US 11,872,225 B2
Pyruvate kinase modulators and use thereof
Giovanni Cianchetta, Boxford, MA (US); Charles Kung, Arlington, MA (US); Tao Liu, Wellesley, MA (US); Anil Kumar Padyana, Lexington, MA (US); Zhihua Sui, Somerville, MA (US); Zhenwei Cai, Shanghai (CN); Dawei Cui, Shanghai (CN); and Jingjing Ji, Shanghai (CN)
Assigned to Agios Pharmaceuticals, Inc., Cambridge, MA (US)
Filed by Agios Pharmaceuticals, Inc., Cambridge, MA (US)
Filed on Jan. 27, 2022, as Appl. No. 17/586,777.
Application 17/586,777 is a continuation of application No. 16/639,086, granted, now 11,464,775, previously published as PCT/US2018/000129, filed on Aug. 15, 2018.
Claims priority of provisional application 62/673,526, filed on May 18, 2018.
Claims priority of provisional application 62/673,533, filed on May 18, 2018.
Claims priority of application No. PCT/CN2017/097496 (WO), filed on Aug. 15, 2017.
Prior Publication US 2022/0233541 A1, Jul. 28, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 513/14 (2006.01); A61K 31/5025 (2006.01); A61K 31/506 (2006.01); A61K 31/519 (2006.01); C07D 241/36 (2006.01); A61K 45/06 (2006.01)
CPC A61K 31/5025 (2013.01) [A61K 31/506 (2013.01); A61K 31/519 (2013.01); C07D 241/36 (2013.01); C07D 513/14 (2013.01); A61K 45/06 (2013.01)] 22 Claims
 
1. A method of treating a disease associated with the aberrant activity of PKM2 in a subject in need thereof comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

OG Complex Work Unit Chemistry
Q is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R1 is hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, —ORo1, —C(═O)Rc1, or a nitrogen protecting group;
L1 is a bond, optionally substituted alkylene, —O—, —S—, —S—CH2—, —S(═O)CH2—, —S(═O)2CH2—, —NR—, —NR3C(═O)—, —C(═O)NR3—, C(═O)—, —OC(═O)—, —C(═O)O—, —NR3C(═O)O—, —OC(═O)NR3—, —NR3C(═O)NR3—, —OC(R4)2—, —C(R4)2O—, —NR3C(R4)2—, —C(R4)2NR3—, —S(═O)2—, —S(═O)—, —S(═O)2O—, —OS(═O)2—, —S(═O)O—, —OS(═O)—, —S(═O)2NR3—, —NR3S(═O)2—, —S(═O)NR3—, —NR3S(═O)—, —NR3S(═O)2O—, —OS(═O)2NR3—,
NR3S(═O)O—, —OS(═O)NR3—, or —S(═O)(═NR3)—, wherein the point of the attachment to R2 is on the left-hand side;
L2 is a bond, optionally substituted alkylene, —C(═O)—, —S(═O)2—, or —S(═O)—, wherein the point of the attachment to Q is on the right-hand side;
R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or a nitrogen protecting group when L1 is —NR—, —NR3C(═O)—, —NR3C(═O)O—, —NR3C(R4)2—, —NR3S(═O)2—, —NR3S(═O)—, —NR3C(═O)NR3—, —NR3S(═O)2O—, or —NR3S(═O)O—, an oxygen protecting group when L1 is —O—, —OC(═O)—, —OC(═O)NR3—, —OC(R4)2—, —OS(═O)2—, —OS(═O)2NR3—, —OS(═O)NR3—, or —OS(═O)—, or a sulfur protecting group when L1 is —S—;
each instance of R3 is independently hydrogen, —ORo2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group;
each instance of Ro1 and Ro2 is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group;
each instance of Rc1 is independently optionally substituted alkyl or —N(Rcn)2 wherein each instance of Rcn is independently hydrogen, —C1-6 alkyl, or a nitrogen protecting group; and
each instance of R4 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
wherein the disease is selected from cancer, obesity, a diabetic disease, atherosclerosis, coronary artery disease (CAD), Bloom Syndrome (BS), and an autoimmune disease.