Functionalized NANOLUC inhibitors

Patent metadata

Field	Value
Publication number	US-10815247-B2
Application number	US-201715856302-A
Country	US
Kind code	B2
Filing date	Dec 28, 2017
Priority date	Dec 28, 2016
Publication date	Oct 27, 2020
Grant date	Oct 27, 2020

Abstract

Compounds that may inhibit Oplophorus-derived luciferases are disclosed as well as compositions and kits comprising the compounds, and methods of using the compounds.

First claim

The invention claimed is:

1. A compound of formula (I), or a salt thereof:

wherein:
A is absent, an optionally substituted phenyl ring, or an optionally substituted thienyl ring,
L 1 is —(CR a1 R a2 ) m1 —, wherein m is 1 to 100, optionally wherein one or more CR a1 R a2 groups are replaced by a heteroatom or heteroatom group selected from the group consisting of O, N(R a3 ), S(═O), and S(═O) 2 , optionally wherein one or more CR a1 R a2 groups are replaced by C(═O), optionally wherein two adjacent CR a1 R a2 groups form CR a1 ═CR a1 , and optionally wherein one or more CR a1 R a2 groups are replaced by a -Cy- group, wherein each Cy is independently selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycle; wherein R a1 , R a2 , and R a3 are independently selected from the group consisting of hydrogen and C 1 -C 4 -alkyl;
Z is C 1 -C 10 haloalkyl, a leaving group Y, a bioactive agent, or a dye, wherein the leaving group Y is selected from the group consisting of OR 4 , halogen, heteroaryl, and heterocyclyl;
R 1 is hydrogen or C 1 -C 8 alkyl;
R 2 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted alkoxyalkyl and optionally substituted alkoxyalkoxyalkyl;
R 3 is hydrogen or C 1 -C 8 alkyl; and
R 4 is selected from the group consisting of optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 -cycloalkyl, optionally substituted C 3 -C 8 -cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclylalkyl.

2. The compound of claim 1 , or a salt thereof, wherein A is an optionally substituted phenyl ring.

3. The compound of claim 1 , or a salt thereof, wherein A is an optionally substituted thienyl ring.

4. The compound of claim 1 , or a salt thereof, wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, halo-C 1 -C 8 -alkyl, alkoxyalkoxyalkyl and arylalkyl.

5. The compound of claim 1 , or a salt thereof, wherein R 2 is optionally substituted aryl.

6. The compound of claim 1 , or a salt thereof, wherein R 2 is phenyl substituted with at least one substituent selected from the group consisting of C 1 -C 4 alkyl, cyano, amido, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and hydroxyalkyl.

7. The compound of claim 1 , or a salt thereof, wherein R 3 is hydrogen.

8. The compound of claim 1 , or a salt thereof, wherein the compound has formula (Ia):

wherein:
A is absent, a phenyl ring, or a thienyl ring;
R 2 is phenyl substituted with at least one C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and
L 2 is —(CR a1 R a2 ) m2 —, wherein m2 is 1 to 90, and wherein each CR a1 R a2 is as defined in claim 1 .

9. The compound of claim 1 , or a salt thereof, wherein the compound has formula (Ib):

wherein:
A is absent, a phenyl ring, or a thienyl ring;
R 2 is phenyl substituted with at least one C 1 -C 4 alkyl or C 1 -C 4 haloalkyl;
R x and R y at each occurrence is independently hydrogen or C 1 -C 4 alkyl;
p is 4, 5, 6, 7, 8, 9, or 10;
t is 0 or 1;
v is 0 or 1; and
L 3 is absent or —(CR a1 R a2 ) m3 —, wherein m3 is 1 to 80, and wherein each CR a1 R a2 is as defined in claim 1 .

10. The compound of claim 9 , or a salt thereof, wherein L 3 is —(CR a1 R a2 ) m3 —, wherein m3 is 1-20, and R a1 and R a2 , at each occurrence are independently hydrogen or C 1 -C 4 alkyl.

11. The compound of claim 9 , or a salt thereof, wherein L 3 is -Q 1 -(CH 2 —CH 2 —O) k1 -Q 2 -(CH 2 —CH 2 —O) k2 -Q 3 -(CH 2 —CH 2 —O) k3 —, wherein:
Q 1 is absent, O, or NH;
Q 2 is absent,

—CO—NH—, —CH 2 —CH 2 —CO—, —CH 2 —CH 2 —NH—CO, or —CH 2 —CH 2 —CO—NH—
Q 3 is absent, —CO—NH—, or —CH 2 —CH 2 —;
k1 is 1-10;
k2 is 0-10; and
k3 is 0-10.

12. The compound of claim 9 , or a salt thereof, wherein L 3 is selected from the group consisting of:

13. The compound of claim 1 , or a salt thereof, wherein Z is C 1 -C 10 haloalkyl.

14. The compound of claim 13 , or a salt thereof, wherein the compound has formula (Ic):

wherein:
A is a phenyl ring or thienyl ring;
R 2 is phenyl substituted with one methyl or ethyl group;
R x and R y at each occurrence is independently hydrogen or C 1 -C 4 alkyl;
p is 4, 5, 6, 7, 8, 9, or 10; and
L 3 is

15. The compound of claim 13 , or a salt thereof, wherein Z is —(CH 2 ) 6 —Cl.

16. The compound of claim 1 , or a salt thereof, wherein Z is a leaving group Y selected from the group consisting of OR 4 , halogen, heteroaryl, and heterocyclyl.

17. The compound of claim 16 , or a salt thereof, wherein the compound has formula (Id):

wherein:
A is a phenyl ring or a thienyl ring,
R 2 is phenyl substituted with one substituent selected from the group consisting of methyl, ethyl, —CH 2 Br, and —CH 2 CH 2 CH 2 Br;
R x and R y at each occurrence is independently hydrogen or C 1 -C 4 alkyl;
p is 4, 5, 6, 7, 8, 9, or 10;
t is 0 or 1;
v is 0 or 1; and
L 3 is absent, C 1 -C 4 alkylene,

18. The compound of claim 17 , or a salt thereof, wherein Z is chloro, bromo, iodo, C 1 -C 4 alkoxy, phenoxy,

19. The compound of claim 17 , or a salt thereof, wherein
L 3 is absent,

and
Z is C 1 -C 4 alkoxy, phenoxy,

20. The compound of claim 17 , or a salt thereof, wherein
L 3 is —CH 2 —CH 2 —, or

and Z is

or
L 3 is C 1 -C 4 alkylene; and Z is chloro, bromo, or iodo.

21. The compound of claim 17 , or a salt thereof wherein,
t is 0;
v is 0;
L 3 is absent; and
Z is bromo, iodo, or

Assignees

• Promega Corp

Inventors

• Flemming Roderick G
• Hall Mary
• Machleidt Thomas
• Meisenheimer Poncho
• Nath Nidhi
• Robers Matthew B
• Walker Joel R
• Zhou Wenhui

Classifications

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• C12Y113/12007

  Photinus-luciferin 4-monooxygenase (ATP-hydrolysing) (1.13.12.7), i.e. firefly-luciferase · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D493/10

  Spiro-condensed systems · CPC title

• C07F5/022

  without C-boron linkages · CPC title