LYN modulators for treatment of neurodegenerative disorders

Abstract

The present disclosure relates to approaches to the prevention and treatment of neurodegenerative disorders with therapeutics comprising Lyn kinase inhibitors. In particular, the disclosure provides compounds, pharmaceutical compositions and methods of treating and preventing such disorders.

Description

LYN MODULATORS FOR TREATMENT OF NEURODEGENERATIVE DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of prior-filed United States provisional application no. 63 / 623.707 filed on January 22, 2024, which is incorporated by reference in its entirety herein.REFERENCE TO GOVERNMENT GRANTS

[0002] This invention was made with government support under contract AG065181 awarded by the National Institutes of Health - National Institute of Aging. The Government has certain rights in the invention.INCORPORATION OF SEQUENCE LISTING

[0003] This application incorporates by reference the material in the ST.26 XML file titled IUIC-157_Sequence-Listing, which was created on January 21, 2025 and is 4,965 bytes.FIELD OF THE DISCLOSURE

[0004] The general field of the present disclosure is therapeutics and methods of treatment for neurodegenerative disorders.BACKGROUND

[0005] Alzheimer’s disease (AD) is a fatal, neurodegenerative disorder characterized by histopathological accumulation of extracellular (3-amyloid (A(3) plaques and intra-neuronal neurofibrillary tangles (NFTs), which 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 model provides that various forms of Ap oligomers and plaques are instrumental in a neuropathological process that triggers subsequent NFT pathology, neuroinflammation, and neuronal loss. However, the mechanisms by which A influences neurotoxic signaling including NFT formation remain an area of intense study. Recently, the amyloid cascade model has come under increased scrutiny due to apparent failures of drugs targeting Ap peptide processing and Ap plaque. See Panza et al., “A critical appraisal of amyloid- beta-targeting therapies for Alzheimer disease,” (2019) Nat Rev Neurol 15: pp. 73-88.

[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, ABCA 7, PLCG2, and INPP5D, which are essential to microglia function. See Malik et al.. “Genetics ignite focus on microglial inflammation in Alzheimer’s disease,” (2015) Mol Neurodegener 10: p. 52. Microglia are the non-neuronal, macrophage-like cells that sene 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) JNenrocytol 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 percent per year, thus providing a mechanism to renew microglia. See Ren 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 A plaques and nemodegeneration 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) Nat 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 12, APOE, and Triggering receptor expressed on myeloid cells-2 (TREM2). TREM2 ligands such as apolipoproteins (APOEs) and A0 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 A(3 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 TREM^4™ variant 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-functioneffects 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 IPs and Ca2+release. See Konishi et al., “Microglial TREM2 / DAP12 Signaling: A Double-Edged Sword in Neural Diseases,” (2018) Front Cell Neurosci 12: p. 206. Importantly, an activating variant of PLCG2, PLCG2F522Ris 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 dampened microglia activity increases risk of neurodegeneration while activated microglia are protective, clearing Ap oligomers and plaques, and mitigating an inflammatory’ microenvironment that is toxic to neurons. See Dcczkowska ct al., 2018.

[0009] The recent approval of the anti-amyloid antibody aducanumab provides evidence for the role of activated 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 the 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, as illustrated in FIG. 1 of the present disclosure. See Brown et al, “Regulation, substrates and functions of src.” BBA-Rev Cancer. Jim 7 1996;1287(2-3):121-149. Even though the primary function of both kinases is to phosphory late 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 phosphorylate ITAMs, along with Fyn and Lek. Interestingly , Lyn is the main SFK known to phosphory late 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 IT AMs or ITIMs. See Silverstein et al, “CD36, a Scavenger Receptor Involved in Immunity, Metabolism. Angiogenesis, and Behavior”. Sci Signal. May 26 2009;2(72). However, it mostly phosphory lates 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 protcin-tyrosinc 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- 2 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 tyrosine 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 at 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 20 l 9:33(3):4300— 13 13. 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 (DAMs), 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 (AP), 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 expressionhas also been found in human and mouse microglia compared to other SFKs. See Portugal et al. “Src family kinases (SFKs): critical regulators of microglial homeostatic functions and neurodegeneration in Parkinson’s and Alzheimer’s diseases”. FF.BSJ. Dec 2022;289(24): 7760-7775. Furthermore, postmortem AD patient brains have also shown elevated Lyn levels in microglia. Interestingly, the broadspectrum Src kinase inhibitor PPI. which mainly targets Lyn, was shown to inhibit AP-triggered neurotoxin production and improve neuronal survival. See Combs et al, “Identification of microglial signal transduction pathways mediating a nemotoxic response to amyloidogenic fragments of betaamyloid and prion proteins”. JNeurosci. Feb 1 1999;19(3):928-39. Additionally, independent studies have documented increased Lyn activation in mouse microglia exposed to A 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”. Newobiol Aging. Oct 2012;33(10):2247-61, and Sondag et al, Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J Nenroinflammation. 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 amyloid beta (AP)-induced neurotoxicity and tau hyperphosphorylation via FcyRIIb2 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 Ap i-42 in mouse neuronal cells. They also found that Lyn activation was inhibited in FcyRIIb2 knockout neurons, suggesting that FcyRIIb2-Ap 1-42 interactions mediated the activation of Lyn. An analysis of AD patient brain tissue revealed a three-fold 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 Api-42-induced cell death in neuroblastoma and hippocampal cell lines, underscoring Lyn’s role in countering A l-42-induccd 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 AP-FcyRIIb2 -mediated neuronal cell death and rescue AP- induced memory impairment in mice. Overall, this study establishes the role of Lyn in Alzheimer’s disease in the context of amyloid P (Api-42)-triggered neurotoxicity and tau hyperphosphorylation, which are the main pathological features of Alzheimer’s disease.

[0012] The role of Lyn in TREM2 -mediated microglia can be elucidated based on the involvement of various activation and inhibitory immune receptors and adaptor proteins bearing IT AM and ITIMs such as DAP12, CD33, and FcgRIIb in the process. Based on the literature findings related to myeloid cells, several roles of Lyn in TREM2 -mediated microglial activation and phagocytosis can be postulated, as depicted in FIG. 2 of the present disclosure. The phosphorylation of inhibitor}' immune receptors such as CD33 and FcgRIIb by Lyn might inhibit TREM2 -mediated microglial activation through theactivation of phosphatases such as SHIP1 and SHP1. In addition, Lyn can directly activate these phosphatases by phosphorylating them. Therefore, inhibiting Lyn would enhance TREM2-mediated microglial activation and phagocytosis, which is known to be beneficial for treating early-stage Alzheimer’s disease. On the other hand, inhibiting Hck, another Src kinase known to inhibit microglial activation and associated with the development of late-onset Alzheimer’s disease in mice, might have different effects. Thus, when using Src kinase inhibitors to evaluate the role of Lyn kinase in TREM2- mediated microglial activation and phagocytosis, it is beneficial to use inhibitors with significant selectivity for Lyn over Hck.

[0013] Taken together, this understanding of Lyn involvement in microglia activation as a limiting node downstream from TREM2 and FCyRIIB, it was proposed that inhibition of Lyn would activate microglia, and would therefore be an effective therapeutic strategy in disease. This therapeutic intervention may be synergistically combined with anti-amyloid and / or TREM2 agonist antibodies. Therefore, inhibitors of Lyn would increase the protective functions of microglia and may therefore be used to prevent or treat disease, reduce tire 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 pharmaceutical composition for the prevention of Alzheimer’s Disease and Alzheimer’s Disease-related Dementias.SUMMARY OF THE DISCLOSURE

[0015] A set of fourteen known Lyn inhibitors was screened against Lyn and Hck. using HotSpot™ Kinase assay. Type II kinase inhibitors were observed to be relatively more Lyn =selective and induce moderate phagocytosis in a high-content imaging assay measuring phagocytosis, cell number, and nuclear intensity that uses the BV2 and HMC3 cell lines to characterize cellular pharmacology and cytotoxicity’. In view of these findings, a novel and structurally diverse series of compounds as potent Lyn inhibitors were designed and synthesized.

[0016] For example, in one aspect, disclosed herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: a. X is -CH2O- or a bond; ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected fromthe group consisting of halogen, hydroxyl. -CN, -NO2. Ci-Cealkyl, and Ci-Cealkoxy; wherein Ci-Cealkyl. and Ci-Cealkoxy may optionally be substituted by one or more halogens; and b. R1is selected from the group consisting of Ci-Cealkyl and hydrogen.

[0017] In another aspect, disclosed herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein; a. X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-, and a bond; b. Rxis independently selected from the group consisting of hydrogen and C 1 -C, alkyl; c. ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA; d. RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, Ci-Cealkyl. and Ci-Cealkoxy; wherein Ci-Cealkyl, and Ci-Cealkoxy may optionally be substituted by one or more halogens; and e. R1is selected from the group consisting of Ci-Cealkyl and hydrogen.

[0018] In another aspect, disclosed herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein; a. X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-, and a bond; b. Rxis independently selected from the group consisting of hydrogen and Ci -Ckalky 1; c. ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA; d. RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, Ci-Csalkyl. and Ci -Cealkoxy; wherein Ci-Cealkyl, and Ci-Cealkoxy may optionally be substituted by one or more halogens; and e. R1is selected from the group consisting of Ci-Cealkyl, halogen, hydroxy, and hydrogen.

[0019] In another aspect, disclosed herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: a. X is -CH2O- or a bond; ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -CN, -NO2, Ci-Cealkyl, and Cj-C alko.xy ; wherein Ci-Cealkyl, and Ci -Ci alkoxy may optionally be substituted by one or more halogens; and b. R1is selected from the group consisting of Ci-Cealkyl, halogen, methoxy, and hydrogen.

[0020] In another aspect, 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 may comprise at least one additional therapeutic agent.

[0021] In still another aspect, disclosed herein are methods for treating neurodegenerative 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.

[0022] 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

[0023] FIG. 1 is a diagram showing the organization of human LYN domains and the sequence comparison betw een the human (UniProt® Accession No.P07948) (SEQ ID No. : 01). mouse (UniProt® Accession No. P25911) (SEQ ID No.: 02), and rat (UniProt® Accession No. Q07014) (SEQ ID No.: 03) isoforms.

[0024] FIGs. 2A-2B shows a cellular pathway diagram for (A) (left-hand side) a proposed role of LYN in TREM2-mediated microglial activation and phagocytosis; and (B) (right-hand side) the role of LYN in A|3-triggered neurotoxicity and tau hyperphosphorylation.

