Pyruvate kinase modulators and use thereof

Patent metadata

Field	Value
Publication number	US-11872225-B2
Application number	US-202217586777-A
Country	US
Kind code	B2
Filing date	Jan 27, 2022
Priority date	Aug 15, 2017
Publication date	Jan 16, 2024
Grant date	Jan 16, 2024

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.

First claim

The invention claimed is:

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:

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;
R 1 is hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, —OR o1 , —C(═O)R c1 , or a nitrogen protecting group;
L 1 is a bond, optionally substituted alkylene, —O—, —S—, —S—CH 2 —, —S(═O)CH 2 —, —S(═O) 2 CH 2 —, —NR—, —NR 3 C(═O)—, —C(═O)NR 3 —, C(═O)—, —OC(═O)—, —C(═O)O—, —NR 3 C(═O)O—, —OC(═O)NR 3 —, —NR 3 C(═O)NR 3 —, —OC(R 4 ) 2 —, —C(R 4 ) 2 O—, —NR 3 C(R 4 ) 2 —, —C(R 4 ) 2 NR 3 —, —S(═O) 2 —, —S(═O)—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O)O—, —OS(═O)—, —S(═O) 2 NR 3 —, —NR 3 S(═O) 2 —, —S(═O)NR 3 —, —NR 3 S(═O)—, —NR 3 S(═O) 2 O—, —OS(═O) 2 NR 3 —,
NR 3 S(═O)O—, —OS(═O)NR 3 —, or —S(═O)(═NR 3 )—, wherein the point of the attachment to R 2 is on the left-hand side;
L 2 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;
R 2 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 L 1 is —NR—, —NR 3 C(═O)—, —NR 3 C(═O)O—, —NR 3 C(R 4 ) 2 —, —NR 3 S(═O) 2 —, —NR 3 S(═O)—, —NR 3 C(═O)NR 3 —, —NR 3 S(═O) 2 O—, or —NR 3 S(═O)O—, an oxygen protecting group when L 1 is —O—, —OC(═O)—, —OC(═O)NR 3 —, —OC(R 4 ) 2 —, —OS(═O) 2 —, —OS(═O) 2 NR 3 —, —OS(═O)NR 3 —, or —OS(═O)—, or a sulfur protecting group when L 1 is —S—;
each instance of R 3 is independently hydrogen, —OR o2 , 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 R o1 and R o2 is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group;
each instance of R c1 is independently optionally substituted alkyl or —N(R cn ) 2 wherein each instance of R cn is independently hydrogen, —C 1-6 alkyl, or a nitrogen protecting group; and
each instance of R 4 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.

