Compounds and methods for treating oxalate-related diseases
AssigneeOxaluRx, Inc.
InventorsAyman Kabakibi, Mehmet Kahraman, Michael Clare, Thomas Leedom
Life of this patent
Estimating the term…
Abstract
Disclosed herein are compounds and compositions for modulating glycolate oxidase, useful for treating oxalate-related diseases, such as hyperoxaluria, where modulating glycolate oxidase is expected to be therapeutic to a patent in need thereof. Methods of modulating glycolate oxidase activity in a human or animal subject are also provided.
Claims34
A method of inhibiting glycolate oxidase (GOX) activity in a biological sample comprising contacting the biological sample with a compound of Formula III,
- or a salt, polymorph, or tautomer thereof, wherein:
- R1 is chosen from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl;
- L is chosen from O, S, CH2, NH, NR4, S (O), SO2, and CR4═CR5;
- each R2 is independently chosen from 5-10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkyl, C6-C10 aryl, cyano, and halogen;
- n is 0, 1, or 2;
- R3 is chosen from 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, C1-C6 alkyl, C1-C6 sulfonyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, C6-C10 aryl, and C6-C10 arylalkyl;
- R4 and R5 are each independently chosen from hydrogen and C1-C6 alkyl, or R4 and R5, together with the atoms to which they are attached, form a cycloalkenyl;
- and
- each R6 is independently chosen from 4-6-membered heterocycloalkyl, 5-10-membered heteroaryl, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, carboxyl, cyano, halogen, hydroxyl, methyl-4-6-membered heterocycloalkyl, and phenyl;
- and
- m is 0, 1, 2, or 3.
A method of treating an oxalate-related disease chosen from hyperoxaluria, idiopathic calcium oxalate stone former (ICSF), urolithiasis, nephrolithiasis, kidney stones, nephrocalcinosis, urinary tract infection, chronic kidney disease (CKD), end-stage renal disease, systemic oxalosis, oxalate poisoning, and Bird's disease in a subject in need thereof, comprising the step of administering to the subject a compound of Formula III,
- or a salt, polymorph, or tautomer thereof, wherein:
- R1 is chosen from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl;
- L is chosen from O, S, CH2, NH, NR4, S (O), SO2, and CR4═CR5;
- each R2 is independently chosen from 5-10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkyl, C6-C10 aryl, cyano, and halogen;
- n is 0, 1, or 2;
- R3 is chosen from 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, C1-C6 alkyl, C1-C6 sulfonyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, C6-C10 aryl, and C6-C10 arylalkyl;
- R4 and R5 are each independently chosen from hydrogen and C1-C6 alkyl, or R4 and R5, together with the atoms to which they are attached, form a cycloalkenyl;
- and
- each R6 is independently chosen from 4-6-membered heterocycloalkyl, 5-10-membered heteroaryl, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, carboxyl, cyano, halogen, hydroxyl, methyl-4-6-membered heterocycloalkyl, and phenyl;
- and
- m is 0, 1, 2, or 3.
A method of treating an oxalate-related disease chosen from hyperoxaluria, idiopathic calcium oxalate stone former (ICSF), urolithiasis, nephrolithiasis, kidney stones, nephrocalcinosis, urinary tract infection, chronic kidney disease (CKD), end-stage renal disease, systemic oxalosis, oxalate poisoning, and Bird's disease in a subject in need thereof, comprising the sequential or co-administration of a compound of Formula III,
- or a salt, polymorph, or tautomer thereof, wherein:
- R1 is chosen from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl;
- L is chosen from O, S, CH2, NH, NR4, S (O), SO2, and CR4═CR5;
- each R2 is independently chosen from 5-10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkyl, C6-C10 aryl, cyano, and halogen;
- n is 0, 1, or 2;
- R3 is chosen from 3-10-membered heterocycloalkyl, 5-10-membered heteroaryl, C1-C6 alkyl, C1-C6 sulfonyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, C6-C10 aryl, and C6-C10 arylalkyl;
- R4 and R5 are each independently chosen from hydrogen and C1-C6 alkyl, or R4 and R5, together with the atoms to which they are attached, form a cycloalkenyl;
- and
- each R6 is independently chosen from 4-6-membered heterocycloalkyl, 5-10-membered heteroaryl, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, carboxyl, cyano, halogen, hydroxyl, methyl-4-6-membered heterocycloalkyl, and phenyl;
- and
- m is 0, 1, 2, or 3, and a second therapeutic agent.
Dependencies are inferred from the claim text.