EAAT2 activators and methods of use thereof

Abstract

To provide compounds that activate excitatory amino acid transporter 2 (EAAT2), as well as methods of using these compounds to treat or prevent diseases, disorders, and conditions associated with glutamate excitotoxicity.SOLUTION: The present invention provides a compound defined by formula 1 or a pharmaceutically acceptable salt, ester, or N-oxide thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 680,418, filed June 4, 2018, and U.S. Provisional Application No. 62 / 680,423, filed June 4, 2018, each of which is incorporated by reference herein in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. U01AG054444 awarded by the National Institute on Aging, part of the National Institutes of Health. The government has certain rights in this invention.

[0003] This application relates generally to compounds that increase the expression of excitatory amino acid transporter 2 (EAAT2) and methods of using these compounds to treat or prevent diseases, disorders and conditions associated with glutamate excitotoxicity. [Background technology]

[0004] Glutamate is the major neurotransmitter in the mammalian central nervous system (CNS) and is essential for normal brain function, including cognition, memory, and learning. However, extracellular concentrations of glutamate must be kept below excitotoxic levels (approximately 1 μM) to avoid overstimulation of glutamate receptors, which can cause neuronal damage or death (Sheldon and Robinson, Neurochem. Int. 2007, 51, 333). Excitotoxicity has been associated with multiple acute neurological conditions, such as ischemic stroke, epilepsy, and trauma, as well as chronic adult-onset neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS) (Guo et al., Hum. Mol. Genet. 2003, 12, 2519; Tian et al., J. Biol. Chem. 2007, 282, 1727; Hazell, Neurochem. Int. 2007 50, 941; Seifert et al., Brain. Res. Rev. 2010, 63, 212; Tian et al., J. Neurochem. 2010, 113, 978), and depression. One potential approach to inhibiting excitotoxicity is to enhance glutamate reuptake. EAAT2 is the primary glutamate transporter and functions to remove glutamate from synapses (Lin et al., Am. J. Physiol. Gastrointest Liver Physiol. 2009, 296, 129). Increasing EAAT2 protein expression and function may provide a means to suppress insufficient glutamate reuptake and, consequently, reduce neuronal damage. Summary of the Invention

[0005] As used herein, Formula I [ka] Formula I During the ceremony Y is O, S or NR 1 and; X 1 is CH or N; X 2is CR 3 or N; X 3 is CR 4 or N; A is selected from the group consisting of 6-10 membered aryl and 5-10 membered heteroaryl, each of which is selected from 1, 2, 3, or 4 independently selected R A optionally substituted by a group; R 1 is H and C 1~6 alkyl; R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; R 3 and R 4 is H and C 1~6 independently selected from alkyl; Each R A and RB Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and RD is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0006] In some embodiments, A can be unsubstituted or can be selected from 1, 2, 3, or 4 independently selected R A In other embodiments, A can be unsubstituted or can be phenyl, which can be substituted by 1, 2, 3, or 4 independently selected R groups. A In some embodiments, A may be a 5- to 10-membered heteroaryl, which may be substituted by a group. In some embodiments, A may be an unsubstituted 5- to 6-membered heteroaryl. In some embodiments, A may be an unsubstituted pyridyl. In some embodiments, A may be selected from the group consisting of unsubstituted 2-pyridyl and unsubstituted 3-pyridyl.

[0007] In some embodiments, Y can be O.

[0008] In some embodiments, X 1 , X 2 and X 3 is N. For example, in some embodiments, X 1 is N and X2 is CR 3 and X 3 is CR 4 In another embodiment, X 1 is CH and X 2 is N and X 3 is CR 4 is.

[0009] In some embodiments, R 3 is H, if present.

[0010] In some embodiments, R 4 is H, if present.

[0011] In some embodiments, the compound has Formula II [ka] Formula II During the ceremony X 1 is CH or N; X 2 is CR 3 or N; X 3 is CR 4 or N; R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; R 3 and R 4 is H and C 1~6 independently selected from alkyl; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2Rb , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, CN, halo, C 1~6 Alkyl, C2~6 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0012] In some embodiments, the compound has formula IIA [ka] Formula IIA During the ceremony R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c Rd , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6Alkyl carbonyl, 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 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0013] In some embodiments, the compound has formula IIB [ka] Formula IIB During the ceremony R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NRc R d , C(O)OR a ,OC(O)R b , OC(O)NR c R d , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C3~10 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 Alkyl)aminosulfonyl, aminosulfonylamino, C1~6 Alkylaminosulfonylamino, di(C 1~6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1~6 Alkylaminocarbonylamino and di(C 1~6 alkyl)aminocarbonylamino; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0014] In some embodiments, the compound has Formula III [ka] Formula III During the ceremony X 1 is CH or N; X 2 is CR 3 or N; X 3 is CR 4 or N; R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R Boptionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; R 3 and R 4 is H and C 1~6 independently selected from alkyl; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)Rb , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and RD together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, CN, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C1~6 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0015] In some embodiments, the compound has formula IIIA [ka] Formula IIIA During the ceremony R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C RD , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NRe )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 3~10 Cycloalkyl-C1~4 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl and di(C 1~6 alkyl)aminosulfonyl; Each R 6 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0016] In some embodiments, the compound has formula IIIB [ka] Formula IIIB During the ceremony R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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, N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 3~10 Cycloalkyl-C 1~4 Alkylene, 4-10 membered heterocycloalkyl-C 1~4 Alkylene, 6-10 membered aryl-C 1~4Alkylene, 5-10 membered heteroaryl-C 1~4 alkylene; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1~6 Alkylaminosulfonylamino, di(C 1~6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1~6Alkylaminocarbonylamino and di(C 1~6 alkyl)aminocarbonylamino; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0017] In some embodiments, R 2 is -(CH2) n R 5 , -(CH(CH3)) n R 5 and (CH2CH(NH2)) n R 5 may be selected from the group consisting of:

[0018] In some embodiments, R 5 is OR C , N.R. C R D , C(O)NR C R D , C 6~10 Aryl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 6~10 Aryl, C 3~10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each selected from 1, 2, 3, or 4 independently selected R B and optionally substituted by groups.

[0019] In some embodiments, R 5 is OR C , N.R. C R D , C(O)NR C R D , phenyl, C 3~6cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said phenyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each may be selected from the group consisting of one or two independently selected R B In one embodiment, R 5 is OR C , N.R. C R D , C(O)NR C R D , phenyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein said phenyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl may each be selected from the group consisting of one or two independently selected R B and optionally substituted by groups.

[0020] In some embodiments, R 5 are OCH3, N(CH3)2, C(O)N(CH3)2, phenyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said phenyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each may be selected from the group consisting of one or two independently selected R B In one embodiment, R 5 are OCH3, N(CH3)2, C(O)N(CH3)2, phenyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein said phenyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl may each be selected from the group consisting of one or two independently selected R B and optionally substituted by groups.

[0021] In some embodiments, R C and R D If present, H, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-6 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-6 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 and optionally substituted with a group.

[0022] In some embodiments, each R B If present, C 1~6 Alkyl and NR c R d In some embodiments, each R B If present, C 1~3 Alkyl and N(C 1~3 alkyl)2.

[0023] In some embodiments, n can be 0, 1, or 2.

[0024] Also provided herein are pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable excipient.

[0025] Also provided herein are methods for treating or preventing glutamate excitotoxicity in a subject in need thereof. These methods can include administering to the subject an effective amount of a compound provided herein.

[0026] Further provided herein is a method for increasing EAAT2 protein expression in a cell or a subject that requires such an increase.These methods can include contacting the cell with an effective amount of the compound provided herein or administering it to the subject.

[0027] Further provided herein are methods for activating the NRF2 pathway in cells or subjects that require activation of the NRF2 pathway.These methods can include contacting cells or administering to subjects an effective amount of the compounds provided herein.

[0028] trauma including ischemic stroke, epilepsy or blunt trauma, abrasion, avulsion, cut, rupture, puncture, penetration, surgical trauma, iatrogenic trauma, spinal cord injury, traumatic brain injury or any combination thereof; chronic neurodegenerative disorders including mild cognitive impairment, Parkinson's disease, Alzheimer's disease, multiple sclerosis, mesial temporal lobe sclerosis, Huntington's disease, AIDS dementia complex, essential tremor or amyotrophic lateral sclerosis (ALS); psychiatric disorders including schizophrenia, bipolar disorder or autism; migraine, temporomandibular joint disorder, neuropathic pain, visceral pain or Also provided herein is a method for treating a disease or disorder in a subject who needs to be treated, the disease or disorder being selected from the group consisting of: pain disorder, including complex regional pain syndrome; addiction, including alcohol addiction, cocaine addiction, heroin addiction, methamphetamine addiction or nicotine addiction; or cancer, including glioblastoma; or mood disorder, including anxiety disorder, depressive disorder, borderline personality disorder, attention deficit hyperactivity disorder, suicidal behavior, eating disorder, post-traumatic stress syndrome, Gulf War illness and obsessive-compulsive disorder.These methods can comprise administering to the subject an effective amount of the compound provided herein or its pharmaceutically acceptable salt. [Brief explanation of the drawings]

[0029] [Figure 1A] FIG. 1A shows the crystal structure of compound 100. [Figure 1B] FIG. 1B shows the crystal structure of compound 101. [Figure 2]Figures 2A-2C show that Compound 100 increases EAAT2 expression and enhances synaptic plasticity in wild-type mice. Mice were treated with 40 mg / kg of compound (or as indicated), and forebrains were harvested for gliosome preparation 24 h after treatment (or as indicated). Figure 2A: Western blot shows a dose-dependent increase in EAAT2 protein levels. Figure 2B: Time-dependent fold increase in EAAT2 protein expression in response to compound treatment at 4 h (1.54 ± 0.13) and 24 h (1.98 ± 0.19) after treatment. Quantification of the EAAT2 expression time course (normalized to flotillin; n = 4 / group). Data are presented as mean ± standard error of the mean and analyzed using one-way ANOVA with Tukey's post-hoc test. *P < 0.05, **p < 0.01. Figure 2C: Compound treatment enhances CA3-CA1 LTP in the hippocampus. Mice were treated with vehicle or compound for 7 days, and acute hippocampal slices were collected for LTP recording. Compound-treated animals (10 slices, 4 animals) showed increased CA1 field potential responses after CA3 afferent theta burst stimulation (TBS) compared with control animals (11 slices, 4 animals). Data are presented as mean ± standard error of the mean and analyzed using one-way ANOVA with Bonferroni post-hoc test. Statistical significance was expressed as ***p<0.001. [Figure 3] FIG. 3 shows the time-dependent increase in EAAT2 protein expression in the brain of beagle dogs in response to treatment with Compound 100 (n=3 / group). [Figure 4]Figures 4A-4G illustrate the efficacy of Compound 100 in rTg(tauP301L)4510 mice at a moderate disease stage. Figures 4A-4D show the results of a behavioral battery (n = 27 / 27 / 23 / 27, respectively). Compound treatment normalized hyperactivity in the open field (Figure 4A), short-term memory in the Y-maze (Figure 4B), recognition memory in novel object recognition (Figure 4C), and cognition in the T-maze (Figure 4D). As shown in Figure 4E, PSD-95 expression in the hippocampal postsynaptic density of rTg4510 mice was significantly reduced (n = 5 / 5 / 4 / 4, respectively), indicating synaptic loss. Compound 100 treatment in rTg4510 mice restored synaptic integrity. As shown in Figure 4F, crude hippocampal membrane preparations (n ​​= 5 / 5 / 4 / 4, respectively) revealed increased EAAT2 in the rTg4510 vehicle group, which was partially normalized by compound treatment. Figure 4G shows representative immunohistochemical images of a subregion of the hippocampus (n = 4 animals / group; averaged over 3 sections / animal). Cell nuclei were stained with DAPI. Quantification (right) is the percent change compared to control vehicle, except for MC1 (compared to rTg4510 vehicle) (dashed line). The control group showed no differences. NeuN immunostaining demonstrated significant neurodegeneration in the CA1 and DG of rTg4510 mice, which was suppressed by compound treatment. Compound treatment maintained CA3 synaptic integrity (synaptophysin) and significantly reduced neurofibrillary tangle accumulation (MC1) in the CA1 of rTg4510 mice. Finally, in both rTg4510 groups, GFAP immunoreactivity was significantly increased, while compound treatment reduced gliosis. Scale bar = 100 μm. *P<0.05, **P<0.01, ***P<0.001. [Figure 5]Figures 5A-5I illustrate the efficacy of Compound 100 in rTg(tauP301L)4510 mice at a severe stage of disease. Figures 5A-5E show the results of the behavioral battery (n = 34 / 21 / 28 / 32, respectively). Chronic compound treatment continued to suppress the development of agitation-like behavior in rTg4510 mice (Figure 5A), while maintaining improved cognition in the Y-maze (Figure 5B), recognition memory in novel object recognition (Figure 5C), and spatial maze in the Barnes maze (Figures 5D, 5E). As shown in Figure 5F, loss of PSD-95 in the rTg4510 hippocampal postsynaptic membrane density was robust (n = 8 / group); compound treatment continued to significantly reduce synaptic degeneration. Figures 5G and 5H show the integrity of PFC tripartite synapses (n = 4 / group). Similar to the hippocampus at 4 months, rTg4510 PFC postsynaptic membrane thickness exhibited increased crude membrane EAAT2 expression (Figure 5G) and decreased PSD-95 expression (Figure 5H). Compound 100 treatment partially normalized both phenotypes. Figure 5I shows representative immunohistochemistry images of the hippocampus (n = 4 / group). Cell nuclei were stained with DAPI. Quantification (right) is the percent change compared to vehicle control (dashed line). Neurodegeneration (assessed by NeuN) was observed in the CA1 and DG of rTg4510 vehicle mice, but compound treatment significantly reduced neuronal loss. A similar pattern was observed for synaptic integrity (synaptophysin). rTg4510 mice exhibited increased GFAP and Iba1 in the CA1, which was reduced and partially normalized by compound treatment. Scale bar = 100 μm. *P<0.05, **P<0.01, ***P<0.001. [Figure 6]Figures 6A-6E illustrate that Compound 100 modifies disease progression in rTg(tauP301L)4510 mice. Treatment was terminated (stopped) in the rTg4510 compound-treated cohort, and behavioral analysis (n = 9 / 9 / 6 / 4, respectively), tissue collection, and long-term potentiation (LTP) were performed 30 days later. Hyperlocomotion in the open field (Figure 6A) and cognitive function in novel object recognition (Figure 6B) remained normalized in the rTg4510 treatment-stopped group compared with the rTg4510 vehicle group. As shown in Figure 6C, PSD-95 protein expression in the hippocampal postsynaptic density of rTg4510 mice remained significantly higher in the treatment-stopped group compared with the vehicle group. Figures 6D and 6E show hippocampal functional connectivity in the CA3-CA1 circuit along the Schaffer collateral pathway (n = 4 / 11; 4 / 17, 3 / 10; 4 / 14, and 2 / 9, respectively). Figure 6D shows input / output curves for all five groups of mice. All rTg4510 mice exhibit decreased synaptic strength compared to controls. However, both the compound cessation and continuation groups exhibit enhanced synaptic strength compared to rTg4510 vehicle mice. Figure 6E shows that vehicle-treated rTg4510 mice exhibited significantly decreased LTP, whereas the compound cessation and continuation groups exhibited LTP indistinguishable from control vehicle mice. Notably, compound-treated controls exhibited significantly increased LTP compared to control vehicle. TBS, theta burst stimulation. *P < 0.05, **P < 0.01, ***P < 0.001. [Figure 7]Figures 7A-7C show that Compound 100 reduces pTau and inhibits GSK3β in rTg(tauP301L)4510 mice. Figures 7A and 7B illustrate the effect of compound treatment on phosphorylated tau in total lysate (TCL) and sarkosyl-insoluble (P3) fractions (n=4 / group). The dashed line represents expression in the rTg4510 vehicle group. As shown in Figure 7A, long-term Compound 100 treatment reduced the phosphorylated (AT8 and PHF1) forms of tau as well as the confirmation-specific (MC1) form. There was a highly significant reduction in total tau in the P3 fraction and a subsequent reduction in phospho-tau expression. As shown in Figure 7B, a single dose of the compound significantly reduced tau phosphorylation. As shown in Figure 7C, treatment with compound 100 significantly increased the phosphorylation of GSK3β at Ser9 in rTg4510 mice by approximately 2-fold within 1 hour of treatment (n=4 / group). *P<0.05, **P<0.01, ***P<0.001. [Figure 8] Figures 8A-8H show that compound 100 suppresses the development of mood (Figures 5A-5E) and cognitive (Figures 5F-5G) impairment in a mouse model of Gulf War illness (GWI) (n=15-18 / group). [Figure 9] Figures 9A-9H show that compound 100 improves mood (Figures 5A-5E) and cognitive (Figures 5F-5H) impairments in a mouse model of Gulf War illness when symptoms are present (n=15-18 / group). [Figure 10] Figures 10A-10B show a dose-dependent increase in EAAT2 protein expression in mouse brain after 7 or 28 days of daily treatment with Compound 101 at the indicated doses. n=6 for each group. Figure 10C shows that Compound 101 treatment enhances CA3-CA1 long-term potentiation (LTP) in the hippocampus in a dose-dependent manner. 8-12 slices, 4 animals for each group. DETAILED DESCRIPTION OF THE INVENTION

