BACKGROUND OF THE INVENTION

Glutamate is the predominant excitatory amino acid neurotransmitter in the mammalian central nervous system (CNS) and is essential for normal brain function, including cognition, memory, learning, developmental plasticity and long-term potentiation. The termination of glutamate neurotransmission is achieved by rapid uptake of the released glutamate by presynaptic and astrocytic sodium-dependent transporters. There are five subtypes of excitatory amino-acid transporters or glutamate transporters: EAAT1 or GLAST, EAAT2 or GLT-1, EAAT3 or EAAC1, EAAT4, and EAAT5. The major regulator of extracellular glutamate levels in the brain is EAAT2, which is expressed in astroglial cells and responsible for about 90% total glutamate uptake in the CNS and about 1% of total brain protein in the CNS.

Glutamate translocation is a multi-step process that uses energy derived from Na+and K+electrochemical gradients to move glutamate against its concentration gradient. The rate-limiting step in the cycle involves translocation of K+and reorientation of the carrier to become accessible for a new substrate molecule in the synaptic cleft. Despite the identification of several crystal structures of a bacterial homolog of glutamate transporters Glt(ph), no rationally designed transporter activator has been identified so far.

Ischemic events in humans and in animals lead to an acute and sustained increase in extracellular glutamate concentrations, indicative of a lack of timely clearance by glutamate transporters. In fact, dysfunctional glutamate transporters are often the initiating event or part of the cascade leading to brain injury. Reductions in EAAT2 activity result in increased predisposition for seizures and susceptibility to damage due to ischemia. Excessive activation of glutamate receptors due to sustained elevation of extracellular glutamate levels results in Ca2+influx and activation of a cascade of phospholipases, endonucleases and proteases such as calpain that can lead to apoptotic or necrotic cell death. Glutamate excitotoxicity has been implicated in acute pathologies, such as traumatic brain injury, hyperexcitability, seizures and epilepsy, stroke, cerebral and retinal ischemia, and chronic pathologies, such as amyotrophic lateral sclerosis (ALS), Alzheimer's Disease, Huntington's Disease, neuropathic pain, and HIV-associated neurocognitive disorder. Also, ischemic events in humans and animals lead to an acute and sustained increase in extracellular glutamate concentrations, which suggests a lack of proper clearance by glutamate transporters. In fact, dysfunctional glutamate transporters are often the initiating event or part of the cascade leading to brain injury.

Reductions in EAAT2 activity result in increased predisposition for seizures and susceptibility to damage due to ischemia. Knockout of the EAAT2 gene resulted in exacerbated damage compared to their wild-type counterparts following cerebral injury in mice and controlled cortical impact in rats. Additionally, a transgenic approach for EAAT2 overexpression with double transgenic mice created from crossing an ALS mouse model to a mouse model overexpressing EAAT2 resulted in animals that display delayed grip strength decline, motor neuron loss, and increased life expectancy.

Several classes of compounds that target stages in these processes, such as NMDA receptor antagonists and calcium influx inhibitors, alleviate cellular damage and neurologic deficits to some extent, but have limited clinical use due to substantial side effects. Transcriptional or translational upregulators of EAAT2, such as GPI-1046, ceftriaxone, harmine and pyridazine derivatives, are neuroprotective through selective augmentation of EAAT2 expression. Nevertheless, these compounds must be administered prophylactically to be neuroprotective, and thus they have low clinical relevance for acute conditions. Some compounds with neuroprotective properties, such as MS-153, riluzole, guanosine and nicergoline, acutely stimulate glutamate uptake by an indirect modulation of transporter activity, but are non-specific and cause numerous side effects.

Currently there is a critical lack of compounds that activate, stimulate and/or upregulate the activity of glutamate transporters, such as but not limited to EAAT2. Such compounds should be used to treat diseases or disorders that are caused, induced or characterized by abnormal reduction in glutamate transporter activity or abnormal increase in extracellular CNS glutamate concentration in a subject. The present invention fulfills this need.

