IP Library › Granted Patent US 12686687

Granted Patent B2

US 12686687 · App. 17/425,013 · Granted Jul 21, 2026

Compounds and uses thereof

Inventors: Sabine K. Ruppel (Cambridge, MA); Zhaoxia Yang (Belmont, MA); Jason T. Lowe (East Bridgewater, MA); Johannes H. Voigt (Cambridge, MA); Matthew Netherton (Cambridge, MA); Francois Brucelle (Belmont, MA)

Assignee: FOGHORN THERAPEUTICS INC.

C07D495/04 A61P35/00 C07D498/04 C07D513/04 C07D519/00

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Quick Facts

Patent No.: US 12686687
App. No.: 17/425,013
Granted: Jul 21, 2026
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates to compositions and methods for the treatment of BAF-related disorders, such as cancers and viral infections.

Claims (260)

1 . A compound having the structure:

B is a degradation moiety;

the degradation moiety is a ubiquitin ligase binding moiety;

R 1 is, independently, H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 carbocyclyl;

Z 1 is CR 2 or N;

R 2 is H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, or optionally substituted C 2 -C 9 heteroaryl;

X 1 is CR X1 ;

R X1 is H or optionally substituted C 1 -C 6 alkyl;

G″ is

each of m, n, o1, o2, and p is, independently, 0 or 1;

E 1 is

b is 0, 1, 2, 3, 4, 5, or 6;

R a is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 6 carbocyclyl;

each of E 2 is, independently, O, S, NR N , optionally substituted C 1-10 alkylene, optionally substituted C 2-10 alkenylene, optionally substituted C 2-10 alkynylene, optionally substituted C 2 -C 10 polyethylene glycol, or optionally substituted C 1-10 heteroalkylene;

each of E 3 is optionally substituted C 1 -C 6 alkylene, optionally substituted C 1 -C 6 heteroalkylene, O, S, or NR N ;

each R N is, independently, H, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 2-6 heterocyclyl, optionally substituted C 6-12 aryl, or optionally substituted C 1-7 heteroalkyl;

each of C 3 is carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; and

each of F 1 , F 2 , and F 3 is, independently, optionally substituted C 3 -C 10 carbocyclylene, optionally substituted C 2-10 heterocyclylene, optionally substituted C 6 -C 10 arylene, or optionally substituted C 2 -C 9 heteroarylene;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein the ubiquitin ligase binding moiety comprises Cereblon ligands, IAP (Inhibitors of Apoptosis) ligands, mouse double minute 2 homolog (MDM2), or von Hippel-Lindau (VHL) ligands.

3 . The compound of claim 1 , wherein the degradation moiety comprises the structure of Formula Y:

wherein

A 2 is a bond between the degradation moiety and the linker;

v1 is 0, 1, 2, 3, 4, or 5;

u1 is 1, 2, or 3;

T 1 is a bond or

T 2 is

R 5A is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

each R J1 is, independently, halogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

J A is absent, O, optionally substituted amino, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl; and

J is absent, optionally substituted C 3 -C 10 carbocyclylene, optionally substituted C 6 -C 10 arylene, optionally substituted C 2 -C 9 heterocyclylene, or optionally substituted C 2 -C 9 heteroarylene,

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 3 , wherein the degradation moiety has the structure of Formula A:

wherein

Y 1 is

R A5 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

R A6 is H or optionally substituted C 1 -C 6 alkyl; and R A7 is H or optionally substituted C 1 -C 6 alkyl; or R A6 and R A7 , together with the carbon atom to which each is bound, combine to form optionally substituted C 3 -C 6 carbocyclyl or optionally substituted C 2 -C 5 heterocyclyl; or R A6 and R A7 , together with the carbon atom to which each is bound, combine to form optionally substituted C 3 -C 6 carbocyclyl or optionally substituted C 2 -C 5 heterocyclyl;