[0030] The compounds provided herein can be useful for activating EAAT2, and thus can be useful in methods for reducing extracellular glutamate levels, thereby reducing glutamate excitotoxicity in cells and tissues, making these compounds therapeutically useful for treating or preventing conditions associated with glutamate excitotoxicity (e.g., acute neurological conditions such as ischemic stroke, epilepsy, and trauma, and chronic adult-onset neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS)). In some embodiments, the compounds provided herein can be therapeutically useful for treating or preventing depression.

[0031] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although methods and materials are described herein for use in the present invention, other suitable methods and materials known in the art can also be used. These materials, methods and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety. In the event of conflict, the present specification, including definitions, will prevail.

[0032] At various places in this specification, divalent linking substituents are described. Where the structure clearly requires a linking group, the Markush variable listed for that group is understood to be the linking group.

[0033] The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in the moiety where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0034] As used herein, the term "optionally substituted" means unsubstituted or substituted. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced with a substituent. It should be understood that substitution at a given atom is limited by valence.

[0035] Through definition, "C n~m " denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. For example, C 1~4 , C 1~6 Examples include:

[0036] As used herein, "C n~m The term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group having n to m carbon atoms, which may be straight-chained or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl. In some embodiments, alkyl groups contain 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0037] As used herein, "C n~m "Alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0038] As used herein, "C n~m"Alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0039] As used herein, "C n~m The term "alkylene," used alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0040] As used herein, "C n~m The term "alkoxy," used alone or in combination with other terms, refers to a group of formula -O-alkyl, where the alkyl group has n to m carbons. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0041] As used herein, "C n~m The term "alkylamino" refers to a group of formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0042] As used herein, "C n~mThe term "alkoxycarbonyl" refers to a group of formula -C(O)O-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0043] As used herein, "C n~m The term "alkylcarbonyl" refers to a group of formula -C(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0044] As used herein, "C n~m The term "alkylcarbonylamino" refers to a group of formula -NHC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0045] As used herein, "C n~m The term "alkylsulfonylamino" refers to a group of formula -NHS(O)2-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0046] The term "aminosulfonyl" as used herein refers to a group of formula -S(O)2NH2.

[0047] As used herein, "C n~m The term "alkylaminosulfonyl" refers to a group of formula -S(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0048] As used herein, "di(C n~mThe term "(alkyl)aminosulfonyl" refers to a group of formula -S(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0049] The term "aminosulfonylamino" as used herein refers to a group of formula -NHS(O)2NH2.

[0050] As used herein, "C n~m The term "alkylaminosulfonylamino" refers to a group of formula -NHS(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0051] As used herein, "di(C n~m The term "NHS(O)N(alkyl)aminosulfonylamino" refers to a group of formula -NHS(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0052] As used herein, the term "aminocarbonylamino," used alone or in combination with other terms, refers to a group of formula -NHC(O)NH2.

[0053] As used herein, "C n~m The term "alkylaminocarbonylamino" refers to a group of formula -NHC(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0054] As used herein, "di(C n~mThe term "NHC(O)N(alkyl)aminocarbonylamino" refers to a group of formula -NHC(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0055] As used herein, "C n~m The term "alkylcarbamyl" refers to a group of formula -C(O)-NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0056] As used herein, the term "thio" refers to a group of formula -SH.

[0057] As used herein, "C n~m The term "alkylsulfinyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0058] As used herein, "C n~m The term "alkylsulfonyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0059] As used herein, the term "amino" refers to a group of formula -NH2.

[0060] As used herein, the term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). n~mThe term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, an aryl group has 6 to about 20 carbon atoms, 6 to about 15 carbon atoms, or 6 to about 10 carbon atoms. In some embodiments, an aryl group is substituted or unsubstituted phenyl.

[0061] The term "carbamyl" as used herein refers to a group of formula -C(O)NH2.

[0062] As used herein, the term "carbonyl" used alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O).

[0063] As used herein, "di(C n~m The term "-N(alkyl)amino" refers to a group of formula -N(alkyl)2, where each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0064] As used herein, "di(C n~m The term "(alkyl)carbamyl" refers to a group of formula -C(O)N(alkyl), where each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0065] The term "halo" as used herein refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br. In some embodiments, halo is F or Cl.

[0066] As used herein, "C n~m"Haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. An example of a haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0067] As used herein, "C n~m The term "haloalkyl," used alone or in combination with other terms, refers to an alkyl group having 1 halogen atom to 2s+1 halogen atoms, which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is exclusively fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0068] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings) and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring carbons (C 3~10). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo or sulfido (e.g., C(O) or C(S)). Cycloalkyl groups also include cycloalkylidenes. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. In some embodiments, a cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, or adamantyl. In some embodiments, a cycloalkyl has 6 to 10 ring-forming carbon atoms. In some embodiments, a cycloalkyl is adamantyl. Moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the cycloalkyl ring, such as benzo or thienyl derivatives of cyclopentane or cyclohexane, are also included in the definition of cycloalkyl. Cycloalkyl groups containing fused aromatic rings can be attached through any ring-forming atom, including a ring-forming atom of the fused aromatic ring.

[0069] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5 to 10 ring atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. A 5-membered heteroaryl ring is a heteroaryl having a ring with 5 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A 6-membered heteroaryl ring is a heteroaryl having a ring with 6 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0070] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups are included in heterocycloalkyl. Heterocycloalkyl groups can also include spirocycles. Examples of heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydrofuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted with oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)). A heterocycloalkyl group can be attached through a ring-forming carbon atom or ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains 0 to 2 double bonds. Moieties having one or more aromatic rings fused to (i.e., sharing a bond with) a cycloalkyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, azepine, and the like, are also included in the definition of heterocycloalkyl. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom, including a ring-forming atom of the fused aromatic ring. In some embodiments, a heterocycloalkyl has 4 to 10, 4 to 7, or 4 to 6 ring atoms, where one or two heteroatoms are independently selected from nitrogen, oxygen, or sulfur, and has one or more oxidized ring members.

[0071] In some places, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise indicated, these rings can be attached to any ring member as long as the atom's valence is not exceeded. For example, an azetidine ring can be attached at any position on the ring, while a pyridin-3-yl ring is attached at the 3-position.

[0072] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structures. Compounds identified herein by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0073] The compounds provided herein also include tautomeric forms. Tautomeric forms occur by swapping a single bond with an adjacent double bond, accompanied by a concomitant proton shift. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H-2H-pyrazole. Tautomeric forms can be in equilibrium, or can be sterically fixed into one form by appropriate substitution.

[0074] In some embodiments, the compounds described herein may contain one or more asymmetric centers and thus may occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers, and diastereomeric mixtures (e.g., R- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, (+) (dextrorotatory) forms, (-) (levorotatory) forms, racemic mixtures thereof, and other mixtures thereof). Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomeric forms of these compounds, as well as mixtures thereof, are expressly included in this description. The compounds described herein may also or may further contain bonds in which bond rotation is restricted about a particular bond, for example, the restriction arises from the presence of a ring or double bond (e.g., a carbon-carbon bond, a carbon-nitrogen bond such as an amide bond). Thus, all cis / trans and E / Z isomers and rotational isomers are expressly included in this description. Unless otherwise stated or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms of that compound.

[0075] Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, including, but not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates, and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972), each of which is incorporated herein by reference in its entirety. It is also understood that the compounds described herein include all possible positional isomers and mixtures thereof that can be obtained in pure form by standard separation procedures known to those skilled in the art, including, but not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.

[0076] Unless otherwise specified, the compounds provided herein may also include all isotopes of atoms present in intermediate or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. Unless otherwise specified, atoms may be isotopes or radioisotopes (e.g., deuterium, [ 11 C], [ 18 F], it is understood that the atom contains that isotope or radioisotope in an amount at least greater than the natural abundance of that isotope or radioisotope. For example, when an atom is designated as "D" or "deuterium," it is understood that the position has deuterium in an abundance of at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% deuterium incorporation).

[0077] All compounds and pharmaceutically acceptable salts thereof may be found together with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0078] In some embodiments, preparation of compounds can involve the addition of acids or bases, for example to catalyze a desired reaction or to affect the formation of salt forms, such as acid addition salts.

[0079] Examples of acids may be inorganic or organic, including, but not limited to, strong and weak acids. Some examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not limited to, acetic acid, propionic acid, butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0080] Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium bicarbonate. Some examples of strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, where alkoxides include the lithium, sodium, and potassium salts of methyl, ethyl, and t-butyl oxides; metal amides include sodium amide, potassium amide, and lithium amide; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamides include the lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trimethylsilyl, and cyclohexyl-substituted amides.

[0081] In some embodiments, the compounds provided herein or their salts are substantially isolated. By "substantially isolated," it is meant that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial separation can include, for example, compositions enriched for the compounds provided herein. Substantial separation can include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least 99% by weight of the compounds provided herein or their salts. Methods for isolating compounds and their salts are routine in the art.

[0082] As used herein, the expressions "ambient temperature" and "room temperature" or "rt" are art-recognized and generally refer to a temperature, e.g., the reaction temperature, which is generally the temperature of the room in which a reaction is carried out, e.g., a temperature of about 20°C to about 30°C.

[0083] The term "pharmaceutically acceptable" is used herein to describe compounds, substances, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0084] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present application include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). Conventional methods for preparing salt forms are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, 2002.

[0085] EAAT2 activator

[0086] As used herein, Formula I [ka] Formula I During the ceremony Y is O, S or NR 1 and; X 1 is CH or N; X 2 is CR 3 or N; X 3 is CR 4 or N; A is selected from the group consisting of 6-10 membered aryl and 5-10 membered heteroaryl, each of which is selected from 1, 2, 3, or 4 independently selected R A optionally substituted by a group; R 1 is H and C 1~6 alkyl; R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; R 3 and R 4 is H and C1~6 independently selected from alkyl; Each R A and R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0087] In some embodiments, A can be unsubstituted or can be selected from 1, 2, 3, or 4 independently selected R A In other embodiments, A can be unsubstituted or can be phenyl, which can be substituted by 1, 2, 3, or 4 independently selected R groups. A In some embodiments, A may be a 5- to 10-membered heteroaryl, which may be substituted by a group. In some embodiments, A may be an unsubstituted 5- to 6-membered heteroaryl. In some embodiments, A may be an unsubstituted pyridyl. In some embodiments, A may be selected from the group consisting of unsubstituted 2-pyridyl and unsubstituted 3-pyridyl. In some embodiments, A may be an unsubstituted 2-pyridyl. In some embodiments, A may be an unsubstituted 3-pyridyl.

