8-hydroxyquinoline derivatives as diagnostic and therapeutic agents

Patent metadata

Field	Value
Publication number	US-11434203-B2
Application number	US-202016997501-A
Country	US
Kind code	B2
Filing date	Aug 19, 2020
Priority date	Aug 12, 2015
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

Abstract

The present application provides compounds useful in methods of treating neurological disorders such as Alzheimer's disease, and cancer such as prostate cancer. Also provided herein are radiolabeled compounds useful for imaging techniques, and techniques for diagnosis and monitoring of treatment of neurological disorders and cancer. An exemplary radiolabeled compound provided herein is useful as a radiotracer for positron emission tomography or single-photon emission computed tomography. Methods for preparing radiolabeled compounds and methods for preparing unlabeled compounds are also provided.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Hal is selected from the group consisting of Cl, F, Br, and I;
n is 1, 2, or 3;
X is selected from the group consisting of O, S, S(O), S(O) 2 , C(O), and NR N ;
L 1 is selected from the group consisting of —C 1-6 alkylene-, —Y—C 1-6 alkylene-, —C 1-4 alkylene-Y—C 1-4 alkylene-, and —(O—C 1-4 alkylene) m -, wherein m is an integer from 1 to 5, and wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino;
L 2 is selected from the group consisting of —C 1-6 alkylene-, —C 1-6 alkylene-Y—, —C 1-4 alkylene-Y—C 1-4 alkylene-, and —(C 1-4 alkylene-O—) m —, wherein m is an integer from 1 to 5, and wherein said alkylene groups are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino;
each Y is independently selected from the group consisting of O, S, S(O), S(O) 2 , C(O), C(O)NR f , NR f C(O), S(O) 2 NR f , NR f S(O) 2 , and NR f ;
each R f is independently selected from the group consisting of H and C 1-3 alkyl;
R N is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R g groups;
group A is selected from the group consisting of a 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R A groups;
alternatively, group A is H;
with the proviso that when X is NR N , L 1 is —C 1-6 alkylene-, L 2 is —C 1-6 alkylene-, and R N is C 1-6 alkyl, group A is not H;
each R A is independently selected from the group consisting of OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino; and
each R g is independently selected from the group consisting of OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.

2. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein:
Hal is selected from the group consisting of: Cl, F, and I;
X is selected from the group consisting of O and NR N ;
L 1 is —C 1-6 alkylene-, wherein said alkylene group is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C 1-3 alkoxy, and amino;
L 2 is —C 1-6 alkylene-, wherein said alkylene group is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C 1-3 alkoxy, and amino;
R N is selected from the group consisting of H and C 1-6 alkyl;
group A is 5 or 6 membered heteroaryl, which is optionally substituted by 1, 2, or 3 independently selected R A groups;
alternatively, group A is H;
with the proviso that when X is NR N , L 1 is —C 1-6 alkylene-, L 2 is —C 1-6 alkylene-, and R N is C 1-6 alkyl, group A is not H; and
each R A is independently selected from the group consisting of OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino.

4. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein:
Hal is selected from the group consisting of Cl, F, and I; and
R 0 is —C 1-6 alkyl, which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C 1-3 alkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.

5. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula Ic:

or a pharmaceutically acceptable salt thereof, wherein:
Hal is selected from the group consisting of Cl, F, and I; and
group A is selected from the group consisting of a 5-6 membered heteroaryl and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R A groups.

6. The compound of claim 1 , wherein group A is a triazolyl of Formula A-1c:

wherein R A is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cyano-C 1-3 alkyl, and HO—C 1-3 alkyl.

7. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , having formula:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , having formula:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , having formula:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , having formula:

Assignees

• Massachusetts Gen Hospital

Inventors

• Vasdev Neil
• Liang Huan Steven

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D215/26

  Alcohols; Ethers thereof · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title