Heteroatom containing deoxyuridine triphosphatase inhibitors

Patent metadata

Field	Value
Publication number	US-9790214-B2
Application number	US-201515109616-A
Country	US
Kind code	B2
Filing date	Jan 2, 2015
Priority date	Jan 3, 2014
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

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

wherein A is

each V is independently O or S,
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,
r is 1, 2, or 3,
Y 10 is O, S, SO, SO 2 , NH or NR 15 ,or L 1 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,
L 1 - is

Y 1 is CH 2 , O, S,
X 10 is NH, NCO 2 R 20 , O, —CO—, —CO—NH—, or CH 2 ,
R 20 C 1 -C 6 alkyl optionally substituted with 1-3 C 6 -C 10 aryl groups,
u is 0, 1, 2, 3, or 4,
R z is hydroxy or hydrogen,
R W is C 1 -C 6 alkyl or hydrogen, and
the phenylene and the heteroarylene rings are optionally substituted,
Z is phenyl or a 5 or 6 member heteroaryl substituted with an R 6 and an R 60 groups, wherein the R 6 and the R 60 are positioned 1,2 with respect to each other,
R 6 is hydrogen, optionally substituted C 1 -C 6 alkoxy, or halo, and
R 60 is —OR 7 or —NHR 7 R 70 ,
R 7 is optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 3 -C 10 heteroaryl, optionally substituted C 3 -C 10 heterocyclyl, or optionally substituted phenyl, and
R 70 is hydrogen or R 7 .

2. The compound of claim 1 , wherein L 1 is

3. The compound of claim 1 , wherein L 1 is

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

wherein Y 10 is O, S, SO, SO 2 , or NH.

5. The compound of claim 1 , wherein A is:

6. The compound of claim 1 , wherein A is:

7. The compound of claim 1 , wherein A is:

8. The compound of claim 1 , wherein Z is selected from:

wherein each R 6 and R 7 independently are defined as in claim 1 above,
each R 61 and R 62 independently is N or CH, provided that at least one of R 61 and R 62 is N,
each R 63 independently is NR 70 , S, O, and
each R 64 independently is N or CH.

9. The compound of claim 1 , of wherein
L l is defined as in claim 1 ,
R 6 is hydrogen, F, Cl, OMe, or OCF 3 , and
R 7 is

wherein t is 1, 2, or 3.

10. A compound, or a tautomer thereof, including any stereoisomer, enantiomer or diastereoisomer, or pharmaceutically acceptable salt and/or a solvate of each thereof, wherein the compound is selected from:

11. A stereochemically pure enantiomer of a compound of claim 1 .

12. A composition comprising the compound of claim 1 and a carrier or an excipient, wherein the carrier or the excipient is a pharmaceutically acceptable carrier or excipient.

13. A method of one or more of inhibiting dUTPase or enhancing the efficacy of a dUTPase directed therapy comprising contacting the dUTPase with the compound of claim 1 .

Assignees

• Univ Southern California

Inventors

• Ladner Robert D
• Giethlen Bruno

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• C07D413/06 Primary

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

• A61K31/513

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