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US 2021/0171503 A1Published application
Glycolate oxidase inhibitors and use thereof
AssigneeOrfan Biotech Inc.
InventorsHans MAAG, Miguel Xavier Fernandes
Life of this patent
Estimating the term…
Abstract
The present invention provides pyrazoles, isoxazoles, isothiazoles, thiadiazoles, and pyridazines according to Formula I as described herein, and pharmaceutically acceptable salts thereof. Pharmaceutical compositions and methods for treating primary hyperoxaluria, type I (PH) and kidney stones are also described.
Claims29
A compound according to Formula I:
- or a pharmaceutically acceptable salt or C1-6 alkyl ester thereof,
- wherein:
- ring A is selected from the group consisting of 1,2,3-thiadiazol-4,5-diyl, (5-methyl)-1H-pyrazol-3,4-diyl, (5-methyl)-isoxazol-3,4-diyl, (5-methyl)-isothiazol-3,4-diyl, and pyridazin-3,4-diyl;
- subscript n is 1, 2, 3, or 0;
- subscript m is 0, 1, or 2;
- W is selected from the group consisting of —NR3—, —C(R3)2—, —O—, —S—, —S(O)—, and —S(O)2—;
- each Y, if present, is independently selected from the group consisting of —O— and —C(R4)2—;
- R1 is selected from the group consisting of halo, cyano, 5- to 6-membered heteroaryl, and -L-(C6-10 aryl), wherein aryl is optionally substituted with R1a;
- R2 is selected from the group consisting of H and C1-6 alkyl;
- each R3 is independently selected from the group consisting of H, C1-6 alkyl, and C7-16 arylalkyl, wherein aryl in arylalkyl is optionally substituted with R3a;
- each R4 is independently selected from the group consisting of H, C1-6 alkyl, and C7-16 arylalkyl, wherein aryl in arylalkyl is optionally substituted with R4a;
- or
- two R4 are taken together to form C2-6 alkenyl;
- R1a is independently selected from the group consisting of halo, cyano, -M-(8- to 12-membered heterocyclyl), -M-(5- to 6-membered heteroaryl), -M-(C3-8 cycloalkyl), and -M-(C6-10 aryl), wherein heterocyclyl, heteroaryl, cycloalkyl, and aryl are optionally substituted with R1b;
- R3a is independently selected from the group consisting of halo, cyano, C1-6 alkyl, C1-6 alkoxy, -M-(8- to 12-membered heterocyclyl), -M-(5- to 6-membered heteroaryl), -M-(C3-8 cycloalkyl), and -M-(C6-10 aryl), wherein heterocyclyl, heteroaryl, cycloalkyl, and aryl are optionally substituted with R3b;
- R4a is independently selected from the group consisting of halo, cyano, -Q-(8- to 12-membered heterocyclyl), -Q-(5- to 6-membered heteroaryl), -Q-(C3-8 cycloalkyl), and -Q-(C6-10 aryl), wherein heterocyclyl, heteroaryl, cycloalkyl, and aryl are optionally substituted with R4b;
- each of R1b, R3b, and R4b is independently selected from the group consisting of halo and cyano;
- L, M, and Q are independently selected from the group consisting of a bond, —O—, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, and 2- to 6-membered heteroalkylene;
- and
- each heterocyclyl is optionally and independently substituted with one or more amine protecting groups;
- provided that if ring A is 1,2,3-thiadiazol-4,5-diyl, W is —NR3—, R3 is butyl, subscript m is 1, Y is —CHR4—, R4 is H, and subscript n is 1, then R1 is other than 4-(2H-tetrazol-5-yl)phenyl;
- provided that if ring A is 1,2,3-thiadiazol-4,5-diyl, W is —CH2— or —NH—, and subscript m is 0, then subscript n is 1, 2, or 3;
- provided that if ring A is 1,2,3-thiadiazol-4,5-diyl, W is —S—, subscript m is 1, and Y is —CH2—, then subscript n is 1, 2, or 3;
- provided that if ring A is 1,2,3-thiadiazol-4,5-diyl, W is S, subscript n is 1, and subscript m is 0, then R1 is other than 4-chloro;
- provided that if ring A is (5-methyl)-isoxazol-3,4-diyl, W is —CH2—, subscript n is 1, and subscript m is 1, then Y is 0;
- provided that if ring A is (5-methyl)-isoxazol-3,4-diyl, W is —CH2—, and subscript m is 0, then subscript n is 1, 2, or 3;
- provided that if ring A is (5-methyl)-isoxazol-3,4-diyl, W is —CH2—, subscript n is 1, and subscript m is 0, then R1 is other than 3-bromo, 4-bromo, 3-chloro, 4-chloro, 3-fluoro, and 4-fluoro;
