Pyruvate kinase modulators and use thereof
Inventors
Cianchetta, Giovanni • Kung, Charles • Liu, Tao • Padyana, Anil Kumar • Sui, Zhihua • Cai, Zhenwei • Cui, DaWei • Ji, Jingjing
Assignees
PHARMARESOURCES (SHANGHAI) CO Ltd • Agios Pharmaceuticals Inc
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Publication Number
US-11872225-B2
Publication Date
2024-01-16
Expiration Date
Abstract
Described herein are methods of using compounds of Formula (I) to modulate PKM2 activity in a subject. These compounds are represented by Formula (I): wherein R1, R2, L1, and L2 are as defined herein.
Core Innovation
The invention relates to a method of treating a disease associated with aberrant activity of PKM2 in a subject in need thereof by administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The disease is selected from cancer, obesity, a diabetic disease, atherosclerosis, coronary artery disease (CAD), Bloom Syndrome (BS), and an autoimmune disease.
The compounds of Formula (I) are defined by structural variables Q, R1, L1, L2, and R2, together with further R-group options and protecting-group possibilities. Q, R1, L1, and L2 include hydrogen and optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, with additional oxygen-, sulfur-, and nitrogen-containing substituent options.
The attachment-point constraints are explicitly stated, including that the point of attachment to R2 is on the left-hand side and the point of attachment to Q is on the right-hand side. The disclosure also includes dependent embodiments identifying diabetic nephropathy (DN) and labeled compound templates including Formula (II) and Formula (III).
Claims Coverage
The claim coverage centers on one independent method claim for treating a disease associated with aberrant PKM2 activity by administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt. Dependent claims further narrow the disease selection and the compound scope using labeled structural templates.
Treatment of PKM2-associated disease using Formula (I) compounds
A method of treating a disease associated with aberrant activity of PKM2 in a subject in need thereof by administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the disease is selected from cancer, obesity, a diabetic disease, atherosclerosis, coronary artery disease (CAD), Bloom Syndrome (BS), and an autoimmune disease.
Formula (I) substituent framework with attachment-point constraints
Formula (I) is defined by Q, R1, L1, L2, and R2 with allowed selections including hydrogen, optionally substituted alkyl/alkenyl/alkynyl/cycloalkyl/heterocyclyl/aryl/heteroaryl, and further linker and protecting-group options, with the point of attachment to R2 on the left-hand side and the point of attachment to Q on the right-hand side.
Disease subtype selection for diabetic nephropathy
The diabetic disease is specifically identified as diabetic nephropathy (DN).
Formula (II) compound template
The method is performed using a compound of Formula (II) or a pharmaceutically acceptable salt thereof, with additional defined substituent variables.
Formula (III) compound template
The method is performed using a compound of Formula (III) or a pharmaceutically acceptable salt thereof, with additional defined substituent variables.
Overall, the claims focus on a PKM2-associated therapeutic method using Formula (I) compounds with detailed substituent definitions and attachment-point constraints, with dependent narrowing to diabetic nephropathy and to Formula (II) and Formula (III) templates.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a disease associated with aberrant PKM2 activity by administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Treating cancer, obesity, a diabetic disease, atherosclerosis, coronary artery disease (CAD), Bloom Syndrome (BS), or an autoimmune disease.
Treating diabetic nephropathy (DN).
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