[0025] FIGs. 3A-3D are diagrams of major domains of LYN kinase, where (A) shows SH3, (B) shows SH2, and (C) shows the LYN catalytic domain and the key structural motifs that determine the active and inactive conformations. There are two major inactive conformations: type II inhibitors target the DFG-out / aC-in conformation, while type I1 / 2 inhibitors target the DFG-in / ocC-out conformations. FIG. 3D shows an Src-family kinase (SFK) phylogenetic tree.DETAILED DESCRIPTION

[0026] 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 quantity in 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 are also included in the disclosure, unless the context clearly dictates otherwise.

[0027] 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).

[0028] 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.

[0029] 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 (FIG. 1). See Brown et al, “Regulation, substrates and functions of src.” BBA-Rev Cancer. Jim 7 1996;1287(2-3):121-149. The UniProt® entries for the amino acid sequences for the human (accession no. P07948) (SEQ ID No. : 1),mouse (accession no. P25911) (SEQ ID No.: 2), and rat (accession no. Q07014) (SEQ ID No.: 3) isoforms of LYN are provided in Table 1, below. Additionally, UniProt® entries P07948, P25911, and Q07014 are incorporated by reference herein in their entireties.

[0030] The role of Lyn in TREM2 -mediated microglia can be elucidated based on the involvement of various activation and inhibitory immune receptors and adaptor proteins bearing IT AM and ITIMs such as DAP12, CD33, and FcgRIIb in the process. Based on the literature findings related to myeloid cells, several roles of Lyn in TREM2-mediated microglial activation and phagocytosis were postulated, as depicted in FIG. 2. The phosphorylation of inhibitory immune receptors such as CD33 and FcgRIIb by Lyn inhibits TREM2 -mediated microglial activation through the activation of phosphatases such as SHIP1 and SHP1. In addition, Lyn can directly activate these phosphatases by phosphory lating them. Therefore, it was determined that inhibiting Lyn early in disease would enhance TREM2 -mediated microglial activation and phagocytosis, which will ultimately increase microglial protective functionsand reduce the rate of disease progression and cognitive decline in neurodegenerative patients (e.g., Alzheimer’s patients).

[0031] 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.

[0032] 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.

[0033] In any of the embodiments disclosed herein, the term “patient” may refer to a human.

[0034] A compound of the present disclosure can react to fonn 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.

[0035] For example, disclosed herein is a compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: a. X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-, and a bond; b. Rxis independently selected from the group consisting of hydrogen and Cj -Ckalk l: c. ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA; d. RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, Ck -Ckalkyl. and Ci -Ckalkoxy: wherein Ci-Cealkyl, and Ci-Cealkoxy may optionally be substituted by one or more halogens; and e. R1is selected from the group consisting of Ci-Cealkyl. halogen, methoxy, and hydrogen.

[0036] In some embodiments, X is -C(RX)2-O-. In other embodiments, X -C(RX)2-O-CH2-. In still other embodiments, X is a bond. In further embodiments, for example, a compound of the present disclosure may be represented by:

[0037] In some embodiments, ring A is phenyl optionally substituted with one. two, or three RA. On other embodiments, ring A is naphthyl optionally substituted with one, two, or three RA. In still other embodiments, ring A is a 6-membered monocyclic heteroaryl having at least one ring nitrogen. In certain embodiments, for example, ring A is pyridyl optionally substituted with one, two, or three RA. In further embodiments, ring A is a 10-mcmbcrcd bicy clic hctcroaryl having at least one ring nitrogen. For example, in certain embodiments ring A is quinolinyl optionally substituted with one, two, or three RA.

[0038] In some embodiments, each Rxis hydrogen. In other embodiments, one Rxis hydrogen and the other of Rxis -CH3. In further embodiments, each Rxis -CH3. For example, in some embodiments X is -CH2-O-. In other embodiments. X is -CH(CH3)-O-. In still other embodiments, X -CH2-O-CH2-. In further embodiments, X is -CH(CH3)-O-CH2-.

[0039] For example, in some embodiments a compound of the present disclosure may be represented by:wherein Y is CH or N.

[0040] In some embodiments, a compound of the present disclosure may be represented by:

[0041] In some embodiments, RAis independently selected for each occurrence from the group consisting of, for example, fluoro, chloro, bromo, iodo, hydroxyl, -CN. -NO2. -CH3. -CF3. -OCH3, and -OCF3.

[0042] In some embodiments, R1is independently selected from the group consisting of Ci-Cealkyl and hydrogen. In some embodiments, R1is Ci-Cealkyl. For example, in certain embodiments R1is - CH3. In some embodiments. R1is independently selected from the group consisting of Ci-Cgalkyl, halogen, methoxy, and hydrogen. In some embodiments, R1is halogen, wherein the halogen is selected from the group consisting of fluoro, chloro, bromo, and iodo.

[0043] In other embodiments, the present disclosure encompasses a method for treating a neurodegenerative disorder in a patient in need thereof, comprising administering to the patient a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In embodiments, the neurodegenerative disorder may be Alzheimer’s disease. 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.

[0044] 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 composition further comprises one or more additional therapeutic agents. In a further embodiment, the presentdisclosure provides a pharmaceutical composition for the treatment of a neurodegenerative disorder, 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 embodiments, the neurodegenerative disorder may be Alzheimer’s disease. 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 a neurode generative disorder, 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 embodiments, the present disclosure provides a pharmaceutical composition for the prevention of a 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.

[0045] 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 a neurodegenerative disorder. Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disorder. 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 a neurodegenerative disorder.

[0046] 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.

[0047] 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 die disclosure, or a pharmaceutically acceptable salt tiiereof, for use in the treatment of 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 the treatment of Alzheimer's disease-related dementias.

[0048] Furthermore, the present disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the prevention of a neurodegenerative disorder. 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 a neurodegenerative disorder.

[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. 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] 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.

[0052] 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.

[0053] Excipients

[0054] Illustrative, non-limiting examples of excipients or carriers include sodium citrate or dicalcium phosphate and / or (a) one or more fillers or extenders (a filler 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, poly vinylpyrrolidinone, 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). (1) 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 alcoholand glycerol mono stearate), (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). Tn the case of capsules, tablets and pills, for example, the dosage form may also comprise buffering agents.

[0055] “Effective or Therapeutic Amount”

[0056] 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.

[0057] 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.

[0058] The present disclosure may be further understood by reference to the following clauses:

[0059] Clause 1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-, and a bond; Rxis independently selected from the group consisting of hy drogen and C i-C, alkyl: ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, Ci -Cealkyl. and Ci-Cealkoxy; wherein Ci-Cealkyl, and Ci-Cealkoxy may optionally be substituted by one or more halogens; andR1is selected from the group consisting of Ci-Cealkyl and hydrogen.

[0060] Clause 2. The compound of clause 1, wherein the compound is represented by.

[0061] Clause 3. The compound of either of clause 1 or 2. wherein ring A is phenyl or naphthyl, and wherein ring A may optionally be substituted with one, two. or three RA.

[0062] Clause 4. The compound of either of clause 1 or 2. wherein ring A is a 6-membered monocyclic heteroaryl or a 10-membered bicyclic heteroaryl, wherein ring A bears at least one ring nitrogen, and wherein ring A may optionally be substituted by one, two or three groups each independently selected from RA.

[0063] Clause 5. The compound of clause 4, wherein ring A is pyridyl or quinolinyl, and wherein ring A may optionally be substituted by one, two or three groups each independently selected from RA.

[0064] Clause 6. The compound of any one of clauses 1-5, w herein X is selected from the group consisting of -CH2-O-, -CH(CH3)-O-, -CH2-O-CH2-. -CH(CH3)-O-CH2-, and a bond.

[0065] Clause 7. The compound of any one of clauses 1-6. wherein the compound is represented by:wherein Y is CH or N.

[0066] Clause 8. The compound of any one of clauses 1-6, wherein the compound is represented

[0067] Clause 9. The compound of any one of clauses 1-8. wherein RAis independently selected for each occurrence from the group consisting of, for example, fluoro, chloro, bromo, iodo, hydroxyl. - CN. -NO2, -CH3, -CF3. -OCH3, and -OCF3.

[0068] Clause 10. The compound of any one of clauses 1-9, wherein R1is -CH3.

[0069] Clause 11. The compound of any one of clauses 1-10. wherein the compound is selected from the group consisting of:N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-2-(3-nitrophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2.4,5-trichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(4-chloro-2-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3.4,6-trichloro-2-pyridyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2,6-xylyloxy)acetamide;N-(3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2-naphthyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}-2 -pyridinecarboxamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-nitrophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(5-chloro-8-quinolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(benzyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-(trifluoromethyl)benzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}[(p-methoxyphenyl)methoxy]acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3,4-dichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2,4-dichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-trifluoroanisamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-cy anobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-iodobenzamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 }p-bromobenzamide ;N- { 3 -[4-(3 -pyridyl) -2-pyrimidiny lamino] -4-toly 1 } p-chlorobenzamide ;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-fluorobenzamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } benzamide ;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-trifluoromethoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}[p-(trifluoromethyl)phenoxy]acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-tolyloxy)acetamide;N-(3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-bromophcnoxy)acctamidc;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-chlorophenoxy)acetamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (m-fluorophenoxy)acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (o-bromophenoxy )acetamide ;N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(o-chlorophenoxy)acetamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (o-fluorophenoxy)acetamide ;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(R)-2 -phenoxypropionamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 }(p-iodophenoxy )acetamide ;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-nitrophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-methoxyphenoxy)acetamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 }(p-methoxy phenoxy )acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino J -4-toly 1 }(p-bromophenoxy )acetamide ;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-chlorophenoxy)acetamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-fluorophenoxy)acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-fluorophenoxy)acetamide ;N- { 3 -[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (2-py ridyloxy )acetamide ;N- { 3 -[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (2-py ridyloxy )acetamide ;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}phenoxyacetamide; andN-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}phenoxy acetamide.

[0070] Clause 12. The compound of any of clauses 1-11, wherein the compound is selected from:

[0071] Clause 13. A pharmaceutical composition comprising a compound of any one of clauses 1-12 and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0072] Clause 14. The pharmaceutical composition of clause 13, further comprising one or more additional therapeutic agents.

[0073] Clause 15. 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 1-12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either of clause 13 or 14.

[0074] Clause 16. 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 1-12. or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either of clause 13 or 14.

