Deoxyuridine triphosphatase inhibitors

Patent metadata

Field	Value
Publication number	US-10577321-B2
Application number	US-201615740783-A
Country	US
Kind code	B2
Filing date	Jul 7, 2016
Priority date	Jul 8, 2015
Publication date	Mar 3, 2020
Grant date	Mar 3, 2020

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, or a deuterium isotope of each of the above wherein up to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium(s), or a pharmaceutically acceptable salt of each of the foregoing, or a pharmaceutically acceptable solvate of each of the above mentioned,
wherein
A is

L 1 is —(CH 2 ) q —, wherein one or more hydrogens are optionally substituted with C 1 -C 3 alkyl and/or at least two or more vicinal hydrogens are optionally substituted with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl; and wherein q is 3, 4, 5, 6, 7, or 8;

wherein one or more hydrogens are optionally substituted with C 1 -C 3 alkyl and/or at least two or more vicinal hydrogens are optionally substituted with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl; and wherein p is 0, 1, 2, 3, 4, or 5 and z is 0, 1, 2, 3, 4, or 5;
—(CH 2 ) m —X 15 —(CH 2 ) n —, wherein one or more hydrogens are optionally substituted with C 1 -C 3 alkyl and/or at least two or more vicinal hydrogens are optionally substituted with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl; and wherein m is 0, 1, 2, or 3 and n is 3, 4, 5, 6, or 7; or

wherein one or more hydrogens are optionally substituted with C 1 -C 3 alkyl and/or at least two or more vicinal hydrogens are optionally substituted with an optionally substituted 3-5 membered heterocyclyl or an optionally substituted 3-5 membered cycloalkyl; and wherein o is 0, 1, 2, or 3; r is 1, 2, or 3; and s is 0, 1, 2, 3, or 4; and
wherein X 15 is NR 40 , O, or S, wherein R 40 is H or C 1 -C 3 alkyl;
L 2 is —SO 2 NR 50 —, wherein the sulfur is attached to L 1 ; —NR 50 SO 2 —, wherein the nitrogen is attached to L 1 ; —C(O)NR 50 —, wherein the carbon is attached to L 1 ; —NR 50 C(O)—, wherein the nitrogen is attached to L 1 ; —NR 50 SO 2 NR 50 —; or —NR 50 CONR 50 —;
each R 50 independently is hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 3 -C 6 heteroalkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 6 heteroalkynyl, or Z;
Z is

each R 51 and R 52 independently is hydrogen or an optionally substituted C 1 -C 10 alkyl;
X is an optionally substituted hydroxy group, an optionally substituted NH 2 group, or an optionally substituted SH group;
L 3 is an optionally substituted C 1 -C 6 alkylene, an optionally substituted C 2 -C 6 heteroalkylene, an optionally substituted C 2 -C 6 alkenylene, an optionally substituted C 3 -C 6 heteroalkenylene, an optionally substituted C 2 -C 6 alkynylene, or an optionally substituted C 3 -C 6 heteroalkynylene; and
B is an optionally substituted 6-10 membered aryl; an optionally substituted 5-15 membered heteroaryl; an optionally substituted 4-15 membered heterocyclyl; or an optionally substituted 3-15 membered cycloalkyl.

2. The compound of claim 1 , wherein A is

3. The compound of claim 1 , wherein B is selected from the group consisting of:

wherein
each R 6 independently is hydrogen, an optionally substituted C 1 -C 6 alkoxy, or halo;
each R 7 independently is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 10 heteroaryl, an optionally substituted C 3 -C 10 heterocyclyl, or an optionally substituted C 6 -C 10 aryl; or
R 6 and R 7 together with the atoms they are attached to form an optionally substituted 5-7 membered ring; or 2 R 6 groups together with the atoms they are attached to form an optionally substituted 5-7 membered ring;
each R 61 and R 62 is independently N or CH, provided that at least one of R 61 and R 62 is N;
each R 63 is independently NR 90 , S, or O;
each R 64 is independently N or CH;
each R 90 is independently hydrogen or R 7 ;
each R 1 -R 3 independently is H, halo, an optionally substituted C 1 -C 6 alkyl, an optionally substituted 4-15 membered heterocyclyl, or —OR 20 or, if two of R 1 -R 3 are on adjacent carbon atoms, then two such substituents together with the atoms they are attached to form an optionally substituted 5-7 membered ring;
R 20 is (CH 2 ) w —R 21 , an optionally substituted C 3 -C 6 cycloalkyl, or an optionally substituted C 1 -C 6 alkyl; and
R 21 is an optionally substituted C 1 -C 10 alkyl, an optionally substituted C 2 -C 10 alkenyl, an optionally substituted C 2 -C 10 alkynyl, an optionally substituted 4-15 membered heterocyclyl, or

wherein
each R 22 -R 24 independently is an optionally substituted C 1 -C 3 alkyl or hydroxy; or
two of R 22 -R 24 together with the carbon atoms they are attached to form a 5-7 membered ring; and
w is 1, 2, 3, 4, or 5.

4. The compound of claim 3 , wherein B is

wherein
R 1 , R 2 , and R 3 are as defined above as in claim 3 ; or
R 1 is H, and R 2 and R 3 are as defined above as in claim 3 ; or
R 3 is H or —OR 20 , and R 1 and R 2 are as defined above as in claim 3 ; or
R 2 is F or H, and R 1 and R 3 are as defined above as in claim 3 ; or
R 1 and R 2 together with the atoms they are attached to form an optionally substituted 5-7 membered ring; or
R 2 and R 3 together with the atoms they are attached to form an optionally substituted 5-7 membered ring.

5. The compound of claim 1 , wherein L 1 is selected from the group consisting of:

wherein R 70 is an optionally substituted C 1 -C 10 alkyl, and wherein the left side of the moieties are attached to A.

6. The compound of claim 1 , wherein L 2 is —S(O) 2 NH— wherein the sulfur is attached to L 1 .

7. The compound of claim 1 , wherein L 3 is selected from the group consisting of:

and optionally substituted versions thereof wherein 1-5 hydrogen atoms are optionally substituted and wherein the left side of the moieties are attached to L 2 .

8. The compound of claim 1 , wherein B is

Assignees

• Univ Southern California
• Cv6 Therapeutics Ni Ltd

Inventors

• Ladner Robert D
• Spyvee Mark
• Shirude Pravin S

Classifications

• C07D207/40 Primary

  2,5-Pyrrolidine-diones · CPC title

• C07D239/22

  with hetero atoms directly attached to ring carbon atoms · CPC title

• C12Q1/6886

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C07D211/88

  attached in positions 2 and 6, e.g. glutarimide · CPC title

• C07D251/20

  with no nitrogen atoms directly attached to a ring carbon atom · CPC title