Activators of human pyruvate kinase

Patent metadata

Field	Value
Publication number	US-9708267-B2
Application number	US-201514643107-A
Country	US
Kind code	B2
Filing date	Mar 10, 2015
Priority date	Apr 29, 2010
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

Disclosed are pyruvate kinase M2 activators which are compounds of Formula (I), including those of Formula (II), wherein A 1 , A 2 , L, R, R 1 to R 3 , X 1 to X 3 , k, n, and m are as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer. A 1 -NR-L-A 2 (I).

First claim

The invention claimed is:

1. A compound of the formula:
wherein R is H;
wherein L is SO 2 or CO;
wherein R′ is

wherein X 1 is NR 6 or N-acetyl and X 2 is O or CR 7 R 8 ;
wherein any CH 2 —CH 2 moiety within the ring containing X 1 and X 2 is optionally replaced with a CH═CH moiety;
wherein any NR—CH 2 moiety within the ring containing X 1 and X 2 is optionally replaced with a N═CH moiety;
wherein one methylene of the ring containing X 1 and X 2 is replaced by a carbonyl;
wherein n and in are each individually 0, 1, or 2, and wherein n+m is 0 to 2;
wherein each R 1 is individually H, halogen, alkyl, alkoxyl, NH 2 , NH—(C 1 -C 4 )alkyl, N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which other than halogen and NH 2 is optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl;
wherein R 6 is H, alkyl, alkylcarboxy, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 3 -C 4 )alkyl; and
wherein R 7 and R 8 are each individually H, alkoxyl, NH 2 , NH—(C 1 -C 4 )alkyl, N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl, aryl, heteroaryl, cyclyl, or heterocyclyl, each of which other than halogen and NH 2 is optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl;
wherein R″ is phenyl, benzyl, pyridinyl, or naphthalenyl, the benzyl substituted with one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, cyano, alkylenedioxy, aryl, benzyl, B(OH) 2 , and C 1 -C 4 alkyl substituted with one or more halogens, and the pyridinyl, and naphthalenyl optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, cyano, alkylenedioxy, aryl, benzyl, B(OH) 2 , and C 1 -C 4 alkyl substituted with one or more halogens, and the phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, cyano, alkylenedioxy, aryl, benzyl, B(OH) 2 , and C 1 -C 4 alkyl substituted with one or more halogens, or is phenyl fused with an aryl, a heteroaryl, a cyclyl, or a heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, alkylenedioxy, aryl, heteroaryl, benzyl, and C 1 -C 4 alkyl substituted with one or more halogens; and
with the proviso that the compound is not

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 , wherein one R 1 is H, F, Cl, Br, methyl, N(Me) 2 , NHMe, 1-piperidinyl, 2-(dimethylamino)ethyl)(methyl)amino, pyrrolidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 2-hydroxy-2-methylpropylamino, isopropylamino, diethylamino, 1-hydroxypropan-2-ylamino, 2-hydroxyethylamino, or phenyl.

3. The compound or salt of claim 1 , wherein R′ is 3,4-dihydroquinolin-2(1H)-onyl, indolin-2-onyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)-onyl, 2H-benzo[b][1,4]oxazin-3(4H)-onyl, 4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-onyl, -(indolin-1-yl)ethanonyl, 1-methyl-1H-indolyl, 1-acetyl-2-methylindolinyl, 7-((2-(dimethylamino)ethyl)(methyl)amino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 2-oxo-7-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolinyl, 7-(3-(dimethylamino)pyrrolidin-1-yl)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(2-hydroxy-2-methylpropylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(isopropylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(diethylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(2-hydroxyethylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, 7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, (S)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl, or (R)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinolinyl.