[0075] Clause 17. A method of preventing a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to tire patient an effective amount of a compound of any one of clauses 1-12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either of clause 13 or 14.

[0076] Clause 18. The method of any one of clauses 15-17, further comprising administering one or more additional therapeutic agents.

[0077] Clause 19. A method of synthesizing a compound of Formula (1):wherein:X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-. and a bond;Rxis independently selected from the group consisting of hydrogen and Ci-Csalkyl; ring A is selected from the group consisting of phenyl, naphthyl. 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN. -NO2. Ci-Cealkyl, and Ci-Cealkoxy; wherein Ci-Cealkyl. and Ci-C, alkoxy may optionally be substituted by one or more halogens; andR1is selected from the group consisting of Ci-Cealkyl and hydrogen; the method comprising: adding a coupling reagent and a non-nucleophilic base to a solution of a compound of Formula (IIA) in an organic solvent;wherein:X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-. and a bond;Rxis independently selected from the group consisting of hydrogen and Ci-Cjalkyl; ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN. -NO2. Ci-Cealkyl, and Ci-Cealkoxy; wherein Ci-Cealkyl. and Ci-Cealkoxy may optionally be substituted by one or more halogens; adding to the solution of a compound of a formula (IIB)wherein R1is selected from the group consisting of Cj-Cealkyl and hydrogen; stirring the solution; evaporating the solution, resulting in a product residue; and purif ing the residue via flash chromatography, thereby yielding the compound of Formula (I).

[0078] Clause 20. The method of clause 19, wherein the non-nucleophilic base is N.N.- diisopropylethyhnine.

[0079] Clause 21. The method of either of clause 19 or 20. wherein the coupling reagent is 1,1'- carbony Idiimidazole .

[0080] Clause 22. The method of any of clauses 19-21, wherein the organic solvent is dichloromethane .

[0081] Clause 23. The method of any of clauses 19-22, wherein the non-nucleophilic base is in an amormt of 1.5 eq relative to the amount of the compound of Formula (IIB).

[0082] Clause 24. The method of any of clauses 19-23, wherein the coupling reagent is in an amount of 3 eq relative to the amount of the compound of Formula (IIB).

[0083] Clause 25. The method of any of clauses 19-24, wherein the compound of Formula (IIA) is in an amount of 1.5 eq relative to the amount of the compound of Formula (IIB).

[0084] Clause 26. The method of any of clauses 19-25, wherein the compound of Formula (I) is selected from the group consisting of:Clause 27. The method of any of clauses 19-26, wherein ring A is phenyl or naphthyl, and wherein ring A may optionally be substituted with one, two, or three RA.Clause 28. The method of any of clauses 19-27, wherein ring A is a 6-membered monocyclic heteroaryl or a 10-membered bicyclic heteroary l, wherein ring A bears at least one ring nitrogen, and wherein ring A may optionally be substituted by one, two or three groups each independently selected from RA.Clause 29. The method of clause 28, wherein ring A is pyridyl or quinolinyl, and wherein ring A may optionally be substituted by one, two or three groups each independently selected from RA.Clause 30. The method of any of clauses 19-29, wherein X is selected from the group consisting of -CH2-O-, -CH(CH3)-O-, -CH2-O-CH2-, -CH(CH3)-O-CH2-, and a bond.Clause 31. The method of any of clauses 19-30, wherein the compound of Formula (I) is a compound selected from the group consisting of:wherein Y is CH or N.

[0085] Clause 32. The method of any of clauses 19-30, wherein the compound of Formula (I) is a compound selected from the group consisting of:

[0086] Clause 33. The method of any of clauses 19-32, wherein RAis independently selected for each occurrence from the group consisting of, for example, fluoro, chloro, bromo, iodo, hydroxyl. -CN,-NO2. -CH3. -CF3, -OCH3, and -OCF3.

[0087] Clause 34. The method of any of clauses 19-33, wherein R1is -CH3.

[0088] Clause 35. The method of any of clauses 19-34. wherein the compound of Formula (I) is a compound selected from the group consisting of:N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-2-(3-nitrophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2.4,5-trichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(4-chloro-2-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3,4,6-trichloro-2-pyridyloxy)acetamide;N- (3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl } (o-methoxy phenoxy )acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2,6-xylyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2-naphthyloxy)acctamidc;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}-2 -pyridinecarboxamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-nitrophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(5-chloro-8-quinolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(benzyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-(trifluoromethyl)benzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}[(p-methoxyphenyl)methoxy]acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3.4-dichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2,4-dichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-trifluoroanisamide;N-(3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-cy anobenzamide;N-(3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-iodobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-bromobcnzamidc;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-chlorobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-fluorobenz amide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}benzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-trifluoromethoxyplienoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}[p-(trifluoromethyl)plienoxy]acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylaminol-4-tolyl}(m-fluorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-fluorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(R)-2-phenoxypropionamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-iodophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-nitrophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-fluorophenoxj)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-fluorophcnoxj')acctamidc;N- { 3 -[4-(3 -pyridyl) -2-pyrimidiny lamino] -4-toly 1 } (2-pyridyloxy )acetamide ; N- { 3 -[4-(3 -pyridyl) -2-pyrimidiny lamino] -4-toly 1 } (2-pyridyloxy )acetamide ; N-{3-[4-(3-pyridyl)-2-pyrimidinylamino] -4-toly l}phenoxyacetamide; and N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}phenoxy acetamide.

[0089] Clause 36. The method of any of clauses 19-35, wherein the compound of Formula (I) is

[0090] Clause 37. Use of a compound of clause of any one of clauses 1-12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either of clause 13 or 14 in the manufacture of a medicament for the treatment of a neurodegenerative disorder.

[0091] Clause 38. The use of clause 37. wherein the neurodegenerative disorder is Alzheimer’s disease.

[0092] Clause 39. A method of synthesizing a compound of formula IIIA, IIIB, IIIC. or IIID:X is C or N; wherein Ri, R2, R3, R4 and R5 are independently, H, F, Cl. Br, I, -CH3, -CN, -NO2, -OCH3, -CF3or -OCF3 or a pharmaceutically acceptable salt thereof.

[0093] Clause 40. A compound as described in the present disclosure.

[0094] Clause 41. A method of synthesis as described in the present disclosure.

[0095] Clause 42. A compound of Formula (1):or a pharmaceutically acceptable salt thereof; wherein: a. X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-, and a bond; b. Rxis independently selected from the group consisting of hydrogen and Ci-CSalkyl: c. ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA; d. RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, Ci -Chalky I. and Ci-Cealkoxy; wherein Ci-Cealkyl, and Ci-Cealkoxy may optionally be substituted by one or more halogens; and e. R1is selected from the group consisting of Ci-Cealkyl, halogen, hydroxy, and hydrogen.

[0096] Clause 43. The compound of Clause 42, wherein the compound is selected from the group consisting of:2-(4-chlorophenoxy)-N-(3-((4-(pyridin-3-yl)pyrimi din-2 -yl)amino)phenyl)acetamide;2-(4-chlorophenoxy)-N-(4-fluoro-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)acetamide;N-(4-chloro-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-2-(4- chlorophenoxy)acetamide; and2-(4-chlorophenoxy)-N-(4-methoxy-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)acetamide.EXAMPLES

[0097] 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.

[0098] General Methods and Assays

[0099] 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-hydroxyethyl)-l -piperazineethanesulfonic acid (HEPES) (pH 7.5), 10 mM MgCh, 1 mM ethylene glycol-bis(P-aminoethyl ethcr)-A / .A. / V'.A / '-tctraacetic acid (EGTA), 0.01% Brij™-35 (polyoxycthylcncglycol dodecyl ether) non-ionic detergent solution, 0.02 mg / ml bovine serum albumin (BSA), 0.1 mM NaXO 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 Echo® 550 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 pM, 10 pM, 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 compounds and inhibitor activities of the compounds are given in Table 2. below.

[0100] pHrodo-mvelin phagocvtosis / cell health assay with microglial cells. This 384-well plate high content imaging assay was developed to quantify phagocytosis and cell health simultaneously using either BV-2 microglial cell line or HMC3 immortalized microglial cell line, or primary microglia isolated from mouse brain. Cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) GlutaMAX™ media (ThermoFisher) containing 10% fetal bovine serum (FBS) and Pen-Strep in 37 °C 5% CO2 incubator.

[0101] Assay Timing

[0102] Day 1: Cells were plated (Corning Falcon® 384-well Optilux Black and clear bottom plates for imaging) with BV-2 at 400 cells / 45pl / well, HMC3 at 600 cells / 45pl / well, or primary at 2000 cell / 45pl / well.

[0103] Dav 2: Cells were treated with 10* serially diluted compounds in a dose range of 60 pM to 3 nM for 48 horns at 37 °C.

[0104] Dav _3: Cells were seeded with pHrodo-myelin (for total 20 hours) 24 hours after starting compound treatment. The pHrodo-myelin stocks were at 1 mg / ml (protein equivalent) stored in -20 °C or -80 °C freezer. Stocks were thawed and diluted with culture media into 10x seeding solution (50pg / ml) and added 5pl / well to 384-well cell plate.

[0105] Dav 4: Cell staining and imaging. Nuclear staining solution was prepared by adding 1 pl of 10 mg / mL Hoechst-33342 stain to every 1 ml culture media that will be added to cell plate at 20pl / well. The final concentration of Hoechst-33342 to cells was about 2.5 pg / ml. Cell plates were incubated for >30 minutes at 37 °C before imaging. Cell plates were scanned with an ArrayScan™ automatic high content imaging system using a 10x objective lens, 4 fields / well collected. Three measurements were obtained: (1) mean total phagocytosis spot intensity per cell, (2) total cell counts per well, and (3) mean average nuclear intensity per cell for cell health. Apoptotic cells showed nuclear intensity increase (early apoptosis) or decrease (later apoptosis).

