Small molecule inhibitors of DYRK1 / CLK and uses thereof

Abstract

This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a 6,5-heterocyclic structure (e.g., compounds having a imidazo-pyridine structure, or compounds having a pyridinyl-purine structure) which function as inhibitors of DYRK1A, DYRK1B, and Clk-1, and are useful as therapeutics for the treatment of Alzheimer's disease, Down syndrome, diabetes (e.g., any type or form of diabetes, including type-1 or type-2), autoimmune diseases, inflammatory disorders (e.g., airway inflammation), cancer (e.g., glioblastoma, prostate cancer), diabetes, and other diseases.

Description

[0001] SMALL MOLECULE INHIBITORS OF DYRK1 / CLK AND USES THEREOF

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to U. S. Provisional Application No. 63 / 713,896, filed October 30, 2024, which is incorporated herein by reference in its entirety.

[0004] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0005] This invention was made with government support under Grant No. AG067926, awarded by National Institutes of Health. The government has certain rights in the invention.

[0006] FIELD OF THE INVENTION

[0007] This invention is in the field of medicinal chemistry. In particular, the invention relates to anew class of small-molecules having a 6,5-heterocyclic structure (e g., compounds having a imidazo-pyridine structure, or compounds having a pyridinyl-purine structure) which function as inhibitors of DYRK1A, DYRK1B, and Clk-1, are devoid of phosphodiesterase 3A (PDE3a) activity, and are useful as therapeutics for the treatment of Alzheimer’s disease, Down syndrome, diabetes, autoimmune diseases, inflammatory disorders (e g., airway inflammation), cancer (e.g., glioblastoma, prostate cancer), and other diseases.

[0008] INTRODUCTION

[0009] With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer’s disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions.

[0010] The underlying treatment of learning and / or memory disorders is a huge and significantly unmet medical need and also included learning and memory repair after, for example, incidents of stroke or significant brain damage. As such, an improved understanding of the dementia (and other neuropathology) and related improved treatment methods are needed.

[0011] SUMMARY OF THE INVENTION

[0012] In addition to the overwhelmingly prominent / -amyloid hypothesis being evaluated in a multitude of clinical trials through small molecule modulation of y- and / / -secretases and numerous immune-based approaches, aberrant phosphorylation of the tau protein is believed to significantly contribute to the development of AD and thus affords an alternate approach for therapeutic development. Tau is a cytoplasmic protein involved in the stabilization of microtubules under normal conditions. In AD, neuronal tau has been found to be excessively phosphorylated, with subsequent generation of aggregates of phosphory lated tau protein, known as “neurofibrillary tangles"’ (NFTs). NFTs and amyloid plaques are considered the most common hallmarks of AD and are correlated with neurofibrillary degeneration, neuronal death, and dementia.

[0013] Interestingly, several protein kinases have been implicated in neuronal development and, in particular, their overexpression and aberrant activation have been shown to play a significant role in the development of AD via tau phosphorylation. Dual specificity tyrosine phosphorylation regulated kinase-1 A (DYRK1 A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimer’s disease (AD) and Down syndrome (DS).

[0014] Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer’s disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases.

[0015] Increased expression of the DYRK1 A gene has been implicated in both the cognitive deficits of Down syndrome (DS) and the early onset of tau and amyloid neuropathologies that are associated with this genetic disorder. DYRK1 A levels are increased in transgenic mouse models of DS and develop DS-like phenotypes including hippocampal-dependent spatial learning and memory' deficits and developmental delays. Together these data strongly support a central function for DYRK1 A in cognitive deficits associated with DS. Moreover, inhibition of excess DYRK1 A activity’ has been shown to improve these DYRK1 A-mediated cognitive deficits after administration of the natural products epigallocatechin-3-gallate (EGCg) and harmine, the standards for DYRK1 A inhibition at the on-set of this translational campaign. However, these probes are not significantly selective and have numerous off-target effects that reduce their practical long-term use. To circumvent many of the detrimental issues observed, in particular with harmine, knowledge-based design efforts herein have unearthed novel small molecule series of structurally unique 6,5-heterocyclic DYRK1A inhibitors, amenable to test the benefits of selective DYRK1 A inhibition in mouse models of DS / AD and a variety of other disease states including Parkinson’s disease, Pick’s disease, Huntington’s and additional tauopathies.