- provided that if ring A is (5-methyl)-1H-pyrazol-3,4-diyl, W is —NR3—, R3 is H or C1-6 alkyl, and subscript m is 0, then subscript n is 1, 2, or 3;
- provided that if ring A is (5-methyl)-1H-pyrazol-3,4-diyl, W is —NR3—, R3 is H or C1-6 alkyl, subscript m is 1, and Y is —CH2—, then subscript n is 1, 2, or 3;
- provided that if ring A is (5-methyl)-isoxazol-3,4-diyl, W is —NH—, subscript n is 1, and subscript m is 0, then R1 is other than 3-cyano, 4-cyano, 3-bromo, 4-bromo, 3-chloro, 4-chloro, 3, fluoro, and 4-fluoro;
- provided that if ring A is (5-methyl)-1H-pyrazol-3,4-diyl, W is —CH2—, subscript n is 1, and subscript m is 1, then Y is 0;
- provided that if ring A is (5-methyl)-1H-pyrazol-3,4-diyl, W is —CH2—, and subscript m is 0, then subscript n is 1, 2, or 3;
- provided that if ring A is (5-methyl)-1H-pyrazol-3,4-diyl, W is —CH2—, subscript n is 1, and subscript m is 0, then R1 is other than 3-cyano, 4-cyano, 4-bromo, 3-chloro, 4-chloro, 3-fluoro, 4-fluoro, 3-pyridin-3-yl, 3-pyridin-4-yl, 3-(4-cyanophenyl), 3-(4-fluorophenyl), 4-(4-fluorophenyl), 3-phenoxyphenyl, and 4-phenoxyphenyl;
- provided that if ring A is pyridazin-3,4-diyl, W is —NR3—, Y is —CHR4—, R3 is propyl, R4 is H, subscript n is 1, and subscript m is 1, then R1 is other than 4-(2H-tetrazol-5-yl)phenyl.
31 more elements
(canceled)
5-7. (canceled)
9-13. (canceled)
15-17. (canceled)
19-20. (canceled)
(canceled)
27-31. (canceled)
33-42. (canceled)
A method for treating primary hyperoxaluria, type I (PH1) comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- ring A is selected from the group consisting of 1,2,3-thiadiazol-4,5-diyl, (5-methyl)-1H-pyrazol-3,4-diyl, (5-methyl)-isoxazol-3,4-diyl, (5-methyl)-isothiazol-3,4-diyl, and pyridazin-3,4-diyl;
- subscript n is 0, 1, 2, or 3;
- subscript m is 0, 1, or 2;
- W is selected from the group consisting of —NR3—, —C(R3)2—, —O—, —S—, —S(O)—, and —S(O)2—;
- each Y is independently selected from the group consisting of —O— and —C(R4)2—;
- R1 is selected from the group consisting of halo, cyano, 5- to 6-membered heteroaryl, and -L-(C6-10 aryl), wherein aryl is optionally substituted with R1a;
- R2 is selected from the group consisting of H and C1-6 alkyl;
- each R3 is independently selected from the group consisting of H, C1-6 alkyl, and C7-16 arylalkyl, wherein aryl in arylalkyl is optionally substituted with R3a;
- each R4 is independently selected from the group consisting of H, C1-6 alkyl, and C7-16 arylalkyl, wherein aryl in arylalkyl is optionally substituted with R4a;
- or
- two R4 are taken together to form C2-6 alkenyl;
- R1a is independently selected from the group consisting of halo, cyano, -M-(8- to 12-membered heterocyclyl), -M-(5- to 6-membered heteroaryl), -M-(C3-8 cycloalkyl), and -M-(C6-10 aryl), wherein heterocyclyl, heteroaryl, cycloalkyl, and aryl are optionally substituted with R1b;
- R3a is independently selected from the group consisting of halo, cyano, C1-6 alkyl, C1-6 alkoxy, -M-(8- to 12-membered heterocyclyl), -M-(5- to 6-membered heteroaryl), -M-(C3-8 cycloalkyl), and -M-(C6-10 aryl), wherein heterocyclyl, heteroaryl, cycloalkyl, and aryl are optionally substituted with R3b;
- R4a is independently selected from the group consisting of halo, cyano, -Q-(8- to 12-membered heterocyclyl), -Q-(5- to 6-membered heteroaryl), -Q-(C3-8 cycloalkyl), and -Q-(C6-10 aryl), wherein heterocyclyl, heteroaryl, cycloalkyl, and aryl are optionally substituted with R4b;
- each of R1, R3b, and R4b is independently selected from the group consisting of halo and cyano;
- L, M, and Q are independently selected from the group consisting of a bond, —O—, 37 C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, and 2- to 6-membered heteroalkylene;
- and
- each heterocyclyl is optionally and independently substituted with one or more amine protecting groups;
- provided that if ring A is 1,2,3-thiadiazol-4,5-diyl, W is S, subscript n is 1, and subscript m is 0, then R1 is other than 4-chloro;
- thereby treating the PH1.
