Treatment of neurodegenerative diseases and disorders

Abstract

Methods and composition are provided for treatment of various disorders associated with decreased neurogenesis, including age-related neurodegeneration, such as Alzheimer' s disease.

Description

[0001] TREATMENT OF NEURODEGENERATIVE DISEASES AND DISORDERS The present application claims the benefit of U.S. provisional application no.63 / 655,590, filed June 3, 2024, which is incorporated by reference herein in its entirety. 1. Field The disclosure relates to methods and composition for providing treatment of various disorders associated with decreased neurogenesis, including age-related neurodegeneration, such as Alzheimer’s disease. 2. Background While there is still controversy regarding the existence of neurogenesis in adult human brain, (Duque et al., 2022, Terreros-Roncal et al., 2022), increasing evidence indicates that neurogenesis is impaired in a number of neurological and neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and major depression (Isaev et al., 2019, Berger et al., 2020, Babcock et al., 2021, Culig et al., 2022). Consequently, it has been suggested that stimulating neurogenesis could provide beneficial effects to reverse or slow down the progression of these diseases (Salta et al., 2023, Vassal et al., 2024). Adult neurogenesis occurs in two main regions of the adult brain, the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. Numerous mechanisms regulate neurogenesis, which consists in the differentiation of precursor neuronal stem cells into adult neurons (Ribeiro and Xapelli, 2021). Targeting these processes has been used to develop potential new therapeutic approaches for the treatment of age-related neurodegenerative diseases and major depressive disorders (Gillotin et al., 2021). SUMMARY The invention relates to a novel therapeutic approach using selective calpain-2 inhibitors to stimulate neurogenesis in the adult brain. We have generated a number of selective calpain-2 inhibitors. We have now found that calpain-2 inhibitors can increase neurogenesis and dendritic spine maturation in vivo, e.g. by preventing or inhibiting MEIS2 cleavage, thereby increasing the production of new neurons in the SVZ and the DG. In one embodiment, the compositions are administered to enhance neurological function in an individual with a neurological disease, neurological injury or age-related neuronal decline or impairment. The compositions are administered over a period of time effective to stimulate new neuron formation, to prevent neuronal loss, or combination thereof. Target neurological dysfunctions and disease states include Alzheimer's disease and Parkinson's disease; neurological injuries, such as those following radiation therapy for brain-related cancers; and age-related memory decline and age-related learning impairments. In one embodiment, the compositions are administered to enhance neurogenesis in the brain, which is associated with Alzheimer's disease. The methods for enhancing neurological function in an individual can be practiced in-vivo and / or ex-vivo. In aspects, methods are provided for treatment and / or prophylaxis of a neurodegenerative disease such as Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome and Korsakoff's disease. In such methods, the subject may be administered one or more of the present compounds to thereby treat the subject for the neurodegenerative disease or symptoms thereof. The compositions can also be administered to improve or restore neurological function by inducing or stimulating the generation of new neurons, protecting against neuronal loss, stimulating or inducing neurite outgrowth and organization or protecting against loss of neurites and neural networks, or combination thereof. In a particular aspect, compounds of the following Formula (I) are provided: wherein A is carbocyclic aryl or heteroaryl; R1is a non-hydrogen substituent such as C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, -CO(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), -CONH(CH2)mN(Ra)(Rb), -CONH-CH(Rc)(Rd),- (CH2)mN(Ra)(Rb), or -O(CH2)mOH; Ra, Rb, Rc, and Rdare independently hydrogen or unsubstituted C1-C6alkyl, which may be linear or branched alkyl; n is independently an integer from 0 (where the ring A is unsubstituted) to the value permitted by the valence of the ring such as 5 where A is phenyl; m is independently an integer from 0 to 6; L1and L2are each the same or different optionally substituted alkylene having one to 6 carbons (e.g. –(CH2)p where p is 1 to 6 and each carbon may have zero, one or two non-hydrogen substituents), R2is non-hydrogen substituent such as optionally substituted C1-C6alkyl, R4and R5are independently hydrogen, or unsubstituted C1-C6alkyl such as methyl; and pharmaceutically acceptable salts thereof. In certain preferred aspect, Raand Rbare independently hydrogen or unsubstituted C1-C6alkyl. In a particular aspect, Raand Rbare independently hydrogen, methyl, ethyl, or propyl (e.g., isopropyl). In a particular aspect, Raand Rbare independently hydrogen or methyl. In a particular aspect, Raand Rbare hydrogen. In a particular aspect, Raand Rbare methyl. In a particular aspect, Rais hydrogen and Rbis methyl. In a particular aspect, Raand Rbare independently hydrogen or isopropyl. In a particular aspect, Rais hydrogen and Rbis isopropyl. In certain preferred aspect, Rcand Rdare independently hydrogen or unsubstituted C1-C6alkyl. In a particular aspect, Rcand Rdare independently hydrogen, methyl, ethyl, or propyl (e.g., isopropyl). In a particular aspect, Rcand Rdare independently hydrogen or methyl. In a particular aspect, Rcand Rdare hydrogen. In a particular aspect, Rcand Rdare methyl. In a particular aspect, Rcis hydrogen and Rdis methyl. In certain preferred aspects, R4and R5are independently hydrogen, methyl or ethyl. In a particular aspect, R4and R5are methyl. In preferred aspects, one or both of L1and L2are unsubstituted alkylene such as methylene (-CH2-) and ethylene (-CH2-CH2-). In additional preferred aspects, the group A is carbocyclic aryl such as phenyl or a heteroaryl with one of more nitrogen ring members such as optionally substituted pyridinyl or optionally substituted pyrazinyl. In certain aspects, n may be 0, 1, 2, or 3, such as 0 or 1, or 1. In certain preferred aspects, provided is the compound having the structure of formula (II): The compound may be a racemate including: . . The compound has preferably the formula (IIA): In a particular aspect, R1is -CO(CH2)mN(Ra)(Rb) wherein m is 0 or 1, preferably m is 0, and Raand Rbare hydrogen or methyl. For example, R1is -CONH2, or –CONHCH3. In a particular aspect, R1is -O(CH2)mN(Ra)(Rb), wherein m is 1, 2, or 3, preferably m is 2, and Raand Rbare hydrogen or methyl. For example, R1is -OCH2CH2N(CH3)2 or - OCH2CH2NHCH3. In a particular aspect, R1is -CONH(CH2)mN(Ra)(Rb), wherein m is 1, 2, or 3, preferably m is 2, and Raand Rbare hydrogen, methyl or isopropyl. For example, R1is - CONHCH2CH2NHCH(CH3)2, -CONHCH2CH2N(CH3)2, or -CONHCH2CH2NH(CH3). In a particular aspect, R1is -CONH-CH(Rc)(Rd) wherein Rcand Rdare independently hydrogen or methyl. For example, R1is -CONHCH(CH3)2, or –CONHCH2CH3. In a particular aspect, R1is -(CH2)mN(Ra)(Rb), wherein m is 1, 2, or 3, preferably m is 1, and Raand Rbare hydrogen or methyl. For example, R1is -CH2NH2,-CH2NH(CH3), or.