LYN modulators for treatment of alzheimer's disease

Abstract

The general field of the present disclosure are novel approaches to the treatment of Alzheimer's and other neurodegenerative disorders using novel therapeutics comprising Lyn kinase inhibitors. Specifically, the disclosure provides compounds, pharmaceutical compositions, and methods of treating and preventing such disorders.

Description

LYN MODULATORS FOR TREATMENT OF ALZHEIMER’S DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of prior-filed United States provisional application no. 63 / 672,364 filed on July 17, 2024, which is incorporated by reference in its entirety herein.

[0002] REFERENCE TO GOVERNMENT GRANTS

[0003] This invention was made with government support under contract AG065181 awarded by the National Institutes of Health. The Government has certain rights in the invention.FIELD OF THE DISCLOSURE

[0004] The general field of the present disclosure is therapeutics and methods of treatment of Alzheimer’s disease and other neurodegenerative disorders. Specifically, the field of the present disclosure includes LYN kinase inhibitors.BACKGROUND

[0005] Alzheimer’s disease (AD) is a fatal, neurodegenerative disorder characterized by histopathological accumulation of extracellular (3-amyloid (A(J) plaques and intra-neuronal neurofibrillary tangles (NFTs), which have been hypothesized to result in neurotoxicity and progressive cognitive decline. See Kumar et al., “A review on Alzheimer's disease pathophysiology and its management: an update, (2015) Pharmacol Rep 67: pp. 195-203; Hardy et al., “Alzheimer's disease: the amyloid cascade hypothesis: an update and reappraisal,” (2006) J Alzheimers Dis 9: pp. 151-153; Shen ct al, “Complement activation by neurofibrillary’ tangles in Alzheimer's disease,” (2001) Neurosci Lett 305: pp. 165-168; Scheltens et al., “Alzheimer's disease,” (2021) Lancet 397: pp. 1577-1590. The amyloid cascade hypothesis postulates that various forms of A[1 oligomers and plaques are instrumental in a neuropatholo gic al process that triggers subsequent NFT pathology, neuroinflammation, and neuronal loss. However, the mechanisms by which A (J influences neurotoxic signaling including NFT formation remain an area of intense study. Despite guiding Alzheimer's disease research for over three decades, the amyloid beta hypothesis has yielded only limited therapeutic success. Amyloid-targeted treatments such as the recently approved anti-amyloid antibodies Lecanemab and Donanemab have been difficult to develop and offer only modest benefits with approximately 30% reduction in cognitive decline at 18 months compared to placebo.

[0006] More recent evidence, including genome-wide association studies (GWAS) and differential gene expression comparing normal to affected Alzheimer’s brain tissue, has identified risk and protective variants in genes such as TREM2, CD33. APOE, ABC A 7, PLCG2. and 1NPP5D, which are essential to microglia function. See Malik et al.. “Genetics ignite focus on microglial inflammation inAlzheimer's disease.” (2015) Mol Neurodegener 10: p. 52. Microglia are the non-neuronal, macrophage-like cells that serve as resident immune cells in the brain. See Vaughan et al., “Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study.” (1974) J Neurocytol 3: pp. 405-429.

[0007] During development microglia originate from stem cells in the yolk sac and differentiate into CD45+, CX3CR1+immune cells that migrate to the central nervous system (CNS). See Kierdorf et al., “Microglia emerge from erythromyeloid precursors via Pu.l- and Irf8-dependent pathways,” (2013) Nat Neurosci 16: pp. 273-280. Once resident, these cells renew slowly in humans at a rate of approximately 28% per year, thus providing a mechanism to renew microglia. See Reu et al., “The Lifespan and Turnover of Microglia in the Human Brain,” (2017) Cell Rep 20: pp. 779-784. Disease- associated microglia (DAM) have been characterized at sites of Ap plaques and neurodegeneration in animal models. See Keren-Shaul et al., “A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease,” (2017) Cell 169: pp. 1276-1290. Although their relevance to human microglia in AD remains a current area of intense study, they have gene signatures associated with lipid metabolism and phagocytosis hypothesized to reflect the neuroprotective role of microglia in the clearance of extracellular toxins. See Olah et al., “Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease.” (2020) Vat Commun 11: pp. 6129. A two-state model of DAM induction has been proposed, in which homeostatic microglia that are associated with and support the health of neurons become activated with increased expression of DAP J 2. APOE, and Triggering receptor expressed on myeloid cells-2 (TREM2). TREM2 ligands such as apolipoproteins (APOEs) and A induce microglial differentiation into stage 2 DAMs with increased expression of LP1. CST7, and AXL. Deczkowska et al., “Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration,” (2018) Cell 173: pp. 1073-1081; Keren-Shaul et al. 2017.

[0008] TREM2 is a receptor expressed on the surface of microglia. Genetic evidence suggests that lower TREM2 expression and inactivating variants increase risk of AD. See Jonsson et al., “Variant of TREM2 associated with the risk of Alzheimer's disease,” (2013) N Engl J Med 368: pp. 107-116. TREM2 binds Ap and APOE, which activates microgliosis and the clearance of extracellular debris. See Yeh et al., “TREM2 Binds to Apolipoproteins, Including APOE and CLU / APOJ. and Thereby Facilitates Uptake of Amyloid-Beta by Microglia,” (2016) Neuron 91: pp. 328-340. The 1REM2^Hvariant reduces the affinity of TREM2 ligands and cellular activation downstream, which requires DAP 12, an adapter protein on the intracellular side of the plasma membrane that associates with numerous signal transduction mediators. See Sudom et al., “Molecular basis for the loss-of-function effects of the Alzheimer's disease-associated R47H variant of the immune receptor TREM2,” (2018) J Biol Chem 293: pp. 12634-12646. For example, recruitment of SYK to phosphorylated tyrosine residues at the C-terminus of DAP12 mediates signaling through phosphorylation of PLCy2 and subsequent formation of intracellular IP3 and Ca2+release. See Konishi et al., “MicroglialTREM2 / DAP12 Signaling: A Double-Edged Sword in Neural Diseases,” (2018) Front Cell Neurosci 12: p. 206. Importantly, an activating variant of PLCG2. PLCG2P522Ris protective in AD. See Magno et al., “Alzheimer's disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph.” (2019) Alzheimer ’s Res Ther 11 : p. 16. This human genetic evidence suggests that certain microglial states increase the risk of neurodegeneration while others are protective, clearing A(3 oligomers and plaques, and mitigating an inflammatory microenvironment that is toxic to neurons. See Deczkowska et al., 2018.

[0009] The recent approval of the anti-amyloid antibodies Aducanumab, Lecanemab, and Donanemab provide evidence for the role of microglia in the treatment of AD. See Dunn et al., “Approval of Aducanumab for Alzheimer Disease-The FDA's Perspective,” (2021) JAMA Intern Med 181: pp. 1276- 1278. Cell-surface Fey receptors (FcyRs) on microglia recognize tire Fc portion of IgG antibodies triggering downstream effector functions. See Boumazos et al., “The role of IgG Fc receptors in antibody -dependent enhancement,” (2020) Nat Rev Immunol 20: pp. 633-643. The clearance of A deposits by Aducanumab has been demonstrated to occur by targeting Ap via the variable region of the antibody coupled to FcyR-mediated enhancement of microglia recruitment and phagocytosis. See Sevigny et al., “The antibody aducanumab reduces Abeta plaques in Alzheimer's disease,” (2016) Nature 537: pp. 50-56.