R A8 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

each of R A1 , R A2 , R A3 , and R A4 is, independently, H, A 2 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted-O-C 3 -C 6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , and/or R A3 and R A4 , together with the carbon atoms to which each is attached, combine to form

and

is optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heteroaryl, or C 2 -C 9 heterocyclyl, any of which is optionally substituted with A 2 ,

wherein one of R A1 , R A2 , R A3 , and R A4 is A 2 , or

is substituted with A 2 , or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 3 , wherein the degradation moiety has the structure of Formula B:

wherein

R A5 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl;

each of R A1 , R A2 , R A3 , and R A4 is, independently, H, A 2 , halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted C 2 -C 9 heterocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted —O—C 3 -C 6 carbocyclyl, hydroxyl, thiol, or optionally substituted amino; or R A1 and R A2 , R A2 and R A3 , and/or R A3 and R A4 , together with the carbon atoms to which each is attached, combine to form

and

wherein one of R A1 , R A2 , R A3 , and R A4 is A 2 , or

is substituted with A 2 ,

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 1 , wherein the degradation moiety comprises the structure of Formula FA:

wherein

or a bicyclic moiety which is substituted with A 2 and substituted with one or more groups independently selected from H, R FF1 , and oxo;

is a single bond or a double bond;

u2 is 0, 1, 2, or 3;

A 2 is a bond between the degrader and the linker;

Y Fa is CR Fb R Fc , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 ;

Y Fb is NH, NR FF1 , CH 2 , CHR FF1 , C(R FF1 ) 2 , O, or S;

Y Fc is CR Fd R Fe , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 ;

each of R Fb , R Fc , R Fd , and R Fe is, independently, H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or —Nalkyl 2 ;

or R Fb and R Fc , together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O;

or R Fd and R Fe , together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O; and

or R Fd and R Fb , together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

each of Y Fd and Y Ff is, independently, CH 2 , CHR FF2 , C(R FF2 ) 2 , C(O), N, NH, NR FF3 , O, S, or S(O);

Y Fe is a bond or a divalent moiety attached to Y Fd and Y Ff that contains 1 to 5 contiguous carbon atoms that form a 3 to 8-membered ring,

wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen, oxygen, or sulfur atom;

wherein one of the ring atoms is substituted with A 2 and the others are substituted with one or more groups independently selected from H and R FF1 ; and

wherein the contiguous atoms of Y Fe can be attached through a single or double bond;

each R FF1 is, independently, H, alkyl, alkenyl, alkynyl, aliphatic, heteroaliphatic, carbocyclyl, halogen, hydroxyl, amino, cyano, alkoxy, aryl, heteroaryl, heterocyclyl, alkylamino, alkylhydroxyl, or haloalkyl;

each R FF2 is, independently, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O(aliphatic, including alkyl), —NH(aliphatic, including alkyl), —N(aliphatic including alkyl)(aliphatic including alkyl), —NHSO 2 alkyl, —N(alkyl) SO 2 alkyl, —NHSOzaryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSOzalkynyl, —N(alkyl)SOzalkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, hetercyclic, carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and

R FF3 is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O) alkyl, or —C(O)Oalkyl,

wherein if Y Fd or Y Ff is substituted with A 2 , then Y Fe is a bond, or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 1 , wherein the degradation moiety comprises the structure of Formula FB:

wherein

or a bicyclic moiety which is substituted with A 2 and substituted with one or more groups independently selected from H, R FF1 , and oxo;

A 2 is a bond between the degrader and the linker;

Y Fa is CR Fb R Fc , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 ;

each of Y Fb and Y Fg is, independently, NH, NR FF1 , CH 2 , CHR FF1 , C(R FF1 ) 2 , O, or S;

