Morpholine derivates as inhibitors of Vps34
Inventors
Stocking, Emily M. • Wrasidlo, Wolfgang J.
Assignees
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Publication Number
US-11236079-B2
Publication Date
2022-02-01
Expiration Date
Abstract
The present disclosure relates to thiazole- or diathiazole-substituted aryl and heteroaryl compounds (I), pharmaceutical compositions containing them, and methods of using them, including treatment of disorders or disease related to regulation of the Vps34/PI3K III signaling pathway.
Core Innovation
The invention relates to a compound of Formula I in which the structural definition is governed by variables R1, L, Y1, and R2. R1 is defined as a C6-C14 aryl, 5- to 10-membered heteroaryl, C3-C6 cycloalkyl, or 4- to 10-membered heterocycloalkyl that is unsubstituted or substituted with one or more selected substituents, and L is —S(O)2—, —O—, —C(O)—, or —CH2—, while Y1 is CH or N. R2 is defined as a 5-membered heteroaryl or a 5-membered heterocycloalkyl that is unsubstituted or substituted with one or more substituents from a specified group.
The compounds include pharmaceutically acceptable salts. The described embodiments include thiazole- or di(thiazole)-substituted aryl/heteroaryl Vps34 (PI3K III) pathway inhibitor compounds according to Formula I, and morpholine and a phenylsulfonyl group linked to an aryl-thiadiazole or aryl-thiazole framework.
Examples include 5-(3-morpholino-5-(phenylsulfonyl)phenyl)-1,2,4-thiadiazol-3-amine and 5-(6-morpholino-4-(phenylsulfonyl)pyridin-2-yl)thiazol-2-amine and related variants. The compounds are presented as inhibitors of the Vps34/PI3K III signaling pathway.
Claims Coverage
The provided claim set includes one explicitly independent claim defining Formula I compounds, with additional dependent claims narrowing structural variables and including therapeutic method coverage linked to regulation of the Vps34/PI3K III signaling pathway. In total, the consolidated coverage reflects one broad structural Formula I claim family plus additional selected compound group claims.
Formula I compound with defined R1, L, Y1, and R2 substituent ranges
A compound of Formula I wherein R1 is C6-C14 aryl, 5- to 10-membered heteroaryl, C3-C6 cycloalkyl, or 4- to 10-membered heterocycloalkyl, each unsubstituted or substituted with one or more selected substituents; L is —S(O)2—, —O—, —C(O)—, or —CH2—; Y1 is CH or N; and R2 is a 5-membered heteroaryl or a 5-membered heterocycloalkyl, each unsubstituted or substituted with one or more selected substituents, including a further limitation when L is —S(O)2— and Y1 is N, and including a pharmaceutically acceptable salt thereof.
Selected depicted compound group for pharmaceutically acceptable salts
A compound selected from a group consisting of depicted compounds, or a pharmaceutically acceptable salt thereof.
Therapeutic treatment linked to regulation of Vps34/PI3K III signaling pathway
A method for treating a disease or medical condition linked to regulation of the Vps34/PI3K III signaling pathway by administering to a subject an effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.
Across the provided claims, the inventive scope is centered on Formula I compounds with defined selectable substituent frameworks for R1, L, Y1, and R2, including pharmaceutically acceptable salts. Additional coverage is provided by selected depicted compound groups and therapeutic methods directed to diseases or medical conditions associated with regulation of the Vps34/PI3K III signaling pathway.
Stated Advantages
Provides IC50 values for inhibition in VPS34 (PI3KC3) and PI3Kα kinase assays for the provided examples.
Documented Applications
Treatment of diseases or medical conditions linked to regulation of the Vps34/PI3K III signaling pathway.
Therapeutic or prophylactic use for diseases or medical conditions linked to regulation of the Vps34/PI3K III signaling pathway by administering an effective amount of at least one Formula I compound or a pharmaceutically acceptable salt thereof.
Treatment/use for diabetes.
Treatment/use for diabetes-associated cardiovascular disease.
Treatment/use for polycystic ovarian syndrome.
Treatment/use for cancer, including glioblastoma, renal cell carcinoma, and melanoma.
Treatment/use for neuro-inflammation.
Treatment/use for ischemic stroke.
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