IP Library › Granted Patent US 10,933,068
Granted Patent B2
US 10,933,068 · App. 16/302,805 · Granted Mar 2, 2021

Modulators of DUX4 for regulation of muscle function

Inventors: Amanda Rickard (San Diego, CA); Anabel De La Garza (San Diego, CA); Uli Schmidt (San Diego, CA); Alexander Kiselyov (San Diego, CA)
Assignee: Sonic Master Limited
A61K31/5377A61K31/4412A61K31/4439A61K31/4545A61K31/496A61K31/52A61K31/551A61K31/5513A61K31/706A61K45/06A61P21/00G01N33/5023G01N33/5061
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 10,933,068
App. No.
16/302,805
Granted
Mar 2, 2021
Kind
B2
Abstract

Disclosed herein are methods and compositions for the treatment of facioscapulohumeral muscular dystrophy and other muscle diseases or disorders. In some cases, the methods and compositions involve the use of methyltransferase inhibitors to inhibit or repress DUX4 expression in muscle cells. Further disclosed herein are methods and cell based assays for screening compounds for the treatment of facioscapulohumeral muscular dystrophy and other muscle diseases.

Claims (63)

1. A method of treating facioscapulohumeral muscular dystrophy (FSHD) in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

C comprises a bond, C 5-12 carbocycle, or 5- to 12-membered heterocycle;

D comprises a bond, C 5-12 carbocycle, or 5- to 12-membered heterocycle;

each of L 1 and L 2 independently comprises a bond, —O—, —S, —N(R 51 ), —N(R 51 )CH 2 —, —C(O), —C(O)O, —OC(O), —OC(O)O, —C(O)N(R 51 ), —C(O)N(R 51 )C(O)—, —C(O)N(R 51 )C(O)N(R 51 ), —N(R 51 )C(O), —N(R 51 )C(O)N(R 51 ), —N(R 51 )C(O)O, —OC(O)N(R 51 ), —C(NR 51 ), —N(R 51 )C(NR 51 ), —C(NR 51 )N(R 51 ), —N(R 51 )C(NR 51 )N(R 51 ), —S(O) 2 , —OS(O), —S(O)O—, —S(O), —OS(O) 2 , —S(O) 2 O, —N(R 51 )S(O) 2 , —S(O) 2 N(R 51 ), —N(R 51 )S(O), —S(O)N(R 51 ), —N(R 51 )S(O) 2 N(R 51 )—, or —N(R 51 )S(O)N(R 51 ) or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene, each of which is optionally substituted with one or more R 50 ;

R 50 is, at each occurrence, independently comprises:

halogen, —NO 2 , CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O) (R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, or ═N(R 52 );

C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents comprises halogen, —NO 2 , CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 3-12 carbocycle, or 3- to 12-membered heterocycle; or

C 3-12 carbocycle and 3- to 12-membered heterocycle,

wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 50 is independently optionally substituted with one or more substituents comprises halogen, —NO 2 , CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 NR 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 —NR 52 C(O)NR 53 R 54 , —C (O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

R 51 , at each occurrence, independently comprises:

hydrogen, —C(O)R 52 , —C(O)OR 52 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 ;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents comprising halogen, —NO 2 , CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 3-12 carbocycle or 3- to 12-membered heterocycle; or

C 3-12 carbocycle and 3- to 12-membered heterocycle,

wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 51 is independently optionally substituted with one or more substituents comprising halogen, —NO 2 , CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

R 52 , at each occurrence, independently comprising hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 carbocycle, or 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , C 3-12 carbocycle, or 3- to 6-membered heterocycle;

R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;

each of R A , R B , and R c independently comprising R 50 ;

R D is, at each occurrence, independently comprising hydrogen or R 50 ; and

each of m, n, p, and q is independently an integer from 0-12,

X is C—R 5 or N;

each of R 1 and R2 is independently R 50 ;

R 3 comprises hydrogen or R 50 ;

R 4 is R 52 ; and

R 5 comprises hydrogen or R 50 ;

thereby treating facioscapulohumeral muscular dystrophy (FSHD) in the subject in need thereof.

2. The method of claim 1 , wherein C comprises a bond, a 6-membered aryl, or a 6-membered heterocycle.

3. The method of claim 1 , wherein C comprises pyridinylene, phenylene, tetrahydropyranylene, or piperidinylene.

4. The method of claim 1 , wherein D comprises a bond and a 6-membered heterocycle.

5. The method of claim 1 , wherein D comprises piperazinyl and morpholinyl.

6. The method of claim 1 , wherein R 3 is H or —CH 3 .

7. The method of claim 1 , wherein R 4 is C 1-5 alkyl or C 1-5 .

8. A method of treating facioscapulohumeral muscular dystrophy (FSHD) in a subject in need thereof, the method comprising: administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

C comprises a bond, C 5-12 carbocycle, or 5- to 12-membered heterocycle:

D comprises a bond, C 5-12 carbocycle, or 5- to 12-membered heterocycle;

each of L 1 and L 2 independently comprises a bond, —O—, —S, —N(R 51 ), —N(R 51 )CH 2 —, —C(O), —C(O)O, —OC(O), —OC(O)O, —C(O)N(R 51 ), —C(O)N(R 51 )C(O)—, —C(O)N(R 51 )C(O)N(R 51 ), —N(R 51 )C(O), —N(R 51 )C(O)N(R 51 ), —N(R 51 )C(O)O, —OC(O)N(R 51 ), —C(NR 51 ), —N(R 51 )C(NR 51 ), —C(NR 51 )N(R 51 ), —N(R 51 )C(NR 51 )N(R 51 ), —S(O) 2 , —OS(O), —S(O)O—, —S(O), —OS(O) 2 , —S(O) 2 O, —N(R 51 )S(O) 2 , —S(O) 2 N(R 51 ), —N(R 51 )S(O), —S(O)N(R 51 ), —N(R 51 )S(O) 2 N(R 51 )—, or —N(R 51 )S(O)N(R 51 ) or from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene, each of which is optionally substituted with one or more R 50 ;

R 50 is, at each occurrence, independently comprising:

halogen, —NO 2 , CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, or ═N(R 52 );

C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents comprising halogen, —NO 2 , CN, —OR 52 , —SR 52 —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O)NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 3-12 carbocycle or 3- to 12-membered heterocycle; or

C 3-12 carbocycle and 3- to 12-membered heterocycle,

wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 50 is independently optionally substituted with one or more substituents comprising halogen, —NO 2 , CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

R 51 , at each occurrence, independently comprising:

hydrogen, —C(O)R 52 , —C(O)OR 52 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 ;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents comprising halogen, —NO 2 , CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O)NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 3-12 carbocycle, or 3- to 12-membered heterocycle; or

C 3-12 carbocycle and 3- to 12-membered heterocycle,

wherein each C 3-12 carbocycle and 3- to 12-membered heterocycle in R 51 is independently optionally substituted with one or more substituents comprising halogen, —NO 2 , CN, —OR 52 , —SR 52 , —N(R 52 ) 2 , —NR 53 R 54 , —S(═O)R 52 , —S(═O) 2 R 52 , —S(═O) 2 N(R 52 ) 2 , —S(═O) 2 NR 53 R 54 , —NR 52 S(═O) 2 R 52 , —NR 52 S(═O) 2 N(R 52 ) 2 , —NR 52 S(═O) 2 NR 53 R 54 , —C(O)R 52 , —C(O)OR 52 , —OC(O)R 52 , —OC(O)OR 52 , —OC(O)N(R 52 ) 2 , —OC(O)NR 53 R 54 , —NR 52 C(O)R 52 , —NR 52 C(O)OR 52 , —NR 52 C(O)N(R 52 ) 2 , —NR 52 C(O)NR 53 R 54 , —C(O)N(R 52 ) 2 , —C(O)NR 53 R 54 , —P(O)(OR 52 ) 2 , —P(O)(R 52 ) 2 , —P(O)(OR 52 )(R 52 ), —P(O)(NR 52 )(R 52 ), —NR 52 P(O)(R 52 ), —P(O)(NR 52 )(OR 52 ), —P(O)(NR 52 ) 2 , ═O, ═S, ═N(R 52 ), C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

R 52 , at each occurrence, independently comprising hydrogen; and C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, 1- to 6-membered heteroalkyl, C 3-12 carbocycle, or 3- to 12-membered heterocycle, each of which is optionally substituted by halogen, —CN, —NO 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , C 3-12 carbocycle, or 3- to 6-membered heterocycle;

R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;

each of R A , R B , and R c independently comprising R 50 ;

R D is, at each occurrence, independently comprising hydrogen or R 50 ; and

each of m, n, p, and q is independently an integer from 0-12,

X is C—R 5 or N;

each of R 1 and R 2 is independently R 50 ; and

R 5 comprises hydrogen or R 50 .

9. The method of claim 8 , wherein L 1 is

10. The method of claim 1 , wherein the compound comprises any one of:

11. The method of claim 1 , further comprising administering to the subject a second therapeutic agent.

12. The method of claim 1 , further comprising administering to the subject a cell therapy.

13. The method of claim 1 , wherein the subject is human.

14. The method of claim 1 , wherein the compound is of the formula:

15. The method of claim 8 , wherein the compound comprises any one of:

.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 19, 2019
From: GENEA BIOCELLS USA (HOLDINGS), INC.
To: SONIC MASTER LIMITED
Reel/Frame 050088/0595 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 6, 2019
From: KISELYOV, ALEXANDER; SCHMIDT, ULI; DE LA GARZA, ANABEL; RICKARD, AMANDA
To: GENEA BIOCELLS US, INC.
Reel/Frame 048257/0521 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 6, 2019
From: GENEA BIOCELLS US, INC.
To: GENEA IP HOLDINGS PTY LIMITED
Reel/Frame 048257/0530 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 6, 2019
From: GENEA IP HOLDINGS PTY LIMITED
To: GENEA BIOCELLS USA (HOLDINGS), INC.
Reel/Frame 048257/0533 →
Continuity (3)
Provisional Application 62342143 · May 26, 2016
Provisional Application 62460186 · Feb 17, 2017
Related Publication 20190298727A1 · Oct 3, 2019