[0088] In some embodiments, Y can be O.

[0089] In some embodiments, X 1 , X 2 and X 3 is N. For example, in some embodiments, X 1 is N and X 2 is CR 3 and X 3 is CR 4 In another embodiment, X 1 is CH and X 2 is N and X 3 is CR 4 is.

[0090] In some embodiments, R 3 is H, if present.

[0091] In some embodiments, R 4 is H, if present.

[0092] In some embodiments, the compound has Formula II [ka] Formula II During the ceremony X 1 is CH or N; X 2 is CR 3 or N; X 3 is CR 4 or N; R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; R 3 and R 4 is H and C 1~6 independently selected from alkyl; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R.c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 3~10 Cycloalkyl-C 1~4 Alkylene, 4-10 membered heterocycloalkyl-C1~4 Alkylene, 6-10 membered aryl-C 1~4 Alkylene and 5-10 membered heteroaryl-C 1~4 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C1~6 Alkylaminosulfonyl and di(C 1~6 alkyl)aminosulfonyl; Each R 6 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0093] In some embodiments, the compound has formula IIA [ka] Formula IIA During the ceremony R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d, N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 1~4alkylene; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each Re are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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 1~6alkyl)aminocarbonylamino; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0094] In some embodiments, the compound has formula IIB [ka] Formula IIB During the ceremony R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0095] In some embodiments, the compound has Formula III [ka] Formula III During the ceremony X 1 is CH or N; X 2 is CR 3 or N; X 3 is CR 4 or N; R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; R 3 and R 4 is H and C 1~6 independently selected from alkyl; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R.c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 3~10 Cycloalkyl-C 1~4 Alkylene, 4-10 membered heterocycloalkyl-C1~4 Alkylene, 6-10 membered aryl-C 1~4 Alkylene and 5-10 membered heteroaryl-C 1~4 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C1~6 Alkylaminosulfonyl and di(C 1~6 alkyl)aminosulfonyl; Each R 6 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0096] In some embodiments, the compound has formula IIIA [ka] Formula IIIA During the ceremony R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d, N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 1~4alkylene; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each Re are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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 1~6alkyl)aminocarbonylamino; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0097] In some embodiments, the compound has formula IIIB [ka] Formula IIIB During the ceremony R 2 is -(CHR E ) n R 5 and; R 5 is OR C , N.R. C R D , C(O)NR C R D , C(O)OR C , H., C. 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each have 1, 2, 3, or 4 independently selected R B optionally substituted by a group; R E is H, C 1~6 Alkyl, C 1~6 alkoxy and amino, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R 6 optionally substituted by a group; Each R B Ha, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 1~4 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c OR d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)NR c R d wherein said C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and C 1~4 Haloalkyl is one, two, three, or four independently selected R 6 optionally substituted with a group; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R a , R b , R c and R d is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10independently selected from cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each independently selected from 1, 2, 3, or 4 R 6 each optionally substituted with a group; Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkyl sulfonyl, C 1~6 Alkyl carbonyl, 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 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0098] In some embodiments, R 2 is -(CH2) n R 5 , -(CH(CH3)) n R 5 and (CH2CH(NH2)) n R 5 In some embodiments, R 2 is -(CH2) n R 5 In some embodiments, R 2 is -(CH(CH3)) n R 5 In some embodiments, R 2 is -(CH2CH(NH2)) n R 5 In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0099] In some embodiments, R 5 is OR C, N.R. C R D , C(O)NR C R D , C 6~10 Aryl, C 3~10 cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said C 6~10 Aryl, C 3~10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each selected from 1, 2, 3, or 4 independently selected R B and optionally substituted by groups.

[0100] In some embodiments, R 5 is OR C , N.R. C R D , C(O)NR C R D , phenyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said phenyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each may be selected from the group consisting of one or two independently selected R B In one embodiment, R 5 is OR C , N.R. C R D , C(O)NR C R D , phenyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein said phenyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl may each be selected from the group consisting of one or two independently selected R B and optionally substituted by groups.

[0101] In some embodiments, R 5 are OCH3, N(CH3)2, C(O)N(CH3)2, phenyl, C 3~6cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein said phenyl, 4- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl each may be selected from the group consisting of one or two independently selected R B In one embodiment, R 5 are OCH3, N(CH3)2, C(O)N(CH3)2, phenyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein said phenyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl may each be selected from the group consisting of one or two independently selected R B and optionally substituted by groups.

[0102] In some embodiments, R 5 may be selected from the group consisting of OCH, N(CH), C(O)NH, C(O)NHCH, C(O)N(CH), C(O)N(CH), phenyl, cyclopentyl, cyclohexyl, oxazolyl, pyridyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, piperidinonyl, pyrrolidinyl, pyrrolidinonyl, benzimidazolyl, and quinolinyl, wherein said phenyl, cyclopentyl, cyclohexyl, oxazolyl, pyridyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, piperidinonyl, pyrrolidinyl, pyrrolidinonyl, benzimidazolyl, and quinolinyl are each selected from one or two independently selected R B and optionally substituted by groups.

[0103] In some embodiments, R 5 is H and C 1~6 alkyl, wherein said C 1~6 Alkyl is one, two, three, or four independently selected R B In some embodiments, R 5 can be hydrogen. In some embodiments, R5 is C optionally substituted with one or more halogens (e.g., fluorine); 1~6 In some embodiments, R 5 can be a trifluoromethyl group.

[0104] In some embodiments, R C and R D If present, 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, 5-6 membered heteroaryl, 4-6 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-6 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 and optionally substituted with a group.

[0105] In some embodiments, each R B If present, C 1~6 Alkyl and NR c R dIn some embodiments, each R B If present, C 1~3 Alkyl and N(C 1~3 alkyl)2.

[0106] In some embodiments, R 2 is not one of the groups shown below. [ka]

[0107] In certain embodiments, the compound has the formula: [ka] During the ceremony R 2 is -(CH2) n NR C R D and; R C and R D is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 3~10 Cycloalkyl-C1~4 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 Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R 6 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1~6 Alkylaminosulfonylamino, di(C 1~6Alkyl)aminosulfonylamino, aminocarbonylamino, C 1~6 Alkylaminocarbonylamino and di(C 1~6 alkyl)aminocarbonylamino; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0108] In certain embodiments, the compound has the formula: [ka] During the ceremony R 2 is -(CH2) n NR C R D and; R C and R D is H, C 1~6 Alkyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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; 1~6 Alkyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 4- to 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 1~4Each alkylene is selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R 6 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0109] In certain embodiments, the compound has the formula: [ka] During the ceremony R 2 is -(CH2) n NR C R D and; R C and R D is H, C 1~6 Alkyl, C 1~4 haloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; 1~6 Alkyl, C 1~4 Haloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atom C and R D together with the N atom to which they are attached, one, two or three independently selected R 6 a 4- to 6-membered heterocycloalkyl group or a 5- to 6-membered heteroaryl group, each optionally substituted with a group; Each R 6 OH, NO2, 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, C1~6 Alkylsulfinyl, C 1~6 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0110] In certain embodiments, the compound has the formula: [ka] During the ceremony R 2 is -(CH2) n NR C R D and; R C and R D is H, C 1~6 Alkyl and C 1~4 haloalkyl; wherein said C 1~6 Alkyl and C 1~4 Haloalkyl is each selected from 1, 2, 3, or 4 independently selected R 6 optionally substituted with a group; or Any R bonded to the same N atomC and R D together with the N atom to which they are attached, one, two or three independently selected R 6 forming a 4-6 membered heterocycloalkyl group optionally substituted with a group; Each R 6 OH, NO2, 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, 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; n is 0, 1, 2, 3, 4 or 5; A compound defined by or a pharmaceutically acceptable salt, ester or N-oxide thereof.

[0111] Examples of compounds are shown below. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0112] synthesis The compounds described herein can be prepared using synthetic methods known in the art. For example, the representative EAAT2 activators described herein can be prepared using the Mitsunobu reaction, as shown in Scheme 1. Scheme 1 [ka]

[0113] Those skilled in the art will understand that the described processes are not the only means by which the compounds provided herein can be synthesized, and that a wide range of synthetic organic reactions may be utilized to synthesize the compounds provided herein. Those skilled in the art will know how to select and implement appropriate synthetic routes. Suitable synthetic methods for starting materials, intermediates, and products can be identified by reference to the literature, including references such as: Advances in Heterocyclic Chemistry,Vols.1-107(Elsevier,1963-2012);Journal of Heterocyclic Chemistry Vols.1-49(Journal of Heterocyclic Chemistry,1964-2012);Carreira,et al.(Ed.)Science of Synthesis,Vols.1-48(2001-2010)and Knowledge Updates KU2010 / 1-4;2011 / 1-4;2012 / 1-2(Thieme,2001-2012);Katritzky, et al.(Ed.)Comprehensive Organic Functional Group Transformations,(Pergamon Press,1996);Katritzky et al.(Ed.);Comprehensive Organic Functional Group Transformations II(Elsevier,2 nd Edition,2004);Katritzky et al.(Ed.),Comprehensive Heterocyclic Chemistry(Pergamon Press,1984);Katritzky et al.,Comprehensive Heterocyclic Chemistry II,(Pergamon Press,1996);Smith et al.,March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,6 thEd. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

[0114] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic chemistry. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (for example, a temperature that can range from the freezing point of the solvent to the boiling point of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent for the specific reaction step can be selected by those skilled in the art.

[0115] Preparation of the compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Protecting group chemistry is described, for example, in T.W. Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999).

[0116] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography.

[0117] How to use Also provided are methods for treating disorders associated with glutamate excitotoxicity in a subject in need thereof. Many such disorders are known in the art and can be easily identified by those skilled in the art. In some embodiments, these methods include a method for treating or preventing glutamate excitotoxicity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof. As used herein, the term "subject" refers to any animal, including mammals. For example, the term "subject" includes, but is not limited to, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

[0118] In some embodiments, the methods described herein can include in vitro methods, e.g., contacting a sample (e.g., a cell or tissue) with a compound provided herein or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the disorder is an acute neurological condition such as ischemic stroke, epilepsy, hypoglycemia, hypoxia, or trauma (see, e.g., J.Neurosci. 2016 Oct 12;36(41):10529-10544; J.Clin.Invest. 2014 Mar;124(3):1255-67; ​​and Neurochem.Int. 2006 Apr;48(5):394-403).

[0120] In some embodiments, the disorder is a chronic neurodegenerative disorder such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, mesial temporal lobe sclerosis, Huntington's disease, AIDS dementia complex, or amyotrophic lateral sclerosis (ALS) (see, e.g., Hu et al., "Glutamate receptors in preclinical research on Alzheimer's disease: Update on recent advances." Pharmacol Biochem Behav. 2011 Apr 22 [Epub ahead of print, doi:10.1016 / j.pbb.2011.04.013]; Wang and Qin, Apoptosis. 15(11):1382-402 (2010); Kaul and Lipton, Curr HIV Res. 4(3):307-18 (2006); Kim et al., J Cell Physiol. 226(10):2484-93 (2011); Sheldon and Robinson,Neurochem Int.51(6-7):333-55(2007);Guo et al.,Hum.Mol.Genet.2003,12,2519;Tian et al.,J.Biol.Chem.282:1727(2007);Hazell,Neurochem.Int.50:941(2007);Seifert et al. al.,Brain.Res.Rev.63:212(2010);Tian et al.,J.Neurochem.113:978(2010);Olney,“Neurotoxicity of excitatory amino acids.” In:McGeer E,Olney J,McGeer P,eds.Kainic Acid as a Tool in Neurobiology.New York:Raven Press;1978:95-121;Olney,APMIS Suppl 40:103-112(2010);J.Exp.Med.2015 Mar 9;212(3):319-32;Neurobiol.Aging.2015 Jul;36(7):2260-71;Neural.Plast.2016;2016:8941327;PLoS One.2008 Sep 5;3(9):e3149; J.Clin.Invest. 2014 Mar;124(3):1255-67; ​​J.Neurochem. 2012 May;121(4):629-38; and Curr.HIV Res. 2012 Jul;10(5):392-406).

[0121] In some embodiments, the disorder is depression (see, e.g., Chen et al., Presynaptic glutamatergic dysfunction in bipolar disorder, Biol. Pshychiatry, 67(11):1007-1009 (2010)).

[0122] In some embodiments, glutamate excitotoxicity can be the result of environmental toxins, such as tributyltin (Nakatsu et al., Toxicol. Sci. (January 2006) 89(1):235-242), lead, and domoic acid.

[0123] In some embodiments, excess glutamate is associated with chronic pain disorders, including migraine, fibromyalgia, temporomandibular joint disorders, neuropathic pain, visceral pain, or complex regional pain syndrome (e.g., Chizh et al., Amino Acids, 23(1-3):169-76 (2002); Descalzi et al., Mol Neurobiol. 40(3):253-9. Epub 2009 Oct 11 (2009); Larsson, Mol Neurobiol. 40(3):260-88 (2009); Yogeswaari et al., Expert Opin Ther Targets. 13(8):925-43 (2009); Vargas, Curr Pain Headache Rep. 13(1):64-6 (2009); Adv. Pharmacol. 2016;75:245-71; J. Neurochem. 2014 Dec;131(6):712-30; Eurasian J Med.2011 Dec;43(3):182-5; and J.Pharmacol.Sci.2010;114(4):347-53).

