8-hydroxyquinoline derivatives as diagnostic and therapeutic agents
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.
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:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , having formula:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comporising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
14. A method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 , wherein the disease neurological disorder selected from the group consisting of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), motor neurone disease (MND), Prion disease, cerebral amyloid angiopathy, vascular cognitive impairment (VCI), dementia, dementia with Lewy bodies, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, hippocampal sclerosis, Binswanger's disease, and Creutzfeldt-Jakob disease.
16. The method of claim 14 , wherein the neurological disorder is Alzheimer's disease (AD).