GLS1 inhibitors for treating disease

Patent metadata

Field	Value
Publication number	US-11713313-B2
Application number	US-202016918897-A
Country	US
Kind code	B2
Filing date	Jul 1, 2020
Priority date	Jun 30, 2015
Publication date	Aug 1, 2023
Grant date	Aug 1, 2023

Abstract

Disclosed herein are compounds and compositions useful in the treatment of GLS1 mediated diseases, such as cancer, having the structure of Formula I:Methods of inhibition GLS1 activity in a human or animal subject are also provided.

First claim

What is claimed is:

1. A method of inhibiting GLS1 activity in a biological sample comprising contacting the biological sample with a compound of a compound of structural Formula I

or a salt thereof, wherein:
n is 1;
R 1 is chosen from NR 3 C(O)R 3 , NR 3 C(O)OR 3 , NR 3 C(O)N(R 3 ) 2 , C(O)N(R 3 ) 2 , and N(R 3 ) 2 ;
each R 3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, wherein each R 3 may be optionally substituted with one to three R x groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an heteroaryl or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups;
R 2 is chosen from NR 4 C(O)R 4 , NR 4 C(O)OR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)N(R 4 ) 2 and N(R 4 ) 2 ;
each R 4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 4 may be optionally substituted with one to three R x groups, wherein two R 4 groups together with the atoms to which they are attached optionally form an heteroaryl or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups;
each R x group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R 5 ) 2 , NR 5 C(O)R 5 , NR 5 C(O)OR 5 , NR 5 C(O)N(R 5 ) 2 , C(O)N(R 5 ) 2 , and C(O)R 5 ;
each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, which may be optionally substituted with one to three R z groups; and
R z is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl;
A is a monocyclic heteroaryl, which may be optionally substituted with one to three R z groups; and
Z is a monocyclic heteroaryl, which may be optionally substituted with one to three R z groups.

2. A method of treating a GLS1-mediated disorder in a subject in need thereof, comprising the step of administering to the subject a compound of structural Formula I

or a salt thereof, wherein:
n is 1;
R 1 is chosen from NR 3 C(O)R 3 , NR 3 C(O)OR 3 , NR 3 C(O)N(R 3 ) 2 , C(O)N(R 3 ) 2 , and N(R 3 ) 2 ;
each R 3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, wherein each R 3 may be optionally substituted with one to three R x groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an heteroaryl or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups;
R 2 is chosen from NR 4 C(O)R 4 , NR 4 C(O)OR 4 , NR 4 C(O)N(R 4 ) 2 , C(O)N(R 4 ) 2 and N(R 4 ) 2 ;
each R 4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 4 may be optionally substituted with one to three R x groups, wherein two R 4 groups together with the atoms to which they are attached optionally form an heteroaryl or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups;
each R x group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalkoxyarylalkyl, haloalkoxycycloalkyl, haloalkoxycycloalkylalkyl, haloalkoxyheteroaryl, haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl, heterocycloalkyloxy, hydroxyl, oxo, N(R 5 ) 2 , NR 5 C(O)R 5 , NR 5 C(O)OR 5 , NR 5 C(O)N(R 5 ) 2 , C(O)N(R 5 ) 2 , and C(O)R 5 ;
each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, which may be optionally substituted with one to three R z groups; and
R z is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl;
A is a monocyclic heteroaryl, which may be optionally substituted with one to three R z groups; and
Z is a monocyclic heteroaryl, which may be optionally substituted with one to three R z groups.

3. The method according to claim 2 , wherein the subject is a human.

4. The method according to claim 2 , wherein the GLS1-mediated disorder is chosen from cancer, immunological disorders, and neurological disorders.

5. The method according to claim 2 , wherein the GLS1-mediated disorder is cancer.

6. The method according to claim 5 , wherein the cancer is chosen from Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, AIDS-Related Cance

Assignees

• Univ Texas

Inventors

• Lewis Richard Thomas
• Jones Philip
• Petrocchi Alessia
• Reyna Naphtali
• Hamilton Matthew
• Soth Michael J
• Heffernan Timothy
• Han Michelle
• Burke Jason P

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title