[0106] Activity of Compound 9 in primary mouse microglia. Cortical tissue from C57BL / 6J neonatal mice (P0-P3) was homogenized in Dulbecco’s Modified Eagle Medium (DMEM), filtered through 250 and 100 pm mesh, and cultured in Advanced Dulbecco’s Modified Eagle Medium / Nutrient Mixture F-12 (DMEM / F-12) supplemented with 10% fetal bovine serum, lx GlutaMAX and lx Penicillin / Streptomycin. At 21 days in vitro (DIV), the cultures were subjected to mild trypsinization using 0.083% tiypsin-ethylenediaminetetraacetic acid (trypsin-EDTA) in DMEM for 30 minutes to detach an intact layer of astrocytes. The microglia attached to the bottom were used as described in pHrodo-myelin phagocytosis assay to measure phagocytosis and cell health. The activity of Compound 10 in primary mouse microglia was obtained in a similar manner to Compound 9. Systemic names and chemical structures of Compound 9 and Compound 10 are shown below for reference:

[0107] General Procedure A (Amide Coupling). To a stirred solution of reagent of Formula(IIA) (1.5 eq)HO' in 6 mL dichloromethane (DCM) were added l,l'-carbonyldiimidazole (CDI). (1.5 eq), and N,N- diisopropylethylamine (DIPEA) (3 eq). The solution was allowed to stir at room temperature for 1 hour.wherein R1is selected from the group consisting of Cl-C6alkyl and hydrogen.The solution was allowed to stir at room temperature for 24 hours. The solution was then evaporated in vacuo and the resulting residue was purified by flash chromatography (9:1 DCM:MeOH).The reagent of Formula (I1A). may be a reagent where X is selected from the group consisting of - C(RX)2-O-, -C(RX)2-O-CH2-, and a bond; Rxis independently selected from the group consisting of hydrogen and Ci-CXalkyl and ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA; and RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN. - NOz, Ci-Cealkyl. and Ci-Cealkoxy; wherein Ci-Cealkyl, and Ci-Cealkoxy may optionally be substituted by one or more halogens.

[0108] 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 cither tunable ultraviolct / visiblc (TUV) and SQ Detector 2 detectors or photo diode array (PDA) and QDa detectors. Flash normal-phase (NP) or reversed-phase (RP) chromatography was performed on a Teledyne-ISCO CombiFlash® NextGen 300 instrument using prepacked silica gel or C 18-functionalized silica gel columns available from T eledyne- 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 evaporative light scattering detector (ELSD) detectors and a Waters XBridge® C 18 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:

[0109] 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.

[0110] Synthesis and Characterization of LYN ModulatorsCompounds

[0111] Example 1

[0112] Compound !

[0113] (N-(4-methyl-3-((4-(pyridin-3 -yl)pyrimidin-2-yl)amino)phenyl)-2-(3- nitrophenoxy)acetamide)

[0114] Compound 1 was synthesized according to general procedure A. CH NMR: (500 MHz, DMSO) 5 10.14 (s, 1H), 9.26 (d, J= 2.3 Hz, 1H), 8.97 (s, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.62 (t, J = 8.2 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.44 (d, J = 5.1 Hz, 1H), 7.34 (dd, J = 8.2, 2.2 Hz, 1H). 7.20 (d, J = 8.3 Hz, 1H). 4.88 (s, 2H), 2.21 (s, 3H). LRMS m / z (ESI+): 457.15 [M+H]+)

[0115] Example 2

[0116] Compound 2

[0117] N- j3-|4-(3-pyridy l)-2-pyrirnidiny la ino|-4-toly I j (2.4.5-trichlorophenoxy (acetamide

[0118] Compound 2 was synthesized according to general procedure A. ( H NMR: (500 MHz, DM SO) 5 10.17 (s, 1H), 9.25 (d, J = 2.3 Hz. 1H), 8.95 (s, 1H), 8.68 (dd, J = 4.7, 1.7 Hz, 1H). 8.51 (d, J = 5.2 Hz, 1H). 8.47 (dt, J = 8.0. 2.0 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H). 7.85 (s, 1H), 7.47 (q, J = 4.1, 3.2 Hz, 2H), 7.44 (d, J = 5.2 Hz, 1H), 7.29 (dd, J = 8.2, 2.2 Hz, 1H), 7.19 (d, J = 8.3 Hz. 1H), 4.94 (s, 2H), 2.21 (s, 3H). LRMS m / z (ESI+): 514.25 [M+H]’)

[0119] Example s

[0120] Compound s

[0121] N- { 3 - [4-(3 -py ridy l)-2-py rimidiny lamino] -4-toly 1 } (4-chloro-2-toly loxy)acetamide

[0122] Compound 3 was synthesized according to general procedure A. ( I I NMR: (500 MHz, DMSO) 5 10.04 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 8.96 (s, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 8.0, 4.8 Hz, 1H), 7.43 (d, J = 5.2 Hz, 1H), 7.31 (dd, J = 8.2, 2.2 Hz, 1H), 7.25 (d, J = 2.7 Hz, 1H), 7.22 - 7.17 (m, 2H), 6.90 (d, J = 8.7 Hz, 1H), 4.74 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H). LRMS m / z (ESI+): 460.15 [M+H]+)

[0123] Example 4

[0124] Compound 4

[0125] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3,4,6-trichloro-2- pyridyloxy)acetamide

[0126] Compound 4 was synthesized according to general procedure A. ( H NMR: (500 MHz, DMSO) 5 10.20 (s, 1H), 9.25 (d, J = 2.3 Hz. 1H), 8.94 (s, 1H), 8.67 (dd, J = 4.8. 1.7 Hz, 1H). 8.51 (d. J = 5.1 Hz, 1H), 8.45 (dt, J = 8.0, 2.0 Hz, 1H). 8.42 (s, 1H). 7.89 (d. J = 2.2 Hz. 1H), 7.46 (dd. J = 8.0.4.8 Hz, 1H), 7.43 (d, J = 5.2 Hz, 1H), 7.26 (dd, J = 8.2, 2.2 Hz. 1H), 7.18 (d, J = 8.3 Hz. 1H), 5.04 (s, 2H). 2.21 (s, 3H). LRMS m / z (ESI+): 515.05 [M+H]+)

[0127] Example 5

[0128] Compound 5

[0129] N-{3-[4-(3-pyridyl)-2-pyrimidiiiylamino]-4-tolyl}(o-methoxyphenoxy)acetamide

[0130] Compound 5 was synthesized according to general procedure A. ( H NMR: (500 MHz, DM SO) 3 10.01 (s, 1H), 9.26 (d, J = 2.2 Hz. 1H), 8.96 (s, 1H), 8.69 (dd, J = 4.8. 1.7 Hz, 1H). 8.51 (d. J = 5.2 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H). 7.49 (dd, J = 8.0, 4.8 Hz, 1H), 7.43 (d. J = 5.2 Hz, 1H). 7.33 (dd, J = 8.1, 2.3 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.04 - 6.93 (m, 3H),6.88 (td, J = 7.6, 1.6 Hz, 1H), 4.68 (s, 2H). 3.80 (s. 3H), 2.21 (s, 3H). LRMS m / z (ESI+): 442.20[M+H]+)

[0131] Example 6

[0132] Compound 6

[0133] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(2,6-xylyloxy)acetamide

[0134] Compound 6 was synthesized according to general procedure A. (’H NMR: 1H NMR (500 MHz, DMSO) 39.98 (s, 1H), 9.27 (dd, J = 2.3, 0.9 Hz, 1H), 8.98 (s, 1H), 8.70 (dd, J = 4.8. 1.7 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H). 8.46 (dt, J = 8.1. 2.0 Hz, 1H), 8.02 (d. J = 2.2 Hz, 1H), 7.53 (ddd, J = 8.1, 4.8. 0.9 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 7.4 Hz, 2H), 6.96 (dd, J = 8.1. 6.8 Hz, 1H), 4.41 (s. 2H), 2.28 (s, 6H), 2.22 (s, 3H). LRMS m / z (ESI+): 440.25 [M+H] ')

[0135] Example 7

[0136] Compound 7

[0137] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(2-naphthyloxy)acetamide

[0138] Compound 7 was synthesized according to general procedure A. ('H NMR: 500 MHz, DMSO 8 10.11 (s, 1H). 9.26 (d. J = 2.3 Hz, 1H). 8.96 (s, 1H), 8.66 (dd, J = 4.7, 1.6 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.45 (dt, J = 8.1. 2.0 Hz, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.86 (dd, J = 11.6, 8.4 Hz. 2H), 7.79 (d, J = 8.2 Hz. 1H), 7.48 - 7.44 (m, 2H), 7.43 (d, J = 5.1 Hz, 1H). 7.39 - 7.35 (m, 2H), 7.35 - 7.30 (m, 2H), 4.83 (s, 2H), 2.21 (s, 3H). LRMS m / z (ESI+): 462.25 [M+H]+).

[0139] Example 8

[0140] Compound 8

[0141] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}-2 -pyridinecarboxamide

[0142] Compound 8 was synthesized according to general procedure A. ( H NMR: (500 MHz, DMSO) 8 10.58 (s, 1H). 9.29 (d. J = 2.3 Hz, 1H), 9.00 (s, 1H). 8.74 (dt, J = 4.7. 1.4 Hz. 1H), 8.69 (dd. J = 4.7, 1.7 Hz. 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.49 (dt. J = 8.1. 2.0 Hz. 1H), 8.27 (d, J = 2.3 Hz. 1H), 8.16 (dt. J = 7.9, 1.2 Hz, 1H). 8.07 (td, J = 7.7, 1.7 Hz. 1H), 7.68 (ddd, J = 7.6, 4.7, 1.3 Hz, 1H). 7.57 (dd, J = 8.2, 2.3 Hz, 1H). 7.53 (dd, J = 8.0, 4.8 Hz, 1H), 7.44 (d, J = 5.1 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H). 2.24 (s, 3H). LRMS m / z (ES1+): 383.20 [M+H]+)

[0143] Example 9

[0144] Compound 9

[0145] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-nitrophenoxy)acetamide

[0146] Compound 9 was synthesized according to general procedure A. C H NMR: (500 MHz, DMSO) 5 10.04 (s, 1H), 9.25 (dd, J = 2.3, 0.8 Hz, 1H), 8.96 (s, 1H), 8.69 (dd, J = 4.9, 1.7 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.46 (dt, J = 8.1, 2.0 Hz, 1H), 7.97 - 7.90 (m, 2H), 7.66 (ddd, J = 8.9, 7.4, 1.7 Hz, 1H), 7.49 (ddd, J = 8.1, 4.8, 0.9 Hz, 1H), 7.44 (d, J = 5.1 Hz, 1H), 7.31 (ddd, J = 16.3, 8.4, 1.7 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 7.16 (td, J = 7.7, 7.3, 1.1 Hz, 1H), 4.95 (s, 2H), 2.21 (s, 3H). LRMS m / z (ESI+): 457.55 [M+H]+)

[0147] Example 10

[0148] Compound 10

[0149] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(5-chloro-8-quinolyloxy)acetamide

[0150] Compound 10 was synthesized according to general procedure A. (' H NMR: 400 MHz, DMSO 8 10.43 (s. 1H), 9.25 (d, J = 2.3 Hz, 1H), 9.03 (dd, J = 4.2, 1.6 Hz, 1H), 8.96 (s, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H). 8.58 - 8.51 (m, 2H). 8.45 (dt, J = 8.1, 2.1 Hz. 1H), 8.00 (d, J = 2.2 Hz. 1H), 7.75 (dd. J = 8.5. 3.8 Hz, 2H), 7.46 (dd, J = 8.3, 5.0 Hz, 2H), 7.41 - 7.31 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 4.99 (s, 2H), 2.23 (s. 3H). LRMS m / z (ESI+): 497.25 [M+HJ+).

