Alpha-cinnamide compounds and compositions as HDAC8 inhibitors

Patent metadata

Field	Value
Publication number	US-9745253-B2
Application number	US-201615067605-A
Country	US
Kind code	B2
Filing date	Mar 11, 2016
Priority date	Mar 13, 2015
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

The present invention relates to inhibitors of histone deacetylases, in particular HDAC8, that are useful for the treatment of cancer and other diseases and disorders, as well as the synthesis and applications of said inhibitors.

First claim

The invention claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, or tautomer thereof,
wherein:
X 1 , X 2 , X 3 , and X 4 are independently, at each occurrence, CH or N, wherein no more than two of X 1 , X 2 , X 3 , and X 4 are N and wherein no two N atoms are contiguous;
R a is hydrogen or C 1 -C 6 alkyl;
R b is hydrogen, —(CH 2 ) n R c , —C(O)R c , —C(O)NHR c , or —S(O) 2 R c ;
or alternatively, R a and R b are combined to form a heterocycle, wherein said heterocycle is optionally substituted with one or more R d ;
R c is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-to-12 membered heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R d or R e ;
R d is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, oxo, C 3 -C 8 cycloalkyl, 3-to-12 membered heterocycloalkyl, aryl, heteroaryl, —(CH 2 ) n R e , —(CH 2 ) n O(CH 2 ) m R e , —(CH 2 ) n NR e R f , —C(O)(CH 2 ) n R e , —(CH 2 ) n C(O)OR e , —C(O)(CH 2 ) n SR e , —(CH 2 ) n C(O)NR e R f , —NH(CH 2 ) n R e , —NHC(O)(CH 2 ) n R e , —NHC(O)(CH 2 ) n OR e , —NHC(O)(CH 2 ) n SR e , —NHS(O) 2 R e , —OR e , or —S(O) 2 R e , wherein each alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R e or R f ;
or two R d when attached to the same carbon atom can form a C 5 -C 12 spirocycle or a 3-to 12-membered spiroheterocycle, wherein the spirocycle or the spiroheterocycle are optionally substituted with one or more R e or R f ;
R e is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)(CH 2 ) n R f , or —(CH 2 ) n C(O)R f , wherein each alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R f ;
R f is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, oxo, cycloalkyl, 3-to-12 membered heterocycloalkyl, aryl, heteroaryl, (C 1 -C 6 )alkylaryl, halogen, —(CH 2 ) n O(CH 2 ) m CH 3 , —(CH 2 ) n N(CH 3 ) 2 , —(CH 2 ) n O(CH 2 ) m N(CH 3 ) 2 , —(CH 2 ) n NR e R f , —N(CH 3 )S(O) 2 CH 3 , —S(CH 2 ) m CH 3 , or —S(O) 2 (CH 2 ) m CH 3 , wherein each alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, oxo, halogen, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
A is hydrogen or fluorine;
n is 0, 1, 2, 3, or 4; and
m is 0, 1, 2, 3, or 4;

with the proviso that:
(1) both R a and R b cannot simultaneously be H nor simultaneously Me; or
(2) when R a is H and R b is —C(O)R c , then R c cannot be phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-styryl or alkyl with unsubstituted phenyl.

2. The compound of claim 1 having the Formula (I-a):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, or tautomer thereof,
wherein:
het is a 3-to-12 membered heterocycle, wherein said heterocycle is optionally substituted with one or more R d .

3. The compound of claim 1 having the Formula (I-b):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, or tautomer thereof.

4. The compound of claim 1 having the Formula (I-c):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, or tautomer thereof.

5. The compound of claim 1 , wherein X 1 is N.

6. The compound of claim 1 , wherein X 2 is N.

7. The compound of claim 1 , wherein X 3 is N.

8. The compound of claim 1 , wherein X 4 is N.

9. A compound of Formula (II):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, or tautomer thereof,
wherein:
X 1 , X 2 , X 3 , and X 4 are independently, at each occurrence, CH or N, wherein no more than two of X 1 , X 2 , X 3 , and X 4 are N and wherein no two N atoms are contiguous;
Z is C(O) or S(O) 2 ;
R z is —NR a R b or —(CH 2 ) n R c ;
R a is hydrogen or C 1 -C 6 alkyl;
R b is hydrogen, —(CH 2 ) n R c , —C(O)R c , —C(O)NHR c , or —S(O) 2 R c ;
or alternatively, R a and R b are combined to form a heterocycle, wherein said heterocycle is optionally substituted with one or more R d ;
R c is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 12 aryl, or 5-12 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R d or R e ;
R d is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, oxo, C 3 -C 8 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 12 aryl, 5-12 membered heteroaryl, —(CH 2 ) n R e , —(CH 2 ) n O(CH 2 ) m R e , —(CH 2 ) n NR e R f , —C(O)(CH 2 ) n R e , —(CH 2 ) n C(O)OR e , —C(O)(CH 2 ) n SR e , —(CH 2 ) n C(O)NR e R f , —NH(CH 2 ) n R e , —NHC(O)(CH 2 ) n R e , —NHC(O)(CH 2 ) n OR e , —NHC(O)(CH 2 ) n SR e , —NHS(O) 2 R e , —OR e , or —S(O) 2 R e , wherein each alkyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R e or R f ;
R e is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 12 aryl, 5-12 membered heteroaryl, wherein each alkyl, alkenyl, alkoky, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R f ;
R f is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, oxo, C 3 -C 8 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 12 aryl, 5-12 membered heteroaryl, halogen, —(CH 2 ) n O(CH 2 ) m CH 3 , —(CH 2 ) n N(CH 3 ) 2 , —(CH 2 ) n O(CH 2 ) m N(CH 3 ) 2 , —(CH 2 ) n NR e R f , —N(CH 3 )S(O) 2 CH 3 , —S(CH 2 ) m CH 3 , or —S(O) 2 (CH 2 ) m CH 3 , —(CH 2 ) n NHC(O)R g , C(O)OR g , —OR g , wherein each alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, oxo, halogen, C 3 -C 8 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 12 aryl, or 5-12 membered heteroaryl;
R g is C 1 -C 6 alkyl or C 6 -C 12 aryl;
A is hydrogen or fluorine;
n is 0, 1, 2, 3, or 4; and
m is 0, 1, 2, 3, or 4;
with the proviso that when Z is S(O) 2 , R z cannot be —NR a R b .

10. The compound of claim 9 having the Formula (II-a):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, or tautomer thereof.

11. The compound of claim 9 having the Formula (II-b):

Assignees

• Forma Therapeutics Inc

Inventors

• Bair Kenneth W
• Barczak Nicholas
• Han Bingsong
• Lancia Jr David R
• Liu Cuixian
• Martin Matthew W
• Ng Pui Yee
• Rudnitskaya Aleksandra
• Thomason Jennifer R
• Zablocki Mary Margaret
• Zheng Xiaozhang

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title