[0016] Experiments conducted during the course of developing embodiments for the present invention designed, synthesized and biologically evaluated compounds having a 6,5-heterocyclic structure (e.g., compounds having a imidazo-pyridine structure, or compounds having a pyridinyl-purine structure) as inhibitors of the dual specificity tyrosine phosphorylation regulated kinase- 1 A (DYRK1A), and their potential for use as therapeutics against AD and other disorders related to DYRK-1A activity (e.g., DS, other neuropathology, cancer (e.g., glioblastoma, prostate cancer, colorectal cancer (see. e.g., Tam et al., Cancer Lett. 2020, March 31: 473:186-197), diabetes (see, e g., Barzowska et al., Cells., 2021, 10(9), 2263), cognitive enhancement). Many of such compounds exhibit activity against dual specificity tyrosine phosphorylation regulated kinase- IB (DYRK1B) and exhibit activity against other kinases implicated in a variety of disease states (e.g., dual specificity protein kinase CLK1 (Clk-1).

[0017] The DYRK1 A inhibitors described herein can also be considered as potential therapeutics for the treatment of developmental diseases such as Down syndrome, and neurodegenerative diseases such as Parkinson’s disease, and Huntington’s disease. Moreover, the DYRK1A inhibitors of the present invention have been also implicated as potential therapeutics for the treatment of glioblastomas and further potential utility is highlighted in the oncology arena (see, e.g., lonescu et al., Mini-reviews in Medicinal Chemistry, 2012, 12, 1315-1329).

[0018] These novel DYRK1A inhibitors may also have utility as general cognitive enhancers, given the published findings that DYRK1 A can phosphorylate sirtuin 1, a key regulator of learning and memory (see, e.g., Michan et al., J. Neurosci. 2010, 30(29), 9695-9707; Guo et al., J Biol. Chem. 2010, 285 (17), 13223-13232). The potential utility of these DYRK1A compound series is further reinforced by findings that harmine, a potent, but relatively less selective DYRK1A inhibitor, enhances memory performance in wild-type rodents (Mennenga et al., Physiol. Behav. 2015, 138, 260-265). Moreover, the effectiveness of small molecule inhibition of DYRK1A in mitigating both insoluble tau aggregates and amyloid plaques has been demonstrated (see, e g., Branca et al., Aging Cell, 2017, 16(5), 1146-1154). The mechanistic rational for this was detailed previously (see Smith et al., ACS Chem. Neuroscience, 2012, 3(11), 857-872). These novel DYRK1A inhibitors may also have further utility as results identify DYRK1 A as a physiologically relevant regulator of Tregcell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. As such, new roles may be found in autoimmune diseases such as inflammatory bowel disease and type 1 diabetes (see, e.g., Khor B, et al., eLife 2015;4:e05920).

[0019] Accordingly, the invention relates to anew class of small-molecules having a 6,5-heterocyclic structure (e.g., compounds having a imidazo-pyridine structure, or compounds having a pyridinyl-purine structure) which function as inhibitors of DYRK1A, DYRK1B, and are useful as therapeutics for the treatment of Alzheimer’s disease, Down syndrome, autoimmune diseases, inflammatory disorders (e.g., airway inflammation), cancer (e.g., glioblastoma, prostate cancer), diabetes, and other diseases.

