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US 12,180,186 B2Granted
Quaternary indazole glucocorticoid receptor antagonists
AssigneeCorcept Therapeutics, Inc.
InventorsHazel Hunt, Lorna Duffy, Ian Strutt, Morgan Jouanneau, Thomas Hornsby, Mark Mills, Andrew William Phillips, Jon-Paul Ward
Life of this patent
Estimating the term…
Abstract
The present disclosure provides compounds of Formula I or II. Compounds of Formula I or II may be used in pharmaceutical formulations, and may be used for modulating glucocorticoid receptors.
Claims21
A method of treating a disorder or condition through modulating a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, a therapeutically effective amount of a compound of Formula IVa,
- or a pharmaceutically acceptable salt thereof, thereby treating the disorder or condition,
- wherein
- R1 is heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms each N, phenyl or a heteroaryl having 5 to 6 ring members and 1 to 2 heteroatoms each N or S, each substituted with 1 to 3 R1a groups;
- and
- each R1a is independently hydrogen, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl halogen, C1-3 haloalkyl, oxo, —CN, C3-6 cycloalkyl, or heterocycloalkyl having 3 to 5 nog members and 1 to 2 heteroatoms each N or O,
- A1, A2, A3 and A4 are each independently ═CR2, or ═N;
- each R2 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxy or —CN;
- each R3a is independently hydrogen —OH or oxo;
- R3b is C1-6 alkyl, C2-6 alkynyl, C2-6 alkoxyalkyl, C2-6 alkynyl-C3-6, cycloalkyl, C1-6 alkyl-C6-12 aryl, C2-6 alkenyl-C6-12 aryl, C2-6 alkynyl-C6-12 aryl, C1-6alkyl-O—C6-12 aryl, C1-6 alkoxyalkyl-C6-12 aryl, —C(O)—C6-12 aryl, or C1-6 alkyl-heteroaryl, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms each independently N, O or S, and wherein each aryl and heteroaryl are substituted with 1 to R3b3 groups;
- each R3b3 is hydrogen C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;
- R4 is C1-6 alkyl, C1-6 haloalkyl, —CN, C3-8 cycloalkyl, 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently N, O or S, C6-12 aryl, or 5 to 10 membered heteroaryl having 1 to 5 heteroatoms each independently N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each dependently substituted with 1 to 5 R4a groups;
- each R4a is hydrogen, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, —CN, —OH, oxo, S(O)2R4b, —S(O)2N(R4b)(R4c), C3-6 cycloalkyl, C6-12 aryl, —O—C6-12 aryl, wherein each aryl is optionally substituted with C1-6 alkoxy;
- each R4b and R4c is hydrogen or C1-6 alkyl;
- L1 is absent;
- and
- L2 is absent, —CH2, —C(O)—, C(O)CH2CH2—, —C(O)CH2)3O—, or —S(O)2—.
13 more elements
A method of treating a disorder or condition through antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, an effective amount of a compound of Formula IVa,
- or a pharmaceutically acceptable salt thereof,
- wherein
- R1 is heterocycloalkyl having 5 to 6 ring members and 1 to 2 heteroatoms each N, phenyl or a heteroaryl having 5 to 6 ring members and 1 to 2 heteroatoms each N or S, each substituted with 1 and 3 R1a groups;
- and
- each R1a is independently hydrogen, C1-3 alkyl, C1-3 deuteroalkyl, C1-3 alkoxy, C1-3 hydroxyalkyl, halogen, C1-3 haloalkyl, oxo, —CN, C3-6 cycloalkyl, or heterocycloalkyl having 3 to 5 ring members and 1 to 2 heteroatoms each N or O;
- A1, A2, A3 and A4 are independently ═CR2— or ═N—,
- each R2 is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxy or —CN;
- each R3a is independently hydrogen, —OH, or oxo;
- R3b is C1-6 alkyl, C2-6 alkynyl, C2-6 alkoxyalkyl, C2-6 alkynyl-C3-6 cycloalkyl, C1-6 alkyl-C6-12 aryl, C2-6 alkenyl-C6-12 aryl, C2-6 alkynyl-C6-12 aryl, C1-6 alkyl-O—C6-12 aryl, C1-6 alkoxyalkyl-C6-12 aryl, —C(O)—C6-12 aryl, or C1-6 alky-heteroaryl, wherein each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatoms each independently N, O or S, and wherein each aryl and heteroaryl are substituted with 1 to 3 R3b3 groups;
- each R3b3 is hydrogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;
- R4 is C1-6 alkyl, C1-6 haloalkyl, —CN, C3-2 cycloalkyl, 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms each independently N, O or S, C6-12 aryl, or 5 to 10 membered heteroaryl having 1 to 5 heteroatoms each independently N, O or S, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently substituted with 1 to 5 R4a groups,
- each R4a is hydrogen, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C1-6 hydroxyalkyl, halogen, C1-6 haloalkyl, —CN, —OH, oxo, —S(O)2R4b, —S(O)2N(R4b)(R4c), C3-6 cycloalkyl, C6-12 aryl, —O—C6-12 aryl, wherein each aryl is optionally substituted with C1-6 alkoxy;
- each R4b and R4c is hydrogen or C1-6 alkyl;
- L1 is absent;
- and
- L2 is absent —CH2—, —C(O)C—, —C(O)CH2—, —C(O)CH2CH2—, —C(O)CH2O—, C(O)(CH2)3O—, or —S(O)2—.
13 more elements
Dependencies are inferred from the claim text.