- CH2N(CH3)2. In a particular aspect, R1is -O(CH2)mOH, wherein m is 1, 2, or 3, preferably m is 2. For example, R1is -OCH2CH2OH. In certain preferred aspects, provided is the compound having the structure of formula (III): , wherein R1Ais cyano, or unsubstituted C1-C6alkyl, and R is C1-C6alkoxy. . The compound may be a racemate including: . The compound has preferably the formula (IIIA): . In a particular aspect, R1Ais cyano (-CN) or unsubstituted alkyl such as methyl and R1Bis C1-C6alkoxy, preferably –OCH3. . In particularly preferred aspects, provided is the compound having the following structure: The compound may be a racemate including: . The compound has preferably the structure of In a particular aspect, compounds of the following Formula (X) are provided: wherein: A is C1-C6alkyl, carboxyl (-C(O)O-), aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; B is carbocyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; L1is a bond, or substituted or unsubstituted C1-C6alkylene, L2is a bond, substituted or unsubstituted C1-C6alkylene, or -S(O)2-, Each R1is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl, -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd), -C(O)OCH(Rc)(Rd), -(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, -S(O)2Rb, or -O(Ph)X; R2is unsubstituted C1-C6alkyl; Each R6is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd), -C(O)OCH(Rc)(Rd), -(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, or -O(Ph)X; Two R6together with atoms attached thereto are optionally joined to form a cycloalkyl, or heterocycloalkyl; Ra, Rb, Rc, and Rdare independently hydrogen, C1-C6alkyl that may be optionally substituted with halogen, -OH, amine, or unsubstituted C3-6cycloalkyl; X is halogen; n is independently an integer from 0 to 12; m is independently an integer from 0 to 6; k is independently an integer from 0 to 12; and pharmaceutically acceptable salts thereof. In certain preferred aspect, A is phenyl and L1is -(CH2)p- wherein p is 1 to 4. The compound has the following Formula (XI). B, R1, n, p, R2, L2, R6and k are as defined above. n is an integer of 0 to 5. In certain preferred aspect, -L2-B- is The compound has the following Formula (XI-a), R1, n, p, R , L , and R are as defined above. k is an integer of 0 to 5. The compound has the following Formula (XI-b), R1, n, p, R , L , and R are as defined above. k is an integer of 0 to 4. The compound has the following Formula (XI-c), (XI-c). R , n, p, R , L , and R6are as defined above. k is an integer of 0 to 3. The compound has the following Formula (XI-d), R1, n, p, R2, L2, and R6are as defined above. k is an integer of 0 to 6. In certain preferred aspects, L1is a bond, methylene, or ethylene and A is C1-4 alkyl, cycloalkyl, or heterocycloalkyl. In particularly certain preferred aspects, -L1-A-R1is . In certain preferred aspect, the compound has the following Formula (XII), R1, p, R2,2 L , and R6are as defined above. k is an integer of 0 to 5 and n is an integer of 0 to 5. In a particular aspect, compounds of the following Formula (XIII) are provided: wherein: Each R1is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl, -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd), -C(O)OCH(Rc)(Rd), -(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, -S(O)2Rb, or -O(Ph)X; R2is unsubstituted C1-C6alkyl; Each R6is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd), -C(O)OCH(Rc)(Rd), -(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, or -O(Ph)X; Two R6together with atoms attached thereto are optionally joined to form a cycloalkyl, or heterocycloalkyl; Ra, Rb, Rc, and Rdare independently hydrogen, C1-C6alkyl that may be optionally substituted with halogen, -OH, amine, or unsubstituted C3-6cycloalkyl; X is halogen; n is independently an integer from 0 to 5; m is independently an integer from 0 to 6; k is independently an integer from 0 to 5; p is independently an integer from 0 to 6; and pharmaceutically acceptable salts thereof. In a particular aspect, compounds of the following Formula (XIV) are provided: wherein: Each R1is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl, -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd),-C(O)OCH(Rc)(Rd),-(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, -S(O)2Rb, or -O(Ph)X; R2is unsubstituted C1-C6alkyl; Each R6is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd), -C(O)OCH(Rc)(Rd), -(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, or -O(Ph)X; Two R6together with atoms attached thereto are optionally joined to form a cycloalkyl, or heterocycloalkyl; Ra, Rb, Rc, and Rdare independently hydrogen, C1-C6alkyl that may be optionally substituted with halogen, -OH, amine, or unsubstituted C3-6cycloalkyl; X is halogen; n is independently an integer from 0 to 5; m is independently an integer from 0 to 6; k is independently an integer from 0 to 5; p is independently an integer from 0 to 6; and pharmaceutically acceptable salts thereof. In preferred aspects, each Ra, Rb, Rc, and Rdis independently hydrogen, methyl, ethyl, propyl or isopropyl. In particularly preferred aspects, provided is the compound having the following structure: The compound may be a racemate including: The compound has preferably the structure of, Preferred calpain-2 inhibitor and methods of synthesis thereof and therapeutic administration of such compounds are also disclosed in US-20230091121 and US2021 / 0179543, both of which are incorporated herein by reference. In certain aspects, a subject for treatment in accordance with the methods and compositions disclosed herein has not suffered from traumatic brain injury, stroke, concussion, intracerebral hemorrhage, acute glaucoma, seizure activity and / or spinal cord injury. In certain aspects, a subject for treatment in accordance with the methods and compositions disclosed herein has not suffered from neuronal cell death and / or has not been identified as suffering from neuronal cell death. The term “calpain-2 inhibitor compound” as used herein unless otherwise specified refers to a compound that has an IC50 of less than 100 µM and preferably less than 10 µM or less than 1 µM for inhibiting human calpain-mediated spectrin breakdown in homogenates of HEK cells lacking calpain-1 [therefore exhibiting only calpain-2], as described in at Section 2.5 of Baudry et al., , G. Identification and neuroprotective properties of NA-184, a calpain-2 inhibitor. Pharmacol Res Perspect.2024 Apr;12(2):e1181. doi: 10.1002 / prp2.1181. That protocol is referred to herein as a spectrin breakdown assay and thus a suitable calpain-2 inhibitor compound has an IC50 of less than 100 µM and preferably less than 10 µM or less than 1 µM in such spectrin breakdown assay. Preferred calpain-2 inhibitor compounds may exhibit an IC50 above 10 µM for inhibiting human calpain-mediated spectrin breakdown in homogenates of HEK cells lacking calpain-2 [therefore exhibiting only calpain-1] in such assay as disclosed in Baudry et al., , G. Identification and neuroprotective properties of NA-184, a calpain-2 inhibitor. Pharmacol Res Perspect.2024 Apr;12(2):e1181. doi: 10.1002 / prp2.1181dd. Other aspects are disclosed infra. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows the structures of a number of calpain inhibitors, and in particular, the structure of NA-184. FIG. 2: NA-184 stimulates neurogenesis in SVZ and DG. Mice were injected with NA- 184 and sacrificed 24 h later. Brains were processed for immunohistochemistry for Ki67, a marker for newly-generated neurons. Results are means ± SEM of 6 experiments. • p < 0.05; ** p < 0.01 (t-test). Scale bar= 100 µm. FIG.3: NA-184 injection increased DCX+ cells in SVZ. Mice were injected with NA-184 and sacrificed 24 h later. Brains were processed for immunohistochemistry for DCX, a marker for newly generated neurons. Results are means ± SEM of 6 experiments. • p < 0.01 (t-test). Scale bar = 100 µm. FIG.4: NA-184 injection increased MEIS2 expression in SVZ and DG. Mice were injected with NA-184 and sacrificed 24 h later. Brains were processed for immunohistochemistry for MEIS2. Results are means ± SEM of 6 experiments. • p < 0.05 (t-test). Scale bar = 100 µm. FIG. 5: MEIS2 expression is increased in calpain-2 knock-out (ko) mice. Brains of adult calpain-2 ko mice were processed for immunohistochemistry for MEIS2 (A). Results were quantified (B) and are means ± SEM of 6 experiments. • p < 0.05; ** p < 0.01. Scale bar = 100 µm. FIG.6: MEIS2 expression is increased in calpain-2 ko mice. Brains of adult calpain-2 ko mice were processed for western blots for MEIS2. Results are means ± SEM of 4-6 experiments. • p < 0.05 (t-test). FIG. 7: Decreased expression of MEIS2 in brains of calpain-1 ko mice. Brains of adult calpain-1ko mice were processed for western blots for MEIS2. Results are means ± SEM of 4 experiments. • p < 0.05 (t-test). FIG.8: Prolonged effects of NA-184 injection on MEIS2 levels in cortex, CA1 and Dentate gyrus. Mice were injected with NA-184 and sacrificed 24, 72 and 96 h later. Brains were processed for immunohistochemistry for MEIS2. Results are means ± SEM of 5 experiments. • p < 0.05; ** p < 0.01; *** P < 0.005 (ANOVA). FIG.9: Prolonged effects of NA-184 injection on MEIS2 levels in SVZ, CA1 and Dentate gyrus. Mice were injected with NA-184 and sacrificed 1, 2 and 3 weeks later. Brains were processed for immunohistochemistry for MEIS2. Results are means ± SEM of 4 experiments. A. Control expression of MEIS2 in SVZ. B. MEIS2 in SVZ at 1 week. C. MEIS2 expression in SVZ at 2 weeks. D. MEIS2 expression at 3 weeks. E. Quantification of MEIS2 expression in SVZ, CA1 and DG. • p < 0.05; ** p < 0.01; *** P < 0.005 (ANOVA). FIG.10: Prolonged effects of NA-184 injection on the number of oligodendrocytes in the fimbria and corpus callosum. Mice were injected with NA-184 and sacrificed 24, 72 and 96 h later. Brains were processed for immunohistochemistry for Olig2, a marker for oligoendrocytes. Results are means ± SEM of 3 experiments. • p < 0.05 (ANOVA). FIG.11: Changes in the distribution of spine morphology in calpain-1 and calpain-2 mice. Adult wild-type (WT), calpain-1 knock-out (C1KO) or calpain-2 knock-out (C2KO) mice were processed for spine morphology analysis. Results are means ± SEM of 4 experiments. **** p < 0.001 vs WT; # p < 0.01 vs WT. FIG.12: Acute injection of NA-184 increased cognition in aged monkeys. Aged monkeys were administered NA-184 subcutaneously and they were then tested on a delayed to matching task, which represents an index of cognitive performance. Results are means ± SEM of 3 animals. FIG. 13: Chronic injection of NA-184 increased cognition in aged monkeys. Aged monkeys were administered NA-184 subcutaneously daily for 2 months and were regularly tested on a delayed to matching task, which represents an index of cognitive performance. Plasma levels of p217-tau were measure before and at the end of the treatment. Results are representative for one monkey with the other 2 exhibiting similar effects. DETAILED DESCRIPTION In preferred aspects, the present compounds are one or more of the compounds shown in Figure 1. In particular aspects, the present compounds may include one or more of NA-112, NA- 113, NA-115, NA-117, and NA-184 (Compounds 12, 13, 15 and 17 in Fig.1). As discussed, in one aspect, compounds of the following Formula (I) are provided: wherein A, R1, n, L1, R2, L2, R4and R5are as defined above. In certain aspects, preferably, R1is absent (n is 0 and the A ring does not contain any non-hydrogen substituents), alkyl, alkoxy or halogen, A is carbocyclic aryl such as phenyl or heteroaryl, L1and L2are each unsubstituted alkylene, particularly methylene (-CH2-), R4and R5are independently hydrogen, or unsubstituted C1-C6alkyl such as methyl. In certain preferred aspects, R4and R5are independently hydrogen, methyl or ethyl. In a particular aspect, R4and R5are methyl. Exemplary preferred A-L1- groups include the following: The above are also preferred A groups with other L1linkers. In certain preferred aspects, the chiral carbon most adjacent L1has an (S) configuration. For certain aspects, the chiral carbon most adjacent to L1has an (R) configuration. In certain preferred aspects, the chiral carbon most adjacent to L2has an (S) configuration. For certain aspects, the chiral carbon most adjacent to L2has an (R) configuration Compounds of the invention may be utilized as racemic or optically enriched mixtures. Particularly preferred compounds of the invention are compounds analog of NA112, which may have the following formula (II) or (III). . In a certain aspect, R1Ais cyano, or unsubstituted C1-C6alkyl, and R1Bis C1-C6alkoxy. In a particular aspect, R1Ais cyano (-CN) or unsubstituted alkyl such as methyl and . R1Bis C1-C6alkoxy, preferably –OCH3. Particularly preferred compound, NA112, has the following structure. In another aspect, provided is a compound of Formula (X), wherein: A is C1-C6alkyl, carboxyl (-C(O)O-), aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; B is carbocyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; L1is a bond, or substituted or unsubstituted C1-C6alkylene, L2is a bond, substituted or unsubstituted C1-C6alkylene, or -S(O)2-, Each R1is a non-hydrogen substituent such as C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd), -C(O)OCH(Rc)(Rd), -(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, -S(O)2Rb, or -O(Ph)X; R2is non-hydrogen substituent such as optionally substituted C1-C6alkyl; Each R6is independently a non-hydrogen substituent such as C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl -C(O)(CH2)mN(Ra)(Rb), - O(CH2)mN(Ra)(Rb), -CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd), -C(O)OCH(Rc)(Rd), - (CH2)mN(Ra)(Rb), -(CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, or - O(Ph)X; Two R6together with atoms attached thereto are optionally joined to form a cycloalkyl, or heterocycloalkyl; Ra, Rb, Rc, and Rdare independently hydrogen, C1-C6alkyl that may be optionally substituted with halogen, -OH, amine, or unsubstituted C3-6cycloalkyl; X is halogen; n is independently an integer from 0 (where the ring A is unsubstituted) to the value permitted by the valence of the ring such as 5 where A is phenyl; m is independently an integer from 0 to 6; k is independently an integer from 0 (where the ring B is unsubstituted) to the value permitted by the valence of the ring such as 5 where B is phenyl; and pharmaceutically acceptable salts thereof. In a certain embodiment, the compound of Formula (X) may be a racemate including R2, L1, L2, R6, n and k are as defined above. In a certain embodiment, L1is optionally substituted C1-C6alkylene having (e.g. –(CH2)p where p is 1 to 6 and each carbon may have zero, one or two non-hydrogen substituents), In a certain embodiment, L2is optionally substituted alkylene having one to 6 carbons (e.g. –(CH2)p where p is 1 to 6 and each carbon may have zero, one or two non-hydrogen substituents), or -S(O)2-. In a certain embodiment, R2is unsubstituted C1-C6alkyl. For example, R2is a linear unsubstituted C1-C6alkyl, or branched C3-C6 alkyl e.g., isopropyl, isobutyl or t-butyl. In a certain embodiment, Raand Rbare independently hydrogen, methyl, ethyl, propyl or isopropyl. In a certain embodiment, Rcand Rdare independently hydrogen or methyl. In certain preferred aspect, Raand Rbare independently hydrogen or unsubstituted C1-C6alkyl. In a particular aspect, Raand Rbare independently hydrogen, methyl, ethyl, or propyl (e.g., isopropyl). In a particular aspect, Raand Rbare independently hydrogen or methyl. In a particular aspect, Raand Rbare hydrogen. In a particular aspect, Raand Rbare methyl. In a particular aspect, Rais hydrogen and Rbis methyl. In a particular aspect, Raand Rbare independently hydrogen or isopropyl. In a particular aspect, Rais hydrogen and Rbis isopropyl. In certain preferred aspect, Rcand Rdare independently hydrogen or unsubstituted C1-C6alkyl. In a particular aspect, Rcand Rdare independently hydrogen, methyl, ethyl, or propyl (e.g., isopropyl). In a particular aspect, Rcand Rdare independently hydrogen or methyl. In a particular aspect, Rcand Rdare hydrogen. In a particular aspect, Rcand Rdare methyl. In a particular aspect, Rcis hydrogen and Rdis methyl. In a certain embodiment, A is phenyl and L1is -(CH2)p- and p is 0 to 6 (when p is 0, L1is a bond). Preferably, p is 1 to 6. The compound may have a Formula (XI). wherein B, R1, p, R2, L2, R6and k are as defined above. n is an integer of 0 to 5. In a certain embodiment, the compound of Formula (XI) may be a racemate including R6, n, p, and k are as defined above. In a certain embodiment, -L2-B- is The compound may have a Formula (XI-a). R2, and R6are as defined above. k is an integer of 0 to 5. In a certain embodiment, the compound of Formula (XI-a) may be a racemate including and R are as defined above. In a certain embodiment, in Formula (XI-a), n is 0. For example, the compound is