4. The compound or salt of claim 1 , wherein R″ is

wherein X 3 is N, the NR-L moiety is linked to a C of the ring containing X 3 ;
wherein for (a), R 2 and R 3 are each individually H, halogen, C 1 -C 4 alkyl, cyano, B(OH) 2 , phenyl, C 1 -C 4 alkyl substituted with one or more halogens, or taken together form alkylenedioxyl,
for (b), R 2 is C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, cyano, B(OH) 2 , phenyl, or C 1 -C 4 alkyl substituted with one or more halogens, R 3 is H, C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, cyano, B(OH) 2 , phenyl, C 1 -C 4 alkyl substituted with one or more halogens, or R 2 and R 3 are taken together to form alkylenedioxyl,
for (c) and (d), R 2 and R 3 are each individually H, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, cyano, B(OH) 2 , phenyl, C 1 -C 4 alkyl substituted with one or more halogens, or taken together form alkylenedioxyl.

5. The compound or salt of claim 4 , wherein R″ is (a), and R 2 and R 3 are each individually F, Cl, Br, methyl, cyano, trifluoromethyl, phenyl, or B(OH) 2 , or taken together form alkylenedioxyl, or is (c) or (d) and R 2 and R 3 are each individually F, Cl, Br, methyl, methoxy, cyano, trifluoromethyl, phenyl, or B(OH) 2 , or taken together form alkylenedioxyl.

6. The compound or salt of claim 1 , wherein R″ is 3,4-dimethylphenyl, 3-chlorophenyl, meta-tolyl, 3-fluorophenyl, 3-trifluoromethylphenyl, biphenyl-3-yl, pyridine-3-yl, 4-chlorophenyl, para-tolyl, 4-fluorophenyl, ortho-tolyl, 2-fluorophenyl, naphthalen-2-yl, naphthalen-1-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 3-chloro-4-methylphenyl, 3,4-dichlorophenyl, 5-chloro-2-methylphenyl, 3-cyanophenyl, 3-chloro-2-methylphenyl,

4-fluoro-3-methylphenyl, 3-fluoro-4-methylphenyl, 4-chloro-3-methylphenyl, or 3-chloro-4-fluorophenyl.

7. The compound or salt of claim 1 , wherein the compound is a compound of formula (II):

wherein R is H;
wherein L is SO 2 or CO;
wherein X 1 is NR 6 or N-acetyl and X 2 is O or CR 7 R 8 ;
wherein X 3 is N or CH wherein when X is N, the NR-L moiety is linked to a C of the ring containing X 3 ;
wherein any CH 2 —CH 2 moiety within the ring containing X 1 and X 2 is optionally replaced with a CH═CH moiety;
wherein any NH—CH 2 moiety within the ring containing X 1 and X 2 is optionally replaced with a N═CH moiety;
wherein one methylene of the ring containing X 1 and X 2 is replaced by a carbonyl;
wherein n and m are each individually 0, 1, or 2, and wherein n m is 0 to 2;
wherein k is 0 or 1,
wherein R 1 is H, halogen, alkyl, alkoxyl, NH 2 , NH—(C 1 -C 4 )alkyl, N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, each of which other than halogen and NH 2 is optionally substituted with one or more substituents selected from the group consisting of NH 2 , OH, NH—(C 1 -C 4 )alkyl and N—(C 1 -C 4 )alkyl-(C 1 -C 4 )alkyl;
wherein R 2 and R 3 are each individually H, halogen, C 1 -C 4 alkyl, cyano, B(OH) 2 , phenyl, C 1 -C 4 alkyl substituted with one or more halogens,

Assignees

• Us Health

Inventors

• Boxer Matthew B
• Shen Min
• Auld Douglas S
• Thomas Craig J
• Walsh Martin J

Classifications

• C07D223/16

  Benzazepines; Hydrogenated benzazepines · CPC title

• C07D209/34

  in position 2 · CPC title

• C07D235/26

  Oxygen atoms · CPC title

• C07D215/36

  Sulfur atoms (C07D215/24 takes precedence) · CPC title

• C07D215/227 Primary

  only one oxygen atom which is attached in position 2 · CPC title