Granted Patent B2

US 12,370,194 · App. 18/443,509 · Granted Jul 29, 2025

Inventor: Christopher M. Yates (Belmont, MA)

Assignee: Eikonizo Therapeutics, Inc.

A61K31/506C07D413/04C07D413/14

Abstract

Claims (49)

1. A compound of Formula I-c

or a pharmaceutically acceptable salt thereof; wherein:

R 3 is haloalkyl or —OR g ;

A is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, or alkyl, wherein each A is optionally substituted with 1-3 independent substituents R 5 ;

each occurrence of R 5 is, independently, halogen, cyano, alkyl, haloalkyl, —NR a R b , —NHSO 2 R c , —(CH 2 ) n NR a R b , —(CH 2 ) n C(O)NR a R b , —(CH 2 ) n NR d SO 2 R d , —S(O)R d , —S(O) 2 R d , —CO 2 R e , —COR f , —(CR e R f ) n OR f , —OR f , or aryl substituted with 0-3 independent halogen, —NR a R b , —NHSO 2 R c , —(CH 2 ) n NR a R b , —(CH 2 )C(O)NR a R b , —(CH 2 ) n NR d SO 2 R d , —S(O)R d , —S(O) 2 R d , —CO 2 R e , —COR f , —(CR e R f ) n OR f , or —OR f ; or two occurrences of R 5 , together with the atoms to which they are attached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each occurrence of R a , R b , R c , R d , R e , and R f is, independently, hydrogen, acyl, alkoxyalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R a and R b together with the atoms to which they are attached form a heterocycloalkyl ring; or R e and R f together with the atoms to which they are attached form a cycloalkyl ring; or 2 instances of R d together with the atoms to which they are attached form a heterocycloalkyl ring; and

R g is haloalkyl;

provided that the compound is further characterized by one or more of the following:

R 3 is —CH 2 F;

A is cycloalkyl, heterocycloalkyl, arylalkyl, or alkyl, wherein each A is optionally substituted with 1-3 independent substituents R 5 ;

A is heteroaryl substituted with 1-3 independent substituents R 5 ;

A is phenyl substituted with 1-3 independent substituents R 5 and at least one R 5 is not Cl, F, —CF 3 , or methoxy; or

A is an aryl other than phenyl, optionally substituted with 1-3 independent substituents R 5 .

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 3 is —CF 3 , —CHF 2 , or —CH 2 F.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

each R 5 is, independently, halogen, cyano, alkyl, haloalkyl, —NR a R b , or —OR f ; and R f is hydrogen, alkyl, or haloalkyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein: each occurrence of R a , R b , and R f is, independently, hydrogen, alkyl, or haloalkyl.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

A is cycloalkyl, heterocycloalkyl, arylalkyl, or alkyl, wherein each A is optionally substituted with 1-3 independent substituents R 5 .

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

A is heteroaryl substituted with 1-3 independent substituents R 5 .

7. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

A is substituted with 1-3 independent substituents R 5 and at least one R 5 is not Cl, F, —CF 3 , or methoxy.

8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

each R 5 is phenyl substituted with 0-3 independent halogen, —NR a R b , or —OR f ; and each occurrence of R a , R b , and R f is, independently, hydrogen, alkyl, or haloalkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

each occurrence of R 5 is, independently, halogen, cyano, alkyl, haloalkyl, or —OR f ; and R f is alkyl, or haloalkyl.

10. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:

each occurrence of R 5 is halogen, cyano, methyl optionally substituted with one or more halogen, or methoxy optionally substituted with one or more halogen.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl.

12. The compound of claim 11 , wherein: A is pyridinyl.

13. The compound of claim 11 , wherein: A is phenyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —CF 3 , —CHF 2 , or —CH 2 F;

A is phenyl substituted with 1-3 independent substituents R 5 ; and

at least one occurrence of R 5 is cyano, alkyl, or —OR f ; and R f is hydrogen, alkyl, or haloalkyl.

15. A method of selectively inhibiting histone deacetylase 6 (HDAC6) activity in vivo over a histone deacetylase enzyme selected from the group consisting of: HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10 and HDAC11, the method administering a compound of Formula I-c:

or a pharmaceutically acceptable salt thereof, to a subject; wherein

R 3 is —CF 2 H;

A is phenyl or pyridyl optionally substituted with 1-3 independent substituents R 5 ; and

each occurrence of R 5 is halogen, cyano, methyl optionally substituted with one or more halogen, or methoxy optionally substituted with one or more halogen.

16. The method of claim 15 , wherein each occurrence of R 5 is, independently, Cl, F, methyl optionally substituted with one or more F, or methoxy optionally substituted with one or more F.

17. The method of claim 15 , wherein each occurrence of R 5 is, independently, F or —CF 3 .

18. The method of claim 15 , wherein the compound is Compound 4 or a pharmaceutically acceptable salt thereof,

19. The method of claim 15 , wherein the compound is Compound 5 or a pharmaceutically acceptable salt thereof,

20. The method of claim 15 , wherein the compound is Compound 11 or a pharmaceutically acceptable salt thereof.

21. The method of claim 15 , wherein the compound is Compound 63 or a pharmaceutically acceptable salt thereof,

Assignments (5)

Continuity (6)

References Cited (400)

Cited By (1)

US 12,590,084