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US 2017/0000768 A1Published application
Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof
AssigneesDuke University, Chaperone Therapeutics, Inc.
InventorsDennis J. Thiele, Daniel W. Neef, Jose S. Mendoza
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Abstract
The present invention relates to HSF activating compounds, methods for their discovery, and their research and therapeutic uses, as well as pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, mixtures (including both R and S enantiomeric forms and racemic mixtures thereof), and pharmaceutical Formulations thereof. In particular, the present invention provides compounds capable of facilitating HSF1 homotrimerization, and methods of using such compounds as therapeutic agents to treat a number of conditions associated with irregular HSF1 activity.
Claims6
A method of treating a patient suffering from a disease ameliorated by the activation of Heat Shock Transcription Factor 1 comprising treatment of the patient with a therapeutic amount of a compound described by a Formula selected from Formulas I, III, VI, VIII, and X:
- wherein R1 and R2 are independently chosen from hydrogen;
- an optionally substituted saturated or unsaturated alkyl;
- S(O)1-2R8, SO2NR8R9, C(O)R9, C(O)OR8, and C(O)NR8R9;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- wherein R8 and R9 are independently chosen from hydrogen, an optionally substituted saturated or unsaturated alkyl;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents;
- is either
- wherein R5 is independently chosen from hydrogen, halogen, and cyano;
- an optionally substituted saturated or unsaturated alkyl;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- wherein R6 and R7 are independently chosen from hydrogen;
- an optionally substituted saturated or unsaturated alkyl;
- S(O)1-2R8, SO2NR8R9, C(O)R9, C(O)OR8, and C(O)NR8R9;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- wherein X is O, S, or NR12c;
- wherein R10 and R11 are A) independently chosen from hydrogen, halogen, cyano, and nitro;
- an optionally substituted saturated or unsaturated alkyl;
- OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, and NR8C(O)OR9;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- or B) together with the atom to which R10 and R11 are attached form one or more substituted or unsubstituted cycloalkyl, cycloaryl, cycloheteroalkyl, or heteroaryl rings;
- wherein R8 and R9 are independently chosen from hydrogen, an optionally substituted saturated or unsaturated alkyl;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents;
- wherein R12a, R12b and R12c are independently chosen from hydrogen;
- an optionally substituted saturated or unsaturated alkyl;
- S(O)1-2R8, SO2NR8R9, C(O)R9, C(O)OR8, and C(O)NR8R9;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- wherein n is 0 to 4;
- wherein m is 0 to 5;
- wherein L is substituted or unsubstituted C;
- wherein Y is O, S, or NR16;
- wherein Z is O or S;
- wherein B is a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- wherein R14a and R14b are independently chosen from hydrogen;
- an optionally substituted group selected from a saturated or unsaturated alkyl;
- OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- wherein R8 and R9 are independently chosen from hydrogen, an optionally substituted saturated or unsaturated alkyl;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents;
- wherein R15 and R16 are independently hydrogen;
- an optionally substituted saturated or unsaturated alkyl;
- S(O)1-2R8, SO2NR8R9, C(O)R9, C(O)OR8, C(O)NR8R9;
- or a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- wherein Q is chosen from O, S and NR19;
- wherein n and m are 0 to 5;
- wherein L1 and L2 are substituted or unsubstituted C;
- wherein R17 and R18 are independently chosen from hydrogen;
- an optionally substituted saturated or unsaturated alkyl;
- OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, and NR8C(O)OR9;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- herein R8 and R9 are independently chosen from hydrogen, an optionally substituted saturated or unsaturated alkyl;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents;
- wherein R19 is independently hydrogen;
- an optionally substituted group selected from a saturated or unsaturated alkyl;
- S(O)1-2R8, SO2NR8R9, C(O)R9, C(O)OR8, and C(O)NR8R9;
- or a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- and
- wherein m, p, and o are 0 to 5;
- wherein n is 1 to 4;
- wherein L3, L4, L5, and L6 are substituted or unsubstituted C;
- wherein T is O, S, or NR24R25;
- wherein R20 and R21 are independently chosen from hydrogen;
- an optionally substituted group selected from a saturated or unsaturated alkyl;
- OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, and NR8C(O)OR9;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- wherein R22 and R23 are A) independently chosen from hydrogen;
- an optionally substituted group selected from a saturated or unsaturated alkyl;
- OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, and NR8C(O)OR9;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, OR8, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- or B) together with the atom to which R22 and R23 are attached form one or more substituted or unsubstituted heterocycloalkyl, or heteroaryl rings;
- wherein R8 and R9 are independently chosen from hydrogen, an optionally substituted saturated or unsaturated alkyl;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents;
- wherein R24 and R25 are independently hydrogen;
- an optionally substituted saturated or unsaturated alkyl;
- S(O)1-2R8, SO2NR8R9, C(O)R9, C(O)OR8, and C(O)NR8R9;
- and a saturated or unsaturated, aromatic or non-aromatic, 3-8 membered monocyclic ring, or 8-12 bicyclic membered ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with 1-5 substituents independently selected from the group consisting of R8, ORB, OC(O)R8, NR8R9, S(O)1-2R8, SO2NR8R9, NR8SO2R9, C(O)R9, C(O)OR8, C(O)NR8R9, NR8C(O)R9, NR8C(O)OR9, halogen, cyano, oxo, and nitro;
- and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, mixtures thereof, including both R and S enantiomeric forms and racemic mixtures thereof, as well as a pharmaceutical Formulation containing the compound.
73 more elements
Dependencies are inferred from the claim text.