[0010] Lyn and Hck belong to the Src family tyrosine kinases (SFKs), where they share a similar structural architecture comprising multiple protein domains, including an N-terminal SH4 domain, a unique domain, SH3 and SH2 domains, and a catalytic SHI domain. See Brown et al. “Regulation, substrates and functions of src,” BBA-Rev Cancer. Jun 7 1996; 1287(2-3): 121-149. Even though the primary function of both kinases is to phosphorylate the tyrosine residues of various cellular targets, Lyn. in particular, phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) and immunoreceptor tyrosine-based inhibition motifs (ITIMs) of various activating and inhibitory cell surface receptors. See Ben et al, “Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation.” Nat Commun. Aug 15 2017;8, 246. In fact, Lyn is one of the few SFKs known to phosphory late ITAMs, along with Fyn and Lek. Interestingly, Lyn is the main SFK known to phosphorylate ITIMs associated with a wide range of inhibitory immune receptors, such as FcgRIIb, CD22, PIR-B. and SIRPla. See Weerawama et al, “Lyn Kinase Structure, Regulation, and Involvement in Neurodegenerative Diseases: A Mini Review.” Kinases and Phosphatases. 2023;l(l):23-38. In addition to Lyn, c-Fgr, a lesser-known SFK, is reported to phosphorylate ITIMs of SIRPla in macrophages. See Gresham et al, “Negative regulation of phagocytosis in murine macrophages by the Src kinase family member, Fgr”. J Exp Med. Feb 7 2000;191(3):515-528. Hck, on the other hand, can also phosphorylate specific tyrosine residues of receptors, such as CD36, that are not part of ITAMs or ITIMs. See Silverstein et al, “CD36, a Scavenger Receptor Involved in Immunity, Metabolism, Angiogenesis, and Behavior”. Sci Signal. May 262009;2(72). However, it mostly phosphorylates protein targets that have enzymatic functions, such as Vavl, Cbl, and Stat5. See Silverstein et al (2009), Bustelo et al, “Vav family exchange factors: an integrated regulatory and functional view.” Small GTPases. 2014;5(2):9, and Duan et al, “The Cbl family and other ubiquitin ligases: destructive forces in control of antigen receptor signaling. Immunity. Jul 2004;21(l):7-17”. Lyn expression is predominant in hematopoietic cells from both the myeloid and lymphoid lineages, excluding T cells. See Yamanashi et al. “Selective expression of a protein-tyrosine kinase, p561yn, in hematopoietic cells and association with production of human T-cell lymphotropic virus type I”. Proc Natl Acad Sci USA. Sep 1989;86(17):6538-42 and Yi et al, “Hematopoietic cells express two forms of lyn kinase differing by 21 amino acids in the amino terminus”. Mol Cell Biol. May 1991 ; 11 (5):2391 8. Additionally, Lyn is expressed in the brain, especially in microglia, implying the existence of shared signaling mechanisms between the immune and central nervous systems. See Umemori et al, “Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated ty rosine kinases, in the central nervous system”. Brain Res Mol Brain Res. Dec 1992;16(3-4):303-10. Similarly, Hck is also reported to be expressed in hematopoietic cells and in the brain. See Yi et al (1991) and Wang et al, “Hck Promotes Neuronal Apoptosis Following Intracerebral Hemorrhage”. Cell Mol Neurobiol . Mar 2017;37(2):251—261. Due to the expression of both kinases in hematopoietic cells, they have been linked to various cancers and autoimmune diseases. See Ingley et al., “Functions of the Lyn tyrosine kinase in health and disease”. Cell Commun Signal. Jul 17 2012;10 and Poh et al., “Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells”. Oncotarget. Jun 30 2015;6(18): 15752-15771.

[0011] The roles of Lyn and Hck in neurodegenerative diseases has recently been reported by others, with particular emphasis on Lyn as an emerging target for the treatment of such diseases. See Gwon et al. “Amelioration of amyloid beta-FcgammaRIIb neurotoxicity and tau pathologies by targeting LYN”. FASEB J. Mar 2019;33(3):4300-4313, and Lim et al, “Inhibition of hematopoietic cell kinase dysregulates microglial function and accelerates early stage Alzheimer's disease-like neuropathology”. Glia. Dec 2018;66(12):2700-2718. Detailed RNA sequencing of AD and aging brains has identified a particular subset known as disease-associated microglia (D AMs), present in both humans and mice. See Keren et al, “A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease”. Cell. Jun 15 2017;169(7): 1276-1290. According to the literature, microglial expression of Lyn increases in response to amyloid beta (A|3), a primary pathological indicator of AD, in mouse models. See Sierksma et al, “Novel Alzheimer risk genes determine the microglia response to amyloidbeta but not to TAU pathology .” EMBO Mol Med. Mar 62020; 12(3) :e 10606. A higher Lyn expression has also been found in human and mouse microglia compared to other Src family kinases (SFKs). See Portugal et al, “Src family kinases (SFKs): critical regulators of microglial homeostatic functions and neurodegeneration in Parkinson's and Alzheimer's diseases”. FEES J. Dec 2022;289(24):7760-7775. Furthermore, post-mortem AD patient brains have also shown elevated Lyn levels in microglia.Interestingly, the broad-spectrum Src kinase inhibitor PPI. which mainly targets Lyn, was shown to inhibit A^-triggered neurotoxin production and improve neuronal survival. See Combs et al, “Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins”. J Neurosci. Feb 1 1999;19(3):928-39. Additionally, independent studies have documented increased Lyn activation in mouse microglia exposed to Ap oligomers, akin to the microglia from the post-mortem AD patient brains. See Dhawan et al “Amyloid-beta oligomers stimulate microglia through a tyrosine kinase dependent mechanism”. Neurobiol Aging. Oct 2012;33(10):2247-61, and Sondag et al, Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J Neuroinflammation. Jan 5 2009;6:l. In a detailed study by Gwon et al., the role of Lyn in Alzheimer's disease (AD) was explored, revealing its significant involvement in amy loid beta (A )-induccd neurotoxicity' and tau hypcrphosphorylation via FcyRI Ib2 phosphorylation. See Gwon et al “Amelioration of amyloid beta-FcgammaRIIb neurotoxicity and tau pathologies by targeting LYN”. FASEB J. Mar 2019;33(3):4300-4313. The study observed a rapid increase in Lyn activity upon exposure to oligomeric A[! I -42 in mouse neuronal cells. They also found that Lyn activation was inhibited in FcyRI Ib2 knockout neurons, suggesting that Fc RI Ib2- A[J 1- 42 interactions mediated the activation of Lyn. An analysis of AD patient brain tissue revealed a threefold increase in Lyn's autophosphorylation in the hippocampus compared to non-AD controls. Further experimentations confirmed the direct phosphorylation of the FcyRIIb2 ITIM at Tyr273 by Lyn upon exposure to oligomeric A[31 42. Interestingly, the knockdown of Lyn expression significantly suppressed A|31-42 -induced cell death in neuroblastoma and hippocampal cell lines, underscoring Lyn's role in countering Ap 1-42 -induced neurotoxicity. Additionally, phosphorylated FcyRIIb2 by Lyn was found to recruit SHIP2 to FcyRIIb2, leading to tau-hyperphosphorylation. Lastly, a novel Lyn inhibitor (KICG2576) was shown to lessen A -FcyRIIb2 -mediated neuronal cell death and rescue A - induced memory impainnent in mice. Overall, this study establishes the role of Lyn in Alzheimer's disease in the context of amyloid P (AP 1-42) -triggered neurotoxicity and tau hyperphosphorylation, which are the main pathological features of Alzheimer's disease.