[0151] Example 11

[0152] Compound 11

[0153] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(benzyloxy)acetamide

[0154] Compound 11 was synthesized according to general procedure A. (’ H NMR: 500 MHz, DMSO 5 9.75 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 8.95 (s, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H). 8.51 (d, J = 5.2 Hz, 1H). 8.45 (dt, J = 8.0. 2.0 Hz, 1H), 7.96 (d. J = 2.2 Hz, 1H), 7.51 (dd, J = 8.0, 4.8 Hz, 1H), 7.45 - 7.28 (m, 7H), 7.17 (d, J = 8.2 Hz, 1H). 4.62 (s. 2H), 4.09 (s, 2H), 2.20 (s, 3H). LRMS m / z (ESI+) 426.35 [M+H]1).

[0155] Example 12

[0156] Compound 12

[0157] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}p-(trifluoromethyl)benzamide

[0158] Compound 12 was synthesized according to general procedure A. (*H NMR: 400 MHz, DMSO 5 10.33 (s, 1H). 9.29 (d. J = 2.2 Hz, 1H). 9.00 (s, 1H). 8.70 (dd, J = 4.8, 1.6 Hz. 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.49 (dt. J = 8.0, 2.0 Hz, 1H). 8.12 - 8.07 (m, 3H), 7.54 (dd, J = 8.2. 4.2 Hz, 3H). 7.51 - 7.43 (m. 2H), 7.23 (d, J = 8.3 Hz, 1H). 2.24 (s. 3H). LRMS m / z (ES1+): 450.25 [M+H]+).

[0159] Example 13

[0160] Compound 13

[0161] N- j3-|4-(3-pyridy l)-2-pyri idiny lamino |-4-toly 11 (m-mcthoxy phenoxy (aceta ide

[0162] Compound 13 was synthesized according to general procedure A. (’ H NMR: 400 MHz, DMSO 5 10.03 (s, 1H), 9.26 (d, J = 2.2 Hz, 1H), 8.96 (s, 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 8.0, 4.8 Hz, 1H), 7.44 (d, J = 5.2 Hz, 1H), 7.35 (dd, J = 8.3, 2.2 Hz, 1H), 7.21 (td. J = 8.4, 3.9 Hz, 2H). 6.61 - 6.55 (m, 3H), 4.68 (s, 2H), 3.74 (s, 3H), 2.21 (s, 3H). LRMS m / z (ESI+): 442.20 [M+H]+).

[0163] Example 14

[0164] Compound 14

[0165] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}[(p- methoxyphenyl)m ethoxy] acetamide

[0166] Compound 14 was synthesized according to general procedure A. ('H NMR: 400 MHz, DMSO 5 9.71 (s, 1H), 9.27 (d, J = 2.2 Hz, 1H). 8.95 (s, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.46 (dt. J = 8.0, 2.1 Hz, 1H). 7.96 (d, J = 2.2 Hz. 1H), 7.52 (dd. J = 8.0. 4.8 Hz, 1H). 7.44 (d. J = 5.1 Hz. 1H), 7.38 - 7.31 (m. 3H), 7.18 (d, J = 8.3 Hz, 1H), 6.97 - 6.90 (m, 2H). 4.55 (s. 2H), 4.05 (s, 2H), 3.76 (s, 3H). 2.21 (s. 3H). LRMS m / z (ES1+): 456.25 [M+H]+).

[0167] Example 15

[0168] Compound 15

[0169] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3,4-dichlorophenoxy)acetamide

[0170] Compound 15 was synthesized according to general procedure A. (' H NMR: LRMS m / z (ESI+): 480.25 [M+H]+)

[0171] Example 16

[0172] Compound 16

[0173] N- j3-|4-(3-pyridy l)-2-py rirnidinvlamino |-4-toly I j (2.4-dichlorophcnoxy (acetamide

[0174] Compound 16 was synthesized according to general procedure A. f1H NMR: 400 MHz, DMSO 5 10.12 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 8.95 (s. 1H), 8.70 (dd. J = 4.8, 1.6 Hz, 1H). 8.52 (d, J = 5.1 Hz, 1H), 8.47 (dt, J = 8.1, 2.0 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H). 7.61 (d, J = 2.6 Hz, 1H), 7.49 (dd. J = 8.0. 4.8 Hz, 1H). 7.44 (d. J = 5.2 Hz, 1H). 7.38 (dd, J = 8.9, 2.6 Hz. 1H), 7.30 (dd. J = 8.2. 2.2 Hz. 1H), 7.19 (d. J = 8.3 Hz, 1H), 7.13 (d, J = 9.0 Hz. 1H), 4.87 (s. 2H), 2.22 (s. 3H). LRMS m / z (ESI+): 480.20 |M+H|+).

[0175] Example 17

[0176] Compound 17

[0177] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}p-trifluoroanisamide

[0178] Compound 17 was synthesized according to general procedure A. (' H NMR: 400 MHz, DMSO 5 10.33 (s, 1H), 9.28 (d, J = 2.3 Hz, 1H), 8.99 (s, 1H), 8.70 (dd, J = 4.7, 1.6 Hz, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.49 (dt, J = 8.1, 2.0 Hz, 1H), 8.13 - 8.04 (m, 3H). 7.53 (dd, J = 8.7, 3.3 Hz. 3H), 7.51 - 7.41 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 2.24 (s, 3H). LRMS m / z (ESI+): 466.20 [M+H]+).

[0179] Example 18

[0180] Compound 18

[0181] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-cy anobenzamide

[0182] Compound 18 was synthesized according to general procedure A. (!H NMR: (500 MHz, DMSO) 5 10.46 (s, 1H), 9.28 (dd, J = 2.3, 0.9 Hz, 1H), 9.00 (s, 1H). 8.69 (dd, J = 4.7, 1.7 Hz, 1H). 8.52 (d. J = 5.2 Hz, 1H). 8.48 (dt, J = 8.1, 1.9 Hz. 1H), 8.14 - 8.09 (m. 3H), 8.06 - 8.00 (m. 2H),7.56 - 7.46 (m. 2H), 7.44 (d, J = 5.1 Hz, 1H). 7.24 (d. J = 8.3 Hz, 1H), 2.24 (s, 3H). LRMS m / z (ESI+):407.30 [M+H]+)

[0183] Example 19

[0184] Compound 19

[0185] N-{3-[4-(3-pyridyl)-2-pyrimidiiiylamino]-4-tolyl}p-iodobenzamide

[0186] Compound 19 was synthesized according to general procedure A. (' H NMR: 400 MHz, DMSO 8 10.26 (s. 1H), 9.29 (d, J = 2.3 Hz, 1H), 8.98 (s. 1H), 8.70 (dd. J = 4.9, 1.6 Hz, 1H). 8.53 (d. J = 5.1 Hz, 1H). 8.49 (dt, J = 8.0. 2.1 Hz. 1H), 8.09 (d, J = 2.2 Hz, 1H). 7.95 - 7.90 (m, 2H). 7.79 - 7.73 (m. 2H), 7.53 (dd, J = 8.0, 4.8 Hz, 1H), 7.48 (dd, J = 8.2. 2.2 Hz, 1H). 7.44 (d. J = 5.2 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H). 2.24 (s, 3H). LRMS m / z (ESI+): 508.30 [M+H]+).

[0187] Example 20

[0188] Compound 20

[0189] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}p-bromobenzamide

[0190] Compound 20 was synthesized according to general procedure A. (’ H NMR: 400 MHz, DMSO 5 10.28 (s, 1H), 9.29 (d, J = 2.3 Hz, 1H), 8.98 (s, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.53 (d, J = 5.1 Hz, 1H). 8.51 - 8.47 (m, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.53 (dd, J = 8.0, 4.8 Hz, 1H), 7.48 (dd, J = 8.3, 2.2 Hz, 1H). 7.45 (d. J = 5.2 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 2.24 (s, 3H). LRMS m / z (ESI+): 460.25 [M+H]+).

[0191] Example 21

[0192] Compound 21

[0193] N- { 3 - [4-(3 -py ridy l)-2-py rimidiny lamino] -4-toly 1 }p-chlorobenzamide

[0194] Compound 21 was synthesized according to general procedure A. (!H NMR: 400 MHz, DMSO 8 10.28 (s, 1H). 9.29 (d. J = 2.2 Hz, 1H). 8.99 (s, 1H), 8.70 (d, J = 4.6 Hz, 1H). 8.53 (d. J = 5.2 Hz, 1H). 8.49 (d. J = 8.3 Hz, 1H). 8.09 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.53 (dd, J = 8.0, 4.8 Hz, 1H). 7.48 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 5.1 Hz, 1H), 7.23 (d, J = 8.3 Hz. 1H), 2.24 (s, 3 H). LRMS m / z (ESI+): 416.25 [M+H]+).

[0195] Example 22

[0196] Compound 22

[0197] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}p-fluorobenzamide

[0198] Compound 22 was synthesized according to general procedure A. (*H NMR: 400 MHz, DMSO 5 10.23 (s, 1H), 9.29 (d, J = 2.2 Hz, 1H), 8.98 (s, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.53 (d, J = 5.1 Hz, 1H), 8.49 (dt. J = 8.1. 2.0 Hz, 1H). 8.08 (d. J = 2.2 Hz, 1H). 8.07 - 8.02 (m, 2H). 7.53 (dd, J = 8.0, 4.8 Hz, 1H). 7.48 (dd, J = 8.2, 2.2 Hz, 1H), 7.44 (d, J = 5.1 Hz, 1H). 7.41 - 7.34 (m, 2H). 7.23 (d, J = 8.2 Hz, 1H). 2.24 (s. 3H). LRMS m / z (ESI+): 400.20 [M+H]+).