[0124] Disruption of glutamate homeostasis is associated with addictive disorders.As substance abuse develops into addiction, neurochemistry shifts from dopamine-based to mainly glutamate-based.Therefore, the subject suffering from drug addiction and dependence, including alcohol and cocaine addiction, can also be treated with the method described herein. See, e.g., Tzschentke, Amino Acids 23(1-3):147-52 (2002); Reissner and Kalivas, Behav Pharmacol. 2010 Sep;21(5-6):514-22 (2010); Myers et al., Neuropsychopharmacology. 36(1):274-93 (2011); World J. Psychiatry. 2016 Mar 22;6(1):31-42; CNS Neurol. Disord. Drug. Targets. 2015;14(6):745-56; Neuroscientist. 2014 Dec;20(6):610-22; and Behav.Pharmacol. 2010 Sep;21(5-6):514-22.

[0125] Glutamate has also been shown to play a role in several psychiatric disorders, including schizophrenia, bipolar disorder, and autism (see, e.g., Curr Mol Pharmacol. 2013 Jul;6(2):66-73; Eur J Pharmacol. 2012 May 5;682(1-3):1-11; Iran J Child Neurol. 2015 Winter;9(1):99-102; J Biomed Sci. 2005 Dec;12(6):975-84). The methods and compounds described herein can be used to treat subjects with psychiatric disorders, such as schizophrenia, bipolar disorder, and autism.

[0126] Glutamate has also been shown to play a role in some cancers, including necrosis in glioblastoma, which is associated with poor prognosis.See, for example, Noch and Khalili, Cancer Biol Ther.8(19):1791-7(2009).Therefore, the compounds and compositions described herein can be used to treat subjects with cancer, for example, brain cancer, such as glioblastoma and glioma.

[0127] Glutamate has been implicated in a variety of mood disorders, including major depressive disorder (Owen, Drugs today, 2012, 48(7):469-78), anxiety disorders (see, e.g., Neuropsychiatr Dis Treat. 2013;9:1101-12), depressive disorders (see, e.g., Expert Rev Clin Pharmacol. 2016 Oct 26; Biol Psychiatry. 2007 Jan 15;61(2):250-2; and Biol Psychiatry. 2007 Jan 15;61(2):137-8), borderline personality disorder (see, e.g., Neuropsychopharmacology. 2016 Jan;41(2):410-8), and attention deficit hyperactivity disorder (see, e.g., Neuropsychopharmacology. 2016 Jan;41(2):410-8; and World J. Biol. Psychiatry. 2016 Dec 15:1-9), suicidal behavior (see, e.g., Prog. Neuropsychopharmacol Biol. Psychiatry. 2016 Oct 27), eating disorders (see, e.g., Curr. Pharm. Des. 2011;17(14):1396-409), post-traumatic stress syndrome (see, e.g., Neurosci. Lett. 2016 Dec 1), Gulf War illness (see, e.g., J. Neurochem. 2011 Oct;119(2):303-13), and obsessive-compulsive disorder (see, e.g., Pharmacol. Ther. 2011 Dec;132(3):314-332).

[0128] The presence of disorders associated with glutamate excitotoxicity can be diagnosed or determined using methods known in the art, including spectroscopy at 0.5 T to observe the combined glutamate and glutamine (glx) peak (see, e.g., Prost et al., Magn Reson Med 1997;37:615-618; Mark et al., American Journal of Neuroradiology 22:1813-1824 (2001)). Other known clinical diagnostic methods can also be used to diagnose the presence of disorders known to be associated with glutamate excitotoxicity, for example, as described herein.

[0129] In some embodiments, glutamate excitotoxicity (and subsequent neuronal damage) can be the result of environmental toxins, such as tributyltin (Nakatsu et al., Toxicol. Sci. (January 2006) 89(1):235-242), lead, and domoic acid. Subjects who have been or will be exposed to such toxins can be considered to have a disorder associated with glutamate excitotoxicity and can be treated using the methods described herein. In some embodiments, subjects exposed to environmental toxins known to cause or contribute to glutamate excitotoxicity can be treated using the methods described herein prior to the onset of clinical (neurological) symptoms to prevent or reduce the risk of a disorder associated with glutamate excitotoxicity.

[0130] Also provided in some embodiments is a method for treating a disease or disorder selected from the group consisting of ischemic stroke, epilepsy, trauma, a chronic neurodegenerative disorder, a psychiatric disorder, a pain disorder, an addiction, cancer, a mood disorder, or depression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound provided herein.

[0131] Also provided in some embodiments is a method for treating a disease or disorder selected from the group consisting of ischemic stroke, epilepsy, trauma, a chronic neurodegenerative disorder, a psychiatric disorder, a pain disorder, an addiction, cancer, or depression in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound provided herein.

[0132] Examples of trauma include, but are not limited to, blunt trauma, abrasion, avulsion, cut, laceration, puncture, penetration, surgical trauma, iatrogenic trauma, spinal cord injury, traumatic brain injury, or any combination thereof.

[0133] In some embodiments, the chronic neurodegenerative disorder is selected from the group consisting of mild cognitive impairment, Parkinson's disease, Alzheimer's disease, multiple sclerosis, mesial temporal sclerosis, Huntington's disease, AIDS dementia complex, essential tremor, and amyotrophic lateral sclerosis (ALS).

[0134] In some embodiments, the psychiatric disorder is selected from the group consisting of schizophrenia, bipolar disorder, and autism.

[0135] In some embodiments, the pain disorder is selected from the group consisting of migraine, temporomandibular joint disorder, neuropathic pain, visceral pain, or complex regional pain syndrome.

[0136] In some embodiments, the addiction is selected from the group consisting of alcohol addiction, cocaine addiction, heroin addiction, methamphetamine addiction, and nicotine addiction. In some embodiments, the addiction is selected from the group consisting of alcohol addiction and cocaine addiction.

[0137] In some embodiments, the cancer is selected from the group consisting of brain cancer, glioblastoma, and glioma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is glioma.

[0138] In some embodiments, the mood disorder is selected from the group consisting of anxiety disorder, depressive disorder, borderline personality disorder, attention deficit hyperactivity disorder, suicidal behavior, eating disorder, post-traumatic stress syndrome, Gulf War illness, and obsessive-compulsive disorder.

[0139] In some embodiments, the depression comprises major depressive disorder. In some embodiments, the depression is major depressive disorder.

[0140] Also provided in some embodiments is a method for treating a disease or disorder in a subject in need thereof selected from the group consisting of ischemic stroke, epilepsy, trauma, or a chronic neurodegenerative disorder including mild cognitive impairment, Parkinson's disease, Alzheimer's disease, multiple sclerosis, mesial temporal lobe sclerosis, Huntington's disease, AIDS dementia complex, essential tremor, or amyotrophic lateral sclerosis (ALS), a psychiatric disorder including schizophrenia, bipolar disorder, and autism, a pain disorder including migraine, temporomandibular joint disorder, neuropathic pain, visceral pain, or complex regional pain syndrome; an addiction including alcohol addiction, cocaine addiction, heroin addiction, methamphetamine addiction, and nicotine addiction; or cancer, including glioblastoma; or depression, comprising administering to the subject an effective amount of a compound provided herein.

[0141] Also provided is a method for increasing EAT2 protein expression in a cell or a subject in need thereof, comprising contacting the cell or administering to the subject an effective amount of a compound provided herein.

[0142] Also provided are methods for activating the NRF2 pathway in a cell or a subject in need thereof, comprising contacting the cell or administering to the subject an effective amount of a compound provided herein.

[0143] As used herein, the term "effective amount" refers to the amount of an active compound or agent that elicits the biological or medical response desired by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human. An effective amount of a compound provided herein can range, for example, from about 0.01 mg / kg to about 1000 mg / kg, (e.g., from about 0.1 mg / kg to about 100 mg / kg, from about 1 mg / kg to about 100 mg / kg). The effective dose will vary depending on the route of administration as well as the possibility of co-administration with other factors.

[0144] As used herein, "treating" refers to alleviating at least one symptom of a disorder associated with glutamate excitotoxicity. Often, glutamate excitotoxicity leads to neuronal cell death, and therefore, treatment can result in a reduction in the rate or amount of neuronal cell death.

[0145] Combination therapy In some embodiments, the methods provided herein further comprise administering to the subject one or more additional therapeutic agents, in some embodiments, each of the one or more additional therapeutic agents is independently selected from the group consisting of a steroid, an anti-allergic agent, an anesthetic (e.g., for use in conjunction with a surgical procedure), an immunosuppressant, an antibacterial agent, an anti-inflammatory agent, and a chemotherapeutic agent.

[0146] Examples of steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

[0147] Examples of anesthetic agents include, but are not limited to, local anesthetics such as lidocaine, procaine, and ropivacaine.

[0148] Examples of immunosuppressants include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

[0149] Examples of antibacterial agents include, but are not limited to, aminoglycosides (eg, gentamicin, neomycin, and streptomycin), penicillins (eg, amoxicillin and ampicillin), and macrolides (eg, erythromycin).

[0150] Examples of anti-inflammatory agents include, but are not limited to, aspirin, choline salicylate, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium plus misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxican, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.

[0151] Examples of chemotherapeutic agents include, but are not limited to, proteosome inhibitors (e.g., bortezomib), thalidomide, Revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, etc. For example, one or more of the following agents may be used in combination with the compounds provided herein, which are presented as a non-limiting list: cytostatic agents, cisplatin, taxol, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, temozolomide, cyclophosphamide, gefitinib, erlotinib hydrochloride, imatinib mesylate, gemcitabine, uracil mustard, chlormethine , ifosfamide, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, folinic acid, pentostatin, vinblastine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deo Xicoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methyltestosterone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, megestrol acetate, Droxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrazole, letrozole, capecitabine, reloxafine, hexamethylmelamine, bevacizumab, Bexar, Velcade, Zevalin, Trisenox, Xeloda, Porfimer, Erbitux,Thiotepa, altretamine, trastuzumab, fulvestrant, exemestane, ifosfamide, rituximab, alemtuzumab, clofarabine, cladribine, aphidicolin, sunitinib, dasatinib, tezacitabine, triapin, trimidox, amidox, bendamustine and ofatumumab.

[0152] Pharmaceutical Compositions When used as pharmaceuticals, the compounds provided herein can be administered in the form of pharmaceutical compositions. These compositions can be prepared as described herein or elsewhere and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic, and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, such as by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial (e.g., intrathecal or intraventricular administration). Parenteral administration can be in the form of a single bolus injection or can be, for example, by a continuous perfusion pump. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are suitable for parenteral administration. In some embodiments, the compounds provided herein are suitable for intravenous administration. In some embodiments, the compounds provided herein are suitable for oral administration. In some embodiments, the compounds provided herein are suitable for topical administration.

[0153] Pharmaceutical compositions and formulations for topical administration may include, but are not limited to, transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc. may be necessary or desirable. In some embodiments, the pharmaceutical compositions provided herein are suitable for parenteral administration. In some embodiments, the pharmaceutical compositions provided herein are suitable for intravenous administration. In some embodiments, the pharmaceutical compositions provided herein are suitable for oral administration. In some embodiments, the pharmaceutical compositions provided herein are suitable for topical administration.

[0154] Also provided is a pharmaceutical composition containing the compound provided herein as an active ingredient, combined with one or more pharmaceutically acceptable carriers (e.g., excipients).When preparing the pharmaceutical compositions provided herein, the active ingredient is usually mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper or other container.When an excipient serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, carrier or medium for the active ingredient.Therefore, the composition can be in the form of, for example, tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaged powders.

[0155] Some examples of suitable excipient include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose.Preparation can also comprise, but are not limited to, lubricating agent such as talc, magnesium stearate and mineral oil; wetting agent; emulsifying and suspending agent; preservative such as methyl benzoate and propyl hydroxybenzoate; sweetener; flavoring agent or combination thereof.

[0156] The active compound may be effective over a wide dosage range and is generally administered in an effective amount. However, it will be understood that the amount of the compound actually administered will usually be determined by a physician according to the relevant circumstances, such as the condition to be treated, the selected route of administration, the actual compound to be administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0157] The compositions provided herein can be administered once or more per day, such as once every two days, to once or more per week.Those skilled in the art will understand that certain factors, including but not limited to the severity of disease or disorder, previous treatment, the general health and / or age of the subject, and other existing diseases, can affect the dosage and timing required to effectively treat a subject.In addition, treatment of a subject with a therapeutically effective amount of the compounds described herein can include a single treatment or a series of treatments.

[0158] The dosage, toxicity, and therapeutic effect of the compounds provided herein can be determined, for example, by the LD 50 (lethal dose for 50% of the population) and ED 50 The dose that is therapeutically effective in 50% of the population can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD50 / ED 50 The therapeutic index can be expressed as: Compounds that exhibit a high therapeutic index are preferred. Compounds that exhibit adverse side effects can be used, but care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells, thereby reducing side effects. [Example]

[0159] The present invention will be described in more detail through specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-critical parameters that can be changed or modified to produce essentially the same results.