[0012] A role for Lyn in receptor-mediated microglial modulation can be hypothesized based on the involvement of various activation and inhibitory immune receptors and adaptor proteins bearing ITAM and ITIMs such as DAP12. CD33, and FcgRIIb in the process. Based on literature findings related to myeloid cells, several roles of Lyn in receptor-mediated microglial modulation and phagocytosis can be postulated. The phosphorylation of inhibitor} immune receptors such as CD33 and FcgRIIb by Lyn suggests receptor-mediated microglial modulation through the activation of phosphatases such as SHIP1 and SHP1. In addition, Lyn can directly activate these phosphatases by phosphorylating them. Therefore, it could be hypothesized that inhibiting Lyn would enhance receptor-mediated microglial phagocytosis, which is known to be beneficial for treating early -stage Alzheimer's disease. On the other hand, inhibiting Hck, another Src kinase, might have different effects. Thus, when using Src kinaseinhibitors to evaluate the role of Lyn kinase in receptor-mediated microglial activation and phagocytosis, it's crucial to use inhibitors with significant selectivity for Lyn over Hck.SUMMARY OF THE DISCLOSURE

[0013] Taken together, this understanding of Lyn involvement in microglial modulation as a limiting node dow nstream from TREM2 and FCyRIIB suggests that inhibition of Lyn w ould activate microglia, and would therefore be an effective therapeutic strategy7in disease. The inventors also believe that this therapeutic intervention could be synergistically combined with anti-amyloid and / or TREM2 agonist antibodies. Therefore, inhibitors of Lyn would increase the protective functions of microglia and could therefore be used to prevent or treat disease, reduce the rate of disease progression and cognitive decline in patients, and reverse neurodegeneration.

[0014] The present disclosure provides novel compounds that are Lyn inhibitors that address the need for a potent and effective treatment for Alzheimer's Disease and Alzheimer's Disease-related Dementias. The present disclosure also provides a pharmacal composition for the prevention of Alzheimer's Disease and Alzheimer's Disease-related Dementias.

[0015] The inventors first performed a virtual screening against Lyn kinase and identified several hits that inhibited Lyn kinase according to the HotSpot kinase assay. Starting from these hits, the inventors designed and synthesized a novel and structurally diverse series of compounds as potent Lyn inhibitors.

[0016] Disclosed herein are compounds of Formula (I), Formula (II). or Formula (III):

[0017] or a pharmaceutically acceptable salt thereof; wherein:

[0018] X is -CH2- or a bond;

[0019] Y is carbonyl of -NH-;

[0020] Z is carbonyl or -NH-; and

[0021] Ri, R2, R3. R4, RS, R«, R7, and R8are independently -H, -F. -CL -Br, -CH3, -OCH3. -CF3, or N- (morpholinmethy 1) ,

[0022] provided that the compound of Formula (III) is not

[0023] Further disclosed herein are methods for treating Alzheimer's disease in a patient in need thereof, which comprises administering to the patient a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Furthermore, the present disclosure encompasses a method for treating Alzheimer's disease-related dementias in a patient, comprising administering to a patient in need thereof a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. The present disclosure further provides a method of treating the progression of mild cognitive impairment to Alzheimer's disease or related dementias in a patient, comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure. The present disclosure further provides a method of preventing Alzheimer's disease or Alzheimer's disease-related dementias, comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure.

[0024] Also disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent.

[0025] In a further embodiment, the present disclosure provides a pharmaceutical composition for the treatment of Alzheimer's disease, comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients. In yet another embodiment, the present disclosure provides a pharmaceutical composition for the treatment of Alzheimer's disease-related dementias, comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more carriers, diluents, or pharmaceutically acceptable excipients. In yet another embodiment, the present disclosure provides a pharmaceutical composition for the prevention of Alzheimer's disease and Alzheimer's disease-related dementias, comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more carriers, diluents, or pharmaceutically acceptable excipients.

[0026] Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy, in particular for the treatment of Alzheimer's disease. Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of Alzheimer's disease. In a further embodiment, the present disclosure provides the use of a compound of the disclosure, of or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Alzheimer's disease.

[0027] In other embodiments, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy, in particular for the treatment of Alzheimer's disease -related dementias. Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of Alzheimer's disease- related dementias. In a further embodiment, the present disclosure provides the use of a compound ofthe disclosure, of or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Alzheimer's disease-related dementias.

[0028] Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the prevention of Alzheimer's disease and Alzheimer's disease -related dementias. Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the prevention of Alzheimer's disease and Alzheimer's disease-related dementias. In a further embodiment, the present disclosure provides the use of a compound of the disclosure, of or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the prevention of Alzheimer's disease and Alzheimer's disease-related dementias.

[0029] The present disclosure also encompasses intennediates and processes useful for the synthesis of a compound of the present disclosure.

[0030] Alzheimer’s disease-related dementias (ADRD) include Lewy body dementia (LBD), frontotemporal degeneration (FTD), vascular cognitive impairment and dementia (VCID), and multiple etiology dementias. Mild cognitive impairment is defined as the potential prodromal phase of dementia associated with Alzheimer's disease based on clinical presentation and on progression of patients exhibiting mild cognitive impairment to Alzheimer's disease over time. See Morris et al., “Mild cognitive impairment represents early-stage Alzheimer disease.” (2001) Arch Neurol 58: pp. 397-405; Petersen et al., “Mild cognitive impairment: clinical characterization and outcome,” (1999) Arch Neurol 56: pp. 303-308.

[0031] These and other embodiments and features of the disclosure will become more apparent through reference to the following description, and the claims. Furthermore, it is to be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and permutations.BRIEF DESCRIPTION OF THE FIGURES

[0032] Figure (“FIG.”) 1 provides general scheme I, in accordance with embodiments described herein.

[0033] FIG. 2 provides general scheme II, in accordance with embodiments described herein.

[0034] FIG. 3 provides general scheme III, in accordance with embodiments described herein.

[0035] FIG. 4 depicts kinome profiling data for Compound 1 at 1 pM inhibitor concentration (panel A) and Compound 17 at 10 pM inhibitor concentration (panel B).DETAILED DESCRIPTION

[0036] Various quantities, such as amounts, sizes, dimensions, proportions, and the like, are presented in a range format throughout this disclosure. It should be understood that the description of a quantityin range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of any embodiment. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as all individual numerical values within that range unless the context clearly dictates otherwise. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual values within that range, for example, 1.1, 2, 2.3, 4.62. 5, and 5.9. This applies regardless of the breadth of the range. The upper and lower limits of these intervening ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits arc also included in the disclosure, unless the context clearly dictates otherwise.

[0037] The terminology used herein is to describe particular embodiments only and is not intended to be limiting of any embodiment. As used herein, the singular forms “a,” “an”, and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “includes”, “comprises”, “including” and / or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. Additionally , it should be appreciated that items included in a list in the form of “at least one of A, B. and C” can mean (A); (B); (C); (A and B); (B and C); (A and C); or (A, B, and C). Similarly, items listed in the form of “at least one of A, B, or C” can mean (A); (B); (C); (A and B); (B and C); (A and C); or (A. B, and C).

[0038] Unless expressly stated or obvious from context, as used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers + / - 10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.

[0039] In any of the embodiments disclosed herein, the term “treating the progression of mild cognitive impairment to Alzheimer's disease” includes restraining, slowing, stopping, or reversing the progression of mild cognitive impairment to Alzheimer's disease in a patient.

[0040] In any of the embodiments disclosed herein, the terms “treating” or “to treat” includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.

[0041] In any of the embodiments disclosed herein, the term “patient” may refer to a human. In any of the embodiments disclosed herein, the term "patient” refers to a human.