BRIEF SUMMARY OF THE INVENTION

The invention provides a compound of formula (I), or an enantiomer, diastereoisomer, salt or solvate thereof:


wherein in (I),

eachbond in ring A is independently a double or a single covalent bond, wherein: (i) when abond is a double covalent bond, each R group substituted at the bond is independently selected from the group consisting of N, CH and C(C1-C6alkyl), wherein the alkyl group is optionally substituted; and (ii) when abond is a single covalent bond, each R group substituted at the bond is independently selected from the group consisting of NH, N(C1-C6alkyl), S, O, CH2, CH(C1-C6alkyl) and C(C1-C6alkyl)2, wherein the alkyl group is optionally substituted;

R1is selected from the group consisting of —C1-C6alkyl, —C1-C6heteroalkyl, —(C0-C3alkyl)-(C3-C6cycloalkyl), —(C0-C3alkyl)-(C4-C10heterocyclyl), —(C0-C3alkyl)-(C6-C10aryl) and —(C0-C3alkyl)-(C5-C10heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are independently optionally substituted;

each occurrence of R2is independently selected from the group consisting of H, —C1-C6alkyl, —OH, —C1-C6alkoxy, halogen, —NH2, —N(CH3)2, —C(═O)OH, trifluoromethyl, —C≡N, —C(═O)O(C1-C4)alkyl, —C(═O)NH2, —SO2NH2, —C(═NH)NH2, and —NO2;

n is an integer ranging from 0 to 4;

R3is selected from the group consisting of —(C═O)0-1(C1-C6alkyl), —(C═O)0-1(C1-C6heteroalkyl), —(C═O)0-1(C0-C3alkyl)-(C3-C6cycloalkyl), —(C═O)0-1(C0-C3alkyl)-(C4-C10heterocyclyl), —(C═O)0-1(C0-C3alkyl)-(C6-C10aryl), —(C═O)0-1(C0-C3alkyl)-(C5-C10heteroaryl), —(SO2)0-1(C1-C6alkyl), —(SO2)0-1(C1-C6heteroalkyl), —(SO2)0-1(C0-C3alkyl)-(C3- C6cycloalkyl), —(SO2)0-1(C0-C3alkyl)-(C4-C10heterocyclyl), —(SO2)0-1(C0-C3alkyl)-(C6-C10aryl) and —(SO2)0-1(C0-C3alkyl)-(C5-C10heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are independently optionally substituted; and,

R4is N or CH.

The invention provides a compound of formula (II), or an enantiomer, diastereoisomer, salt or solvate thereof:


wherein in (II):

R1is selected from the group consisting of —C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, —C1-C6heteroalkyl, —C1-C6heteroalkenyl and —C1-C6heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl are independently optionally substituted;

each occurrence of R2is independently selected from the group consisting of H, —C1-C6alkyl, —OH, —C1-C6alkoxy, halogen, —NH2, —N(CH3)2, —C(═O)OH, trifluoromethyl, —C≡N, —C(═O)O(C1-C4)alkyl, —C(═O)NH2, —SO2NH2, —C(═NH)NH2, and —NO2;

n is an integer ranging from 0 to 4;

R3is selected from the group consisting of —(C1-C6alkyl)-Ox—(C3-C6cycloalkyl), —(C1-C6alkyl)-Ox—(C4-C10heterocyclyl), —(C1-C6alkyl)-Ox—(C6-C10aryl) and —(C1-C6alkyl)-Ox—(C5-C10heteroaryl), wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are independently optionally substituted; and

x is 0 or 1.

The invention provides a compound of formula (III), or an enantiomer, diastereoisomer, salt or solvate thereof:


wherein in (III):

R1is selected from the group consisting of —(C0-C3alkyl-(C6-C10aryl) and —(C0-C3alkyl)-(C5-C10heteroaryl), wherein the alkyl, aryl and heteroaryl groups are independently optionally substituted;

R2is NH, NR6, S or O;

R3is N or CH;

R4is —C(═O)— or —S(═O)2—;

R5is —C(═O)— or —S(═O)2—; and,

R6is selected from the group consisting of —C1-C6alkyl, —C1-C6heteroalkyl, —(C0-C3alkyl)-(C3-C6cycloalkyl), —(C0-C3alkyl)-(C4-C10heterocyclyl), —(C0-C3alkyl)-(C6-C10aryl) and —(C0-C3alkyl)-(C5-C10heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are independently optionally substituted.

In certain embodiments, the compound of formula (I) is selected from the group consisting of:



In certain embodiments, in the compound of Formula (I), R1is selected from the group consisting of —(C1-C3alkyl)-(C3-C6cycloalkyl), —(C1-C3alkyl)-(C4-C10heterocyclyl), —(C1-C3alkyl)-(C6-C10aryl) and —(C1-C3alkyl)-(C5-C10heteroaryl), wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are independently optionally substituted.

