Triazole glycolate oxidase inhibitors
AssigneeCantero Therapeutics, Inc.
InventorsHans MAAG, Miguel Xavier FERNANDES, Robert ZAMBONI, Elham AKBARIROMANI, Marc-Andre BEAULIEU, Yves LEBLANC, Pallavi THAKUR
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Abstract
The present invention provides triazole carboxylic acids and related compounds, as well as pharmaceutically acceptable salts thereof, which are useful as glycolate oxidase inhibitors. Pharmaceutical compositions and methods for treating primary hyperoxaluria, type I (PH) and kidney stones are also described.
Claims23
A compound according to Formula Ia:
- or a pharmaceutically acceptable salt thereof, wherein:
- L is ;
- the dashed line connected to Z1 is a single bond, Z1 is NR5, the dashed line connected to Z2 is a double bond, and Z2 is N, or
- the dashed line connected to Z1 is a double bond, Z1 is N, the dashed line connected to Z2 is a single bond, and Z2 is NR5;
- R1 is selected from H, unsubstituted C1-6 alkyl, substituted C1-6 alkyl, —(C1—6 alkylene)—OC(O)—(C1—6 alkyl), and —(C1—6 alkylene)—OC(O)—(C1—6 alkoxy);
- R2 is selected from the group consisting of H and halogen;
- R3 is selected from the group consisting of H, halogen, C1-12 alkyl, and C1-12 alkoxy ;
- R4 is selected from the group consisting of C6-12 aryl and 5- to 12-membered heteroaryl;
- R4 is substituted with one or more R4a;
- each R4a is independently C3-8 halocycloalkyl ;
- and
- R5 is selected from the group consisting of H, unsubstituted C1-6 alkyl, substituted C1-6 alkyl, C2-7 acyl, —(C1—6 alkylene)—OC(O)—(C1—6 alkyl), and —(C1—6 alkylene)—OC(O)—(C1—6 alkoxy);
- .
5-15. (canceled)
(canceled)
19-29. (canceled)
(canceled)
36-43. (canceled)
A compound, represented by the formula:
- or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof.
A process for preparing a compound represented by formula (36):
- or a tautomer thereof, and/or a salt thereof, comprising:
- a) combining a compound of formula (9a) or (9b):
- or a salt thereof, with a compound of formula (33):
- Pd(dppf)Cl2 or Pd(dppf)Cl2-CH2Cl2, and potassium carbonate in a mixture of 1,4-dioxane and water to form a compound of formula (34) or (34b):
- or a salt thereof;
- b) treating the compound of formula (34) or (34b), or the salt thereof, with trifluoroacetic acid and anisole in dichloromethane to provide a compound of formula (35) or (35b):
- a tautomer thereof, or a salt thereof;
- c) saponifying the compound of formula (35) or (35b), the tautomer thereof, or the salt thereof with an aqueous solution of sodium hydroxide in tetrahydrofuran;
- and
- d) acidifying with an aqueous solution of HCl to provide the compound of formula (36), the tautomer thereof, or the salt thereof.
Dependencies are inferred from the claim text.