[0042] A compound of the present disclosure can react to form pharmaceutically acceptable salts. Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, for example, P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection and Use (Manual of Pharmaceutical Salts: Properties, Selection and Use), 2nd revised edition (Wiley-VCH, 2011); SM Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0043] For example, disclosed herein arc compounds of Formula (I), Formula (II), or Formula (III):

[0044] or a pharmaceutically acceptable salt thereof; wherein:X is -CH2- or a bond;Y is carbonyl or -NH-;Z is carbonyl or -NH-; andRi, R2, R3. R4, Rs, R' - R7, and Rs are independently -H, -F, -Cl. -Br, -CH3, -OCH3. -CF3, or N- (morpholinomethyl). provided that the compound of Formula (III) is not

[0045] In other embodiments, the present disclosure encompasses a method for treating Alzheimer's disease in a patient in need thereof, which comprises administering to the patient a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Furthermore, the present disclosure encompasses a method for treating Alzheimer's disease-related dementias in a patient in need thereof, comprising administering to the patient a compound of the present disclosure or a pharmaceutically acceptable salt thereof. The present disclosure further provides a method of treating the progression of mild cognitive impairment to Alzheimer's disease or related dementias in a patient in need thereof, comprising administering to the patient an effective amount of a compound of the present disclosure. The present disclosure further provides a method of preventing Alzheimer's disease or Alzheimer's disease-related dementias in a patient in need thereof, comprising administering to the patient an effective amount of a compound of the present disclosure.

[0046] The present disclosure provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients. In another embodiment, the compositionfurther comprises one or more additional therapeutic agents. In a further embodiment, the present disclosure provides a pharmaceutical composition for the treatment of Alzheimer's disease, comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients. In yet another embodiment, the present disclosure provides a pharmaceutical composition for the treatment of Alzheimer's disease- related dementias, comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more carriers, diluents, or pharmaceutically acceptable excipients. In yet another embodiment, the present disclosure provides a pharmaceutical composition for the prevention of Alzheimer's disease and Alzheimer's disease-related dementias, comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more carriers, diluents, or pharmaceutically acceptable excipients.

[0047] Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy, for example, for the treatment of Alzheimer's disease. Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of Alzheimer's disease. In a further embodiment, the present disclosure provides the use of a compound of the disclosure, of or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Alzheimer's disease.

[0048] In other embodiments, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy, for example, for the treatment of Alzheimer's disease -related dementias. Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of Alzheimer's disease- related dementias. Tn a further embodiment, the present disclosure provides the use of a compound of the disclosure, of or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Alzheimer's disease-related dementias.

[0049] Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the prevention of Alzheimer's disease and Alzheimer's disease -related dementias. Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the prevention of Alzheimer's disease and Alzheimer's disease-related dementias. In a further embodiment, the present disclosure provides the use of a compound of the disclosure, of or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the prevention of Alzheimer's disease and Alzheimer's disease-related dementias.

[0050] The present disclosure also encompasses intermediates and processes useful for the synthesis of a compound of the present disclosure.

[0051] In some embodiments, the disclosure provides for a composition comprising a Lyn inhibitor for use in combination with an antibody or antigen-binding fragment for treating Alzheimer's disease and Alzheimer's disease-related dementias.

[0052] Excipients

[0053] Illustrative, non-limiting examples of excipients or carriers include sodium citrate or dicalcium phosphate and / or a) one or more fillers or extenders (a fdler or extender may be, but is not limited to, one or more selected from starches, lactose, sucrose, glucose, mannitol, and silicic acid), b) one or more binders (binders may be selected from, but not limited to, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), c) one or more humectants (a humectant may be, but is not limited to. glycerol), d) one or more disintegrating agents (disintegrating agents may be selected from, but are not limited to. agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, silicates, and sodium carbonate), e) one or more solution retarding agents (for example, but not limited to, paraffin), f) one or more absorption accelerators (selected from, but not limited to. quaternary ammonium compounds), g) one or more wetting agents (for example, but not limited to. acetyl alcohol and glycerol monostearate), h) one or more absorbents (selected from, but not limited to, kaolin and bentonite clay), and i) one or more lubricants (selected from, but not limited to. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate). In the case of capsules, tablets and pills, for example, the dosage form may also comprise buffering agents.

[0054] “Effective or Therapeutic Amount”

[0055] Effective or therapeutic amounts of the compositions of this disclosure include any amount sufficient to inhibit (e.g., slow or stop) the progression of a neurode generative disorder. In some embodiments, effective amounts of the compositions include any amount sufficient to inhibit (e.g., slow or stop) the deterioration of the cognitive function of a patient.

[0056] The amount of the active ingredient that may be combined with the optional carrier materials to produce a single dosage form may vary depending upon the host treated and the particular mode of administration. The specific dose level for any particular patient may depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disorder or disease undergoing therapy. A therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.

[0057] Clauses

[0058] 1. A compound of Formula I, Formula (II), or Formula (III):(I) (II) (III); or a pharmaceutically acceptable salt thereof; wherein:X is -CH2- or a bond;Y is carbonyl or -NH-;Z is carbonyl or -NH-; andRi, R2, R3, R4, Rs, Re, R7, and Rs are independently -H, -F, -Cl, -Br. -CH3, OCH3, - CF3, or N-(morpholinomethyl), provided that the compound of Formula (III) is not

[0059] 2. The compound of clause 1. wherein X is -CH2-.

[0060] 3. The compound of clause 1, wherein X is a bond.

[0061] 4. The compound of clause 1, wherein Y is carbonyl.

[0062] 5. The compound of clause 1, wherein Y is -NH-.

[0063] 6. The compound of clause 1, wherein Z is carbonyl.

[0064] 7. The compound of clause 1, wherein Z is -NH-.

[0065] 8. The compound of any one of clauses 1-7, wherein Z is carbonyl and X is a bond.

[0066] 9. The compound of clause 1, wherein the compound is represented by:

[0067] 10. A pharmaceutical composition comprising a compound of any one of clauses 1-7 or 9 and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0068] 11. The pharmaceutical composition of clause 10, further comprising one or more one or more additional therapeutic agents.

[0069] 12. A method of treating a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of clauses 1-7 or 9, or a pharmaceutically acceptable salt thereof.

[0070] 13. A method of treating a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical composition of clause 10.

[0071] 14. A method for treating the progression of a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of clauses 1-7 or 9, or a pharmaceutically acceptable salt thereof.

[0072] 15. A method for treating the progression of a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount the pharmaceutical composition of clause 10.

[0073] 16. A method of preventing a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount of a compotmd of any one of clauses 1-7 or 9, or a pharmaceutically acceptable salt thereof.

[0074] 17. A method of preventing a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to die patient an effective amount of the pharmaceutical composition of clause 10.

[0075] 18. The method of any one of clauses 13, 15. or 17, further comprising administering one or more additional therapeutic agents.

[0076] 19. The method of clause 12, further comprising administering one or more additional therapeutic agents.

[0077] 20. The method of clause 14, further comprising administering one or more additional therapeutic agents.

[0078] 21. The method of clause 16, further comprising administering one or more additional therapeutic agents.EXAMPLES

[0079] The following examples are provided for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are provided only as examples, and are not intended as limitations on the scope of the disclosure. Changes therein and other uses that are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.

