Histone deacetylase inhibitors

Patent metadata

Field	Value
Publication number	US-9540395-B2
Application number	US-201213823708-A
Country	US
Kind code	B2
Filing date	Feb 28, 2012
Priority date	Feb 28, 2011
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

Abstract

This invention relates to generally inhibiting histone deacetylase (HDAC) enzymes (e.g., HDAC1, HDAC2, and HDAC3).

First claim

We claimed:

1. A compound of the formula (I):

wherein
Ar/Het is selected from the group consisting of pyrazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, furanyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, and 1,2,4-triazolyl;
Y is bond, CR c ═CR d , O, NR e , or S(O) m ;
a is 1-3;
b is 0-3;
m is 0-2;
each occurrence of R a and R b is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
each of R c and R d is, independently, selected from H, F, OH, C1-C6 alkyl, C3-C5 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
each occurrence of R e is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R h , C(═O)O(C1-C6 alkyl), C(═O)N(R i ) 2 , SO 2 —R h , wherein R h is selected from C1-C6 alkyl, CH 2 -(heteroaryl having 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl; and each occurrence of R i is independently selected from H, C1-C6 alkyl, CH 2 -(heteroaryl having 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl and the aryl or heteroaryl portion in R h and R i can be optionally substituted with one or more independently selected substituents selected from the group consisting of F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
each of R4 and R5 is, independently, selected from H, C1-C6 alkyl and F;
R1 is:
(i) hydrogen; or
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 R o ; or
(iii) monocyclic or bicyclic heteroaryl having from 5-10 ring atoms, which is optionally substituted with from 1-3 R o ; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R o , and S; or
(iv) heterocyclyl having from 4-10 ring atoms, which is optionally substituted with from 1-3 R o ; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R o , and S; and
each occurrence of R o is independently selected from the group consisting of: halogen; C1-C6 alkyl; fluoro(C1-C6alkyl); hydroxyl; hydroxy(C1-C4alkyl); C1-C6 alkoxy; fluoro(C1-C6alkoxy); (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—; formyl; formyl(C1-C4alkyl); cyano; cyano(C1-C4alkyl); benzyl; benzyloxy; SO 2 —(C1-C6alkyl); SO—(C1-C6alkyl); and nitro;
R2 is selected from H, F, Cl, CF 3 , CF 2 CF 3 , CH 2 CF 3 , OCF 3 , OCHF 2 , phenyl; phenyl substituted with from 1-3 substituents independently selected from F, OH, C1-C6 alkyl, fluoro(C1-C6 alkyl) C3-C6 cycloalkyl, NH 2 , C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; thienyl; thiazolyl; and pyrazol-1-yl; and
R3 is H, F, or Cl;

or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 , wherein each occurrence of R a and R b is independently selected from H, F, and C1-C6 alkyl.

3. The compound or salt of claim 2 , wherein each occurrence of R a and R b is H.

4. The compound or salt of claim 1 , wherein Y is CR c ═CR d , O, or NR e .

5. The compound or salt of claim 1 , wherein each of R4 and R5 is H.

6. The compound or salt of claim 1 , wherein one of the following applies: (i) R2 is F, Cl, CF 3 , CF 2 CF 3 , CH 2 CF 3 , OCF 3 , OCHF 2 , phenyl; phenyl substituted with from 1-3 substituents independently selected from F, OH, C1-C6 alkyl, fluoro(C1-C6 alkyl), C3-C6cycloalkyl, NH 2 , C1-C6alkoxy, C1-C6 fluoroalkoxy, and cyano; thienyl; thiazolyl; or pyrazol-1-yl, and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is F or Cl.

7. The compound or salt of claim 1 , wherein each of R2 and R3 is hydrogen.

8. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, as claimed in claim 1 and a pharmaceutically acceptable carrier.

10. The compound or salt of claim 1 , wherein Y is CR c ═CR d .

11. The compound or salt of claim 1 , wherein —Y—[C(R a ) 2 ] a —[C(R b ) 2 ] b — is —CH═CH—C(R a ) 2 —C(R b ) 2 .

12. The compound or salt of claim 1 , wherein —Y—[C(R a ) 2 ] a —[C(R b ) 2 ] b — is —CH═CH—CH 2 — or —CH═CH—CH 2 —CH 2 —.

13. The compound or salt of claim 1 , wherein Y is O or NR e .

14. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl.

15. The compound or salt of claim 1 , wherein R1 is phenyl.

16. The compound or salt of claim 1 , wherein R1 is pyridyl.

17. The compound or salt of claim 1 , wherein R1 is H.

18. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl, R a and R b are H, Y is a bond, and R1 is H.

19. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl, R a and R b are H, and R1 is phenyl.

20. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl, R a and R b are H, Y is O or NR e , and R1 is phenyl.

21. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl, R a and R b are H, Y is O, and R1 is phenyl.

22. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl, R a and R b are H, Y is CR c ═CR d , and R1 is phenyl.

23. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl, R a and R b are H, Y is a bond, and R1 is phenyl.

24. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl, Y is a bond, CR c ═CR d , O, or NR e , and R1 is phenyl.

25. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl, Y is a CR c ═CR d , and R1 is phenyl.

26. The compound or salt of claim 1 , wherein Ar/Het is pyrazolyl, Y is a bond, and R1 is phenyl.

Assignees

• Jacques Vincent
• Rusche James R
• Peet Norton P
• Singh Jasbir
• Biomarin Pharm Inc

Inventors

• Jacques Vincent
• Rusche James R
• Peet Norton P
• Singh Jasbir

Classifications

• C07D211/70

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D261/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D231/12 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title