[0160] Preparation of compounds Synthesis of Compound 100: 2-(2-(dimethylamino)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one [ka]

[0161] A flask was charged with triphenylphosphine (1.83 g, 7 mmol) and di-tert-butylazadicarboylate (1.21 g, 5.25 mmol). The flask was degassed with argon, and then the solid was dissolved in DCM (20 mL) at 0 °C. A separate flask was charged with 6-(pyridin-2-yl)pyridazin-3(2H)-one (600 mg, 3.5 mmol). DCM (15 mL) and N,N-dimethylethanolamine (0.42 mL, 4.2 mmol) were added to the solid. After 20 min, the triphenylphosphine and di-tert-butyl-butylazadicarboylate solution was added dropwise to the slurry of 6-(pyridin-2-yl)pyridazin-3(2H)-one and N,N-dimethylethanolamine. After 3 hours at room temperature, the reaction was concentrated, reconstituted in toluene (35 mL), and then concentrated again. The crude material was reconstituted in ethyl acetate (35 mL), filtered, and 1.7 mL of 2 M HCl in diethyl ether was immediately added to the filtrate. The slurry was stirred for 15 minutes at 0°C, briefly cooled to -78°C, and then the solid was collected by vacuum filtration. The solid was recrystallized from an ethanol:ethyl acetate solution and filtered to give the monohydrochloride salt of 2-(2-(dimethylamino)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one (330 mg, 34%) as a white solid. 1 H NMR(400MHz,DMSO):10.78(s,1H),8.67(m,1H),8.27(d,J=4Hz 1H),8.13(d,J=8Hz 1H),7.94(td,J=7.8,1.2Hz 1H),7.48(m,1H),7.12(d,J=10Hz 1H), 4.59(m, 2H), 3.56(m, 2H), 2.82(s, 6H). [M+1] + =245.1

[0162] A sample of the monohydrochloride salt of 2-(2-(dimethylamino)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one was recrystallized from ethanol:ethyl acetate, and X-ray analysis confirmed the structure as shown in Figure 1A.

[0163] Synthesis of Compound 101: 2-(2-(methylamino)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one hydrochloride [ka]

[0164] 6-(pyridin-2-yl)pyridazin-3(2H)-one (5 g, 29 mmol), triphenylphosphine (15.1 g, 57 mmol), and di-tert-butyl azodicarboxylate (10.01 g, 43 mmol) were placed in a 500 mL flask and dissolved in DCM (250 mL). 2-Methylaminoethanol (2.79 mL) was added dropwise to the stirred solution. After stirring at room temperature for 4 hours, LCMS indicated the reaction was complete, and the mixture was concentrated under reduced pressure. The residue was purified by chromatography using a DCM / methanol / NH3 (95 / 4 / 1 / ) solvent system to give a pale orange oil (4.9 g). The oil was dissolved in ethyl acetate (approximately 250 mL) and then salted with 2 M HCl in ether (12.5 mL). The solid was collected by vacuum filtration to give the product as a white powder (4.6 g). 1 H NMR(400MHz,DMSO):9.25(s,2H),8.67(m,1H),8.30(d,J=4Hz 1H),8.20(d,J=8Hz 1H),7.99(td,J=8,1Hz 1H),7.49(m,1H),7.10(d,J=10Hz 1H),4.47(m,2H),3.35(m,2H),2.56(s,3H). [M+1] + =231

[0165] A sample of the monohydrochloride salt of 2-(2-(methylamino)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one was recrystallized from ethyl acetate:hexane, and X-ray analysis confirmed the structure as shown in Figure 1B.

[0166] The following compounds were prepared analogously to compound 100 (2-(2-(dimethylamino)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one).

[0167] Compound 181: 2-Isopentyl-6-(pyridin-2-yl)pyridazin-3(2H)-one [ka] 1 H NMR 400Hz(CDCl3):δ8.50(d,1H,J=3.6Hz),8.32(d,1H,J=9.6Hz),8.14(d,1H,J=8Hz),7.79(td,1H,J=2 and 8Hz),7.32-7.30(m,1H),7.01(d,1H,J=7.6Hz),4.30-4.27(m,2H),1.80-1.75(m,2H),1.72-1.67(m,1H),1.00(d,6H,J=5.2Hz). [M+1] + =244

[0168] Compound 126: 2-(2-morpholinoethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one hydrochloride [ka] 1 H NMR 400Hz(DMSO):δ11.47(s,1H)8.70(d,1H,J=3.6Hz),8.31(d,1H,J=10Hz),8.17(d,1H,J=6.8Hz),8.01(td,1H,J 1.2 and 6.2Hz),7.54-7.51(m,1H),7.13(d,1H,J=8Hz),4.61(t,2H,5.2Hz),3.96(d,2H,9.2Hz),3 .81(t,2H,J=9.6Hz),3.63(s,2H),3.56(d,2H,J=9.6Hz),3.17-3.16(m,2H),2.50(m,1H). [M+1] + =287

[0169] Compound 198: 6-(pyridin-2-yl)-2-(1-(pyridin-2-yl)ethyl)pyridazin-3(2H)-one [ka] 1 H NMR 400Hz(CDCl3):δ8.60-8.57(m,2H),8.33(d,1H,J=9.6Hz),8.04(d,1H,J=8Hz),7.72(td,1H,J1=1.6 and 7.8Hz),7.62(td,1H,J1=2 and 7.6Hz)7.29-7.25(m,2H),7.16(dd,1H,J=1.2 and 5Hz),7.10(d,1H,J=9.6Hz),6.43(q,1H,J=7.2Hz),1.93(d,3H,J=6.8Hz). [M+1] + =279

[0170] Compound 145: 6-(pyridin-2-yl)-2-(thiazol-2-ylmethyl)pyridazin-3(2H)-one [ka] 1 H NMR 400Hz(CDCl3):δ8.61(d,1H J=4.8Hz),8.38(d,1H,J=9.6Hz),8.15(d,1H,J=8Hz),7.76(td,1H,J=2 and 9.4Hz),7.76(s,1H),7.32(d,1H,J=3.6Hz),7.30(dd,1H,J=1.2 and 2.6Hz),7.07(d,1H,J=9.6Hz),5.74(s,2H). [M+1] + =271

[0171] Compound 199: 2-methyl-6-(pyridin-2-yl)pyridazin-3(2H)-one [ka] 1H NMR 400Hz(CDCl3): δ8.62(d,1H,J=4.8Hz),8.33(d,1H,J=10Hz),8.12(d,1H,J=8.4Hz),7.77(td,1H,J1=1.6 and 7.8Hz), 7.32-7.28(m, 1H), 7.02(d, 1H, J=9.6Hz), 3.88(s, 3H).

[0172] Compound 166: 2-(3-(dimethylamino)propyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one hydrochloride [ka] 1 H NMR 400Hz(DMSO):δ10.71(s,1H)8.67(d,1H,J=4.4Hz),8.29(d,1H,J=10Hz),8.15(d,1H,J=8Hz),7.97(td,1H,J 1.2 and 6.2Hz),7.51-7.51(m,1H),7.09(d,1H,J=9.6Hz),4.22(t,2H,J=6.8Hz),3.14-3.08(m,2H),2.70(d,6H,J=5.2Hz),2.25-2.17(m,2H). [M+1] + =259

[0173] Compound 146: 2-(oxazol-2-ylmethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one [ka] 1 H NMR 400Hz(CDCl3):δ8.61(d,1H J=4.8Hz),8.39(d,1H,J=9.6Hz),8.06(d,1H,J=8Hz),7.74(td,1H,J=2 and 9.4Hz),7.64(s,1H),7.31-7.28(m,1H),7.11(s,1H)7.07(d,1H,J=9.6Hz),5.55(s,2H). [M+1] + =255

[0174] Compound 172: 2-(2-methoxyethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one [ka] 1 H NMR 400Hz(CDCl3):δ8.72(d,1H,J=3.6Hz),8.31(d,1H,J=9.6Hz),8.10(d,1H,J=8Hz),7.89(td,1H,J=2 and 8Hz),7.43-7.40(m,1H),7.14(d,1H,J=9.6Hz),4.49(t,2H,J=5.6Hz),3.89(t,2H,J=5.6Hz),3.38(s,3H). [M+1] + =232

[0175] Compound 105: 2-(2-(diethylamino)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one hydrochloride [ka] 1 H NMR 400Hz(DMSO):δ10.37(s,1H)8.68(d,1H,J=4.4Hz),8.31(d,1H,J=10Hz),8.15(d,1H,J=8Hz),7.98(td,1H,J=1.2 and 6.2Hz),7.51-7.48(m,1H),7.13(d,1H,J=9.6Hz),4.54(t,2H,J=6.4Hz),3.55-3.50(m,2H),3.23-3.19(m,4H).

[0176] Compound 110: 2-(2-(methyl(phenyl)amino)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one [ka] 1H-NMR 400Hz(DMSO): δ8.65(d,1H,J=4.8Hz),8.18(d,1H,J=9.6Hz),8.04(d,1H,J=8Hz),7.97(t,1H,J=8Hz),7.49(t,1H,J=6.4Hz),7 .14-7.11(m,2H),6.98(d,1H,J=9.6Hz),6.92(s,2H),6.70(s,1H),4.35(t,2H,J=6.4Hz),3.86(t,2H,J=6.4Hz),2.93(s,3H). [M+1] + =307

[0177] Compound 102: 2-(2-aminoethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one hydrochloride [ka] 1 H NMR 400Hz(DMSO):δ8.69-8.68(m,1H),8.31(d,1H,J=10Hz),8.17-8.15(m,1H),7.96(td,1H,J=2 and 8Hz),7.50-7.47(m,1H),7.12(d,1H,J=9.6Hz),4.41(t,2H,J=7.2Hz),3.28(t,3H,J=6Hz). [M+1] + =217

[0178] Compound 200: 6-(6-azidopyridin-2-yl)-2-(2-(methyl(prop-2-yn-1-yl)amino)ethyl)pyridazin-3(2H)-one [ka] 1 H NMR 400Hz(MeOD): δ8.44(d,1H,J=10Hz),8.20(d,1H,J=8.8Hz),(m,1H),7.97(dd,1H,J=7.2 and 9.2Hz),7.87-7.82(m,1H),7.17(d,1H,J=9.6Hz),3.47-4.35(m,2H),3.05-2.99(m,2H),2.64-2.61(m,1H),2.401(s,6H).

[0179] Compound 133: 2-(2-(2-oxopyrrolidin-1-yl)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one [ka] 1 H NMR 400Hz(DMSO): δ8.65(d,1H,J=4.4Hz),8.24(d,1H,J=10Hz),8.07(d,1H,J=8Hz),7.94(td,1H,J=1.2 and 8Hz),7.46-7.43(m,1H),7.01(d,1H,J=10Hz),4.28(t,2H,J=5.6Hz),3.61(t ,2H,J=5.2Hz),3.40(t,2H,J=6.8Hz),1.99-1.95(m,2H),1.86-1.78(m,2H). [M+1] + =285

[0180] Compound 201: 2-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one [ka] 1 H-NMR 400Hz(DMSO): δ8.64(d,1H,J=4.4Hz),8.28(d,1H,J=9.6Hz),7.92-7.90(m,2H),7.45-7 .42(m,1H),7.10(s,1H),7.08(d,1H,J=9.6Hz),6.77(s,1H),5.38(s,2H),3.72(s,3H). [M+1] + =268

[0181] Synthesis of Compound 202: 2-(2-(dimethylamino)ethyl)-6-(pyridin-2-yl)pyridazine-3(2H)-thione [ka]

[0182] Step 1: To 2-(2-(dimethylamino)ethyl)-6-(pyridin-2-yl)pyridazin-3(2H)-one (100 mg, 0.4 mmol) in pyridine (3 mL) was added phosphorus pentasulfide (182 mg, 0.41 mmol). ℃ The mixture was heated at rt for 18 h. The mixture was evaporated, partitioned between 1 M sodium hydroxide (5 mL), and extracted with 20% IPA in dichloromethane (3 × 10 mL). The combined extracts were dried (MgSO) and evaporated to give the title compound, 2-(2-(dimethylamino)ethyl)-6-(pyridin-2-yl)pyridazine-3(2H)-thione, as a yellow solid (87 mg). 1 H NMR 400Hz(CDCl3): δ8.66(d,1H,J=3.2Hz),8.17(d,1H,J=8Hz),8.06(d,1H,J=9.2Hz),7.89(d,1H,J=8.4Hz),7.81(td,1H,J=2 and 8Hz),7.37-7.34(m,1H),4.93(t,2H,J=7.2Hz),2.95(t,2H,J=7.2Hz),2.37(s,6H).

[0183] Synthesis of Compound 195: 2-(2-(dimethylamino)ethyl)-4-methyl-6-(pyridin-2-yl)pyridazin-3(2H)-one hydrochloride [ka]

[0184] Step 1. A flask was charged with potassium hydroxide (0.074 mol). The solid was dissolved in water, and then acetylpyridine (0.0166 mol) was immediately added. The solution was stirred for 30 minutes, and then pyruvic acid (0.02475 mol) was immediately added. After stirring for 3 hours, additional pyruvic acid (0.02475 mol) was added. After 3 hours, the pH was adjusted to 2 using 12 M HCl. The aqueous solution was extracted 10 times with 10 mL of 20% isopropanol in dichloromethane solution (total 100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The oil was treated with 2 M ammonia in methanol, concentrated, and then triturated with ethyl acetate to give an oily solid. The solid was dried under reduced pressure to give 2-hydroxy-2-methyl-4-oxo-4-(pyridin-2-yl)butanoate (2.2 g, 63%) as an orange powder which was used in the next step.

[0185] Step 2. A flask was charged with crude solid 2-hydroxy-2-methyl-4-oxo-4-(pyridin-2-yl)butanoate (0.0105 mol). The powder was dissolved in water, and then acetic acid (0.05 mol) and hydrazine monohydrate (0.021 mol) were immediately added. After stirring at 80°C for 2 days, the reaction was cooled to 0°C and the product was collected by vacuum filtration to give 4-methyl-6-(pyridin-2-yl)pyridazin-3(2H)-one (800 mg, 26%) as a tan solid, which was used in the next step.