[0080] General Methods and Assays

[0081] Hotspot Kinase Assay Protocol. The assay was carried out at Reaction Biology’ Corporation according to a previously described protocol. The corresponding substrate was first prepared in a freshly constituted base reaction buffer (20 mM 4-(2 -hydroxy ethyl)-l -piperazineethanesulfonic acid (HEPES) (pH 7.5), 10 mM MgC12, 1 mM ethylene glycol-bis(P-aminoethyl cthciJ-ACA.A'.A'-tctraacctic acid (EGTA), 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM Na;,VO i. 2 mM dithiothreitol (DTT), 1% dimethyl sulfoxide (DMSO)) and necessary cofactors were introduced to the substrate solution. After that, the kinase was added, ensuring gentle mixing for a homogeneous solution. Using the Echo550 acoustic technology, inhibitors dissolved in 100% DMSO (10 mM) were introduced into the kinase-substrate-cofactor mixture in nanoliter volumes to create a 10-point, three-fold dilution series starting from 100, 10, or 1 pM inhibitor concentrations. This mixture was subsequently incubated at room temperature for 20 minutes to facilitate optimal interactions. The kinase reaction was initiated by adding33P-ATP (lOpM) into the mixture. Following this, the reaction was allowed to proceed for 2 hours at room temperature to ensure completion. After the incubation, the kinase activity was detected using the P81 filter-binding method. The inhibitor activities of the compounds are given in Table 2, below.

[0082] Synthetic Procedures: Compounds 1 to 14, having the general formula I, were prepared according to General Scheme I, as shown in FIG. 1. In General Scheme I, intermediate B was synthesized by reacting the commercially available bromide intermediate A with carbon monoxide under the specified conditions. The resulting product was then subjected to hydrolysis with a base under the specified conditions to obtain intermediate C. Intermediate F was prepared by reacting the corresponding amine (intermediate D), having various substitutions as specified in Formula I, with commercially available intermediate E (where Ri can be either H or F) under the amide coupling conditions specified in General Scheme I. After that, the nitro functional group of intermediate F was converted to an amine to obtain intermediate G under the specified conditions. Intermediate G was then coupled with intermediate C under the amide coupling conditions given in General Scheme I to obtain compounds 1 to 14.

[0083] Compounds 15 to 17. having the general formula II, were prepared according to General Scheme II, as shown in FIG. 2. In General Scheme II, the corresponding key heteroarylbromide intermediates L and R were synthesized by a series of chemical transformations starting from commercially available intermediates H and M, respectively, under the specified conditions. After that, these bromides, or the commercially available bromide intermediate S, were subjected to Buchwald amination with intermediate G (whose preparation is given in General Scheme I (FIG. 1), where Ri = H and X is a bond) under the specified conditions to obtain compounds 15 to 17.

[0084] Compounds 19 to 23, having the general formula III, were prepared according to General Scheme III, as shown in FIG. 3. In General Scheme III, the key ester intermediate U was prepared by reacting the commercially available heteroarylbromide with carbon monoxide under the specified conditions. The key amine intermediate Y was prepared as shown in General Scheme III by first reacting the commercially available amine intermediate V with the commercially available acid intermediate W under amide coupling conditions to obtain intermediate X, followed by conversion of the nitro functionality to an amine in the presence of Zn dust as shown in General Scheme III to yield intermediate Y. After that, intermediate G (for compounds 19 to 21), prepared according to the specified conditions in General Scheme I (FIG. 1), or intennediate Y (for compounds 22 to 23), was reacted with ester intennediate U in the presence of TMA to obtain compounds 19 to 23.

[0085] Kinobeads Kinome Profiling Protocol. BV2 cells were lysed using Lysis buffer (0.8% NP40, 50 mM Tris-HCl pH 7.5, 5% glycerol, 1.5 mM MgC12, 150 mM NaCl, 1 mM Na3VO4, 25 mM NaF,1 mM DTT. supplemented with protease inhibitors (SigmaFast, Sigma), and phosphatase inhibitors), and the protein concentration was adjusted to 5 mg / mL. A kinase inhibitor was introduced into 1 mL lysate at concentrations of 10 nM. 100 nM, and 1 pM (including a DMSO control), followed by incubation for 45 min at 4°C. Subsequently, the mixture was further incubated with 35 pL settled kinobeads for 30 min at 4°C. Proteins adhering to the kinobeads were eluted using the LDS sample buffer (NuPAGE, Invitrogen) containing 50 mM DTT and stored until required. Kinobeads eluates were then alkylated with chloroacetamide (55 mM) and run on a 4-12% NuPAGE gel (Invitrogen) for approximately 1 cm. Standard procedures were used for in-gel digestion. The resulting peptides were analyzed using LC-MS / MS on a nanoLC-Ultra 1D+ (Eksigent) connected to an LTQ Orbitrap Elite mass spectrometer (Thermo Fisher Scientific). Peptide and protein identification, as well as quantification, were carried out using MaxQuant (version 1.5.3.30)51 by searching the MS2 data against all canonical protein sequences annotated in the Swissprot reference database (consisting solely of human proteins, 20, 193 entries, internally annotated with PFAM domains) with the embedded search engine Andromeda.

[0086] HPLC Procedure. Reaction monitoring liquid chromatography-mass spectrometry (LC-MS) and high-performance liquid chromatography (HPLC) purity data were obtained on a Waters Acquity UPLC system equipped with a Waters Acquity BEH C18 column (1.7 pm. 50 mm x 2.1 mm) or other specified column (below), and either TUV and SQD2 detectors or PDA and QDa detectors. Flash NP or RP chromatography were performed on a Teledyne-ISCO NextGen 300 instrument using prepacked silica gel or C18-functionalized silica gel columns available from Teledyne-ISCO, or on a Teledyne- ISCO Combiflash using prepacked silica gel columns available from Agela or Welch. Preparative RP HPLC was performed on a Waters AutoPurification HPLC system equipped with PDA and ELSD detectors and a Waters XBridge C18 Prep column (10 pm, 250 mm x 19 mm). All compounds had >95% purity as determined by LC-MS. Following specific LC-MS method was used to determine test compound purity:

[0087] Method: gradient table C; column Shimadzu Nexcol C18 (5 pm, 50 mm x 3.0 mm); mobile phase A, 1% formic acid in H2O; mobile phase B, 1% formic acid in acetonitrile (ACN); flow rate, 0.5 mL / min; detection wavelength, 214 nM; column temperature, 40 °C.

[0088] Compounds

[0089] Example 1

[0090] Compound 1

[0091] N-(2-inethyl-5-((3 -(trifluoromethyl)phenyl)carbamoy l)phenyl)-6,7-dihy dro-5H-pyrrolo [1,2- a] imidazole -3 -carboxamide

[0092] Compound 1 was synthesized according to general scheme I. ’H NMR (400 MHz, DMSO) 5 10.49 (s, 1H), 9.76 (s, 1H), 8.24 (t,J= 2.0 Hz. 1H), 8.11 - 8.04 (m. 1H), 7.95 (d, J= 1.9 Hz, 1H), 7.85 - 7.78 (m. 2H), 7.60 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 4.16 (t. J = 7.1 Hz, 2H), 2.80 (t, J = 7.6 Hz, 2H). 2.56 (q. J= 1.3 Hz, 3H). 2.31 (s, 3H); LRMS m / z (ESI+): 429.40 [M+H]+.

[0093] Example 2

[0094] Compound 2

[0095] N-(2-methyl-5-((2-(trifluoromethyl)benzyl)carbamoyl)phenyl)-6,7-dihydro-5H-pyrrolo[l,2- a] imidazole -3 -carboxamideCompound 2 was synthesized according to general scheme I.1H NMR: (400 MHz, DMSO) 6 10.16 (s, 1H), 9.12 (t, J = 5.9 Hz, 1H), 8.13 (s, 1H). 7.87 (d,J = 1.8 Hz, 1H), 7.80 (dd, J= 8.0, 1.9 Hz, 1H), 7.77 - 7.71 (in. 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.44 (t. J = 7.9 Hz, 1H). 4.66 (d. J = 5.6 Hz, 2H), 4.31 (t, J = 7.3 Hz, 2H), 3.03 (d, J= 7.7 Hz. 2H), 2.63 (d, J= 7.4 Hz, 2H). 2.28 (s, 3H); LRMS m / z (ESI+): 443.20 [M+H]1.

