IP Library › Granted Patent US 12692267
Granted Patent B2
US 12692267 · App. 19/340,689 · Granted Jul 28, 2026

Use of caseinolytic protease P function as a biomarker of drug response to imipridone-like agents

Inventor: Edwin Iwanowicz (Cary, NC)
Assignee: Madera Therapeutics, LLC
C07D471/14C07D271/06C07D471/04C07D487/14G01N33/5011C07B2200/05G01N2333/96433
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Quick Facts
Patent No.
US 12692267
App. No.
19/340,689
Granted
Jul 28, 2026
Kind
B2
Abstract

Use of caseinolytic protease P (ClpP) function and/or concentration as a biomarker for predicting the response of a neoplastic disease, preferably cancer or another disease where enhancing ClpP activity may provide a therapeutic benefit, to a compound of Formula I. In other aspects it relates to methods and kits, as well as methods of treatment involving the use of the biomarker.

Claims (55)

1 . A compound of the general Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Z1 is:

Q is:

Z2 is:

Ar1 and Ar2 are independently selected from aryl, thiophenyl and phenyl;

Ar1 may be optionally substituted with from 1 to 3 J groups;

Ar2 is substituted with from 1 to 3 JJ groups;

J is independently selected from halogen, —CN, —CF 3 , (C1-C3)haloalkyl, (C1-C6) optionally substituted alkyl, (C2-C3)alkynyl, (C1-C3)haloalkyoxy, (C1-C3) optionally substituted alkoxy, —C(O)OR15 and —C(O)R15;

JJ is independently selected from halogen, —CF 3 , —CH 3 , (C1-C3)haloalkyl, (C1-C6) optionally substituted alkyl, (C2-C6)alkynyl, —CN, (C1-C3)haloalkyoxy, —C(O)OR15, —C(O)NR17R18, and (C1-C3) optionally substituted alkoxy;

R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from hydrogen, halogen, —CH 3 , (C1-C3)alkyl and (C1-C3) optionally substituted alkyl;

R14 is independently selected from hydrogen, halogen, —CN, —CH 3 , (C1-C3)alkyl, (C1-C6) optionally substituted alkyl, —NR17R18 and —C(O)R15; and

R15, R17 and R18 are independently selected from hydrogen, —CH 3 , (C1-C3)alkyl, and (C1-C6) optionally substituted alkyl.

2 . The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein:

R1, R2, R3 and R4 are each hydrogen;

Ar1 is phenyl;

Ar2 is phenyl;

J is independently selected from halogen, —CN, —CF 3 , (C1-C3)haloalkyl, (C1-C6) optionally substituted alkyl, (C2-C3)alkynyl, (C1-C3)haloalkyoxy, (C1-C3) optionally substituted alkoxy, —C(O)OR15 and —C(O)R15;

JJ is independently selected from halogen, —CF 3 , —CH 3 , (C1-C3)haloalkyl, (C1-C6) optionally substituted alkyl, (C2-C6)alkynyl, —CN, (C1-C3)haloalkyoxy, —C(O)R15 and (C1-C3) optionally substituted alkoxy; and

R15, R17 and R18 are independently selected from hydrogen, —CH 3 and (C1-C3)alkyl.

3 . The compound of claim 2 or pharmaceutically acceptable salt thereof, wherein:

J is independently selected from halogen, —CN, —CF 3 , (C1-C3)haloalkyl, (C1-C6) optionally substituted alkyl, (C2-C3)alkynyl and (C1-C3)haloalkyoxy, (C1-C3) optionally substituted alkoxy;

JJ is independently selected from halogen, —CF 3 , —CH 3 and (C1-C3)haloalkyl; and

R5, R6, R7 and R8 are hydrogen.

4 . A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein:

J is independently selected from halogen, —CN, —CF 3 and (C2-C3)alkynyl; and

JJ is independently selected from halogen and —CF 3 .

5 . A compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein:

J is halogen;

Z1 is independently selected from:

which is optionally substituted with 1-3 J groups; and

Z2 is independently selected from:

6 . A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein:

R14 is independently selected from hydrogen, halogen, —CN, —CH 3 , (C1-C3)alkyl and (C1-C6) optionally substituted alkyl; and

R5, R6, R7 and R8 are each independently selected from hydrogen, halogen, —CH 3 and (C1-C3)alkyl.

7 . A compound of claim 6 or pharmaceutically acceptable salt thereof, wherein:

J is independently selected from halogen, —CN, —CF 3 , (C1-C3)haloalkyl, (C1-C6) optionally substituted alkyl, (C2-C3)alkynyl and (C1-C3)haloalkyoxy, (C1-C3) optionally substituted alkoxy;

JJ is independently selected from halogen, —CF 3 , —CH 3 and (C1-C3)haloalkyl;

R5, R6, R7 and R8 are hydrogen; and

R14 is independently selected from hydrogen, halogen, —CH 3 , (C1-C3)alkyl.

8 . A compound of claim 7 or pharmaceutically acceptable salt thereof, wherein:

J is independently selected from halogen, —CN, —CF 3 and (C2-C3)alkynyl;

JJ is independently selected from halogen and —CF 3 and

R14 is independently selected from hydrogen, —CH 3 and (C1-C3)alkyl.

9 . A compound of claim 8 or pharmaceutically acceptable salt thereof, wherein:

J is independently selected from halogen, —CN and —CF 3 ; and

R14 is independently selected from hydrogen and —CH 3 .

10 . A compound of claim 9 or pharmaceutically acceptable salt thereof, wherein:

Z1 is independently selected from:

which is optionally substituted with 1-3 J groups; and

Z2 is independently selected from:

11 . A compound of claim 10 or pharmaceutically acceptable salt thereof, wherein:

Z1 is:

12 . A compound or a pharmaceutically acceptable salt thereof, which is:

13 . A pharmaceutical composition, comprising a compound of any of the preceding claims 1-12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.