18 more elements
A method for treating kidney stones comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- ring A is selected from the group consisting of 1,2,3-thiadiazol-4,5-diyl, (5-methyl)-1H-pyrazol-3,4-diyl, (5-methyl)-isoxazol-3,4-diyl, (5-methyl)-isothiazol-3,4-diyl, and pyridazin-3,4-diyl;
- subscript n is 0, 1, 2, or 3;
- subscript m is 0, 1, or 2;
- W is selected from the group consisting of —NR3—, —C(R3)2—, —O—, —S—, —S(O)—, and —S(O)2—;
- each Y is independently selected from the group consisting of —O— and —C(R4)2—;
- R1 is selected from the group consisting of halo, cyano, 5- to 6-membered heteroaryl, and -L-(C6-10 aryl), wherein aryl is optionally substituted with R1a;
- R2 is selected from the group consisting of H and C1-6 alkyl;
- each R3 is independently selected from the group consisting of H, C1-6 alkyl, and C7-16 arylalkyl, wherein aryl in arylalkyl is optionally substituted with R3a;
- each R4 is independently selected from the group consisting of H, C1-6 alkyl, and C7-16 arylalkyl, wherein aryl in arylalkyl is optionally substituted with R4a;
- or
- two R4 are taken together to form C2-6 alkenyl;
- R1a is independently selected from the group consisting of halo, cyano, -M-(8- to 12-membered heterocyclyl), -M-(5- to 6-membered heteroaryl), -M-(C3-8 cycloalkyl), and -M-(C6-10 aryl), wherein heterocyclyl, heteroaryl, cycloalkyl, and aryl are optionally substituted with R1b;
- R3a is independently selected from the group consisting of halo, cyano, C1-6 alkyl, C1-6 alkoxy, -M-(8- to 12-membered heterocyclyl), -M-(5- to 6-membered heteroaryl), -M-(C3-8 cycloalkyl), and -M-(C6-10 aryl), wherein heterocyclyl, heteroaryl, cycloalkyl, and aryl are optionally substituted with R3b;
- R4a is independently selected from the group consisting of halo, cyano, -Q-(8- to 12-membered heterocyclyl), -Q-(5- to 6-membered heteroaryl), -Q-(C3-8 cycloalkyl), and -Q-(C6-10 aryl), wherein heterocyclyl, heteroaryl, cycloalkyl, and aryl are optionally substituted with R4b;
- each of R1b, R3b, and R4b is independently selected from the group consisting of halo and cyano;
- L, M, and Q are independently selected from the group consisting of a bond, —O—, 37 C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, and 2- to 6-membered heteroalkylene;
- and
- each heterocyclyl is optionally and independently substituted with one or more amine protecting groups;
- provided that if ring A is 1,2,3-thiadiazol-4,5-diyl, W is S, subscript n is 1, and subscript m is 0, then R1 is other than 4-chloro;
- thereby treating the kidney stones.
18 more elements
51-54. (canceled)
Dependencies are inferred from the claim text.