[0002] In a certain embodiment, in Formula (XI-a), n is 1 to 2. For example, the compound is

[0003] The compound may have a Formula (XI-b). and R are as defined above. n is an integer of 0 to 5 and k is an integer of 0 to 4. In a certain embodiment, the compound of Formula (XI-b) may be a racemate including and R6are as defined above. For example, the compound is The compound may have a Formula (XI-c). and R6are as defined above. k is an integer of 0 to 3. In a certain embodiment, the compound of Formula (XI-c) may be a racemate including are as defined above. For example, the compound is The compound may have a Formula (XI-d), and R6are as defined above. k is an integer of 0 to 6. In a certain embodiment, the compound of Formula (XI-d) may be a racemate including are as defined above. For example, the compound is In a certain embodiment, L1is a bond, methylene, or ethylene and A is C1-4alkyl, cycloalkyl (e.g., adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocycloalkyl (e.g., 5 to 12 membered heterocycloalkylene). In a certain embodiment, the -L1-A-R1is

[0004] For example, the compound is

[0005] In a certain embodiment, -L2-B is In a certain embodiment, the compound has a Formula (XII). R1, p, R2, and R6are as defined above. n is an integer of 0 to 5 and k is an integer of 0 to 5. In a certain embodiment, the compound of Formula (XII) may be a racemate including , and R6 are as defined above. In a certain embodiment, two R6together with atoms attached thereto are joined to form a cycloalkyl, or heterocycloalkyl. The compound of Formula (XII) may have the structure of

[0006] In an aspect, the compound has a Formula (XIII), wherein: Each R1is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl, -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd), -C(O)OCH(Rc)(Rd), -(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, -S(O)2Rb, or -O(Ph)X; R2is unsubstituted C1-C6alkyl; Each R6is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd),-C(O)OCH(Rc)(Rd),-(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, or -O(Ph)X; Two R6together with atoms attached thereto are optionally joined to form a cycloalkyl, or heterocycloalkyl; Ra, Rb, Rc, and Rdare independently hydrogen, C1-C6alkyl that may be optionally substituted with halogen, -OH, amine, or unsubstituted C3-6cycloalkyl; X is halogen; n is independently an integer from 0 to 5; m is independently an integer from 0 to 6; k is independently an integer from 0 to 5; p is independently an integer from 0 to 6; and pharmaceutically acceptable salts thereof. In a certain embodiment, the compound of Formula (XIII) may be a racemate including and R6are as defined above. For example, the compound is In an aspect, the compound may have a Formula (XIV), wherein: Each R1is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl, -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd), -C(O)OCH(Rc)(Rd), -(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, -S(O)2Rb, or -O(Ph)X; R2is unsubstituted C1-C6alkyl; Each R6is independently C1-C6alkyl, halogen, cyano, nitro, C1-C6alkoxy, aryl, heterocycloaryl, heterocycloalkyl -C(O)(CH2)mN(Ra)(Rb), -O(CH2)mN(Ra)(Rb), - CONH(CH2)mN(Ra)(Rb), -C(O)NH-CH(Rc)(Rd),-C(O)OCH(Rc)(Rd),-(CH2)mN(Ra)(Rb), - (CH2)mN(Ra)C(O)Rb, -(CH2)mN(Ra)C(O)ORb,-O(CH2)mRc, -O(CH2)mOH, or -O(Ph)X; Two R6together with atoms attached thereto are optionally joined to form a cycloalkyl, or heterocycloalkyl; Ra, Rb, Rc, and Rdare independently hydrogen, C1-C6alkyl that may be optionally substituted with halogen, -OH, amine, or unsubstituted C3-6cycloalkyl; X is halogen; n is independently an integer from 0 to 5; m is independently an integer from 0 to 6; k is independently an integer from 0 to 5; p is independently an integer from 0 to 6; and pharmaceutically acceptable salts thereof. In a certain embodiment, the compound of Formula (XIV) may be a racemate including For example, the compound is