[0096] Example 3

[0097] Compound 3

[0098] N-(5-((2-chlorobenzyl)carbamoyl)-2-methylphenyl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole- 3-carboxamideCompound 3 was synthesized according to general scheme I.1H NMR: (400 MHz, DMSO) 5 10.16 (s, 1H), 9.06 (t, J= 5.9 Hz, 1H), 8.13 (s, 1H), 7.86 (d,J = 1.8 Hz, 1H), 7.79 (dd, J= 7.9, 1.9 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.37 - 7.28 (m, 3H), 4.54 (d, J = 5.7 Hz, 2H), 4.36 - 4.28 (m, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.65 (t, J= 7.0 Hz, 3H), 2.28 (s, 3H); LRMS m / z (ESI+): 409.15 [M+H]+.

[0099] Example 4

[0100] Compound 4

[0101] N-(2-methyl-5-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)-6.7-dihydro-5H- pyrrolo[ 1.2-a]imidazole-3-carboxamideCompound 4 was synthesized according to general scheme I.1H NMR: (400 MHz, DMSO) 8 10.14 (s, 1H), 9.15 (t, .7 = 6.0 Hz, 1H), 8.13 (s, 1H), 7.84 (d,J = 1.8 Hz, 1H), 7.75 (dd, J = 1.9. 1.9 Hz, 1H), 7.68 - 7.53 (m, 4H), 7.41 (d, J = 8.0 Hz, 1H), 4.55 (d, J = 5.9 Hz. 2H), 4.31 (dd. J = 8.2, 6.3 Hz, 2H), 3.04 (s, 2H), 2.65 (q, J = 7.6 Hz, 2H), 2.27 (s, 3H); LRMS m / z (ESI+): 443.40 [M+H]+.

[0102] Example 5

[0103] Compound 5

[0104] N-(2-methyl-5-((4-(morpholinomethyl)phenyl)carbamoyl)phenyl)-6,7-dihydro-5H- py rrolo [ 1.2-a] imidazole-3 -carboxamideCompound 5 was synthesized according to general scheme I. ' H NMR: (400 MHz, DMSO) 8 8.12 (s, 1H). 7.84 (d. J = 1.9 Hz, 1H). 7.79 (td, J = 7.5, 2.0 Hz. 3H), 7.46 (dd. J = 8.6, 2.9 Hz, 3H). 4.32 (t,J =7.3 Hz, 2H), 4.26 (s, 2H). 4.02 - 3.93 (m, 2H). 3.60 (s, 2H). 3.21 (s. 2H), 3.07 (t. J= 7.7 Hz, 5H). 2.66 (p. J= 8.0 Hz, 3H), 2.27 (s. 3H); LRMS m / z (ESI+): 460.40 [M+H]+.

[0105] Example 6

[0106] Compound 6

[0107] N-(2-methyl-5-((3-(morpholinomethyl)phenyl)carbamoyl)phenyl)-6,7-dihydro-5H- py rrolo [ 1 ,2-a] imidazole-3 -carboxamideCompound 6 was synthesized according to general scheme I. 'H NMR: 1H NMR (400 MHz, DMSO) 5 10.40 (s, 1H), 10.10 (s, 1H). 8.09 (s, 2H). 7.93 (d. J = 1.9 Hz, 1H), 7.83 (dd,J= 8.0, 1.9 Hz, 1H). 7.72 (dd, J= 8.0, 2.1 Hz, 1H). 7.47 (dt, J= 1.9, 3.9 Hz. 2H), 7.24 (d, J= 7.6 Hz. 1H), 4.35 (s, 2H), 4.28 (t, J= 7.2 Hz, 2H), 3.95 (s, 2H), 3.64 (s. 2H), 3.16 (s, 4H), 3.00 (t, J= 7.7 Hz, 2H), 2.62 (q, J = 7.5 Hz, 2H). 2.31 (s, 3H); LRMS m / z (ESI+): 460.40 [M+H]+.

[0108] Example 7

[0109] Compound 7

[0110] N-(5-((2 -bromobe nzyl)carbamoyl)-2-methylphenyl)-6,7-dihydro-5H-pyrrolo[ 1,2- a] imidazole -3 -carboxamideCompound 7 was synthesized according to general scheme I. ’H NMR: 400 MHz, DMSO 5 10.16 (s. 1H), 9.07 (t, J = 5.8 Hz, 1H), 8.13 (s, 1H). 7.86 (d,J= 1.8 Hz, 1H), 7.79 (dd, J = 7.9, 1.9 Hz, 1H), 7.63 (dd, J = 7.9, 1.2 Hz, 1H). 7.42 (d. J = 8.0 Hz, 1H). 7.39 - 7.28 (m, 2H). 7.22 (td, J = 7.5. 2.0 Hz. 1H), 4.50 (d, J = 5.7 Hz, 2H), 4.32 (t, J = 7.3 Hz. 2H), 3.05 (s, 2H). 2.63 (d. J = 7.5 Hz, 2H). 2.28 (s. 3H); LRMS m / z (ESI+): 453.30 [M+H]+.

[0111] Example 8

[0112] Compound s

[0113] N-(5-((2-methoxybenzyl)carbamoyl)-2-methylphenyl)-6,7-dihydro-5H-pyrrolo[l,2- a] imidazole -3 -carboxamideCompound 8 was synthesized according to general scheme I.NMR: (400 MHz, DMSO) 6 7.80 - 7.72 (m, 2H), 7.67 (dd, J= 8.0, 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.13 (d,J = 7.1 Hz, 1H), 6.97 (d, J= 8.2 Hz, 1H), 6.92 - 6.81 (m, 2H), 4.40 (s, 2H), 4.12 (t, J = 7.2 Hz, 2H), 2.76 (t, J= 7.4 Hz, 2H), 2.23 (s, 3H); LRMS m / z (ESI+): 405.20 [M+H]+.

[0114] Example 9

[0115] Compound 9

[0116] N-(2-methyl-5-(phenylcarbamoyl)phenyl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole-3-carboxamideCompound 9 was synthesized according to general scheme I.1H NMR: (400 MHz, DMSO) 5 10.23 (s, 1H), 10.19 (s, 1H), 8.15 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 7.9, 1.9 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.15 - 7.06 (m, 1H), 4.32 (t, J = 7.2 Hz, 2H), 3.05 (t, J= 7.7 Hz, 2H), 2.64 (q, J= 7.3 Hz, 2H), 2.30 (s, 3H); LRMS m / z (ESI+): 361.20 [M+H]+.

[0117] Example 10

[0118] Compound 10

[0119] N-(5-((3-fhiorophenyl)carbamoyl)-2-methylphenyl)-6,7-dihydro-5H-pyrrolo[l,2- a] imidazole -3 -carboxamideCompound 10 was synthesized according to general scheme I. 'H NMR: 400 MHz, DMSO 8 10.41 (s,1H). 10.15 (s, 1H). 8.11 (s, 1H). 7.91 (d. J= 1.9 Hz, 1H). 7.84 (dd,J = 7.9, 1.9 Hz. 1H), 7.75 (dt, J = 11.8, 2.3 Hz. 1H), 7.57 (dd. J= 8.4, 2.2 Hz, 1H). 7.47 (d. J = 8.0 Hz, 1H). 7.39 (td. J = 8.3. 6.8 Hz, 1H). 6.94 (td, .7 = 8.0, 2.4 Hz. 1H), 4.30 (t..7= 7.2 Hz, 2H). 3.02 (t, .7= 7.7 Hz, 3H), 2.63 (q,.7= 7.4 Hz, 3H). 2.31 (s, 3H); LRMS m / z (ESI+): 379.25 [M+H]+.

