Heterocyclic hydroxamic acids as protein deacetylase inhibitors and dual protein deacetylase-protein kinase inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9840520-B2
Application number	US-201515310743-A
Country	US
Kind code	B2
Filing date	May 14, 2015
Priority date	May 14, 2014
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

The present invention relates to novel hydroxamic acids which are specific histone deacetylase (HDAC) inhibitors and/or TTK/Mps1 kinase inhibitors, including pharmaceutically acceptable salts thereof, which are useful for modulating HDAC and/or TTK/Mps1 kinase activity, pharmaceutical compositions comprising these compounds, and processes for their preparation.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
Z is NH or CH 2 ;
X is O, S, SO, SO 2 , CO, CR 2 R 3 , NR 4 , SO 2 NR 4 , NR 4 SO 2 , CONR 4 , NR 4 CO, NR 4 CO 2 , NR 4 (CO)NR 5 or a bond;
M is CR 6 or N;
Q 1 and Q 2 are independently N or CH;
Q 3 is CR 7 or Q 3 is NR 8 when R 1 is not present;
n is 0-6;
Y is H, CN, Cl, Br, I, F, C 1 -C 6 alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, OR 9 , SR 9 , COR 9 , COOR 9 , SOR 9 , SO 2 R 9 , SO 2 NR 10 R 11 , NR 10 R 11 , NR 10 SO 2 R 9 , NR 10 COR 9 , NR 10 CO 2 R 9 , CONR 10 R 11 , CO 2 NR 10 R 11 , NR 10 (CO)NR 11 , each of which may be optionally substituted and where R 10 and R 11 taken together may form a heterocyclic ring which may be optionally substituted;
R 1 is H, C 1 -C 6 alkyl, haloalkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclic, carbocyclic or absent, each of which may be optionally substituted;
R 2 is H, C 1 -C 6 alkyl, hydroxy, alkoxy, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted;
R 3 is H, C 1 -C 6 alkyl, alkoxy, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted;
R 4 is H, C 1 -C 6 alkyl, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted;
R 5 is H, C 1 -C 6 alkyl, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted;
R 6 is H, CN, Cl, Br, I, F, C 1 -C 6 alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, OR 9 , SR 9 , COR 9 , COOR 9 , SOR 9 , SO 2 R 9 , SO 2 NR 10 R 11 , NR 10 R 11 , NR 10 SO 2 R 9 , NR 10 COR 9 , NR 10 CO 2 R 9 , CONR 10 R 11 , CO 2 NR 10 R 11 or absent, where R 10 and R 11 taken together may form a 4-7 membered ring which may be optionally substituted;
R 7 is H, C 1 -C 6 alkyl, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted;
R 8 is H, C 1 -C 6 alkyl, haloalkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclic, carbocyclic or absent, each of which may be optionally substituted;
R 9 is H, C 1 -C 6 alkyl, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted;
R 10 is H, C 1 -C 6 alkyl, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted; and
R 11 is H, C 1 -C 6 alkyl, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted.

2. The compound according to claim 1 ,
wherein:
Y is NR 10 R 11 ;
R 10 is alkyl, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl; and
R 11 is alkyl or H, and
where R 3 and R 4 taken together may form a 4-7 membered ring which is optionally substituted.

3. The compound according to claim 1 , wherein X is O, S, SO 2 , SO 2 NR 4 or CONR 4 .

4. The compound according to claim 1 ,
wherein:
R 1 is H or C 1 -C 6 alkyl;
Q 3 is NR 8 where R 8 is absent; and
M is CR 6 where R 6 is H.

5. The compound according to claim 1 ,
wherein:
R 1 is H or C 1 -C 6 alkyl;
Q 3 is CR 7 where R 7 is H; and
M is N.

6. The compound according to claim 1 , wherein Y is aryl, heteroaryl or NR 10 R 11 .

7. The compound according to claim 1 , having the formula (II):

or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein:
Ring A is an optionally substituted aryl or optionally substituted heteroaryl;
Ring B is an optionally substituted aryl or optionally substituted heteroaryl;
Ring C is an optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
Z is N, CR 2 , O, S, C═O, SO or SO 2 ;
R 1 is H, absent, C 1 -C 6 alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, aryl, aryl-alkyl, heteroaryl, heterocyclic or carbocyclic, each of which may be optionally substituted, and wherein when Z is CR 2 , R 1 and R 2 taken together may form a 3-7 membered ring which may be optionally substituted;
X is O, S, SO, SO 2 , CO, CR 2 R 3 , NR 4 , SO 2 NR 4 , NR 4 SO 2 , CONR 4 , NR 4 CO, NR 4 CO 2 , NR 4 (CO)NR 5 or a bond;
Y is H, CN, Cl, Br, I, F, C 1 -C 6 alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, OR 3 , SR 3 , COR 3 , COOR 3 , SOR 3 , SO 2 R 3 , SO 2 NR 4 R 5 , NR 4 R 5 , NR 4 SO 2 R 3 , NR 4 COR 3 , NR 4 CO 2 R 3 , CONR 4 R 5 , CO 2 NR 4 R 5 , NR 4 (CO)NR 5 or absent, each of which may be optionally substituted and where R 4 and R 5 taken together may form a 4-7 membered ring which may be optionally substituted;
L is C 1 -C 9 alkylene, C 2 -C 9 alkenylene or C 2 -C 9 alkynylene, any of which is substituted or unsubstituted, wherein one or more of the carbon atoms of the alkylene, alkenylene or alkynylene is optionally replaced with O, S, SO, SO 2 , SO 2 NR 4 , NR 4 SO 2 , NR 4 , CO, CONR 4 , NR 4 CO, CO 2 NR 4 , NR 4 CO 2 , NR 4 (CO)NR 5 , a cycloalkyl or a heterocycle, with the proviso that heteroatoms are not bonded directly to alkenyl or alkynyl carbons, and that the carbon atom adjacent to X shall not be optionally replaced such that a heteroatom-heteroatom bond results;
R 2 is H, C 1 -C 6 alkyl, hydroxy, alkoxy, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted;
R 3 is H, C 1 -C 6 alkyl, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted;
R 4 is H, C 1 -C 6 alkyl, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocycle, any of which is substituted or unsubstituted;
R 5 is H, C 1 -C 6 alkyl, aryl, (CH 2 ) n -aryl, heteroaryl, (CH 2 ) n -heteroaryl, cycloalkyl or heterocyclic, any of which is substituted or unsubstituted; and
n is 1-4.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, pyridinyl, pyrimidinyl or pyrazinyl.

9. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl, pyridinyl, pyrimidinyl or pyrazinyl.

10. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein ring C is independently selected from a 5-membered heteroaryl or a 5-membered heterocycloalkyl.

11. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein Y is aryl, heteroaryl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, NH 2 , NH(alkyl), N(alkyl)(alkyl), N(aryl)(alkyl), NH(cycloalkyl), N(alkyl)(cycloalkyl), NH(heteroaryl), NH(heterocycle), N(alkyl)(heteroaryl), N(alkyl)(heterocycle), NH(alkylheteroaryl), NH(alkylheterocycle), N(alkyl)(alkyl heteroaryl) or N(alkyl)(alkylheterocycle).

12. The compound according to claim 1 , h

Assignees

• Univ Colorado Regents

Inventors

• Liu Xuedong
• Zhang Gan
• Chan Daniel Chuen-Fong
• Piscopio Anthony D

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title