[0199] Example 23

[0200] Compound 23

[0201] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}benzamide

[0202] Compound 23 was synthesized according to general procedure A. (' H NMR: 500 MHz, DMSO 8 10.22 (s. 1H), 9.28 (dd, J = 2.3, 0.9 Hz, 1H), 8.99 (s, 1H). 8.69 (dd, J = 4.8, 1.6 Hz. 1H), 8.52 (dd. J = 5.2. 1.2 Hz, 1H), 8.49 (dt, J = 8.1, 1.9 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.98 - 7.94 (m, 2H), 7.62 - 7.57 (m, 1H), 7.56 - 7.53 (m, 2H), 7.53 - 7.48 (m, 2H), 7.44 (dd, J = 5.1, 1.2 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 2.23 (s, 3H).LRMS m / z (ESI+): 382.20 [M+H]+).

[0203] Example 24

[0204] Compound 24

[0205] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(p- trifluoromethoxyphenoxy)acetamide

[0206] Compound 24 was synthesized according to general procedure A. (' H NMR: (500 MHz, DMSO) 5 10.08 (s, 1H), 9.26 (dd, J = 2.4, 0.8 Hz, 1H), 8.96 (s, 1H). 8.69 (dd, J = 4.7, 1.7 Hz, 1H), 8.51 (d. J = 5.1 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.49 (ddd, J = 8.1, 4.9, 0.9 Hz, 1H), 7.43 (d, J = 5.2 Hz, 1H), 7.36 - 7.29 (m. 3H), 7.19 (d, J = 8.3 Hz, 1H), 7.13 - 7.06 (m, 2H), 4.75 (s, 2H), 2.21 (s, 3H). LRMS m / z (ESI+): 496.30 [M+H]+)

[0207] Example 25

[0208] Compound 25

[0209] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}[p-(trifluoromethy l)phenoxy | acetamide

[0210] Compound 25 was synthesized according to general procedure A. (' H NMR: (500 MHz, DMSO) 5 10.13 (s, 1H), 9.26 (dd, J = 2.4, 0.9 Hz, 1H), 8.96 (s, 1H), 8.68 (dd, J = 4.9, 1.7 Hz, 1H), 8.51 (d, J = 5.1 Hz. 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H). 7.96 (d. J = 2.2 Hz, 1H). 7.69 (d. J = 8.8 Hz, 2H), 7.47 (ddd, J = 8.1, 4.8, 0.9 Hz, 1H), 7.43 (d, J = 5.2 Hz, 1H). 7.33 (dd, J = 8.2, 2.2 Hz, 1H), 7.19 (dd, J = 8.7, 2.3 Hz. 3H), 4.83 (s, 2H), 2.21 (s, 3H). LRMS m / z (ESI+): 480.35 [M+H]+)

[0211] Example 26

[0212] Compound 26

[0213] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(p-tolyloxy)acetamide

[0214] Compound 26 was synthesized according to general procedure A. (’H NMR: (500 MHz, DMSO) 5 10.01 (s, 1H), 9.26 (d. J = 2.3 Hz, 1H), 8.95 (s, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.45 (dt, J = 8.0, 2.0 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.0, 4.8 Hz, 1H), 7.43 (d, J = 5.1 Hz, 1H), 7.34 (dd, J = 8.2, 2.2 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.3 Hz, 2H), 6.92 - 6.86 (m, 2H), 4.64 (s, 2H), 2.23 (s, 3H), 2.21 (s. 3H). LRMS m / z (ESI+): 426.20 [M+H]+).

[0215] Example 27

[0216] Compound 27

[0217] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(m-tolyloxy)acctamidc

[0218] Compound 27 was synthesized according to general procedure A. t' H NMR: (500 MHz, DMSO) 5 10.01 (s, 1H), 9.26 (d. J = 2.2 Hz, 1H), 8.95 (s, 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.96 (d, J = 2.2 Hz. 1H), 7.49 (dd. J = 8.0, 4.8 Hz, 1H), 7.43 (d, J = 5.1 Hz, 1H), 7.34 (dd, J = 8.2, 2.2 Hz, 1H), 7.18 (dt. J = 7.8, 3.7 Hz, 2H). 6.84 (t, J = 2.0 Hz, 1H), 6.79 (dd, J = 8.4. 2.4 Hz, 2H), 4.66 (s, 2H). 2.28 (s. 3H), 2.21 (s, 3H). LRMS m / z (ESI+): 426.20 [M+H]+).

[0219] Example 28

[0220] Compound 28

[0221] N- { 3 - [4-(3 -py ridy l)-2-py rimidiny lamino] -4-toly 1 } (o-toly loxy )acetamide

[0222] Compound 28 was synthesized according to general procedure A. (’H NMR: (500 MHz, DMSO) 5 10.01 (s, 1H), 9.25 (d. J = 2.3 Hz, 1H), 8.95 (s, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.46 (dt, J = 8.1, 2.0 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.0, 4.8 Hz, 1H), 7.43 (d, J = 5.2 Hz, 1H), 7.32 (dd. J = 8.2, 2.2 Hz, 1H), 7.21 - 7.10 (m, 3H), 6.87 (t. J = 7.8 Hz, 2H), 4.71 (s. 2H), 2.24 (s, 3H), 2.21 (s, 3H). LRMS rn / z (ESI+): 426.25 [M+H]+).

[0223] Example 29

[0224] Compound 29

[0225] N- { 3 - [4-(3 -py ridy l)-2-py rimidiny lamino] -4-toly 1 } (m -bromophenoxy )acetamide

[0226] Compound 29 was synthesized according to general procedure A. t' H NMR: (500 MHz, DMSO) 5 10.05 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 8.95 (s, 1H), 8.69 (dd, J = 4.8, 1.6 Hz. 1H),8.51 (d, J = 5.1 Hz. 1H), 8.46 (dt. J = 8.1, 2.0 Hz, 1H). 7.96 (d. J = 2.2 Hz, 1H). 7.48 (dd, J = 8.1, 4.8 Hz, 1H). 7.43 (d. J = 5.2 Hz, 1H). 7.34 (dd, J = 8.1, 2.2 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.22 - 7.15 (m, 2H). 7.06 - 7.00 (m, 1H). 4.74 (s, 2H), 2.21 (s. 3H). LRMS m / z (EST+): 490.35 [M+H]+).

[0227] Example 30

[0228] Compound 30

[0229] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-chlorophenoxy)acetamide

[0230] Compound 30 was synthesized according to general procedure A. (' H NMR: 400 MHz, DMSO 5 10.05 (s. 1H), 9.27 (d, J = 2.3 Hz, 1H), 8.96 (s. 1H), 8.70 (dd. J = 4.8, 1.6 Hz, 1H). 8.52 (d. J = 5.1 Hz, 1H), 8.47 (dt, J = 8.0, 2.0 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H). 7.50 (dd, J = 8.0, 4.8 Hz, 1H), 7.44 (d. J = 5.1 Hz, 1H). 7.35 (ddd. J = 8.2. 5.2. 3.0 Hz. 2H), 7.20 (d, J = 8.3 Hz. 1H), 7.12 (t, J = 2.2 Hz, 1H), 7.02 (ddd, J = 17.9, 8.1, 2.2 Hz, 2H), 4.75 (s, 2H), 2.22 (s, 3H).LRMS m / z (ESI+): 446.30[M+H]+).

[0231] Example 31

[0232] Compound 31

[0233] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-fluorophcnoxy)acctamidc

[0234] Compound 31 was synthesized according to general procedure A. H NMR: 400 MHz,DMSO 5 10.05 (s, 1H), 9.27 (d, J = 2.3 Hz, 1H), 8.96 (s. 1H), 8.69 (dd. J = 4.8, 1.7 Hz, 1H). 8.52 (d, J = 5.2 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.0, 4.8 Hz, 1H), 7.44 (d. J = 5.1 Hz, 1H). 7.39 - 7.29 (m, 2H), 7.19 (d, J = 8.3 Hz. 1H), 6.95 - 6.74 (m, 3H), 4.74 (s, 2H), 2.22 (s, 3H). LRMS m / z (ESI+): 430.40 [M+H]+).

[0235] Example 32

[0236] Compound 32

[0237] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-bromophenoxy)acetamide

[0238] Compound 32 was synthesized according to general procedure A. ( ' H NMR: 400 MHz, DMSO 5 10.05 (s, 1H), 9.26 (d. J = 2.3 Hz, 1H). 8.96 (s, 1H), 8.70 (dd, J = 4.7, 1.6 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H). 8.47 (dt, J = 8.0, 2.0 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 7.9, 1.6 Hz. 1H), 7.49 (dd, J = 8.0, 4.8 Hz, 1H), 7.44 (d, J = 5.2 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 7.11 - 7.05 (m, 1H), 6.93 (td, J = 7.6, 1.3 Hz, 1H), 4.83 (s, 2H), 2.22 (s, 3H).LRMS m / z (ESI+): 490.20 [M+H]+).

[0239] Example 33

[0240] Compound 33

[0241] N-{ 3-| 4-(3-pyridyl)-2-pyrimidmylamino | -4-toly 1 }(o-chlorophenoxy)acetamide

[0242] Compound 33 was synthesized according to general procedure A. (' H NMR: (500 MHz, DMSO) 5 10.11 (s, 1H), 9.25 (d, J = 2.3 Hz, 1H). 8.95 (s. 1H), 8.69 (dd. J = 4.8. 1.7 Hz. 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.46 (dt. J = 8.0. 2.0 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.50 - 7.41 (m. 3H), 7.33 - 7.26 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 7.09 (dd, J = 8.3, 1.4 Hz. 1H), 6.99 (td, J = 7.6, 1.4 Hz, 1H), 4.83 (s, 2H), 2.21 (s, 3H). LRMS m / z (ESI+): 446.25 [M+H]+).

[0243] Example 34

[0244] Compound 34

[0245] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-fluorophenoxy)acetamide

[0246] Compound 34 was synthesized according to general procedure A. (' H NMR: 400 MHz. DMSO 5 10.13 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 8.96 (s, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.52 (d, J = 5.2 Hz, 1H). 8.47 (dt. J = 8.1. 2.0 Hz. 1H), 7.95 (d, J = 2.2 Hz. 1H), 7.49 (dd. J = 8.0. 4.8 Hz. 1H), 7.44 (d, J = 5.1 Hz. 1H), 7.32 (dd, J = 8.2. 2.2 Hz, 1H), 7.29 - 7.22 (m. 1H), 7.19 (d, J = 8.3 Hz. 1H), 7.16 - 7.1 (m. 2H), 6.98 (ddd, J = 1 1 .5, 6.4, 3.7 Hz, 1H), 4.81 (s, 2H). 2.22 (s, 3H). LRMS m / z (ESI+): 430.25 [M+H]+).

