Heteroatom containing deoxyuridine triphosphatase inhibitors

Patent metadata

Field	Value
Publication number	US-10457673-B2
Application number	US-201715719165-A
Country	US
Kind code	B2
Filing date	Sep 28, 2017
Priority date	Jan 3, 2014
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions in a method of treating cancer. The dUTPase inhibitors disclosed contain a uracil isostere in the molecule represented by a 2,6-diketopiperazine moiety. Thioanalogs of the uracil isostere where a thione replaces each of the ketone are also disclosed.

First claim

The invention claimed is:

1. A compound of formula (I):

or a tautomer thereof, including any stereoisomer, enantiomer or diastereoisomer,
or a pharmaceutically acceptable salt and/or a solvate of each thereof, of formula (I):
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein

is

Y 10 is O, S, SO, SO 2 , NH or NR 15 ;
R 11 is hydrogen, halo, R 12 or —O—R 12 , wherein R 12 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl optionally substituted with 1-3 hydroxy, fluoro, chloro, and amino substituent, or R 11 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl wherein each alkyl, alkenyl, and alkynyl is optionally substituted with 1-3 hydroxy, fluoro, chloro, and amino substituent;
r is 1, 2, or 3;
R 15 is C 1 -C 6 alkyl optionally substituted with 1-3 C 1 -C 6 alkoxy, hydroxy, amino, and oxo groups;
W is a bond or optionally substituted —CH 2 —;
X is a bond, O, S, NR 19 , optionally substituted C 1 -C 6 alkylene, optionally substituted C 2 -C 6 alkenylene, or optionally substituted C 1 -C 6 alkynylene group, a divalent optionally substituted C 6 -C 10 aromatic hydrocarbon group, or a divalent optionally substituted saturated or unsaturated C 2 -C 10 heterocyclic or optionally substituted C 1 -C 10 heteroaryl group;
R 19 is hydrogen, optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 8 cycloalkyl;
Y is an optionally substituted C 1 -C 10 alkylene which further optionally has a cycloalkylidene structure on one carbon atom, or is optionally substituted C 2 -C 6 alkenylene, or optionally substituted C 2 -C 6 alkynylene group, or Y is -L 10 -B 1 -L 11 -;
L 10 and L 11 independently are optionally substituted C 1 -C 6 alkylene, optionally substituted C 2 -C 6 alkenylene, or optionally substituted C 2 -C 6 alkynylene group;
B 1 is a divalent optionally substituted C 1 -C 10 heteroaryl group;
Z is —SO 2 NR 31 R 32 , —NR 3 SO 2 —R 4 , or R 4 wherein R 31 and R 32 are the same or different and each represents a hydrogen atom, optionally substituted C 1 -C 6 alkyl group optionally substituted with an aryl group;
R 3 is hydrogen or optionally substituted C 1 -C 6 alkyl; and
R 4 is optionally substituted C 6 -C 10 aryl, an optionally substituted C 2 -C 10 heterocyclic group, or an optionally substituted C 1 -C 10 heteroaryl group;
provided that if W is a bond, X cannot be a bond.

2. The compound of claim 1 , wherein each R 19 independently is hydrogen or methyl.

3. The compound of claim 1 , wherein the uracil isostere A is:

4. The compound of claim 1 , wherein the uracil isostere A is:

5. The compound of claim 1 of formula:

wherein A is:

R 11 is hydrogen, halo, R 12 or —O—R 12 , wherein R 12 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl optionally substituted with 1-3 hydroxy, fluoro, chloro, and amino substituent, or R 11 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl wherein each alkyl, alkenyl, and alkynyl is optionally substituted with 1-3 hydroxy, fluoro, chloro, and amino substituent;
r is 1, 2, or 3,
Y 10 is O, S, SO, SO 2 , NH or NR 15 , or X 10 is joined at Y 10 with Y 10 being a nitrogen atom;
R 15 is C 1 -C 6 alkyl optionally substituted with 1-3 C 1 -C 6 alkoxy, hydroxy, amino, and oxo groups;
X 10 is NH, O, or CH 2 ; and
u is 0, 1, 2, 3, or 4.

6. The compound of claim 5 , wherein A is:

7. The compound of claim 5 , wherein A is:

Assignees

• Univ Southern California

Inventors

• Ladner Robert D
• Giethlen Bruno

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• C07D403/06

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