[0186] Step 3. A vial was charged with triphenylphosphine (0.75 mmol) and di-tert-butyl azodicarboxylate (0.56 mmol). The solid was added to a solution of 4-methyl-6-(pyridin-2-yl)pyridazin-3(2H)-one (0.37 mmol) in dichloromethane (3.5 mL), followed by immediate addition of N,N-dimethylethanolamine (0.45 mol). After stirring for 1 hour, the reaction was concentrated under reduced pressure and purified on a 20 g silica gel column using a dichloromethane:methanol (1% NH) solvent system. The desired product eluted with 5-9% methanol. Concentration of fractions gave a yellow oil. The oil was dissolved in ethyl acetate and then acidified with 2 M HCl in diethyl ether (0.6 mL). The resulting salt was collected by vacuum filtration to give the title compound (168 mg, 53%) as a white solid. 1 H NMR 400Hz(DMSO): δ10.48(s,1H)8.66(d,1H,J=4.8Hz),8.21(d,1H,J=1.2Hz),8.14(d,1H,J=8Hz),7.96(td,1H,J=1.2 and 6.2Hz),7.49-7.47(m,1H),4.54(t,2H,J=6.4Hz),3.57-3.56(m,2H),2.83(d,6H,J=4.4Hz),2.19(s,3H). [M+1] + =259

[0187] Synthesis of Compound 196: N,N-2-(2-(dimethylamino)ethyl)-5-methyl-6-(pyridin-2-yl)pyridazin-3(2H)-one hydrochloride [ka]

[0188] Step 1. A flask was charged with potassium carbonate (8.8 mmol). The solid was dissolved in water, then 1-(pyridin-2-yl)propan-1-one (4.4 mmol) was added immediately. The solution was stirred for 30 minutes, then glyoxylic acid was added immediately (4.4 mmol). After stirring overnight, the reaction was acidified with acetic acid (17.6 mmol), then hydrazine monohydrate was added in one portion (8.8 mmol). The reaction was stirred for 6 days, with an additional 2 mL of acetic acid added every two days. The reaction was partially concentrated under reduced pressure, then extracted with 20% isopropanol in dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to provide 5-methyl-6-(pyridin-2-yl)pyridazin-3(2H)-one as a solid (800 mg).

[0189] Step 2. A flask was charged with triphenylphosphine (8.6 mmol), di-tert-butyl azodicarboxylate (6.5 mmol), and 5-methyl-6-(pyridin-2-yl)pyridazin-3(2H)-one (4.3 mmol). The solid was dissolved in dichloromethane, and then N,N-dimethylethanolamine (5.2 mmol) was added immediately. After 4 hours, the reaction was concentrated under reduced pressure, reconstituted in ethyl acetate, and then acidified with 1 equivalent of 2M HCl in diethyl ether. The resulting salt was collected by vacuum filtration. The salt was dissolved in 3M HCl (8.2 mmol) and stirred at 90°C overnight. After stirring overnight, the solution was cooled to 0°C, and then solid NaOH (13.7 mmol) was added. The aqueous solution was extracted with a solution of 20% isopropanol in DCM, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by ISCO silica flash chromatography using a dichloromethane:methanol solvent system. The desired product eluted with 10% methanol. Fractions containing the desired product were concentrated, reconstituted in ethyl acetate, and then the hydrochloride salt was generated using one equivalent of 2M HCl in diethyl ether. The salt was collected by vacuum filtration to give a tan solid (70 mg). 1H-NMR 400Hz(DMSO):δ10.21(s,1H)8.67(d,1H,J=5.2Hz),7.99(t,1H,J=7.6Hz),7.81(d,1H,J=8Hz),7 .52-7.49(m,1H),4.46(t,2H,J=6.4Hz),3.53-3.49(m,2H),2.82(d,6H,J=4.8Hz),2.30(s,3H). [M+1] + =259

[0190] Synthesis of Compound 118: 2-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)-N-phenylacetamide [ka]

[0191] Step 1. Methyl 2-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)acetate (5.8 mmol) (prepared by the representative procedure above using methyl glycolate) was dissolved in a 1:1 solution of water and THF. 15 mL of 3 M NaOH was then added to the cloudy suspension and stirred at room temperature. After 1.5 hours, the tan slurry was partially concentrated and then washed three times with ethyl acetate and once with DCM. The aqueous layer was adjusted to pH 1 and then extracted with a 20% solution of isopropanol in dichloromethane. The organics were dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 2-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)acetic acid (400 mg, 30%) as an orange-white solid.

[0192] Step 2. 2-(6-Oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)acetic acid (0.87 mmol), EDC HCl (1.30 mmol) and HATU (1.3 mmol) were placed in a vial and dissolved in DMF. Aniline (1.3 mmol) was added immediately. The reaction was stirred for 2 days and then quenched with water. The resulting slurry was filtered to give the title compound as a white solid (83 mg, 31%). M+1=307.3

[0193] The following compounds were prepared analogously to compound 118 (2-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)-N-phenylacetamide):

[0194] Compound 120: 2-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)-N-(pyridin-2-yl)acetamide [ka] 1 H-NMR 400Hz(DMSO):δ10.90(s,1H)8.67(d,1H,J=4.8Hz),8.35-8.32(m,2H),8.06(d,1H,J=8Hz) ,7.99-7.90(m,2H),7.78-7.74(m,1H),7.47-7.45(m,1H),7.13-7.09(m,2H),5.07(s,2H).

[0195] Compound 203: N-(2-(2-(dimethylamino)ethoxy)phenyl)-2-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)acetamide [ka] 1 H NMR 400Hz(DMSO): δ10.46(s,1H),9.76(s,1H),8.68(d,1H,J=4Hz),8.34(d,1H,J=9Hz),8.07(d,1H,J=8Hz)7.94(td,1H,J=1.6 and 8Hz),7.49-7.46(m,2H),7.25(t,1H,d=8Hz),7.12(d,1H,J=9.6Hz),7.07-7.05(m,1H),6.71(dd,1H,J=2 and 8.2Hz),5.00(s,2H),4.26(t,2H,J=5.2Hz),3.49-3.45(m,2H),2.81(d,6H,J=4.8Hz). [M+1] + =394

[0196] Compound 121: N-(2-fluorophenyl)-2-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)acetamide [ka] 1 H NMR 400Hz(DMSO): δ10.18(s,1H),8.67(d,1H,J=4Hz),8.33(d,1H,J=9.6Hz),8.07(d,1H,J=8Hz),7.95-7.87(m,2H),7.46(dd,1H,J1=1.2 and 5Hz), 7.29-7.23(m, 1H), 7.15-7.10(m, 3H), 5.07(s, 2H).

[0197] Compound 114: N-methyl-2-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)acetamide [ka] 1 H NMR 400Hz(CDCl3):δ8.64-8.63(m,1H),8.44(d,1H,J=9.6Hz),8.16(d,1H,J=8Hz),7.78(td,1H,J=2 and 8Hz),7.34-7.31(m,1H),7.10(d,1H,J=9.6Hz),4.94(s,2H),2.82(d,3H,J=4.8Hz).

[0198] Compound 115: 2-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)acetamide [ka] 1 H NMR 400Hz(CDCl3):δ8.64-8.63(m,1H),8.44(d,1H,J=9.6Hz),8.16(d,1H,J=8Hz),7.78(td,1H,J=2 and 8Hz), 7.34-7.31(m, 1H), 7.10(d, 1H, J=9.6Hz), 4.94(s, 2H).

[0199] Compound 123: N-methyl-3-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)propanamide [ka] 1 H NMR 400Hz(CDCl3):δ8.63-8.61(m,1H),8.3(d,1H,J=9.6Hz),8.12(d,1H,J=8Hz),7.78(td,1H,J=2 and 8Hz),7.33-7.25(m,1H),7.03(d,1H,J=9.6Hz),4.57(t,2H,J=7.2Hz),2.82-2.78(m,5H). [M+1] + =259

[0200] Compound 124: 3-(6-oxo-3-(pyridin-2-yl)pyridazin-1(6H)-yl)propanamide [ka] 1 H NMR 400Hz(CDCl3):δ8.65-8.64(m,1H),8.26(d,1H,J=9.6Hz),8.11(d,1H,J=8Hz),7.91(td,1H,J=2 and 8Hz), 7.46-7.43(m, 1H), 7.04(d, 1H), 4.33-4.29(m, 1H), 2.63-2.60(m, 2H).

[0201] Synthesis of Compound 204: 2-(2-(dimethylamino)ethyl)-6-phenylpyridazin-3(2H)-one hydrochloride [ka]

[0202] Step 1. 6-Bromopyridazin-3(2h)-one (0.57 mmol), triphenylphosphine (1.14 mmol), and di-tert-butyl azodicarboxylate (0.855 mmol) were placed in a vial and dissolved in dichloromethane. N,N-Dimethylethanolamine (0.684 mmol) was added immediately. After stirring overnight, the reaction was concentrated. The residue was purified by ISCO silica flash chromatography using a dichloromethane:methanol solvent system. The desired product eluted with 8% methanol. Fractions containing the desired product were concentrated to give 6-bromo-2-(2-dimethylamino)ethyl)pyridazin-3(2H)-one as a white solid (60 mg, 42%).

[0203] Step 2. 6-Bromo-2-(2-(dimethylamino)ethyl)pyridazin-3(2H)-one (0.244 mmol), phenylboronic acid pinacol ester (0.41 mmol), and sodium carbonate (1 mmol) were placed in a vial and degassed with argon. Tetrakis(triphenylphosphine)palladium(0) (5 mol%) was then added, and the vial was degassed once more with argon. The solid was dissolved in acetonitrile / water (15% water). The reaction was heated to 60° C. and stirred overnight. The reaction was quenched with brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude material was purified by ISCO silica flash chromatography using a dichloromethane:methanol solvent system. The desired product eluted with 1% methanol. Concentration of fractions gave a clear oil. This oil was reconstituted in ethyl acetate, followed by salt generation using 1 equivalent of 2M HCl in diethyl ether. The salt was collected by filtration to give the title compound as a white powder (21 mg, 35%). 1 H-NMR 400Hz(DMSO):δ10.08(s,1H)8.08(d,1H,J=9.6Hz),7.92-7.89(m,2H),7.52-7 .46(m,3H),7.10(d,1H,J=10Hz),4.51-4.48(m,2H),3.54(m,2H),2.84(s,6H). [M+1] + =244

[0204] The following compounds were prepared analogously to compound 204 (2-(2-(dimethylamino)ethyl)-6-phenylpyridazin-3(2H)-one hydrochloride):

[0205] Compound 205: 2-(2-(dimethylamino)ethyl)-6-(2-fluorophenyl)pyridazin-3(2H)-one hydrochloride [ka] 1 H NMR 400Hz(MeOD):δ7.89-7.86(m,1H),7.79(dt,1H,J=2 and 7.8Hz),7.54-7.49(m,1H),7.34-7.23(m,2H),7.12(d,1H,J=10Hz),7.12(d,1H,J=9.6Hz),4.67-4.64(m,2H),3.71-3.68(m,2H),3.02(s,6H).

[0206] Compound 206: 2-(2-(dimethylamino)ethyl)-6-(2-methoxyphenyl)pyridazin-3(2H)-one hydrochloride [ka] 1 H NMR 400Hz(DMSO): δ10.13(s,1H),7.75(d,1H,J=9.6Hz),7.54(dd,1H,J=1.6 and 7.6Hz),7.45(td,1H,J=1.6 and 7.6Hz),7.15(d,1H,J=8Hz),7.04(t,1H,J=7.6Hz),6.98(d,1H,J=9.6Hz),4. 46(t,2H,J=6Hz),3.81(s,3H),3.51(q,2H,J=5.6Hz),2.83(d,6H,J=4.8Hz). [M+1] + =274

[0207] Compound 207: 2-(2-(dimethylamino)ethyl)-6-(3-methoxyphenyl)pyridazin-3(2H)-one hydrochloride [ka] 1 H NMR 400Hz(DMSO): δ10.67(s,1H),8.07(d,1H,J=10Hz),7.48-7.38(m,3H),7.06(d,1H,J=9.6Hz),7.03(dd,1H,J=2.4 and 7.6Hz), 4.51(t,2H,J=6Hz),3.81(s,3H),3.52(q,2H,J=5.6Hz),2.82(d,6H,J=5.2Hz). [M+1] + =274

[0208] Compound 208: 2-(2-(dimethylamino)ethyl)-6-(4-methoxyphenyl)pyridazin-3(2H)-one hydrochloride [ka] 1 H-NMR 400Hz(DMSO):δ10.70(s,1H),8.02(d,1H,J=10Hz),7.85(d,2H,J=8.8Hz),7.05-7 .01(m,3H),4.50(m,2H),3.79(s,3H),3.51(q,2H,J=6Hz),2.81(d,6H,J=5.2Hz). [M+1] + =274

[0209] Synthesis of Compound 209: 2-(2-(methylamino)ethyl)-6-(thiazol-2-yl)pyridazin-3(2H)-one hydrochloride [ka]

[0210] Step 1. A flask was charged with potassium carbonate (1.04 g, 7.8 mmol). The solid was dissolved in water, then 2-acetylthiazole (0.5 g, 4 mmol) was added immediately. The solution was stirred for 30 minutes, then glyoxylic acid (363 mg, 4.0 mmol) was added immediately. After stirring overnight, the reaction was acidified with acetic acid (1 mL), then hydrazine monohydrate (0.25 mL) was added in one portion. The reaction was allowed to stand for 85 minutes.℃ The mixture was heated at rt for 6 h, cooled, and filtered to collect the solid, which was washed with water and used in the next step as 6-(thiazol-2-yl)pyridazin-3(2H)-one (400 mg).