[0247] Example 35

[0248] Compound 35

[0249] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(R)-2-phcnoxypropionamidc

[0250] Compound 35 was synthesized according to general procedure A. f1H NMR: 400 MHz, DMSO 5 10.08 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 8.95 (s. 1H), 8.70 (dd. J = 4.7, 1.6 Hz, 1H). 8.52 (d, J = 5.1 Hz, 1H). 8.45 (dt, J = 8.1, 2.0 Hz. 1H), 7.99 (d, J = 2.2 Hz. 1H), 7.50 - 7.38 (m, 2H), 7.30 (td. J = 8.3. 7.3. 2.2 Hz. 3H), 7.17 (d, J = 8.3 Hz. 1H), 6.96 (dd, J = 10.7, 7.8 Hz, 3H). 4.88 (q. J = 6.6 Hz, 1H), 2.20 (s, 3H), 1.57 (d, J = 6.6 Hz. 3H). LRMS m / z (ESI+): 426.20 [M+H]+).

[0251] Example 36

[0252] Compound 36

[0253] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(p-iodophenoxy)acetamide

[0254] Compound 36 was sy nthesized according to general procedure A. (’ H NMR: 400 MHz, DMSO 5 10.06 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 8.95 (s, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.48 (dd, J = 8.1, 4.7 Hz, 1H), 7.44 (d, J = 5.1 Hz. 1H), 7.33 (dd, J = 8.1, 2.2 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.90 - 6.83 (m, 2H), 4.71 (s, 2H). 2.22 (s, 3H). LRMS m / z (ESI+): 538.20 [M+H]+).

[0255] Example 37

[0256] Compound 37

[0257] N- { 3 - [4-(3 -py ridy l)-2-py rimidmy lamino] -4-toly 1 } (p-nitrophenoxy )acetamide

[0258] Compound 37 was synthesized according to general procedure A. ( ' H NMR: LRMS m / z (ESI+): 457.30 [M+H]+)

[0259] Example 38

[0260] Compound 38

[0261] N- {3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl }(p-methoxyphenoxy)acetamide

[0262] Compound 38 was synthesized according to general procedure A. t' H NMR: (400 MHz, DMSO) 59.97 (s, 1H). 9.25 (d. J = 2.2 Hz, 1H), 8.94 (s, 1H). 8.68 (dd, J = 4.9, 1.7 Hz, 1H), 8.50 (d, J = 5.1 Hz. 1H), 8.45 (dt, J = 8.0, 2.0 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.49 (dd. J = 8.0, 4.7 Hz, 1H), 7.42 (d, J = 5.1 Hz, 1H), 7.34 (dd, J = 8.3, 2.2 Hz, 1H). 7.17 (d. J = 8.3 Hz, 1H). 6.98 - 6.92 (m, 2H), 6.91 - 6.84 (m, 2H), 4.61 (s. 2H), 2.20 (s, 3H). LRMS m / z (ESI+): 442.35 [M+H]+).

[0263] Example 39

[0264] Compound 39

[0265] N- { 3 - [4-(3 -py ridy l)-2-py rimidiny lamino] -4-toly 1 } (p-bromophenoxy )acetamide

[0266] Compound 39 was synthesized according to general procedure A. (’H NMR: (500 MHz, DMSO) 5 10.07 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 8.96 (s, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.46 (dt, J = 8.0, 2.0 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.51 - 7.45 (m, 3H), 7.43 (d, J = 5.2 Hz, 1H), 7.33 (dd, J = 8.2, 2.2 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.02 - 6.95 (m, 2H), 4.71 (s, 2H), 2.21 (s, 3H). LRMS m / z (ESI+): 490.30 [M+H]+)

[0267] Example 40

[0268] Compound 40

[0269] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(p-chlorophenoxy)acetamide

[0270] Compound 40 was synthesized according to general procedure A. i1H NMR: 400 MHz,DMSO 5 10.05 (s, 1H), 9.25 (d, J = 2.3 Hz, 1H). 8.94 (s, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.50 (d, J = 5.1 Hz, 1H). 8.45 (dt, J = 8.1, 2.1 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.0, 4.8 Hz, 1H),7.43 (d, J = 5.1 Hz, 1H), 7.39 - 7.29 (m, 3H). 7.18 (d. J = 8.3 Hz, 1H). 7.05 - 7.00 (m. 2H), 4.70 (s, 2H). 2.20 (s, 3H). LRMS m / z (ESI+): 446.15 [M+H]+).

[0271] Example 41

[0272] Compound 41

[0273] N-{3-[4-(3-pyridyl)-2-pyrimidmylamino]-4-tolyl}(p-fluoroplienoxy)acetamide

[0274] Compound 41 was synthesized according to general procedure A. t' H NMR: (500 MHz. DMSO) 5 10.04 (s, 1H). 9.29 - 9.23 (m, 1H). 8.96 (s. 1H), 8.69 (dd. J = 4.7. 1.7 Hz, 1H), 8.51 (d, J = 5.1 Hz. 1H), 8.46 (dt, J = 8.1, 1.9 Hz, 1H). 7.95 (d, J = 2.2 Hz, 1H), 7.50 (ddd. J = 7.9, 4.7. 0.9 Hz. 1H), 7.43 (d, J = 5.2 Hz. 1H), 7.34 (dd. J = 8.2, 2.2 Hz, 1H). 7.22 - 7.12 (m, 3H). 7.06 - 7.00 (m, 2H), 4.68 (s, 2H), 2.21 (s, 3H). LRMS m / z (ESI+): 430.25 [M+H]+)

[0275] Example 42

[0276] Compound 42

[0277] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2-pyridyloxy)acetamide

[0278] Compound 42 was synthesized according to general procedure A. f1H NMR: 400 MHz, DMSO 5 10.27 (s, 1H), 9.24 (d, J = 2.3 Hz, 1H), 8.90 (s, 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.47 (dt, J = 8.0, 2.0 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 7.0, 2.1 Hz, 1H), 7.51 (dd, J = 8.0, 4.8 Hz. 1H), 7.48 - 7.40 (m. 2H), 7.27 (dd, J = 8.2. 2.2 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.40 (d, J = 9.1 Hz, 1H), 6.24 (td, J = 6.7, 1.4 Hz, 1H), 4.74 (s, 2H), 2.20 (s, 3H). LRMS m / z (ESI+): 413.20 [M+H]+).

[0279] Example 43

[0280] Compound 43

[0281] N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}phenoxyacetamide

[0282] Compound 43 was synthesized according to general procedure A. ( ' H NMR: 400 MHz, DMSO 8 10.02 (s, 1H), 9.25 (d. J = 2.3 Hz, 1H). 8.94 (s, 1H), 8.68 (dd, J = 4.8, 1.6 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H). 8.45 (dt, J = 8.0, 2.1 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.0, 4.7 Hz. 1H), 7.42 (d, J = 5.2 Hz, 1H), 7.37 - 7 ,T1 (m, 3H), 7.18 (d, J = 8.2 Hz, 1H), 6.98 (dd, J = 17.1, 7.9 Hz, 3H), 4.69 (s, 2H), 2.20 (s, 3H).LRMS m / z (ESI+): 412.30 [M+H]+).

[0283] Example 44

[0284] Compound 44

[0285] 2-(4-chlorophenoxy)-N-(3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acetamide

[0286] Compound 44 was synthesized according to general procedure A. (1 H NMR: 400 MHz, DMSO 3 10.10 (s, 1H), 9.80 (s, 1H), 9.34 (d, J = 1.5 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.59 (t, J = 8.9, 5.1 Hz, 2H), 8.27 (s, 1H), 7.52 (d, J = 5.1 Hz, 1H), 7.49-7.46 (m, J = 5.16 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 7.27-7.19 (m, 2H), 7.04 (d, J = 8.9 Hz, 2H), 4.74 (s, 2H). LRMS m / z (ESI+): 432.3 [M+H]+).

[0287] Example 45

[0288] Compound 45

[0289] 2-(4-chlorophenoxy)-N-(4-fluoro-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)acetamide

[0290] Compound 45 was synthesized according to general procedure A. (1H NMR: 400 MHz, DMSO 3 10.17 (s, 1H), 9.27 (d, J = 6.9 Hz, 2H), 8.69 (d, J = 3.6 Hz, 1H), 8.55 (d, J = 4.8 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 5.4, 1H), 7.52-7.46 (tn. 2H), 7.35 (d, J = 8.4 Hz, 3H), 7.24-7.20 (m, 1H), 7.03 (d, J = 8.5 2H), 4.74 (s. 2H). LRMS m / z (ESI+): 450.3 [M+H]+).

[0291] Example 46

[0292] Compound 46

[0293] N-(4-chloro-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-2-(4- chlorophenoxy)acetamide

[0294] Compound 46 was synthesized according to general procedure A. (1 H NMR: 400 MHz, DMSO 8 10.28 (s, 1H). 9.28 (d. J = 1.9 Hz, 1H). 8.98 (s, 1H), 8.69 (dd, J = 4.8, 1.4 Hz, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.49 (d, J = 8.0, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.52 (d. J = 5.16 Hz, 1H), 7.48-7.40 (m, 3H), 7.35 (d. J = 8.9 2H). 7.03 (d, J = 9.0 Hz, 2H), 4.74 (s, 2H). LRMS m / z (ESI+): 466.0 [M+H]+).

[0295] Example 47

[0296] Compound 47

[0297] 2-(4-chlorophenoxy)-N-(4-methoxy-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)acetamide

[0298] Compound 47 was synthesized according to general procedure A. (1H NMR: 400 MHz, DMSO 8 10.02 (s, 1H), 9.34 (d, J = 1.4 Hz, 1H), 8.70 (d, J = 3.6 Hz, 1H), 8.63-8.58 (m, 3H), 8.24 (s, 1H), 7.55 (d, J = 5.2, 1H), 7.43 (dd, J = 7.8, 4.9 Hz, 1H), 7.36 (d, J = 8.9 Hz, 2H), 7.25 (dd. J = 8.8, 2.2 Hz 1H), 7.07-7.02 (m, 3H), 4.72 (s, 2H), 3.85 (s, 3H). LRMS m / z (ESI+): 462.3 [M+H]+).INCORPORATION BY REFERENCE

[0299] 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) :or a pharmaceutically acceptable salt thereof; wherein:X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-, and a bond;Rxis independently selected from the group consisting of hydrogen and C i-C, alkyl: ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, Ci-Cealkyl. and Ci-Cealkoxy; wherein Ci-Cealkyl, and Ci-Cealkoxy may optionally be substituted by one or more halogens; andR1is selected from the group consisting of Ci-Cealkyl and hydrogen.