[0007] Preferred compound, NA184, has the following structure. The compound may be a racemate including: Particularly preferred compound, NA184, is S-S isomer having the following structure These compounds can be calpain-2 selective inhibitors. A “calpain-2 selective inhibitor” or a “selective calpain-2 inhibitor” as referred to herein is a compound with a calpain-2 inhibition constant (Ki) lower than its Ki for calpain-1. For example, a calpain-2 selective inhibitor is a compound with a Ki for calpain-2 that is 2-fold to 10-fold lower than its Ki for calpain-1. Preferably, a calpain-2 selective inhibitor is a compound with an IC50value for calpain-2 that is 10-50-fold lower than its IC50for calpain-1 in an in situ assay. For example, IC50values for NA112 on the activity of in situ calpain-1 and calpain-2 activities were measured (Wang et al., 2014). The selectivity of NA112 for calpain-2, measured as a ratio of IC50calpain- 1 / IC50calpain-2 was about 13. Compounds of the invention possess asymmetric carbon atoms (optical or chiral centers); the enantiomers, racemates, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-isomers, and individual isomers are encompassed within the scope of the present invention. The present invention is meant to include compounds in racemic and optically pure forms as discussed above. Optically active (R)- and (S)-isomers maybe prepared using chiral synthons or chiral reagents or resolved using conventional techniques. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. “Alkyl” refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12alkyl), from one to eight carbon atoms (C1-C8alkyl) or from one to six carbon atoms ( C1-C6alkyl), and which is attached to the rest of the molecule by a single bond. Exemplary alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon (alkyl) chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, respectively. Alkylenes can have from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule can be through one carbon or any two carbons within the chain. “Optionally substituted alkylene” refers to alkylene or substituted alkylene. “Alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl having the indicated number of carbon atoms as defined above. Examples of alkoxy groups include without limitation –O-methyl (methoxy), -O-ethyl (ethoxy), -O-propyl (propoxy), -O-isopropyl (iso propoxy) and the like. “Cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran- 3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. “Carbocyclic aryl” or “cycloalkyl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, but without any hetero (N, O or S) ring members in the aromatic ring. Exemplary carbocyclic aryls are hydrocarbon ring system radical comprising hydrogen and 6 to 9 carbon atoms and at least one aromatic ring; hydrocarbon ring system radical comprising hydrogen and 9 to 12 carbon atoms and at least one aromatic ring; hydrocarbon ring system radical comprising hydrogen and 12 to 15 carbon atoms and at least one aromatic ring; or hydrocarbon ring system radical comprising hydrogen and 15 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the carbocyclic aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Carbocyclic aryl radicals include, but are not limited to, carbocyclic aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. “Optionally substituted carbocyclic aryl” refers to an unsubstituted carbocyclic aryl group or a substituted carbocylic aryl group. A cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system. In embodiments, monocyclic cycloalkenyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon carbon double bond), but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. In embodiments, bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form (CH2)w, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. In embodiments, the multicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, multicyclic cycloalkenyl rings contain a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. A heterocycloalkyl is a heterocyclyl. The term “heterocyclyl” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3- dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3- dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10- dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl. The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical may be a stable 5-12 membered ring, a stable 5-10 membered ring, a stable 5-9 membered ring, a stable 5-8 membered ring, a stable 5-7 membered ring, or a stable 6 membered ring that comprises at least 1 heteroatom, at least 2 heteroatoms, at least 3 heteroatoms, at least 4 heteroatoms, at least 5 heteroatoms or at least 6 heteroatoms. Heteroaryls may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. The heteroatom may be a member of an aromatic or non-aromatic ring, provided at least one ring in the heteroaryl is aromatic. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). The symbol “ ” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula. Various compounds and substituents that are "optionally substituted" or “substituted” may be suitably substituted at one or more available positions by, but not limited to, halogen (F, Cl, Br, I); nitro; hydroxy; amino; alkyl such as C1-C4alkyl; alkenyl such as C2-C8alkenyl; alkoxy e.g. C1-C6alkxoy, alkylamino such as C1-C8alkylamino; carbocyclic aryl such as phenyl, naphthyl, anthracenyl, etc; heteroaryl; and the like. Composition, Pharmaceutical Composition and Formulation In aspects, pharmaceutical compositions of the invention comprise one or more calpain 2 inhibitors, such as one or more compounds of Formula I, and a pharmaceutically acceptable excipient. In preferred aspects, the present pharmaceutical compositions comprise one or more of NA112 or NA184, and a pharmaceutically acceptable excipient. Excipients used in pharmaceutical composition of the invention are safe and provide the appropriate delivery for the desired route of administration, e.g.an effective amount of NA112, or NA184. A compound of the invention, as described above, can be formulated as a pharmaceutical dosage form and administered to a subject in need of treatment, for example, a mammal, such as a human patient, in a variety of forms adapted to the chosen route of administration. The compositions of the present invention may be administered in a variety of different ways, including oral administration, intravenous injection, intramuscular injection, subcutaneous injection or by intranasal delivery. For example, the compounds may be included in solutions, suspensions and other dosage forms adapted for intravenous or subcutaneous injection. Solutions of the compounds of the invention can be prepared in water or a physiologically acceptable buffer, optionally mixed with a nontoxic surfactant, including cyclodextrins. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, liposomes, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the compounds of the invention which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the compounds of the invention in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. Useful dosages of compounds of the invention can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949. The amount of the compounds of the invention required for use in treatment will vary depending on the particular therapeutic agent, the composition, if there is one, that comprises the therapeutic agent, the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. A therapeutically effective dose can be determined empirically, by conventional procedures known to those of skill in the art. See, e.g., The Pharmacological Basis of Therapeutics, Goodman and Gilman, eds., Macmillan Publishing Co., New York. For example, an effective dose can be estimated initially either in cell culture assays or in suitable animal models. The animal model may also be used to determine the appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. A therapeutic dose can also be selected by analogy to dosages for comparable therapeutic agents. The particular mode of administration and the dosage regimen will be selected by the attending clinician, considering the particulars of the case (e.g., the subject, the disease, the disease state involved, and whether the treatment is prophylactic). Treatment may involve daily or multi-daily doses of compound(s) over a period of a few days to months, or even years. The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art. The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. Methods Methods provided herein are methods for treating Alzheimers disease, and / or a neurogenerative diseases or disorder and / or one or more of or more of Parkinson's disease, Huntington's disease, Pick’s disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome or Korsakoff's disease. Preferred method includes administering to a patient in need thereof an effective amount of a compound or composition as described herein. In an aspect, provided is a method of treating a subject suffering from a disorder or symptom associated with Alzheimer’s disease, and the method includes administering to the subject an effective amount of a compound