Fused pyrimidine-based hydroxamate derivatives

Patent metadata

Field	Value
Publication number	US-9957270-B2
Application number	US-201515124654-A
Country	US
Kind code	B2
Filing date	Mar 13, 2015
Priority date	Mar 13, 2014
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

The present invention relates to fused pyrimidine-based hydroxamate compounds of formula (I), comprising a hydroxamate group, that are inhibitors of histone deacetylase (HDAC) and kinases. More particularly, the present invention relates to hydroxamate substituted purine or 5H-pyrrolo[3,2-d]pyrimidine derivatives, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of disorders/conditions/diseases involving, relating to or associated with enzymes having histone deacetylase, non-histone deacetylase and kinase activities/functions and/or via unspecified/multi-targeted mechanisms.

First claim

The invention claimed is:

1. A compound of Formula (I);

wherein X, Y and Z are independently selected from N, CHR 3 or CR 3 , wherein at least one of X, Y or Z is N;
is a single or double bond, as valency allows;
R 1 is selected from the group consisting of optionally substituted amino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
R 2 is selected from the group consisting of halogen, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted amino, and optionally substituted heterocycloalkyl;
R 4 is optionally substituted alkyl;
at least one of R 1 , R 2 , R 3 or R 4 is further independently substituted by an hydroxamate group -L 1 -R 5 -L 2 -R 6 -L 3 -CON(R a )OR b , wherein;
R a and R b are hydrogen;
L 1 , L 2 and L 3 are independently selected from the group consisting of a bond, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl;
R 5 and R 6 are independently selected from the group consisting of a bond, O, NR c , S(O) n , optionally substituted amide, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; wherein;
R c is independently selected from the group consisting of hydrogen or, optionally substituted alkyl; and
n is an integer from 0 to 2;

or a pharmaceutically acceptable form thereof.

2. The compound according to claim 1 , wherein X, Y and Z are N; both X and Z are N and Y is CR 3 ; X is CH, Y is CR 3 and Z is N; or X is CH 2 , Y is CHR 3 and Z is N.

3. The compound according to claim 1 , wherein the compound has the following Formula (Ia), (Ib), (Ic) or (Id):

4. The compound according to claim 1 , wherein R 1 is optionally substituted cycloamino, optionally substituted heterocycloamino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylamino or optionally substituted heteroarylamino; or R 1 is an optionally substituted phenyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl, optionally substituted pyrazinyl, optionally substituted thiomorpholino or optionally substituted morphilino, or R 2 is a halogen, optionally substituted cycloalkyl, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted amino, optionally substituted alkylamino, optionally substituted cycloamino, optionally substituted heterocycloamino, optionally substituted aryl or optionally substituted heteroaryl; or R 2 is a Cl, Br, F, NH 2 , dimethylamino, diethylamino, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholino, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substituted benzimidazolyl.

5. The compound according to claim 1 , wherein R 3 is hydrogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkylamino, optionally substituted cycloamino, optionally substituted heterocycloamino; or R 3 is NH 2 , diethylamino, optionally substituted pyrrolidinyl or optionally substituted piperidinyl; or R 4 is optionally substituted alkyl; or R 4 is ethyl, 1-propyl, 2-propyl, 2-butyl, 3-pentyl or cyclopentyl.

6. The compound according to claim 1 , wherein R a and R b are hydrogen; L 1 , L 2 and L 3 are independently a bond, optionally substituted alkyl or optionally substituted alkenyl; or R 5 and R 6 are independently a bond, —O—, —S—, —NH—, —N(Me)-, —N(Ac)—, —S(O)—, —S(O) 2 —, —CONH—, —NHCO, optionally substituted heterocycloalkyl or optionally substituted aryl; or R 5 and R 6 are independently a bond, —O—, —NH—, —N(Me)-, —NHCO—, 1,3-piperidinylene, 1,4-piperidinylene, 2,4-pyrimidinylene, 2,5-pyrimidinylene, 1,2-phenylene, 1,3-phenylene or 1,4-phenylene.

7. The compound according to claim 1 , wherein the hydroxamate group -L 1 -R 5 -L 2 -R 6 -L 3 -CON(R a )OR b is selected from the following structures;

wherein R 7 is selected from the group consisting of a bond, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, O, S, optionally substituted amino, —CH 2 O—, —OCH 2 —, —CH 2 S(O) n —, —S(O) n —, —CH 2 N(R c )—, —N(R c )CH 2 —, —N(R c )—, —CO—, —C(═NOR a )—, —CON(R a )—, and —N(R c )CO—; and m is an integer from 0 to 10.

8. The compound according to claim 1 , wherein R 2 or R 4 contains the hydroxamate group -L 1 -R 5 -L 2 -R 6 -L 3 -CON(R a )OR b .

9. The compound according to claim 1 , wherein R 1 is not a morpholine when R 2 or R 3 contains the hydroxamate group.

10. The compound according to claim 1 , wherein R 1 is a substituted amino when R 2 or R 3 contains the hydroxamate group.

11. A compound according to claim 1 , wherein the compound is selected from the group consisting of;

EX
Chemical Structure and Name

1

2

N-hydroxy-7-(2-(3-(hydroxymethyl)phenyl)-6-

morpholino-9H-purin-9-yl)heptanamide

3

4

5

6

Assignees

• Agency Science Tech & Res

Inventors

• Wang Haishan
• Chen Dizhong
• Soh Chang Kai

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/08

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

• A61P7/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title