[0211] Step 2. A flask was charged with triphenylphosphine (293 mg, 1.1 mmol), di-tert-butyl azodicarboxylate (194 mg, 0.85 mmol), and 6-(thiazol-2-yl)pyridazin-3(2H)-one (100 mg, 0.56 mmol). The solid was dissolved in dichloromethane, and then 2-methylaminoethanol (0.054 mL, 0.67 mmol) was added immediately. After 4 hours, the reaction was concentrated under reduced pressure, and the residue was purified by ISCO silica flash chromatography using a dichloromethane:methanol solvent system. One equivalent of 2 M HCl in diethyl ether was used to generate the hydrochloride salt of 2-(2-(methylamino)ethyl)-6-(thiazol-2-yl)pyridazin-3(2H)-one. 1 H NMR 400Hz (DMSO): δ8.98(s,2H),8.09(d,1H,J=9.6Hz),7.98(d,1H,J=3.2Hz),7.90(d,1H,J=3.2Hz),4.41(t,2H,J=6Hz),3.32(m,2H),2.57(s,3H).

[0212] Synthesis of Compound 210: 2-(2-(dimethylamino)ethyl)-6-(pyridin-3-yl)pyridazin-3(2H)-one [ka]

[0213] Step 1. A flask was charged with potassium carbonate (1.2 g). The solid was dissolved in water, then 3-acetylpyridine (0.5 g, 4.1 mmol) was added immediately. The solution was stirred for 30 minutes, then glyoxylic acid (380 mg, 4.1 mmol) was added immediately. After stirring overnight, the reaction was acidified with acetic acid (1 mL), then hydrazine monohydrate (0.25 mL) was added in one portion. The reaction was allowed to stand for 85 minutes. ℃ The mixture was heated at rt for 6 h, cooled, and filtered to collect the solid, which was washed with water and 6-(pyridin-3-yl)pyridazin-3(2H)-one was used in the next step.

[0214] Step 2. A flask was charged with triphenylphosphine (760 mg, 3 mmol), di-tert-butyl azodicarboxylate (501 mg, 2.2 mmol), and 6-(pyridin-3-yl)pyridazin-3(2H)-one (250 mg, 1.45 mmol). The solid was dissolved in dichloromethane, and then dimethylethanolamine (0.174 mL, 1.74 mmol) was added immediately. After 3 hours, the reaction was concentrated under reduced pressure, and the residue was purified by ISCO silica flash chromatography using a dichloromethane:methanol solvent system. One equivalent of 2 M HCl in diethyl ether was used to generate the hydrochloride salt of 2-(2-(dimethylamino)ethyl)-6-(pyridin-3-yl)pyridazin-3(2H)-one. 1 H NMR 400Hz(DMSO): δ10.32(s,1H),9.24(d,1H,J=2Hz),8.77(dd,1H,J=1.2 and 5.2Hz),8.57(d,1H,J=8.4Hz),8.17(d,1H,J=9.6Hz),7.77(dd,1H,J1=5.2Hz,J2=8Hz) ,7.17(d,1H,10Hz),4.52(t,2H,J=6Hz),3.57(q,2H,J=5.6Hz),2.83(d,6H,J=4.8Hz).

[0215] Synthesis of Compound 211: 2-(2-(dimethylamino)ethyl)-6-(pyridin-4-yl)pyridazin-3(2H)-one hydrochloride

[0216] Using the same procedure as above, but using 4-acetylpyridine, 2-(2-(dimethylamino)ethyl)-6-(pyridin-4-yl)pyridazin-3(2H)-one hydrochloride was prepared. [ka] 1 H-NMR 400Hz(DMSO): δ10.74(s,1H),8.94(d,2H,J=6.4Hz),8.37(d,2H,J=6.4Hz),8.28(d,1H,J=9. 6Hz), 7.20(d,1H,J=10Hz),4.57(t,2H,J=6Hz),3.56(q,2H,J=5.2Hz),2.81(d,6H,J=3.6Hz).

[0217] Synthesis of Compound 212: 1-(2-(dimethylamino)ethyl)-5-(pyridin-2-yl)pyrimidin-2(1H)-one [ka]

[0218] Using the same procedure as for compound 100, compound 212 was prepared from commercially available 5-(pyridin-2-yl)pyrimidin-2-ol and N,N-dimethylethanolamine. 1 H-NMR 400Hz(CDCl3):δ9.15(d,1H,J=3.1Hz),8.61(s,1H),8.48(s,1H),7.77-7.73(m,1H),7.56-7 .54(m,1H),7.24-7.21(m,1H),4.07(t,2H,J=5.84Hz),2.72(t,2H,J=5.88Hz),2.27(s,6H).

[0219] Synthesis of Compound 213: 1'-(2-(dimethylamino)ethyl)-[2,3'-bipyridin]-6'(1'H)-one hydrochloride [ka]

[0220] Using the same procedure as for compound 100, compound 213 was prepared from commercially available 5-(pyridin-2-yl)pyridin-2(1H)-one and N,N-dimethylethanolamine. 1 H-NMR 400Hz(DMSO):δ8.72-8.54(m,1H),8.20(d,1H,J=9.6Hz),8.13-7.80(m,2H),7. 60-7.28(m,1H),6.57(d,1H,J=9.6Hz),4.39(s,2H),3.48(s,2H),2.83(s,6H). [M+1] + =244

[0221] Synthesis of Compound 214: 1-(2-(dimethylamino)ethyl)-5-(pyridin-2-yl)pyrazin-2(1H)-one hydrochloride [ka]

[0222] To a solution of commercially available 5-(pyridin-2-yl)pyrazin-2-ol (50 mg, 0.29 mmol) in DMF was added sodium hydride (0.58 mmol) and 2-bromo-N,N-dimethylethanamine (0.4 mmol). ℃ The mixture was heated at rt for 48 h, cooled to room temperature, and partitioned between ethyl acetate and sodium bicarbonate solution. The mixture was further extracted with ethyl acetate, and the combined extracts were washed with brine. The extracts were dried, evaporated, and purified by ISCO silica flash chromatography using a dichloromethane:methanol solvent system. The hydrochloride salt of 2-(2-(dimethylamino)ethyl)-6-(pyridin-3-yl)pyridazin-3(2H)-one was generated using one equivalent of 2M HCl in diethyl ether. 1H NMR 400Hz(MeOD): δ7.05(d,1H,J=4.8Hz),8.47(s,1H),(m,1H),8.17(s,1H)8.12(d,1H,J=8Hz),7.87(td,1H,J=7.8 and 6Hz),7.34-7.30(m,1H),4.34(t,2H,J=6Hz),3.20(t,1H,J=6Hz),2.68(s,6H). [M+1] + =245

[0223] Evaluation of the biological activity of example compounds Compounds were evaluated in PA-EAAT2 cells, primary astrocytes stably expressing human EAAT2 mRNA (Kong et al., J Clin Invest. 2014:1255-67). Cells were treated with 0.0375, 0.075, 0.15, 0.3, 0.6, 1.25, 2.5, 5, and 10 μM of compound for 24 hours and then harvested to measure EAAT2 protein levels by Western blot analysis. The table below shows the fold increase in EAAT2 protein levels compared to DMSO at the indicated concentrations that achieved maximum activity. [Table 13] [Table 14] [Table 15]

[0224] For the EAAT2 induction in vivo studies, 2-3 month old wild-type C57BL / 6 mice were orally treated (voluntary ingestion of the compound in honey) with 10 mg / kg / day of Compound 100 for the indicated number of days. Mice were then euthanized and brains were collected for EAAT2 protein levels by Western blot analysis. Data obtained for Compound 100 are included in Table 1 below. Table 1. Summary of EAAT2 induction activity of compound 100. [Table 16]

[0225] Compound 100 increases EAAT2 protein levels and enhances synaptic plasticity in the brains of wild-type mice Wild-type FVB / NJ mice (3–4 months old) were orally treated with Compound 100 at 1, 2.5, 5, 10, 20, or 40 mg / kg. Twenty-four hours after treatment, mice were euthanized, and forebrains were collected. Gliosomes (astroglial processes) were then isolated to measure EAAT2 protein levels by Western blot analysis. As shown in Figure 2A, compound treatment induced EAAT2 expression in a dose-dependent manner. This induction was visible as early as 4 hours after treatment (Figure 2B). To determine the functional significance of increased EAAT2 on synaptic plasticity, wild-type mice were treated with vehicle or 10 mg / kg Compound 100 for 7 days. Acute hippocampal slices were then collected and evaluated for changes in long-term potentiation (LTP). As shown in Figure 2C, field potential recordings from the CA1 of compound-treated mice (10 slices, 4 animals) showed significantly increased responses to stimulation of CA3 afferents by 30 min after LTP induction compared with vehicle-treated animals (11 slices, 4 animals). These results indicate that compound treatment increases EAAT2 protein levels and subsequently enhances synaptic plasticity in the hippocampus.

[0226] Compound 100 increases EAAT2 protein levels in the dog brain Male beagle dogs were orally treated with 20 mg / kg of Compound 100. At 0.5, 4, and 24 hours after treatment, the mice were euthanized, and brains were collected to measure EAAT2 protein levels by Western blot analysis. Furthermore, we also measured EAAT2 protein levels after seven daily treatments. As shown in Figure 3, EAAT2 levels increased in a time-dependent manner.

[0227] Compound 100 inhibits neurodegeneration, improves cognitive function, enhances synaptic plasticity, reduces tau hyperphosphorylation, and slows disease progression in a tauopathy model of Alzheimer's disease rTg(tauP301L)4510 mice develop progressive age-related Alzheimer's disease (AD)-like pathology. These mice exhibit hippocampal hyperexcitability at approximately 3 months of age. Hippocampal-dependent spatial, short-term, and long-term memory deficits can be detected as early as 1, 2, and 4 months, respectively. Mild to moderate tau pathology is observed within the hippocampus by approximately 4 months and within the cortex by approximately 5-6 months of age. By approximately 5-6 months of age, rTg4510 mice exhibit approximately 60% loss of hippocampal pyramidal neurons.

[0228] To examine the effects of Compound 100 in rTg4510 mice in the early symptomatic stage, litter-matched mice with the same sex distribution were divided into four groups: control (wild-type) / vehicle; control / compound; rTg4510 / vehicle; and rTg4510 / compound (n = 30–35 / group). Mice were administered 10 mg / kg / day of the compound via voluntary ingestion of the compound in honey starting at 2 months of age. At 4 months of age (moderate disease stage), mice were subjected to an open-field test to assess agitation-like behavior, followed by three cognitive tests, including the Y-maze, novel object recognition, and T-maze tests. The examiners were blinded to the treatment. At the end of the behavioral evaluation, a portion of the mice (n = 10–12 / group) were euthanized for pathological studies, while the remaining mice continued to receive treatment. At 8 months of age (severe disease stage), mice were again subjected to the open-field test and cognitive tests. After behavioral testing, mice were euthanized for pathological or electrophysiological studies.

[0229] The results of behavioral and pathological assessments at 4 months of age are shown in Figures 4A–4G. No significant differences were observed between the sexes. Open field results showed that compound treatment completely alleviated agitation-like behavior in rTg4510 mice (Figure 4A). In all three cognitive tests, vehicle-treated rTg4510 mice showed extremely significant impairments. Importantly, compound treatment significantly improved short-term memory (Y-maze; Figure 4B), non-spatial long-term memory (novel object recognition; Figure 4C), and spatial learning and memory (T-maze; Figure 4D). Upon completion of behavioral assessments, mice were euthanized for pathological studies. To assess synaptic integrity, we isolated postsynaptic density complexes prepared from the hippocampus. The levels of the postsynaptic density protein, postsynaptic density 95 (PSD-95), were measured by Western blot analysis. The results showed that vehicle-treated rTg4510 mice exhibited significantly reduced PSD-95 levels in the postsynaptic density complex, suggesting a reduced number of synapses, which was normalized in compound-treated rTg4510 mice (Figure 4E). We examined EAAT2 levels in the hippocampus by performing crude cell membrane preparations to assess membrane-bound EAAT2. Unexpectedly, the results showed increased EAAT2 expression in vehicle-treated rTg4510 mice, which was partially normalized by compound treatment (Figure 4F). Furthermore, immunohistochemical analysis of the hippocampal region revealed that vehicle-treated rTg4510 mice exhibited severe neurodegeneration in the CA1 and DG regions, as assessed by NeuN immunostaining, whereas neuronal loss was almost completely suppressed in compound-treated rTg4510 mice (Figure 4G). Furthermore, expression of the presynaptic marker synaptophysin (a surrogate for synaptic integrity) was completely lost in the CA3 region of vehicle-treated rTg4510 mice but was well preserved in compound-treated rTg4510 mice (Fig. 4G). Neurofibrillary tangles detected in the CA1 region of vehicle-treated rTg4510 mice by MC1 immunostaining were significantly reduced in compound-treated rTg4510 mice (Fig. 4G).We examined astrocyte activation and gliosis by GFAP (glial fibrillary acidic protein) immunostaining and found a significant increase in GFAP immunoreactivity in the CA1 region of vehicle-treated rTg4510 mice, which was significantly reduced in compound-treated rTg4510 mice (Figure 4G). Overall, we found that when treatment began at 2 months of age, rTg4510 mice exhibited nearly normal cognition and behavior at 4 months of age, virtually indistinguishable from control mice. This indicates the exceptional efficacy of Compound 100.