2. The method of claim 1 , wherein:
Q is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted 6- to 14-membered aryl, or optionally substituted 5- to 14-membered heteroaryl;
R 1 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 haloalkyl, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 2 -C 6 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted 6- to 12-membered aryl, —OR o1 , —C(═O)R c1 , or a nitrogen protecting group;
L 1 is a bond, optionally substituted C 1-6 alkylene, —O—, —S—, —S—CH 2 —, —S(═O)CH 2 —, —S(═O) 2 CH 2 —, —NR—, —NR 3 C(═O)—, —C(═O)NR 3 —, C(═O)—, —OC(═O)—, —C(═O)O—, —NR 3 C(═O)O—, —OC(═O)NR 3 —, —NR 3 C(═O)NR 3 —, —OC(R 4 ) 2 —, —C(R 4 ) 2 O—, —NR 3 C(R 4 ) 2 —,—C(R 4 ) 2 NR 3 —, —S(═O) 2 —, —S(═O)—, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O)O—, —OS(═O)—, —S(═O) 2 NR 3 —, —NR 3 S(═O) 2 —, —S(═O)NR 3 —, —NR 3 S(═O)—, —NR 3 S(═O) 2 O—, —OS(═O) 2 NR 3 —, —NR 3 S(═O)O—, —OS(═O)NR 3 —, or —S(═O)(═NR 3 )—, wherein the point of the attachment to R 2 is on the left-hand side;
L 2 is a bond, optionally substituted C 1 -C 6 alkylene, —C(═O)—, —S(═O) 2 —, or —S(═O)—wherein the point of the attachment to Q is on the right-hand side;
R 2 is hydrogen, halogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxy, optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted —C 6 -C 12 aryl, or optionally substituted 3- to 14-membered heteroaryl, or a nitrogen protecting group when L 1 is —NR—, —NR 3 C(═O)—, —NR 3 C(═O)O—, —NR 3 C(R 4 ) 2 —, —NR 3 S(═O) 2 —, —NR 3 S(═O)—, —NR 3 C(═O)NR 3 —, —NR 3 S(═O) 2 O—, or —NR 3 S(═O)O—, an oxygen protecting group when L 1 is —O—, —OC(═O)—, —OC(═O)NR 3 —, —OC(R 4 ) 2 —, —OS(═O)—, —OS(═O) 2 —, —OS(═O) 2 NR 3 —, —OS(═O)NR 3 —, or —OS(═O)—, or a sulfur protecting group when L 1 is —S—;
each instance of R 3 is independently hydrogen, —OR o2 , optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 2 -C 6 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 heterocyclyl, optionally substituted C 6 -C 12 aryl, optionally substituted C 5 -C 12 heteroaryl, or a nitrogen protecting group;
each instance of R o1 and R o2 is independently hydrogen, optionally substituted —C 1 -C 6 alkyl, or an oxygen protecting group;
each instance of R cn is independently optionally substituted —C 1 -C 6 alkyl or —N(R cn ) 2 , wherein each instance of R cn is independently hydrogen, —C 1 -C 6 alkyl, or a nitrogen protecting group;
each instance of R 4 is independently hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 2 -C 6 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted C 6 -C 12 aryl, or optionally substituted 5- to 14-membered heteroaryl.

3. The method of claim 1 , wherein:
Q is C 6 -C 12 aryl, 5- to 6-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic heteroaryl, each of which is substituted with 0-3 occurrences of R c ;
R 1 is selected from hydrogen, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, C 3 -C 7 monocyclic cycloalkyl and 3- to 14-membered heterocyclyl, —OR o1 , —C(═O)R c1 , or a nitrogen protecting group; wherein each alkyl, cycloalkyl or heterocyclyl is substituted with 0-3 occurrences of R d ;
R 2 is selected from hydrogen, halogen, —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, C 3 -C 7 monocyclic cycloalkyl, C 6 -C 12 bicyclic cycloalkyl, 3- to 14-membered heterocyclyl, C 6 -C 12 aryl, 5- to 6-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is substituted with 0-3 occurrences of R e , or a nitrogen protecting group when L 1 is —NR 3 —, —NR 3 C(═O)—, —NR 3 C(═O)O—, —NR 3 C(R 4 ) 2 —, —NR 3 S(═O) 2 —, —NR 3 S(═O)—, —NR 3 C(═O)NR 3 —, —NR 3 S(═O) 2 O—, or —NR 3 S(═O)O—, an oxygen protecting group when L 1 is —O—, —OC(═O)—, —OC(═O)NR 3 —, —OC(R 4 ) 2 —, —OS(═O)—, —OS(═O) 2 —, —OS(═O) 2 NR 3 —, —OS(═O)NR 3 —, or —OS(═O)—,

Assignees

• Agios Pharmaceuticals Inc

Inventors

• Cianchetta Giovanni
• Kung Charles
• Liu Tao
• Padyana Anil Kumar
• Sui Zhihua
• Cai Zhenwei
• Cui Dawei
• Ji Jingjing

Classifications

• A61K31/5025 Primary

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D241/36

  condensed with carbocyclic rings or ring systems · CPC title

• C07D513/14 Primary

  Ortho-condensed systems · CPC title