Y Fc is CR Fd R Fe , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 ;

each of R Fb , R Fc , R Fd , R Fe , R Ff , and R Fg is, independently, H, alkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, carbocyclyl, hydroxyl, alkoxy, amino, —NHalkyl, or —Nalkyl 2 ;

or R Ff and R Fg , together with the carbon atom to which each is attached, combine to form a 3-, 4-, 5-, or 6-membered spirocarbocyclylene, or a 4-, 5-, or 6-membered spiroheterocyclylene comprising 1 or 2 heteroatoms selected from N and O;

or R Fd and R Fb , together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

or R Fd and R Ff , together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

or R Fb and R Fg , together with the carbon atoms to which each is attached, combine to form a 1, 2, 3, or 4 carbon bridged ring;

each of Y Fd and Y Ff is, independently, CH 2 , CHR FF2 , C(R FF2 ) 2 , C (O), N, NH, NR FF3 , O, S, or S(O);

Y Fe is a bond or a divalent moiety attached to Y Fd and Y Ff that contains 1 to 5 contiguous carbon atoms that form a 3 to 8-membered ring,

wherein 1, 2, or 3 carbon atoms can be replaced with a nitrogen, oxygen, or sulfur atom;

wherein one of the ring atoms is substituted with A 2 and the others are substituted with one or more groups independently selected from H and R FF1 ; and

wherein the contiguous atoms of Y Fe can be attached through a single or double bond;

each R FF2 is, independently, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —C(O)H, —C(O)OH, —C(O)(aliphatic, including alkyl), —C(O)O (aliphatic, including alkyl), —NH (aliphatic, including alkyl), —N(aliphatic including alkyl) (aliphatic including alkyl), —NHSO 2 alkyl, —N(alkyl) SO 2 alkyl, —NHSOzaryl, —N(alkyl) SO 2 aryl, —NHSOzalkenyl, —N(alkyl)SO 2 alkenyl, —NHSOzalkynyl, —N(alkyl)SOzalkynyl, aliphatic, heteroaliphatic, aryl, heteroaryl, hetercyclic, carbocyclic, cyano, nitro, nitroso, —SH, —Salkyl, or haloalkyl; and

R FF3 is alkyl, alkenyl, alkynyl, —C(O)H, —C(O)OH, —C(O) alkyl, or —C(O)Oalkyl,

wherein if Y Fd or Y Ff is substituted with A 2 , then Y Fe is a bond, or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 1 , wherein the degradation moiety comprises the structure of Formula F 1 :

wherein

A 2 is a bond between the degrader and the linker; and

R F1 is absent or O,

or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 1 , wherein the degradation moiety comprises the structure of Formula F2:

wherein

A 2 is a bond between the degrader and the linker; and

R F1 is absent or O,

Y 2 is CH 2 or NH,

or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 1 , wherein the degradation moiety comprises the structure of Formula G:

wherein

A 2 is a bond between the degrader and the linker; and

R F1 is absent or O,

Y 3 is CH 2 or NH,

or a pharmaceutically acceptable salt thereof.

11 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

12 . A method of treating a synovial sarcoma in a subject in need thereof, the method including administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

13 . A compound, wherein the compound has the structure of any one of compounds:

Com-

pound

No.

Structure

D10

D11

D12

D13

D15

D16

D17

D18

D19

D24

D25

D28

D29

D31

D33

D34

D35

D36

D37

D38

D39

D40

D41

D42

D43

D44

D45

D46

D47

D48

D49

D50

D51

D52

D53

D54

D55

D56

D57

D58

D59

D60

D61

D62

D63

D64

D65

D66

D67

D68

D69

D70

D71

D72

D73

D74

D75

D76

D77

D78

D79

D80

D81

D82

D83

D84

D85

D86

D87

D88

D89

D90

D93

D95

D96

D98

D102

D103

D105

D108

D109

D112

D114

D115

D116

D117

D118

D124

D126

D127

D128

D129

D130

D131

D134

D135

D137

D140

D141

D142

D143

D145

D146

D148

D149

D150

D151

D152

D155

D156

D157

D159

D162

D163

D164

D165

D166

D167

D171

D175

D177

D179

D180

D181

D182

D187

D190

D191

D192

D195

D196

D200

or a pharmaceutically acceptable salt thereof.