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US 2026/0258000 A1Published application
Thymidylate synthase inhibitors and uses thereof
AssigneeUniversity of Florida Research Foundation, Inc.
InventorsMaria Zajac-Kaye, Robert William Huigens
Life of this patent
Estimating the term…
Abstract
Provided herein are compounds of Formula (I) or (II), and pharmaceutically acceptable salts), solvates, hydrates, stereoisomers, polymorphs, tautomers, co-crystals, isotopically labeled derivatives, and prodrugs thereof, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating and/or preventing diseases and/or conditions (e.g., proliferative disease, such as, cancers), or other diseases associated with a folate-dependent enzyme (e.g., thymidylate synthase, dihydrofolate reductase) in a subject. Provided are methods of inhibiting a folate-dependent enzyme (e.g., thymidylate synthase, dihydrofolate reductase) in a subject and/or biological sample.
Claims32
A compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein:
- R1A is hydrogen or optionally substituted alkyl;
- each instance of R1 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
- or optionally two instances of R1 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
- each instance of R2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
- or optionally two instances of R2 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
- each instance of Ra is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO2, —ORD1, —N(RD1a)2, or —SRD1, wherein RD1 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
- wherein each occurrence of RD1a is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- or optionally two instances of RD1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
- R is hydrogen, unsubstituted alkyl, or a nitrogen protecting group;
- R′ is
- R3 is optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
- each occurrence of RA is independently —SO2, —SRD1, —NO2, —N3, or —CN, or optionally two instances of RA are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
- R4 is —OR4A or —N(R4B)2;
- R4A is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
- each occurrence of R4B is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- or optionally two instances of R4B are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
- m is 0, 1, 2, or 3;
- p is 1, 2, 3, 4, 5, or 6;
- q is 1, 2, 3, 4, 5, or 6;
- r is 1, 2, 3, 4, 5, or 6;
- s is 1, 2, 3, 4, 5, or 6;
- and
- x is 1, 2, 3, 4, or 5.
21 more elements
A compound of Formula (II):
- or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof, wherein:
- X is —O— or —S—;
- R1A is hydrogen or optionally substituted alkyl;
- each instance of R1 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
- or optionally two instances of R1 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
- each instance of R2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, or a nitrogen protecting group;
- or optionally two instances of R2 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
- each instance of Ra is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO2, —ORD1, —N(RD1a)2, or —SRD1, wherein RD1 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
- wherein each occurrence of RD1a is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- or optionally two instances of RD1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
- R1′ is
- optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- R4 is —OR4A or —N(R4B)2;
- R5 is hydrogen, —ORD1, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- R4A is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
- each occurrence of R4B is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
- or optionally two instances of R4B are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
- m is 0, 1, 2, or 3;
- q is 1, 2, 3, 4, 5, or 6;
- r is 1, 2, 3, 4, 5, or 6;
- s is 1, 2, 3, 4, 5, or 6;
- and
- t is 1, 2, 3, 4, 5, or 6.
20 more elements
4-5. (canceled)
(canceled)
9-13. (canceled)
15-20. (canceled)
(canceled)
25-30. (canceled)
32-33. (canceled)
37-42. (canceled)
A compound of formula:
- or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph, tautomer, isotopically enriched form, or prodrug thereof.
(canceled)
(canceled)
51-68. (canceled)
(canceled)
Dependencies are inferred from the claim text.