Deoxyuridine triphosphatase inhibitors

Patent metadata

Field	Value
Publication number	US-10227326-B2
Application number	US-201715711680-A
Country	US
Kind code	B2
Filing date	Sep 21, 2017
Priority date	Jan 7, 2013
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.

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 of each thereof, wherein

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,
r is 1, 2, or 3,
—W—X—Y— is —CH 2 —X—SO 2 —NH—CH(R Y )—, —CH 2 —X—SO 2 —NH—C(R Y ) 2 —, or —CH 2 —X—B—CH 2 CR Z R W —
X is optionally substituted C 1 -C 6 alkylene wherein one of the methylene groups within the alkylene chain is optionally replaced with an O or S atom, such that X is optionally substituted alkylene or a heteroalkylene;
B is a optionally substituted C 3 -C 10 heteroaryl;
R Y an R w are independently hydrogen or optionally substituted C 1 -C 6 alkyl; and
R z is hydrogen or hydroxyl; or
—W—X—Y— is

wherein Y 1 is CH 2 , O or S, X 10 is NH, NCO 2 R 20 , O, or CH 2 , R 20 is C 1 -C 6 alkyl optionally substituted with 1-3 C 6 -C 10 aryl groups, u is 0, 1, 2, 3, or 4, and R z is hydroxy or hydrogen, and R w is C 1 -C 6 alkyl or hydrogen, and the phenylene and the heteroarylene rings are optionally substituted; and
Z is optionally substituted C 6 -C 10 aryl or optionally substituted C 1 -C 10 heteroaryl group.

2. A compound of claim 1 , wherein the compound is selected from:

3. A compound of claim 1 which is a compound of formula (III):

wherein A is

R 11 is hydrogen, halo, R 12 or —O—R 12 ,
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,
L 1 is

wherein Y 1 is CH 2 , O, S,
X 10 is NH, NCO 2 R 20 , O, or CH 2 ,
R 20 is 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,
Z is phenyl 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,
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 .

4. The compound of claim 3 , wherein Z is:

5. The compound of claim 3 of formula:

6. The compound of claim 1 of formula:

wherein A is selected from:

X 10 is NH, NCO 2 R 20 , O, or CH 2 ;
R 20 is 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 11 is hydrogen, 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; and
r is 1, 2, or 3.

7. The compound of claim 6 , selected from:

or a diastereomer or an enantiomer thereof,
or a pharmaceutically acceptable salt thereof.

8. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

9. 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 .

10. A method of one or more of inhibiting dUTPase or enhancing the efficacy of a dUTPase directed therapy comprising contacting the dUTPase with the composition of claim 8 .

11. A method of treating but not preventing a disease whose treatment is impeded by the expression or over expression of dUTPase, comprising administering to a patient in need of such treatment an effective amount of the compound of claim 1 .

12. A method of treating but not preventing a disease whose treatment is impeded by the expression or over expression of dUTPase, comprising administering to a patient in need of such treatment an effective amount of the composition of claim 8 .

13. A method of inhibiting the growth of a cancer cell comprising contacting the cell with an effective amount of the compound of claim 1 and an effective amount of a dUTPase-directed therapeutic, thereby inhibiting the growth of the cancer cell.

14. A method of inhibiting the growth of a cancer cell comprising contacting the cell with an effective amount of the composition of claim 8 and an effective amount of a dUTPase-directed therapeutic, thereby inhibiting the growth of the cancer cell.

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

• C07D265/18

  with hetero atoms directly attached in position 2 · CPC title

• C07D401/06 Primary

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