In certain embodiments, in the compound of Formula (I), R1is selected from the group consisting of —(C1-C3alkyl)-(C6-C10aryl) and —(C1-C3alkyl)-(C5-C10heteroaryl), wherein the alkyl, aryl and heteroaryl groups are independently optionally substituted.

In certain embodiments, in the compound of Formula (I), each occurrence of R2is independently selected from the group consisting of H, —C1-C6alkyl, —OH, —C1-C6alkoxy, halogen, —NH2, —N(CH3)2, —C(═O)OH, trifluoromethyl, —C≡N and —NO2.

In certain embodiments, in the compound of Formula (I), R3is selected from the group consisting of —(C1-C6alkyl), —(C1-C6heteroalkyl), —(C0-C3alkyl)-(C3-C6cycloalkyl), —(C0-C3alkyl)-(C4-C10heterocyclyl), —(C0-C3alkyl)-(C6-C10aryl), —(C0-C3alkyl)-(C5-C10heteroaryl), —(C═O)(C0-C3alkyl)-(C6-C10aryl), and —(C═O)(C0-C3alkyl)-(C5-C10heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are independently optionally substituted.

In certain embodiments, in the compound of Formula (I), n is 2 or 3.

In certain embodiments, the compound of Formula (I) is:


In certain embodiments, the compound of Formula (I) is:


wherein R2a, R2c, and R2dare independently selected from the group consisting of H and C1-C6alkyl, and R2bis OH or C1-C6alkoxy. In certain embodiments, R2a, R2c, and R2dare each H. In certain embodiments, the compound of Formula (I) is:


In certain embodiments, the compound of Formula (I) is:


In certain embodiments, in the compound of formula (I) R3is optionally substituted cyclohexyl or phenyl.

In certain embodiments, the compound of Formula (I) is selected from the group consisting of: 3-((4-cyclohexylpiperazin-1-yl)(1-phenethyl-1H-tetrazol-5-yl)methyl)-6-methoxy-quinolin-2(1H)-one (GT949); 6-methoxy-3-((1-phenethyl-1H-tetrazol-5-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)quinolin-2(1H)-one (GT951); 3-((4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)(1-phenethyl-1H-tetrazol-5-yl)methyl)-6,7-dimethylquinolin-2(1H)-one (GT835); 3-((4-(furan-2-carbonyl)piperazin-1-yl)(1-phenethyl-1H-tetrazol-5-yl)methyl)-6,8-dimethylquinolin-2(1H)-one (GT729); 3-((4-(furan-2-carbonyl)piperazin-1-yl)(1-phenethyl-1H-tetrazol-5-yl)methyl)-5,7-dimethylquinolin-2(1H)-one (GT996); 3-((4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)(1-phenethyl-1H-tetrazol-5-yl)methyl)-5,8-dimethylquinolin-2(1H)-one (GT867); an enantiomer, diastereoisomer, salt or solvate thereof, and any mixtures thereof.

In certain embodiments, in the compound of Formula (II), n is 0. In certain embodiments, in the compound of Formula (II), x is 1. In certain embodiments, in the compound of Formula (II), R1is selected from the group consisting of —C2-C6alkenyl and —C2-C6alkynyl, wherein the alkenyl and alkynyl are independently optionally substituted. In certain embodiments, in the compound of Formula (II), R3is selected from the group consisting of —(C1-C6alkyl)-Ox—(C6-C10aryl) and —(C1-C6alkyl)-Ox—(C5-C10heteroaryl), wherein the alkyl, aryl and heteroaryl groups are independently optionally substituted.

In certain embodiments, the compound of Formula (II) is selected from the group consisting of: 1-allyl-4-(1-(4-(4-chloro-3-methylphenoxy)butyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (GT939); 1-allyl-4-(1-(4-(3,4-dimethylphenoxy)butyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (GT938); 1-allyl-4-(1-(3-(4-(sec-butyl)phenoxy)propyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one (GT922); an enantiomer, diastereoisomer, salt or solvate thereof, and any mixtures thereof.

In certain embodiments, in the compound of Formula (III), R1is —C6-C10aryl or —C5-C10heteroaryl, wherein the aryl and heteroaryl groups are independently optionally substituted. In certain embodiments, in the compound of Formula (III), R2is S. In certain embodiments, in the compound of Formula (III), R3is N. In certain embodiments, in the compound of Formula (III), R4is —C(═O)—. In certain embodiments, in the compound of Formula (III), R5is —S(═O)2—. In certain embodiments, in the compound of Formula (III), R6is —C1-C6heteroalkyl or —C4-C10heterocyclyl, wherein the heteroalkyl and heterocyclyl groups are independently optionally substituted.