[0230] The results of behavioral and pathological assessments at 8 months of age are shown in Figures 5A-5I. Compound treatment still normalized agitation-like behavior, as assessed by the open field test (Figure 5A). Regarding cognitive assessment, Compound 100 still significantly suppressed short-term memory decline (Y-maze; Figure 5B) and non-spatial long-term memory decline (novel object recognition; Figure 5C). To assess spatial learning and memory, we used the Barnes maze test instead of the T-maze test. Vehicle-treated rTg4510 mice took significantly longer to find the target hole (Figure 5D) and spent significantly less time in the goal quadrant of the maze (Figure 5E). On the other hand, compound-treated rTg4510 mice found the target hole significantly faster (Figure 5D) and spent more time in the goal quadrant (Figure 5E). These behavioral studies demonstrated that compound treatment still provided significant beneficial effects on cognitive function at this late stage of the disease. Follow-up pathological studies showed that vehicle-treated rTg4510 mice exhibited extremely reduced PSD-95 levels in postsynaptic density complexes prepared from the hippocampus (Figure 5F). Compound-treated rTg4510 mice maintained significantly higher PSD-95 expression than vehicle-treated rTg4510 mice. Unlike at 4 months of age, EAAT2 expression in the hippocampus showed no difference between treated and untreated rTg4510 mice. However, by 8 months of age, the prefrontal cortex exhibited synaptic pathology similar to that observed in the hippocampus at 4 months of age. We found a significant increase in EAAT2 expression and a significant loss of PSD-95 protein in the prefrontal cortex of vehicle-treated rTg4510 mice (Figures 5G and 5H). Compound treatment partially normalized the expression of both PSD-95 and EAAT2. Furthermore, immunohistochemical analysis of the hippocampal region revealed that at this stage of disease progression, both vehicle- and compound-treated rTg4510 mice exhibited significant neurodegeneration in the CA1 and DG, as assessed by NeuN immunostaining.However, compound-treated rTg4510 mice showed significantly reduced levels of neurodegeneration in both regions (Figure 5I). Furthermore, synaptophysin expression was partially preserved in compound-treated rTg4510 mice (Figure 5I). While both rTg4510 groups exhibited increased GFAP immunoreactivity, compound treatment significantly reduced GFAP immunoreactivity in CA1 (Figure 5I). Vehicle-treated rTg4510 mice had a significant increase in Iba1 immunoreactivity. The increase in Iba1 immunoreactivity was significantly lower in compound-treated mice (Figure 5I). Overall, compound 100 continues to confer disease-modifying and disease-delaying benefits for all phenotypes tested after long-term treatment.

[0231] To determine how long the benefits of treatment could be sustained, a cohort of compound-treated rTg4510 mice was switched to vehicle treatment (stop treatment) at 8 months of age. One month after treatment cessation, behavioral tests and subsequent pathological studies were performed to compare the stop-treated rTg4510 group with the continued-treated rTg4510 group, the vehicle rTg4510 group, and the control vehicle group. Surprisingly, locomotor activity levels in the open field remained normalized in the stop-treated group (Figure 6A). Novel object recognition results indicated that long-term memory was preserved in the stop-treated rTg4510 mice (Figure 6B). For both behavioral tasks, the stop-treated and continued-treated groups performed essentially identically. Follow-up pathological studies showed that all rTg4510 groups exhibited a significant decrease in PSD-95 levels in the hippocampal postsynaptic density, but the stop-treatment group showed a significant increase of approximately twofold in PSD-95 levels compared to the vehicle group (Figure 6C). The expression levels of PSD-95 in the stop-treatment group were indistinguishable from those in the continuation-treatment group. These results suggested that Compound 100 directly modifies disease pathology and does not act as a palliative.

[0232] Furthermore, we conducted electrophysiological studies to examine the integrity of hippocampal synaptic circuits. We analyzed changes in LTP in the hippocampal CA3-CA1 circuit along the Schaffer collateral pathway. By examining the input / output curves alone, it was clear that all three rTg4510 groups had reduced synaptic strength (Figure 6D). However, the vehicle rTg4510 group had the most significant reduction in synaptic strength, while the continued and stopped treatment groups showed intermediate reductions. The vehicle rTg4510 group showed minimal LTP (Figure 6E). Both the stopped and continued treatment rTg4510 groups were found to have significantly enhanced LTP compared with the vehicle rTg4510 group, which was statistically indistinguishable from the control vehicle group. This is surprising because both the continued and stopped treatment groups exhibited neurodegeneration and reduced synaptic integrity compared to controls, yet both were able to form relatively normal LTP. Notably, compound-treated controls were found to have highly elevated levels of LTP after stimulation compared with vehicle-treated controls, suggesting that these mice exhibit enhanced synaptic plasticity. These results indicate that the benefits of Compound 100 are maintained one month after cessation of treatment.

[0233] As shown in Figure 4G, we observed reduced neurofibrillary tangles in rTg4510 mice treated with the compound for long periods. Therefore, we investigated whether this compound could reduce toxic forms of tau. We examined tau expression levels in total cell lysates (TCL) and sarkosyl-insoluble fractions (P3) prepared from the forebrains of rTg4510 mice collected at 4 months of age (2 months after treatment) by Western blot analysis. Four antibodies recognizing different phosphorylation sites or pathological forms of tau were used: PHF1 recognizes Ser396 and Ser404, AT8 recognizes Ser202 and Thr205, MC-1 recognizes neurofibrillary tangles, and Tau5 recognizes all forms of tau (phosphorylated and unphosphorylated isoforms). The results showed a robust reduction in the expression of all phosphorylated tau forms tested in compound-treated rTg4510 samples (both TCL and P3 fractions) (Figure 7A). For each antibody tested, there was a very significant reduction in the 64 kDa (hyperphosphorylated) variant, which has been reported to strongly correlate with neurodegeneration. Importantly, there was no reduction in total tau, so transgene expression of tau was not negatively affected. Rather, a slight increase in the level of total tau expression was observed, which the inventors attributed to an increase in the number of surviving neurons.

[0234] Next, we asked whether this reduction in tau phosphorylation and deposition was a direct effect of Compound 100 or due to compensatory changes following long-term compound treatment. To accomplish this, naive rTg4510 mice were given a single dose of vehicle or Compound 100, and 24 hours later, forebrains were collected and processed for sarkosyl isolation. We found that even after a single dose, there was a significant reduction in pTau (AT8 and PHF1), but no change in total tau (Tau-5) or tau aggregates (MC1) in TCLs (Figure 7B). More notably, there was a very clear reduction in all forms of tau in the P3 fraction (Figure 7B). This indicated a direct effect of the compound mediating reduced pTau and suggested that the compound may activate / inhibit kinases / phosphatases to mediate this effect. To identify which kinases / phosphatases were involved, forebrain TCL samples were collected from rTg4510 mice 1 hour after a single dose. The phosphorylation (activation) status of kinases that have been reported to target tau as a substrate was assessed. Of all kinases tested, only GSK3β showed a significant change—a two-fold upregulation of phosphorylation at Ser9 (Figure 7C). This phosphorylated form inhibits GSK3β activity. Therefore, inactivation of GSK3β kinase may mediate the reduced tau phosphorylation in rTg4510 mice after compound treatment. These results indicate that Compound 100 reduces tau hyperphosphorylation / deposition by modifying kinase activity.

[0235] In summary, these data demonstrate that Compound 100 exhibits significant beneficial effects in rTg4510 mice, a model for age-related Alzheimer's disease (AD)-like pathology.

[0236] Compound 100 prevents and reduces anxiety, depression, and cognitive problems in a mouse model of Gulf War illness Gulf War Illness (GWI) afflicts approximately 30% of the 700,000 military personnel who served in the Gulf War. Central nervous system dysfunction is the most prevalent of GWI's various symptoms, primarily consisting of anxiety, depression, and cognitive difficulties. These clinical symptoms are widely believed to be related to a combination of exposures encountered by those serving in the military. These include significant exposure to pyridostigmine (an anti-nerve gas drug), permethrin (an insecticide), and N,N-diethyl-m-toluamide (DEET; an insect repellent), as well as war-related stress. Literature indicates that chronic exposure to these GWI-related chemicals and stress leads to increased extracellular glutamate levels and increased dyshomeostasis of the brain's glutaminergic system, which may be associated with memory and mood disorders.

[0237] We investigated whether increased glutamate transporter EAAT2 expression by Compound 100 could normalize glutamatergic dyshomeostasis and subsequently improve cognitive and mood disorders. Three-month-old C57BL / 6J mice were randomly divided into three groups: control (no GWI, vehicle), GWI with vehicle, and GWI with compound. For the GWI group, mice were exposed to GWI chemicals and unpredictable long-term stress daily for 6 weeks. The GWI chemicals included pyridostigmine (1.3 mg / kg), permethrin (0.13 mg / kg), and DEET (40 mg / kg). The stress regimen involved daily exposure to two different stressors. The stressors used in this study included restraint, cage rotation, heat stress, cold stress, predator sounds, dark periods during the light phase, wet bedding, bedding replacement with water, cage tilt at a 45° angle, and strobe lighting. Mice were given either Compound 100 (20 mg / kg) or vehicle daily, starting at the beginning of the 6-week exposure. Three months after exposure, mice were subjected to several behavioral tests to assess mood and cognitive function. These tests included light-dark exploration, elevated plus maze, novel environment-induced food inhibition, tail-suspension open field, novel object recognition, and Barnes maze tests.

[0238] The results showed that GWI-conditioned mice developed anxiety-like and depression-like behaviors (Figures 8A-8E; GWI / vehicle group), and these GWI-conditioned mice also showed decreased cognitive function (Figures 8F-8H; GWI / vehicle group). Importantly, anxiety-like and depression-like behaviors were significantly reduced in GWI compound-treated mice (Figures 8A-8E). Compound-treated mice also demonstrated improved cognitive function (Figures 8F-8H). These results indicate that Compound 100 can suppress the development of cognitive and mood disorders in GWI mice.

[0239] Next, we conducted a treatment study: GWI mice were treated with Compound 100 (20 mg / kg) 5 months after exposure, when the lesions occurred. After one month of treatment, the mood and cognitive function of the mice improved. The results showed that compound treatment reduced anxiety-like and depression-like behaviors (Figures 9A-9E). Cognitive function also improved significantly (Figures 9F-9H). These results indicate that Compound 100 can reduce mood and cognitive impairment when symptoms are present.

[0240] Compound 101 increases EAAT2 protein levels and enhances synaptic plasticity in the brains of wild-type mice Wild-type C57BL / 6 mice (2–3 months old) were orally treated with Compound 101 at 0.01, 0.033, 0.1, 0.33, 1, 3.33, 10, 20, 40, 60, and 100 mg / kg / day for 7 or 28 days (voluntary ingestion of the compound in honey). The mice were then euthanized, and brains were collected for EAAT2 protein levels by Western blot analysis. Results showed that EAAT2 protein levels were increased in a dose-dependent manner (Figures 10A and 10B). To determine the functional significance of increased EAAT2 on synaptic plasticity, wild-type mice were treated with vehicle or Compound 101 at 0.033, 0.33, and 3.3 mg / kg for 7 days. The mice were then euthanized, and acute hippocampal slices were collected and evaluated for changes in long-term potentiation (LTP). As shown in Figure 10C, field potential recordings from the CA1 of compound-treated mice showed significantly increased responses to stimulation of CA3 afferents by 30 minutes after LTP induction compared with vehicle-treated animals (8 to 12 slices / 4 animals for each group). These results indicate that compound treatment increases EAAT2 protein levels and subsequently enhances synaptic plasticity in the hippocampus.

[0241] The compounds, compositions, and methods of the appended claims are not limited in scope by the specific compounds, compositions, and methods described herein, which are intended to be illustrative of several aspects of the claims. Any functionally equivalent compounds, compositions, and methods are intended to be within the scope of the claims. In addition to the compounds, compositions, and methods shown and described herein, various modifications of these compounds, compositions, and methods are intended to be within the scope of the appended claims. Furthermore, although only certain representative compounds, components, compositions, and method steps disclosed herein are specifically recited, other combinations of compounds, components, compositions, and method steps are also intended to be within the scope of the appended claims, even if not specifically set forth. Thus, although a combination of steps, elements, components, or ingredients may be explicitly referred to herein or hereinafter, other combinations of steps, elements, components, or ingredients are included, even if not explicitly set forth.

[0242] As used herein, the term "comprising" and variations thereof are used synonymously with the term "including" and variations thereof and are open, non-limiting terms. Although the terms "comprising" and "including" have been used herein to describe various embodiments, the terms "consisting essentially of" and "consisting of" can be used in place of "comprising" and "including" to provide more specific embodiments of the present invention, which are also disclosed. Unless otherwise specified, all numbers representing shapes, dimensions, and the like used in the specification and claims should be understood, at the very least, as not an attempt to limit the application of the doctrine of equivalents to the scope of the claims, and should be interpreted in light of the number of significant digits and ordinary rounding approaches.

[0243] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Publications cited herein and the material for which they are cited are specifically incorporated by reference.

Claims

1. The following 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 or a pharmaceutically acceptable salt thereof.

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

3. 10. A pharmaceutical composition for treating or preventing glutamate excitotoxicity, comprising an effective amount of a compound of claim 1.

4. ischemic stroke, epilepsy or trauma including blunt trauma, abrasion, avulsion, cut, rupture, puncture, penetration, surgical trauma, iatrogenic trauma, spinal cord injury, traumatic brain injury or any combination thereof; chronic neurodegenerative disorders 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); psychiatric disorders including schizophrenia, bipolar disorder or autism; migraine, temporomandibular joint disorder, neuropathic pain 10. A pharmaceutical composition comprising an effective amount of a compound of claim 1 for treating a disease or disorder selected from the group consisting of pain disorders including steroid use, steroid addiction, steroid use disorders ...

5. A pharmaceutical composition for increasing EEAT2 protein expression, comprising an effective amount of a compound according to claim 1.

6. A pharmaceutical composition for activating the NRF2 pathway, comprising an effective amount of a compound of claim 1.

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