or composition as described herein. In a certain embodiment, the patient has been identified as suffering or susceptible to a disorder or symptom associated with Alzheimer’s disease and the compound is administered to the identified subject. In a further aspect, provided is a method of treating a subject suffering from a disorder or symptom associated with neurodegenerative disease or disorder, and the method includes administering to the subject an effective amount of a compound or composition as described herein. In a certain embodiment, the patient has been identified as suffering or susceptible to a disorder or symptom associated with a neurodegenerative disease or disorder and the compound is administered to the identified subject. In a further aspect, provided is a method of treating a subject suffering from a disorder or symptom associated with Parkinson's disease, Huntington's disease, Pick’s disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome or Korsakoff's disease, and the method includes administering to the subject an effective amount of a compound or composition as described herein. In a certain embodiment, the patient has been identified as suffering or susceptible to a disorder or symptom associated with one or more of Parkinson's disease, Huntington's disease, Pick’s disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome or Korsakoff's disease and the compound is administered to the identified subject. In a further aspect, provided is a method of treating a subject suffering from a disorder or symptom associated with Age-Associated Memory Impairment (AAMI), and the method includes administering to the subject an effective amount of a compound or composition as described herein. In a certain embodiment, the patient has been identified as suffering or susceptible to a disorder or symptom associated with Age-Associated Memory Impairment (AAMI), and the compound is administered to the identified subject. In preferred aspects, administration of a compound or composition described herein can leads to an improvement, or enhancement, of neurological function in an individual with a neurological disease, neurological injury, or age-related neuronal decline or impairment. Neural deterioration can be the result of any condition which compromises neural function which is likely to lead to neural loss, Neural function can be compromised by, for example, altered biochemistry, physiology, or anatomy of a neuron, including its neurite. Deterioration of a neuron may include membrane, dendritic, or synaptic changes which are detrimental to normal neuronal functioning. The cause of the neuron deterioration, impairment, and / or death may be unknown. Alternatively, it may be the result of age-, injury- and / or disease-related neurological changes which occur in the nervous system of an individual. When neural loss is described herein as “age-related”, it is intended to include neural loss resulting from known and unknown bodily changes of an individual that are associated with aging. When neural loss is described herein as “disease-related”, it is intended to include neural loss resulting from known and unknown bodily changes of an individual which are associated with disease. When neural loss is described herein as “injury-related”, it is intended to include neural loss resulting from known and unknown bodily changes of an individual which are associated with injury or trauma. Examples of trauma include brain injuries due to explosions, for example from explosive devices, or other traumas, such as gun shots and / or stabbings. It should be understood, however, that these terms are not mutually exclusive and that, in fact, many conditions that result in the loss of neural cells and / or neural connections can be related to age, disease and / or injury. Some of the more common age-related neuropathies associated with neural loss and changes in neural morphology include, for example, Alzheimer's disease, Pick's disease, Parkinson's disease, vascular disease, Huntington's disease, and Age-Associated Memory Impairment. In Alzheimer's patients, neural loss is most notable in the hippocampus, frontal, parietal, and anterior temporal cortices, amygdala, and the olfactory system. The most prominently affected zones of the hippocampus include the CA1 region, the subiculum, and the entorhinal cortex. Memory loss is considered the earliest and most representative cognitive change because the hippocampus is well known to play a crucial role in memory. Pick's disease is characterized by severe neural degeneration in the neocortex of the frontal and anterior temporal lobes which is sometimes accompanied by death of neurons in the striatum. Parkinson's disease can be identified by the loss of neural cells in the substantia nigra and the locus ceruleus. Huntington's disease is characterized by degeneration of the intrastriatal and cortical cholinergic neural cells and GABA-ergic neural cells. Parkinson's and -Huntington's diseases are usually associated with movement disorders, but often show cognitive impairment (memory loss) as well. Age-Associated Memory Impairment (AAMI) is another age-associated disorder that is characterized by memory loss in healthy, elderly individuals in the later decades of life. Presently, the neural basis for AAMI has not been precisely defined. However, neural death with aging has been reported to occur in many species in brain regions implicated in memory, including cortex, hippocampus, amygdala, basal ganglia, cholinergic basal forebrain, locus ceruleus, raphe nuclei, and cerebellum. In a certain embodiment, the compound or composition is administered via a method selected from the group consisting of oral administration, intravitreal injection, intraocular injection, intraocular perfusion, periocular injection and sub-Tenon injection. The following Examples are illustrative. Example 1: We determined the Ki for these compounds against human calpain-1 and recombinant human calpain-2 as well as their IC50 against mouse calpain-1 and calpain-2 (Table I). Table I: Ki values for calpain-1 and calpain-2 for a number of calpain inhibitors. Several of these inhibitors were more selective for calpain-2 than for calpain-1. NA-184 stimulates neurogenesis. Adult mice (5-7 weeks) were injected twice with NA-184 (time 0 and 8 h), a selective calpain-2 inhibitor (i.p., 1 mg / kg) and were sacrificed 24 h later. Neurogenesis was evaluated by analyzing the number of Ki67-positive cells (Ki67 is a marker of newly generated neurons) in the subventricular zone (SVZ) and the Dentate Gyrus (DG) of the hippocampus (Figure 2). ± SEM of 4 experiments. • p < 0,05; ** p < 0.01. We also used doublecortin (DCX), another marker of neurogenesis. The number of both Ki67+ and DCX+ cells were increased following treatment with NA-184 (Fig.3). NA-184 injection increased DCX+ cells in SVZ. Mice were injected with NA-184 and sacrificed 24 h later. Brains were processed for immunohistochemistry for DCX, a marker for newly-generated neurons. Results are means ± SEM of 4 experiments. • p < 0,05 The levels of MEIS2 were also increased following NA-184 treatment (Fig.4). Figure 4. NA-184 injection increased MEIS2 expression in SVZ and DG. Mice were injected with NA-184 and sacrificed 24 h later. Brains were processed for immunohistochemistry for MEIS2. Results are means ± SEM of 4 experiments. • p < 0,05. We also determined the levels of MEIS2 in the hippocampus and cortex of conditional calpain-2 knock-out mice (C2CKO), which lack calpain-2 in excitatory cells of the forebrain. Levels of MEIS2 were elevated in various brain regions of adult C2CKO mice, clearly confirming that MEIS2 is a target of calpain-2 (Fig.5). In Figure 5, MEIS2 expression is increased in calpain- 2 ko mice. Brains of adult calpain-2 ko mice were processed for immunohistochemistry for MEIS2. Results are means ± SEM of 4 experiments. • p < 0,05; ** p < 0.01. These results were confirmed by western blot analysis (Fig 6). In Figure 6. MEIS2 expression is increased in calpain-2 ko mice. Brains of adult calpain-2 ko mice were processed for western blots for MEIS2. Results are means ± SEM of 4 experiments. • p < 0,05. To further confirm the specificity of MEIS2 cleavage by calpain-2, we analyzed MEIS2 levels in brains from calpain-1 ko mice (Fig.7). Surprisingly, levels of MEIS2 in cortex and hippocampus of calpain-1 ko mice were decreased. While these results confirm that MEIS2 is not a substrate of calpain-1, they also suggest that some type of compensatory mechanisms is present in the brains of calpain-1 ko mice. Figures 7 shows decreased expression of MEIS2 in brains of calpain-1 ko mice. Brains of adult calpain-1ko mice were processed for western blots for MEIS2. Results are means ± SEM of 4 experiments. • p < 0,05. Prolonged effects of NA-184 on MEIS2. We evaluated the effects of the two injections of NA-184 on brain levels of MEIS2 at various times after the injections (Figures 8, 9). We first evaluated MEIS levels in various brain regions at 24, 72 and 96 h after injection (Fig. 8). Surprisingly, MEIS2 levels were elevated and kept increasing up to 96 h after NA-184 injection. We then extended