[0120] Example 11

[0121] Compound 11

[0122] N-(2-methyl-5-((2-methylbenzyl)carbamoyl)phenyl)-6.7-dihydro-5H-pyrrolo[l,2- a] imidazole -3 -carboxamideCompound 11 was synthesized according to general scheme I. ' H NMR: 400 MHz, DMSO 5 10.15 (s, 1H), 8.91 (t. .7= 5.8 Hz, 1H). 8.13 (s, 1H). 7.84 (d.J = 1.8 Hz, 1H). 7.77 (dd, J = 1.9, 1.9 Hz. 1H), 7.40 (d. J = 8.0 Hz, 1H), 7.26 - 7.19 (m, 1H). 7.19 - 7.12 (m, 3H). 4.45 (d. J = 5.7 Hz, 2H). 4.35 - 4.27 (m, 2H). 3.04 (s, 2H). 2.64 (p. J= 7.8 Hz. 3H), 2.32 (s. 3H), 2.27 (s, 3H); LRMS m / z (ESI+) 389.25 [M+H]+.

[0123] Example 12

[0124] Compound 12

[0125] N-(5-((2-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-6.7-dihydro-5H-pyrrolo [ 1 ,2-a] imidazole-3-carboxamideCompound 12 was synthesized according to general scheme I.1H NMR: 400 MHz, DMSO 6 10.37 (s, 1H), 10.20 (s, 1H), 8.15 (s. 1H), 8.06 (dd. J = 6.9, 2.4 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.86 (dd, J = 8.0, 1.9 Hz, 1H). 7.68 (ddd, J = 8.6. 4.4. 2.4 Hz, 1H), 7.57 (t, J = 9.4 Hz, 1H), 7.49 (d,J= 8.1 Hz, 1H), 4.33 (t, J= 7.2 Hz. 2H), 3.05 (t, J = 7.7 Hz, 2H). 2.71 - 2.59 (m, 3H). 2.31 (s, 3H); LRMS m / z (ESI+): 447.05 [M+H]+.

[0126] Example 13

[0127] Compound 13

[0128] N-(5-((2-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-6.7-dihydro-5H-pyrrolo [ 1 ,2-a] imidazole-3-carboxamideCompound 13 was synthesized according to general scheme I. 'H NMR: 400 MHz, DMSO 5 10.40 (s, 1H), 10.25 (s, 1H). 8.19 (s, 1H), 7.97 - 7.90 (m, 2H), 7.87 (dd, J= 7.9, 2.0 Hz, 1H), 7.66 (s, 1H), 7.52 - 7.41 (m, 2H), 4.34 (t, J = 7.2 Hz, 2H), 3.08 (s, 2H), 2.66 (dt, J = 14.5, 7.7 Hz, 2H), 2.32 (s, 3H); LRMS in / z (ESI+): 447.05 [M+H]+.

[0129] Example 14

[0130] Compound 14

[0131] N-(4-fluoro-2-methyl-5-((3-(trifluoromethyl)plienyl)carbamoyl)phenyl)-6,7-dihydro-5H-pyrrolo| l,2-a|imidazole-3-carboxamideCompound 14 was synthesized according to general scheme I. *H NMR: 400 MHz. DMSO 5 10.68 (s. 1H), 9.73 (s. 1H), 8.19 (t, J= 2.0 Hz, 1H). 7.95 (d, J= 8.5 Hz, 1H), 7.78 (s, 1H), 7.60 (dt, J= 8.1, 4.6 Hz, 2H). 7.47 (ddd. J = 7.7. 1.9. 1.0 Hz, 1H). 7.33 (d. J= 10.9 Hz. 1H), 4.13 (t, J= 1A Hz, 2H). 2.82 - 2.73 (m. 2H), 2.60 - 2.52 (m, 2H), 2.28 (s. 3H); LRMS m / z (ESI+): 447.40 [M+H]+.

[0132] Example 15

[0133] Compound 15

[0134] 3-((6-fluoroimidazo[l,5-a]pyridin-8-yl)amino)-4-methyl-N-(3-(trifluoromethyl)phenyl) benzamideCompound 15 was synthesized according to general scheme II. ’H NMR (400 MHz, DMSO) 5 10.49 (s. 1H), 8.46 (s, 1H), 8.33 - 8.28 (m. 1H), 8.23 (t, J = 2.1 Hz, 1H). 8.09 - 8.03 (m, 1H). 8.02 - 7.96 (m, 1H). 7.93 (d, .7= 1.9 Hz, 1H), 7.87 (dd, J= 8.0, 2.0 Hz. 1H), 7.70 (s. 1H), 7.59 (t, .7= 8.0 Hz, 1H). 7.54 (d, .7= 8.0 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 5.45 (dd, J= 10.9, 1.8 Hz. 1H), 2.30 (s, 3H); LRMS m / z (ESI+): 429.00 [M+H]+.

[0135] Example 16

[0136] Compound 16

[0137] 3-((5-fluoroimidazo[l,5-a]pyridin-8-yl)amino)-4-methyl-N-(3-(trifluoromethyl)phenyl) benzamideCompound 16 was synthesized according to general scheme II. ' l l NMR: 400 MHz, DMSO 3 10.45 (s, 1H), 8.60 (s, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.03 (dd, .7= 8.0, 2.1 Hz, 1H), 7.96 (s, 1H), 7.80 - 7.70 (m, 3H), 7.58 (t, J= 8.0 Hz, 2H), 7.46 (dd, J= 13.3, 7.9 Hz, 3H), 6.45 (dd, J= 7.8, 5.7 Hz, 1H), 5.75 (dd. J= 7.8, 4.4 Hz, 1H). 2.30 (s, 3H); LRMS m / z (ESI+): 429.05 [M+H]+.

[0138] Example 17

[0139] Compound 17

[0140] 3-(imidazo[1.5-a]pyridin-8-ylamino)-4-methyl-N-(3-(trifluorom ethy l)pheny l)ben zam i deCompound 17 was synthesized according to general scheme II. *H NMR: 400 MHz, DMSO 6 10.47 (s, 1H). 8.33 (s. 1H), 8.23 (s. 1H), 8.05 (d, J = 8.4 Hz. 1H), 7.96 (s, 1H). 7.87 - 7.81 (m, 2H). 7.77 (dd, J = 8.0, 2.0 Hz, 1H). 7.67 - 7.53 (m, 2H). 7.46 (dd, J= 15.6. 7.9 Hz, 2H), 6.48 (t. J = 7.1 Hz, 1H). 5.65 (d, J = 7.2 Hz, 1H). 2.29 (s. 3H); LRMS m / z (ESI+): 411.40 [M+H]+.

[0141] Example 18

[0142] Compound 18

[0143] N-(5-benzamido-2-methylphenyl)-4-methylquinoline-6-carboxamideCompound 18 was commercially obtained.

[0144] Example 19

[0145] Compound 19

[0146] 4-methyl-N-(2-methyl-5-(m-tolylcarbamoyl)phenyl)quinoline-6-carboxamideCompound 19 was synthesized according to general scheme III. ' H NMR: 400 MHz, DMSO 5 10.45 (s, 1H), 10.16 (s, 1H), 8.98 (d, J = 4.7 Hz, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.39 (dd,J= 8.8, 1.9 Hz, 1H), 8.19 (d, J= 8.7 Hz, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.86 (dd, J= 7.9, 2.0 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.61 - 7.55 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.23 (t, J= 7.8 Hz, 1H), 6.92 (d,J= 7.5 Hz, 1H), 2.88 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H); LRMS m / z (ESI+): 410.20 [M+H]+.

