Estrogen receptor modulators and uses thereof

Inventors

Smith, Nicholas D. • Govek, Steven P. • Kahraman, Mehmet • Julien, Jackaline D. • Nagasawa, Johnny Y. • Douglas, Karensa L. • Bonnefous, Celine • Lai, Andiliy G.

Assignees

Seragon Pharmaceuticals Inc

Abstract

Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

Core Innovation

The invention relates to compounds of Formula (III), including pharmaceutically acceptable salts and N-oxides thereof. Ring B is selected from phenyl, thiophenyl, pyridinyl, pyrimidinyl, and pyrazinyl, and ring C is selected from phenyl, pyridinyl, pyrimidinyl, and pyrazinyl. The compounds include R1 as —C(=O)—Z, where Z is selected from —OH, —OR9, —NR7R8, —NR7S(=O)2R9, —NHOH, or NR7OR9.

The scaffold further constrains Ra, Rb, Rc, R4, R5, R6, R7, R8, R9, and the parameters m, n, p, and r by enumerated substituent sets and integer ranges. The permitted substituent classes include halogen, cyano, hydroxyl, alkoxy, thio-related groups, sulfonyl and sulfonamide-related groups, carbonyl-containing groups, alkyl, alkenyl, alkynyl, fluoroalkyl, heteroalkyl, phenyl, monocyclic heteroaryl, cycloalkyl, heterocycloalkyl, and benzyl. The claims and description also include explicit provisos excluding specified (E)-3-(4-((E)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid and related acrylic acid or acrylamide exemplars.

The disclosure presents explicit examples of Formula (III) compounds within an (E)- and (Z)-acrylic acid derivative family, including substituted indazole-linked aromatic systems, cyclobutyl and cyclopropyl groups, and various aryl or heteroaryl substituents such as fluorophenyl, chloropyridyl, methoxy, cyano, thiophenyl, benzo[d]thiazolyl, benzo[d]oxazolyl, benzo[d]triazolyl, imidazo[1,2-a]pyridine, oxadiazol-5(4H)-one, oxadiazole, hydroxyacrylimidamide, pyrazol vinyl, carbazole, cyanobenzofuran, and tetrahydro-2H-pyran substituted variants. The disclosure also includes pharmaceutically acceptable salts, solvates, metabolites, and prodrugs in some passages.

Claims Coverage

The independent claim coverage centers on one Formula (III) compound class with specified ring B and ring C selections, an R1 —C(=O)—Z motif, broad but enumerated substituent-variable constraints, fixed parameter ranges for m, n, p, and r, and explicit exclusions of listed (E)-acrylic acid and acrylamide exemplars. The consolidated claim coverage identifies 1 core independent inventive feature set, with dependent claims additionally covering pharmaceutical compositions and cancer-treatment methods.

Overall, the claim coverage defines a constrained Formula (III) compound family with specified ring B and ring C options, an R1—C(=O)—Z motif, extensive enumerated substituent allowances, bounded integer parameters, and explicit carve-outs for listed (E)-acrylic acid and acrylamide embodiments. Additional claim coverage extends to pharmaceutical compositions and methods for treating defined cancer types in a mammal.

Stated Advantages

Documented Applications