this period and analyzed levels of MEIS2 at 1, 2 and 3 weeks after NA-184 injection. Similarly. MEIS2 levels were elevated and continued to increase up to 3 weeks after NA-184 injection (Fig.9). Figure 8 shows effects of NA-184 injection on MEIS2 levels in cortex, CA1 and Dentate gyrus. Mice were injected with NA-184 and sacrificed 24, 72 and 96 h later. Brains were processed for immunohistochemistry for MEIS2. Results are means ± SEM of 5 experiments. • p < 0.05; ** p < 0.01; *** P < 0.005 (ANOVA). Figure 9 shows effects of NA-184 injection on MEIS2 levels in SVZ, CA1 and Dentate gyrus. Mice were injected with NA-184 and sacrificed 1, 2 and 3 weeks later. Brains were processed for immunohistochemistry for MEIS2. Results are means ± SEM of 4 experiments. A. Control expression of MEIS2 in SVZ. B. MEIS2 in SVZ at 1 week. C. MEIS2 expression in SVZ at 2 weeks. D. MEIS2 expression at 3 weeks. E. Quantification of MEIS2 expression in SVZ, CA1 and DG. • p < 0.05; ** p < 0.01; *** P < 0.005 (ANOVA). Prolonged effects of NA-184 injection on oligodendrocytes. Because MEIS2 is widely expressed in the brain, we also evaluated the effects of NA-184 injection on another type of brain cells, the oligodendrocytes. Interestingly, the numbers of cells labeled with Olig2, a marker for brain oligodendrocytes, were also elevated in the corpus callosum and the fimbria, two major nerve fiber tracts in the brain, and this effect became significant at 72- 96 h after injection (Figure 10). These results indicate that NA-184 can increase the number of oligodendrocytes, which could have a significant impact on brain functions. In Figure 10, effects of NA-184 injection on the number of oligodendrocytes in the fimbria and corpus callosum. Mice were injected with NA-184 and sacrificed 24, 72 and 96 h later. Brains were processed for immunohistochemistry for Olig2, a marker for oligoendrocytes. Results are means ± SEM of 3 experiments. • p < 0.05 (ANOVA). Increased spine maturation in calpain-2 knock-out mice. As MEIS2 has also been implicated in neuronal maturation, we analyzed the morphology of dendritic spines in hippocampus of calpain-1 and calpain-2 ko mice. Interestingly, the number of mature dendritic spines was increased in the hippocampus of adult C2CKO mice, while it was decreased in calpain-1 ko mice (Fig. 11). Conversely, the number of filopodia (immature) spines was increased in calpain-1 ko mice, it was decreased in calpain-2 ko mice. The total number of spines was not significantly different between the 3 strains of mice. In Figure 11, changes in the distribution of spine morphology in calpain-1 and calpain-2 mice are shown. Adult wild-type (WT), calpain-1 knock-out (C1KO) or calpain-2 knock-out (C2KO) mice were processed for spine morphology analysis. Results are means ± SEM of 4 experiments. **** p < 0.001 vs WT; # p < 0.01 vs WT. Acute as well as chronic NA-184 increased cognitive performance in aged monkeys. We previously reported that acute administration of a selective calpain-2 inhibitor increased cognitive performance in normal adult mice (Liu et al, 2016). We therefore tested the effects of NA-184 administration on cognitive performance in aged monkeys (Figs.12,13). Acute subcutaneous (sc) injections of various doses of NA-184 enhanced performance in a delayed to matching task, an index of cognitive performance, in aged macaque monkeys (Fig.12). Three monkeys were then treated with daily sc injections of NA-184 at 0.01 mg / kg for 2 months, and they were regularly tested on the delayed to matching task (Fig.13). At the end of the testing, blood levels of phosphorylated tau were measured. Daily injections of NA-184 resulted in continuous improvement of cognitive performance and was accompanied by a decrease in plasma levels of p-tau, a marker for Alzheimer’s disease. In Figure 12, results are shown of acute injection of NA-184 increased cognition in aged monkeys. Aged monkeys were administered NA-184 subcutaneously and they were then tested on a delayed to matching task, which represents an index of cognitive performance. Results are means ± SEM of 3 animals. In Figure 13, results are shown of chronic injection of NA-184 increased cognition in aged monkeys. Aged monkeys were administered NA-184 subcutaneously daily for 2 months and were regularly tested on a delayed to matching task, which represents an index of cognitive performance. Plasma levels of p217-tau were measure before and at the end of the treatment. Results are representative for one monkey with the other 2 exhibiting similar effects. Discussion From these results, it is shown that MEIS2 is a calpain-2 substrate, and calpain-2 inhibition or deletion results in increased levels of MEIS2 throughout the brain, including the SVZ and the DG. Administration of a calpain-2 inhibitor (including acute administration) results in increased neurogenesis in the SVZ and the DG of adult mice. Administration of NA-184 (including acute administration) results in a prolonged increase (up to 3 weeks) I MEIS2 expression in the brain. Administration of NA-184 (including acute administration) results in a prolonged increase in oligodendrocytes in two major brain fiber tracts. Down-regulation of calpain-2 results in increased mature spines in adult hippocampus. We conclude that a selective calpain-2 inhibitor could be beneficial for the treatment of a number of disorders associated with impaired neurogenesis, including Alzheimer’s disease. References Babcock, K. R., J. S. Page, J. R. Fallon and A. E. Webb (2021). "Adult Hippocampal Neurogenesis in Aging and Alzheimer's Disease." Stem Cell Reports 16(4): 681-693. Baudry, M., W. Su, J. Seinfeld, J. Sun and X. Bi (2021). "Role of Calpain-1 in Neurogenesis." Front Mol Biosci 8: 685938. Baudry, M., Y. Wang, X. Bi, Y. L. Luo, Z. Wang, Z. Kamal, A. Shirokov, E. Sullivan, D. Lagasca, H. Khalil, G. Lee, K. Fosnaugh, P. Bey, S. Mehdi and G. Coulter (2024). "Identification and neuroprotective properties of NA-184, a calpain-2 inhibitor." Pharmacol Res Perspect 12(2): e1181. Berger, T., H. Lee, A. H. Young, D. Aarsland and S. Thuret (2020). "Adult Hippocampal Neurogenesis in Major Depressive Disorder and Alzheimer's Disease." Trends Mol Med 26(9): 803-818. Chung, K. M., H. Park, S. Jung, S. Ha, S. J. Yoo, H. Woo, H. J. Lee, S. W. Kim, E. K. Kim, C. Moon and S. W. Yu (2015). "Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal." Stem Cells 33(10): 3052- 3064. Culig, L., X. Chu and V. A. Bohr (2022). "Neurogenesis in aging and age-related neurodegenerative diseases." Ageing Res Rev 78: 101636. Duque, A., J. I. Arellano and P. Rakic (2022). "An assessment of the existence of adult neurogenesis in humans and value of its rodent models for neuropsychiatric diseases." Mol Psychiatry 27(1): 377-382. Gillotin, S., V. Sahni, T. Lepko, M. A. Hanspal, J. E. Swartz, Z. Alexopoulou and F. H. Marshall (2021). "Targeting impaired adult hippocampal neurogenesis in ageing by leveraging intrinsic mechanisms regulating Neural Stem Cell activity." Ageing Res Rev 71: 101447. Huttenlocher, A., S. P. Palecek, Q. Lu, W. Zhang, R. L. Mellgren, D. A. Lauffenburger, M. H. Ginsberg and A. F. Horwitz (1997). "Regulation of cell migration by the calcium-dependent protease calpain." J Biol Chem 272(52): 32719-32722. Isaev, N. K., E. V. Stelmashook and E. E. Genrikhs (2019). "Neurogenesis and brain aging." Rev Neurosci 30(6): 573-580. Jessberger, S., F. H. Gage, A. J. Eisch and D. C. Lagace (2009). "Making a neuron: Cdk5 in embryonic and adult neurogenesis." Trends Neurosci 32(11): 575-582. Moudilou, E. N., N. Mouterfi, J. M. Exbrayat and C. Brun (2010). "Calpains expression during Xenopus laevis development." Tissue Cell 42(5): 275-281. Moyen, C., S. Goudenege, S. Poussard, A. H. Sassi, J. J. Brustis and P. Cottin (2004). "Involvement of micro-calpain (CAPN 1) in muscle cell differentiation." Int J Biochem Cell Biol 36(4): 728-743. Muller, T., M. Reichlmeir, A. C. Hau, I. Wittig and D. Schulte (2024). "The neuronal transcription factor MEIS2 is a calpain-2 protease target." J Cell Sci 137(4). Ribeiro, F. F. and S. Xapelli (2021). "An Overview of Adult Neurogenesis." Adv Exp Med Biol 1331: 77-94. Salta, E., O. Lazarov, C. P. Fitzsimons, R. Tanzi, P. J. Lucassen and S. H. Choi (2023). "Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance." Cell Stem Cell 30(2): 120-136. Santos, D. M., J. M. Xavier, A. L. Morgado, S. Sola and C. M. Rodrigues (2012). "Distinct regulatory functions of calpain 1 and 2 during neural stem cell self-renewal and differentiation." PLoS One 7(3): e33468. Terreros-Roncal, J., E. P. Moreno-Jimenez, M. Flor-Garcia, C. B. Rodriguez-Moreno, M. F. Trinchero, B. Marquez-Valadez, F. Cafini, A. Rabano and M. Llorens-Martin (2022). "Response to Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis"." Science 376(6590): eabn7270. Vassal, M., F. Martins, B. Monteiro, S. Tambaro, R. Martinez-Murillo and S. Rebelo (2024). "Emerging Pro-neurogenic Therapeutic Strategies for Neurodegenerative Diseases: A Review of Pre-clinical and Clinical Research." Mol Neurobiol. Yajima, Y. and S. Kawashima (2002). "Calpain function in the differentiation of mesenchymal stem cells." Biol Chem 383(5): 757-764.