In certain embodiments, the compound of Formula (III) is (4-(2-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)(4-(pyrrolidin-1-ylsulfonyl) phenyl) methanone (GT988), or an enantiomer, diastereoisomer, salt or solvate thereof.

In certain embodiments, the substituted alkyl, cycloalkyl (such as for example cyclohexyl), alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, or heterocyclyl is independently substituted with at least selected from the group consisting of C1-C6alkyl, —OH, C1-C6alkoxy, halogen, NH2, NH(CH3), N(CH3)2, —C(═O)OH, trifluoromethyl, —C≡N, —C(═O)O(C1-C4)alkyl, —C(═O)NH2, —NHC(═O)(aryl or alkyl), —SO2NH2, —C(═NH)NH2, —NO2, or any combinations thereof.

In certain embodiments, the substituted phenyl or heteroaryl is independently substituted with at least selected from the group consisting of C1-C6alkyl, —OH, C1-C6alkoxy, halogen, NH2, NH(CH3), N(CH3)2, —C(═O)OH, trifluoromethyl, —C≡N, —C(═O)O(C1-C4)alkyl, —C(═O)NH2, —NHC(═O)(aryl or alkyl), —SO2NH2, —C(═NH)NH2, —NO2, or any combinations thereof.

The invention further provides a pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier.

The invention further provides a method of treating, ameliorating or preventing a disease or disorder that is caused, induced or characterized by abnormal reduction in glutamate transporter activity or abnormal increase in extracellular CNS glutamate concentration in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of at least one compound of the invention, or an enantiomer, diastereoisomer, salt or solvate thereof.

In certain embodiments, the disease or disorder is at least one selected from the group consisting of ischemia, seizure, traumatic brain injury, stroke, epilepsy, schizophrenia, and neurodegenerative diseases or disorders. In certain embodiments, the at least one compound of the invention activates, stimulates and/or upregulates the activity of a glutamate transporter in the subject. In certain embodiments, the transporter comprises EAAT2. In certain embodiments, administration of the at least one compound of the invention regulates extracellular glutamate concentrations in the subject. In certain embodiments, administration of the at least one compound of the invention increases, induces or upregulates removal of glutamate from the neuronal synaptic cleft into neuroglia and neurons of the subject. In certain embodiments, administration of the at least one compound of the invention inhibits glutamate transport in the subject.

In certain embodiments, the at least one compound of the invention is selected from the group consisting of: 1-allyl-4-(1-(4-(4-chloro-3-methylphenoxy)butyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one; 3-((4-cyclohexylpiperazin-1-yl)(1-phenethyl-1H-tetrazol-5-yl)methyl)-6-methoxy-quinolin-2(1H)-one; 6-methoxy-3-((1-phenethyl-1H-tetrazol-5-yl)(4-(3-(trifluoromethyl) phenyl)piperazin-1-yl)methyl)quinolin-2(1H)-one; an enantiomer, diastereoisomer, salt or solvate thereof, and any mixtures thereof.

In certain embodiments, the at least one compound of the invention is selected from the group consisting of: (+)-3-((4-cyclohexylpiperazin-1-yl)(1-phenethyl-1H-tetrazol-5-yl)methyl)-6-methoxy-quinolin-2(1H)-one, (−)-3-((4-cyclohexylpiperazin-1-yl)(1-phenethyl-1H-tetrazol-5-yl)methyl)-6-methoxy-quinolin-2(1H)-one, (+)-6-methoxy-3-((1-phenethyl-1H-tetrazol-5-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)quinolin-2(1H)-one, (−)-6-methoxy-3-((1-phenethyl-1H-tetrazol-5-yl)(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)quinolin-2(1H)-one, and any mixtures thereof.

In certain embodiments, the at least one compound of the invention is administered to the subject as part of a pharmaceutical composition.

In certain embodiments, the subject is further administered at least one additional therapeutic agent. In certain embodiments, the at least one compound of the invention and the at least one additional therapeutic agent are co-administered to the subject. In certain embodiments, the at least one compound of the invention and the at least one additional therapeutic agent are co-formulated. In certain embodiments, the at least one compound of the invention is administered to the subject a given period of time before or after the at least one additional therapeutic agent is administered to the subject.

In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is human

