2 heteroatoms selected from N, O and S; Ring C is a five- or six-membered aryl or heteroaryl ring containing from 0 to 2 heteroatoms selected from N, O and S; each R1 and each R2 are independently selected from the recited substituent groups; n and m are each selected from 0, 1, or 2; and R3 and R4 are H.
Linkage D with defined spacer y
D is selected from the recited oxygen- and nitrogen-containing linker groups, including O(CH2)yC(=O)NR5R6, OC(=O)(CH2)yNR5R6, O(CH2)yNR5R6, NHC(=O)(CH2)yNR5R6, NHC(=O)(CH2)yR7, and NH(CH2)yNR5R6, with y selected from 1, 2, or 3.
R5 and R6 selection with optional heterocycle formation
R5 and R6 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C1-C6 alkyl)-O(C1-C6 alkyl), aryl, aralkyl, heteroaryl, and C3-C6 cycloalkyl, and may be taken together with the nitrogen to form a 5- to 6-membered heterocyclic ring having up to 3 heteroatoms selected from N, O, and S.
R7 selection and Ring B sub-structure refinement
R7 is selected from aryl, heteroaryl, and a heterocyclic group, and the compound of claim 1 has a specified sub-structure B selected from illustrated heteroaryl fused ring sub-structures where X is O or S and R11 is H or C1-C6 alkyl, optionally extended to C3-C6 cycloalkyl.
Formula IIIa compound definition
A compound, or a pharmaceutically acceptable salt thereof, defined by formula IIIa with Ring B as a five- or six-membered N/O/S-containing heterocycle, with the selections for R1, R2, D, R5, R6, and R7, while R3 and R4 are fixed as H and y is selected from 1 to 3.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
Method of inhibiting tumor growth or metastasis
A method of inhibiting tumor growth or metastasis comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 4.
Coverage is centered on a formula I compound with constrained Ring B and Ring C compositions, defined linker D options and spacer length y, and substituent rules for R1, R2, R5, R6, and R7, including optional heterocycle formation from R5 and R6. Dependent claims further refine the scaffold with a specified sub-structure B and a formula IIIa definition, and extend to a pharmaceutical composition and a method of inhibiting tumor growth or metastasis.
Stated Advantages
Inhibits tumor growth or metastasis.
Documented Applications
A method of inhibiting tumor growth or metastasis by administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition.
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