2. The compound of claim 1, wherein the compound is represented by3. The compound of either of claim 1 or 2, wherein ring A is phenyl or naphthyl, and wherein ring A may optionally be substituted with one. two, or three RA.

4. The compound of either of claim 1 or 2, wherein ring A is a 6-membered monocyclic heteroaryl or a 10-membered bicyclic heteroaryl, wherein ring A bears at least one ring nitrogen, and wherein ring A may optionally be substituted by one, two or three groups each independently selected from RA.

5. The compound of claim 4, wherein ring A is pyridyl or quinolinyl, and wherein ring A may optionally be substituted by one, two or three groups each independently selected from RA.

6. The compound of any one of claims 1-5, wherein X is selected from the group consisting of - CH2-O-, -CH(CH3)-O-, -CH2-O-CH2-, -CH(CH3)-O-CH2-, and a bond.

7. The compound of any one of claims 1-6, wherein the compound is represented by:wherein Y is CH or N.

8. The compound of any one of claims 1-6, wherein the compound is represented by:

9. The compound of any one of claims 1-8. wherein RAis independently selected for each occurrence from the group consisting of. for example, fluoro, chloro, bromo, iodo, hydroxyl, -CN, - NO2, -CH3, -CF3. -OCH3. and -OCF3.

10. The compound of any one of claims 1-9, wherein R1is -CH3.

11. The compound of any one of claims 1-10, wherein the compound is selected from the group consisting of:N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-2-(3-nitrophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2,4,5-trichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(4-chloro-2-tolyloxy)acctamidc;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3,4,6-trichloro-2-pyridyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2,6-xylyloxy)acetamide;N- {3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl }(2-naphthyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}-2-pyridinecarboxamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-nitrophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(5-chloro-8-quinolyloxy)acetamide:N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(benzyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-(trifluoromethyl)benzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylaminol-4-tolyl}[(p-methoxyphenyl)methoxylacetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3,4-dichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2,4-dichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-trifluoroanisamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-cy anobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-iodobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-bromobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-chlorobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-fluorobenz amide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}benzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-trifluoromethoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}[p-(trifluoromethyl)phenoxy]acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-tolyloxy)acetamide;N-(3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-tolyloxy)acctamidc;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-bromophenoxy)acetamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (m-ch loro phenoxy Jacctam ide:N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (m -fluorophenoxy )acetamide ;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-fluorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(R)-2-phenoxypropionamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-iodophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-nitrophenoxy)acetamide;N-(3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-mcthoxyphcnoxy)acctamidc;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-bromophenoxy )acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-bromophenoxy )acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-ch lorophcnoxy )acetam ide ;N-{3-[4-(3-pyridyl)-2-p rimidinylamino]-4-tol l}(p-chlorophenoxy)acetamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-fluorophenoxy)acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-fluorophenoxy)acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 }(2-py ridy loxy )acetamide :N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2-pyridyloxy)acetamide:N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}phenoxyacetamide; and N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}phenoxy acetamide.

12. The compound of any of claims 1-11. wherein the compound is selected from:

13. A pharmaceutical composition comprising a compound of any one of claims 1-12 and one or more pharmaceutically acceptable carriers, diluents or excipients.

14. The pharmaceutical composition of claim 13. further comprising one or more additional therapeutic agents.

15. 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 claims 1-12. or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either of claim 13 or 14.

16. A method for treating the progression of a neurodegenerative disorder or related condition in a patient in need thereof, comprising administering to tire patient an effective amount of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either of claim 13 or 14.

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 a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either of claim 13 or 14.

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

19. A method of synthesizing a compound of Formula (I):wherein:X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-, and a bond;Rxis independently selected from the group consisting of hydrogen and Ci-Csalkyl; ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, Ci -Ckalkyk and Ci-Cealkoxy; wherein Ci-Cealkyl, and Ci-Cealkoxy may optionally be substituted by one or more halogens; andR1is selected from the group consisting of Cj -Cealkyl and hy drogen;the method comprising: adding a coupling reagent and a non-nucleophilic base to a solution of a compound of Formula (IIA) in an organic solvent;wherein:X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-, and a bond;Rxis independently selected from the group consisting of hydrogen and Ci- C3alkyl; ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN. -NO2. Ci-Cealkyl. and Ci-Cealkoxy; wherein Ci-Cealkyl. and Ci-Cealkoxy may optionally be substituted by one or more halogens; adding to the solution of a compound of a formula (IIB)wherein R1is selected from the group consisting of Ci-Cealkyl and hydrogen; stirring the solution; evaporating the solution, resulting in a product residue; and purifying tire residue via flash chromatography, thereby yielding the compound of Formula (I).

20. The method of claim 19, wherein the non-nucleophilic base is X. '.-diisopropylcth lminc.

21. The method of either of claim 19 or 20, wherein the coupling reagent is 1.1'- carbony Idiimidazole .

22. The method of any of claims 19-21, wherein the organic solvent is dichloromethane.

23. The method of any of claims 19-22. wherein the non-nucleophilic base is in an amount of 1.5 eq relative to the amount of the compound of Formula (IIB).

24. The method of any of claims 19-23. wherein the coupling reagent is in an amount of 3 eq relative to the amount of the compound of Formula (IIB).

25. The method of any of claims 19-24. wherein the compound of Formula (IIA) is in an amount of 1.5 eq relative to the amount of the compound of Formula (IIB).

26. The method of any of claims 19-25, wherein the compound of Formula (I) is selected from the group consisting of:

27. The method of any of claims 19-26. wherein ring A is phenyl or naphthyl, and wherein ring A may optionally be substituted with one, two. or three RA.

28. The method of any of claims 19-27. wherein ring A is a 6-membered monocyclic heteroaryl or a 10-membered bicyclic heteroaryl, wherein ring A bears at least one ring nitrogen, and wherein ring A may optionally be substituted by one, two or three groups each independently selected from RA.

29. The method of claim 28, wherein ring A is pyridyl or quinolinyl, and wherein ring A may optionally be substituted by one, two or three groups each independently selected from RA.

30. The method of any of claims 19-29. wherein X is selected from the group consisting of -CH2- O-, -CH(CH3)-O-, -CH2-O-CH2-, -CH(CH3)-O-CH2-_ and a bond.

31. The method of any of claims 19-30. wherein the compound of Formula (I) is a compound selected from the group consisting of:wherein Y is CH or N.

32. The method of any of claims 19-30, wherein the compound of Formula (I) is a compound selected from the group consisting of:

33. The method of any of claims 19-32, wherein RAis independently selected for each occurrence from the group consisting of, for example, fluoro, chloro, bromo, iodo, hydroxyl. -CN, - NO2, -CH3. -CF3, -OCH3, and -OCF3.

34. The method of any of claims 19-33. wherein R1is -CH3.

35. The method of any of claims 19-34. wherein the compound of Formula (I) is a compound selected from the group consisting of:N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-2-(3-nitrophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2.4,5-trichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(4-chloro-2-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3.4,6-trichloro-2-pyridyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2,6-xylyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2-naphthyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}-2 -pyridinecarboxamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-nitrophcnoxy)acctamidc;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(5-chloro-8-quinolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(benzyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-(trifluoromethyl)benzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-methoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}[(p-methoxyphenyl)methoxy]acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(3,4-dichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(2,4-dichlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-trifluoroanisamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-cy anobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-iodobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylaminol-4-tolyl}p-bromobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-chlorobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}p-fluorobenzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}benzamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-trifluoromethoxyphenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}[p-(trifluoromethyl)phenoxy]acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-tolyloxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(m-fluorophenoxy)acetamide;N-(3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(o-fluorophcnoxy)acctamidc;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(R)-2 -phenoxypropionamide;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-iodophenoxy )acetamide ;N- { 3 -[4-(3 -pyridyl) -2-pyrimidiny lamino] -4-toly 1 } (p-nitrophenoxy )acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-methoxy phenoxy )acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (p-methoxy phenoxy )acetamide ;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-bromophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-chlorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-fluorophenoxy)acetamide;N-{3-[4-(3-pyridyl)-2-pyrimidinylamino]-4-tolyl}(p-fluorophcnoxy)acctamidc;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (2-py ridy loxy )acetamide ;N- {3 -[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } (2-py ridyloxy )acetamide ;N-{3-[4-(3 -pyridyl) -2-py rimidiny lamino] -4-toly 1 } phenoxy acetamide ; and N-{3-[4-(3 -py ridy 1) -2-py rimidiny lamino] -4-toly 1 } phenoxy acetamide .

36. The method of any of claims 19-35, wherein the compound of Formula (I) is37. Use of a compound of claim of any one of claims 1-12. or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of either of claim 13 or 14 in the manufacture of a medicament for the treatment of a neurode generative disorder.

38. The use of claim 37, wherein the ne mode generative disorder is Alzheimer’s disease.

39. A compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:X is selected from the group consisting of -C(RX)2-O-, -C(RX)2-O-CH2-, and a bond;Rxis independently selected from the group consisting of hydrogen and Ci-Csalkyl; ring A is selected from the group consisting of phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, and 8-10 membered bicyclic heteroaryl; wherein ring A may optionally be substituted by one or more substituents each independently selected from RA;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN. -NO2, Ci-Cgalkyl, and Cj -Cf.alkoxy: wherein Ci-Cealkyl, and Ci -G, alkoxy may optionally be substituted by one or more halogens; andR1is selected from the group consisting of Ci-Cgalkyl, halogen, hydroxy', and hydrogen.

40. The compound of claim 39, wherein the compound is selected from the group consisting of:2-(4-chlorophenoxy)-N-(3-((4-(pyridin-3-yl)pyrimi din-2 -yl)amino)phenyl)acetamide;2-(4-chlorophenoxy)-N-(4-fluoro-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)acetamide;N-(4-chloro-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-2-(4- chlorophenoxy)acetamide; and2-(4-chlorophenoxy)-N-(4-methoxy-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)acetamide.

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