EAAT2 activators and methods of using thereof

1. A compound defined by Formula I

wherein

Y is O;

X 1 is N;

X 2 is CR 3 ;

X 3 is CR 4 ;

A is pyridyl, wherein A is substituted by 1, 2, 3, or 4 independently selected R A groups;

R 2 is —(CHR E ) n R 5 ;

R 5 is selected from the group consisting of OR C , NR C R D , C(O)OR C , C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and wherein the C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R B groups;

R E is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, and amino, wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R 6 groups;

R 3 and R 4 are independently selected from H and C 1-6 alkyl;

each R A and R B is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c OR d , NR c C(O)R b , NR c C(O)OAR a , NR c C(O)NR c R d , C(═NR c )R b , C(═NR c )NR c R d , NR c C(═NR c )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl are optionally substituted with 1, 2, 3, or 4 independently selected R 6 groups;

R C and R D are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-4 alkylene, 4-10 membered heterocycloalkyl-C 1-4 alkylene, 6-10 membered aryl-C 1-4 alkylene, 5-10 membered heteroaryl-C 1-4 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-4 alkylene, 4-10 membered heterocycloalkyl-C 1-4 alkylene, 6-10 membered aryl-C 1-4 alkylene, and 5-10 membered heteroaryl-C 1-4 alkylene are each optionally substituted with 1, 2, 3, or 4 independently selected R 6 groups; or

alternatively, any R C and R D attached to the same N atom, together with the N atom to which they are attached, form a 4-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, each optionally substituted with 1, 2, or 3 independently selected R 6 groups;

each R a , R b , R c , and R d is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 6 groups;

each R e is independently selected from H, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkylaminosulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl;

each R 6 is independently selected from 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

n is 1 or 2;

or a pharmaceutically acceptable salt, ester, or N-oxide thereof.

2. The compound of claim 1 , wherein A is substituted by 1, 2, or 3 independently selected R A groups.

3. The compound of claim 1 , wherein R 3 is H.

4. The compound of claim 1 , wherein R 4 is H.

5. The compound of claim 1 , wherein R 5 is selected from the group consisting of OR C , NR C R D , C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, wherein the C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R B groups.

6. The compound of claim 1 , wherein R 5 is selected from the group consisting of OR C , NR C R D , C 3-6 cycloalkyl, and 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted by 1 or 2 independently selected R B groups.

7. The compound of claim 2 , wherein R 2 is —(CHR E ) n R 5 , and R 5 is selected from the group consisting of C 3-10 cycloalkyl; and 4-10 membered heterocycloalkyl wherein the C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R B groups.

8. The compound of claim 1 , wherein R 5 is selected from the group consisting of OCH 3 , N(CH 3 ) 2 , C 3-6 cycloalkyl, and 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl; is optionally substituted by 1 or 2 independently selected R B groups.

9. The compound of claim 7 , wherein each R B , when present, is independently selected from the group consisting of halo, C 1-6 alkyl and NR c R d .

10. The compound of claim 9 , wherein each R B is independently selected from the group consisting of halo, C 1-3 alkyl and N(C 1-3 alkyl) 2 .

11. The compound of claim 1 , wherein n is 1.

12. The compound of claim 1 , wherein the compound is selected from the following

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

14. A method for treating glutamate excitotoxicity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 .

15. A method for increasing EAAT2 protein expression in a cell or a subject in need thereof, the method comprising contacting the cell or administering to the subject an effective amount of a compound of claim 1 .

16. A method for activating the NRF2 pathway in a cell or a subject in need thereof, the method comprising contacting the cell or administering to the subject an effective amount of a compound of claim 1 .

17. A method for treating a disease or disorder selected from the group consisting of ischemic stroke, epilepsy, or a trauma, including blunt trauma, an abrasion, an avulsion, an incision, a laceration, a puncture, a penetration, a surgical trauma, iatrogenic trauma, a spinal cord injury, a traumatic brain injury, or any combination thereof, a chronic neurodegenerative disorder, including mild cognitive impairment, Parkinson's disease, Alzheimer's disease, multiple sclerosis, mesial temporal sclerosis, Huntington's disease, AIDS dementia complex, essential tremor, or amyotrophic lateral sclerosis (ALS); a psychotic disorder including schizophrenia, bipolar disorder, or autism; a pain disorder including migraine, temporomandibular disorders, neuropathic pain, visceral pain, or complex regional pain syndrome; an addiction including alcohol addiction, cocaine addiction, heroin addiction, methamphetamine addiction, or nicotine addiction; or a cancer, including glioblastoma; or a mood disorder, including anxiety disorders, depressive disorders, borderline personality disorder, attention-deficit-hyperactivity disorder, suicidal behavior, eating disorders, posttraumatic stress disorder, gulf war illness, and obsessive-Compulsive Disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 .

18. The compound of claim 1 , wherein R A is independently selected from halo, C 1-6 alkyl, C 1-4 haloalkyl, and OR a .

19. The compound of claim 18 , wherein R a is selected from C 1-6 alkyl and C 1-4 haloalkyl.