Pyruvate kinase activators for use in treating blood disorders

Patent metadata

Field	Value
Publication number	US-11364240-B2
Application number	US-201816639075-A
Country	US
Kind code	B2
Filing date	Aug 15, 2018
Priority date	Aug 15, 2017
Publication date	Jun 21, 2022
Grant date	Jun 21, 2022

Abstract

Described herein are compounds that activate pyruvate kinase R, pharmaceutical compositions and methods of use thereof. 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 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 3 —, —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 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) 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;
provided that Q and R 2 are not both optionally substituted 5- or 6-membered monocyclic heteroaryl when L 1 and L 2 are optionally substituted methylene.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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 3 —, —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 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)—, or a sulfur protecting group when L 1 is —S—;
each instance of R 3 is independently hydrogen, —OR′, 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 c1 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 compound of claim 2 or a pharmaceutically acceptable salt thereof, 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, —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)—, or a sulfur protecting group when L 1 is —S—;
R 3 is selected from h

Assignees

• Agios Pharmaceuticals Inc

Inventors

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

Classifications

• A61P7/08

  Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04) · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D241/36

  condensed with carbocyclic rings or ring systems · CPC title

• C07D513/14 Primary

  Ortho-condensed systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title