[0147] Example 20

[0148] Compound 20

[0149] 4-methyl-N-(2-methyl-5-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)quinoline-6- carboxamideCompound 20 was synthesized according to general scheme III. H NMR: 400 MHz, DMSO 8 10.55 (s. 1H), 10.42 (s, 1H), 8.87 (d, .7= 4.4 Hz, 1H). 8.82 (d,J= 2.0 Hz, 1H). 8.31 (dd, J = 8.8, 2.0 Hz. 1H), 8.25 (t, J = 2.0 Hz. 1H), 8.17 - 8.08 (m. 2H), 8.05 (d, J= 1.9 Hz, 1H), 7.88 (dd, J = 7.9, 1.9 Hz. 1H), 7.61 (t, J= 8.0 Hz. 1H), 7.54 - 7.49 (m. 2H), 7.46 (ddt, J = 7.8, 1.8, 0.9 Hz, 1H), 2.81 (d, J = 1.0 Hz, 3H), 2.38 (s, 3H); LRMS m / z (ESI+): 464.20 [M+H]+.

[0150] Example 21

[0151] Compound 21

[0152] 4-methyl-N-(2-methyl-5-((3-(trifluoromethyl)benzyl)carbamoyl)phenyl)quinoline-6- carboxamideCompound 21 was synthesized according to general scheme III. 'H NMR: 400 MHz, DMSO 5 10.35 (s. 1H), 9.15 (t, J = 6.0 Hz. 1H), 8.86 (d, J = 4.3 Hz. 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.28 (dd, J = 8.8, 1.9 Hz, 1H), 8.13 (d, .7= 8.7 Hz. 1H), 7.94 (d, .7= 1.9 Hz, 1 H). 7.77 (dd, .7= 7.9, 1.9 Hz. 1H), 7.61 (ddd, J= 21.1. 15.8, 8.3 Hz, 4H), 7.49 (dd, J= 4.3, 1.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H). 4.57 (d. J = 5.9 Hz, 2H). 2.82 - 2.77 (m, 3H). 2.34 (s, 3H); LRMS m / z (ESI+): 478.440 [M+H]’.

[0153] Example 22

[0154] Compound 22

[0155] 4-methyl-N-(2-methyl-5-(3-methylbenzamido)phenyl)quinoline-6-carboxamideCompound 22 was synthesized according to general scheme III. ' H NMR: 400 MHz, DMSO 3 10.25 (d, J = 11.8 Hz, 2H). 8.86 (d. J = 4.3 Hz, 1H). 8.79 (d. J = 2.0 Hz, 1H). 8.28 (dd, J = 8.8, 1.9 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.81 - 7.72 (m, 2H). 7.61 (dd, J= 8.3, 2.3 Hz, 1H), 7.49 (dd, J= 4.4, 1.1 Hz, 1H), 7.46 - 7.37 (m, 2H), 7.28 (d, J= 8.4 Hz, 1H), 2.80 (d, J= 0.9 Hz, 3H), 2.40 (s, 3H), 2.26 (s. 3H); LRMS m / z (ESI+): 410.38 [M+H]+.

[0156] Example 23

[0157] Compound 23

[0158] 4-methyl -N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)quinoline-6- carboxamideCompound 23 was synthesized according to general scheme III. ' H NMR: 400 MHz, DMSO 8 10.50 (s, 1H), 10.26 (s. 1H), 8.87 (d, J = 4.3 Hz. 1H), 8.79 (d, J = 2.0 Hz. 1H), 8.34 - 8.25 (m, 3H), 8.13 (d, .7= 8.7 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.91 (d, .7 = 2.4 Hz. 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.3, 2.2 Hz, 1H), 7.50 (d, J= 4.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 2.81 (s, 3H), 2.28 (s, 3H); LRMS m / z (ESI+): 464.32 [M+H]+.

[0159] Two of the selected compounds with potent Lyn inhibitory activity (1 and 17) were subjected to kinobeads-based kinome profiling, as described in the general procedure above. The results revealed that both compounds selectively target Lyn at 1 and 10 pM, respectively, in addition to p38a, a kinase involved in the p38 MAPK pathway (FIG. 4). In addition to Lyn and p38a, compound 17 also targeted Abl2 as an additional target.

[0160] Based on this lead, compound 1 was screened against a panel of p38 kinase isoforms, which revealed that compound 1 is a potent and selective inhibitor of the p38a isoform over the other isoforms. See Table 2.

[0161] Potent Lyn inhibitors were described herein with low nM inhibitor activities with Lyn over Hck selectivity that would increase the protective functions of microglia. The current disclosure provides methods and compounds directed to inhibiting Lyn in order to modulate microglia. The methods and compounds disclosed herein allow for the inhibition of Lyn early in neurodegenerative diseases leading to increased microglial protective functions and reduced rate of disease progression and cognitive decline, for example, in Alzheimer’s patients.

[0162] The matter set forth in the foregoing description and accompanying drawings is offered by way of illustration only and not as a limitation. While particular embodiments have been shown and described, it will be apparent to those skilled in the art that changes and modifications may be made without departing from the broader aspects of the inventors’ contribution. The actual scope of the protection sought is intended to be defined in the following claims when viewed in their proper perspective based on the prior art.INCORPORATION BY REFERENCE

[0163] All United States patents and published patent applications, foreign patents and published patent applications, non-patent literature publications referenced in the present disclosure are hereby incorporated by reference in their entireties.

Claims

CLAIMS1. A compound of Formula I, Formula (II). or Formula (III):or a pharmaceutically acceptable salt thereof; wherein:X is -CH2- or a bond;Y is carbonyl or -NH-;Z is carbonyl or -NH-; andRi, R2, R3, R4, Rs, Re, R7, and Rx are independently -H, -F, -Cl, -Br, -CH3, -OCH3, -CF3, or N- (morpliolinomethy 1) . provided that the compound of Formula (III) is not2. The compound of claim 1, wherein X is -CH2-.

3. The compound of claim 1, wherein X is a bond.

4. The compound of claim 1, wherein Y is carbonyl.

5. The compound of claim 1, wherein Y is -NH-.

6. The compound of claim 1, wherein Z is carbony l.

7. The compound of claim 1, wherein Z is -NH-.

8. The compomid of any one of claims 1-7, wherein Z is carbonyl and X is a bond.

9. The compound of claim 1, wherein the compound is represented by:

10. A pharmaceutical composition comprising a compound of any one of claims 1-7 or 9 and one or more pharmaceutically acceptable carriers, diluents or excipients.

11. The pharmaceutical composition of claim 10, further comprising one or more one or more additional therapeutic agents.

12. A method of treating a neurode generative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-7 or 9, or a pharmaceutically acceptable salt thereof.

13. A method of treating a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount of the pharmacal composition of claim 10.

14. A method for treating the progression of a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-7 or 9. or a pharmaceutically acceptable salt thereof.

15. A method for treating the progression of a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount the pharmaceutical composition of claim 10.

16. A method of preventing a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-7 or 9, or a pharmaceutically acceptable salt thereof.

17. A method of preventing a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to the patient an effective amount of the pharmaceutical composition of claim 10.

18. The method of any one of claims 13, 15, or 17, further comprising administering one or more additional therapeutic agents.

19. The method of claim 12, further comprising administering one or more additional therapeutic agents.

20. The method of claim 14, further comprising administering one or more additional therapeutic agents.

21. The method of claim 16, further comprising administering one or more additional therapeutic agents.

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