Claims

What is claimed is:

1. A method to treat a subject suffering from or susceptible to Alzheimer's disease or dementia, comprising: administering to the subject an effective amount of one or more calpain-2 inhibitor compounds.

2. A method to treat a subject suffering from or susceptible to as neurodegenerative disease or disorder, comprising: administering to the subject an effective amount of one or more calpain-2 inhibitor compounds.

3. A method to treat a subject suffering from or susceptible to Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down's Syndrome or Korsakoff's disease, the method comprising: administering to the subject an effective amount of one or more calpain-2 inhibitor compounds.

4. A method to treat a subject suffering from or susceptible to Age-Associated Memory Impairment (AAMI), the method comprising: administering to the subject an effective amount of one or more calpain-2 inhibitor compounds.

5. The method of claim 1 wherein the subject is identified as suffering from Alzheimer’s disease and the one or more calpain-2 inhibitor compounds are administered to the identified subject.

6. The method of claim 2 wherein the subject is identified as suffering from neurodegenerative disease or disorder and the one or more calpain-2 inhibitor compounds are administered to the identified subject.

7. The method of claim 3 wherein the subject is identified as suffering from Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome or Korsakoff's disease and the one or more calpain-2 inhibitor compounds are administered to the identified subject.

8. The method of claim 4 wherein the subject is identified as suffering from Age- Associated Memory Impairment (AAMI) and the one or more calpain-2 inhibitor compounds are administered to the identified subject.

9. The method of any one of claims 1 to 8 wherein the one or more calpain-2 inhibitors comprise NA-184, ((S)-2-(3-benzylureido)-N-((R,S)-1-((3-chloro-2-methoxybenzyl)amino)-1,2- dioxopentan-3-yl)-4-methylpentanamide).

10. The method of any one of claims 1 to 9 wherein the one or more calpain-2 inhibitors comprise a compound of any of Formulae I, II, III and / or X or XI.

11. The method of any one of claims 1 to 10 wherein the one or more compounds are administered are administered daily or multiple times each week for multiple weeks.

12. The method of any one of claims 1 to 10 wherein the one or more compounds are administered are administered daily or multiple times each week for at least one month.

13. The method of any one of claims 1 to 10 wherein the one or more compounds are administered are administered daily or multiple times each week for at least two, three, four, five or six months.

14. The method of any of claims 1 to 10 wherein the one or more compounds are administered are administered once each 2, 3, 4, 5 or 6 weeks.

15. The method of any one of claims 1 to 10 wherein a pharmaceutical composition comprising the one or more compounds is administered to the subject.

16. A pharmaceutical composition comprising: a) one or more calpain-2 inhibitor compounds; and b) instructions for use of the one or more compound to treat Alzheimer’s disease or a symptom thereof.

17. A pharmaceutical composition comprising: a) one or more calpain-2 inhibitor compounds; and b) instructions for use of the one or more compound to treat a neurodegenerative disease or disorder or a symptom thereof.

18. A pharmaceutical composition comprising: a) one or more calpain-2 inhibitor compounds; and b) instructions for use of the one or more compound to treat Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Down's Syndrome or Korsakoff's disease or a symptom thereof.

19. A pharmaceutical composition comprising: a) one or more calpain-2 inhibitor compounds; and b) instructions for use of the one or more compound to treat Age-Associated Memory Impairment (AAMI) or Korsakoff's disease or a symptom thereof.

20. A pharmaceutical composition of any one of claims 16 to 19 wherein the one or more calpain-2 inhibitors comprise NA-184, ((S)-2-(3-benzylureido)-N-((R,S)-1-((3-chloro-2- methoxybenzyl)amino)-1,2-dioxopentan-3-yl)-4-methylpentanamide).

21. A pharmaceutical composition of any one of claims 16 to 19 wherein the one or more calpain-2 inhibitors comprise a compound of any of Formulae I, II, III and / or X or XI.

22. A pharmaceutical composition of any one of claims 16 to 21 wherein the instructions are in written form.

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