[0020] Certain compounds of the present invention may exist as stereoisomers including optical isomers. The invention includes all stereoisomers, both as pure individual stereoisomer preparations and enriched preparations of each, and both the racemic mixtures of such stereoisomers as well as the individual diastereomers and enantiomers that may be separated according to methods that are well known to those of skill in the art.

[0021] In a particular embodiment, compounds encompassed within Formula I:

[0022]

[0023] u; ug pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0024] Formulas 1 and II are independently not limited to a particular chemical moiety for X, Y, Rl, R2, R3, R4, and R5. In some embodiments, the particular chemical moiety for X, Y, Rl, R2, R3, R4, and R5 independently include any chemical moiety that permits the resulting compound to inhibit DYRK1A activity. In some embodiments, the particular chemical moiety for X, Y. Rl, R2, R3, R4, and R5 independently include any chemical moiety that permits the resulting compound to inhibit one or more of: DYRK1 A related PI3K / Akt signaling; DYRK1 A related tau phosphorylation; DYRK1 A related NF AT phosphorylation; DYRK1 A related ASK1 / JNK1 pathway activation; DYRK1 A related p53 phosphorylation; DYRK1 A related Amph 1 phosphorylation; DYRK1A related Dynamin 1 phosphory lation; DYRK1 A related Synaptojanin phosphorylation; DYRK1 A related presenilin 1 (the catalytic sub-unit of y-secretase) activity; DYRK1A related amyloid precursor protein phosphory lation; DYRK1A related SIRT1 activation; DYRK2 activity; DYRK1B activity; CMGC / CLK kinase activity; CLK2 activity; CLK.3 activity; and CLK.4 activity.

[0025] In some embodiments, X and Y are each independently selected from either C or N. For example, in some embodiments, X and Y are each C and the resulting formulas are represented

[0026]

[0027] example, in some embodiments, X and Y are each N and the resulting formulas are represented

[0028]

[0029] some embodiments, X is C and Y is N or X is N and Y is C and the resulting formulas are

[0030]

[0031]

[0032]

[0033] In some embodiments, R1 is heterocycle chemical moiety comprising a hydrogen-bond acceptor (e.g., morpholine).

[0034] ?

[0035] In some embodiments, R2 is selected from Hydrogen, F, Cl, CH3, CN (> ), and OCH3

[0036]

[0037] In some embodiments,. R2 is either hydrogen or halogen (e.g., F, Cl, Br, I).

[0038] In some embodiments, R3 is selected from Hydrogen, F, Cl, CH3, CN (5), and OCH3

[0039]

[0040] In some embodiments, R3 is either hydrogen or halogen (e.g.. F, Cl, Br, I). In some embodiments, X and Y are C and R1 combines with R2 such that the resulting

[0041]

[0042] In some embodiments, X and Y are C and R1 combines with R3 such that the resulting

[0043]

[0044] In some embodiments, R4 is selected from Hydrogen, NH2 or CH3. For example, in some embodiments, R4 is H and the resulting formula is represented by

[0045]

[0046] In some embodiments, R5 is selected from Hydrogen, NH2 or CH3. For example, in some embodiments, R5 is H and the resulting formula is represented by

[0047]

[0048] some embodiments, R5 is CH3 and the resulting formula is represented by

[0049]

[0050] in some embodiments, R5 is NH2 and the resulting formula is represented by

[0051]

[0052] In some embodiments, R4 is H and R5 is H, and the resulting formula is represented by

[0053]

[0054] embodiments, R4 is H and R5 is NH2, and the resulting formula is represented by

[0055]

[0056]

[0057] In some embodiments, the compound is recited in Table 1. Table 1 includes the results of affinity testing of the compounds of the present invention with DYRK1 A (DYRK1 A Affinity Key (+++ KD O.lnM to lOOnM, ++ lOOnM to luM (KD: dissociation constant))).

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] The invention further provides processes for preparing any of the compounds of the present invention.

[0064] The invention also provides the use of compounds to not only inhibit DYRK1A activity but also signaling pathways dependent upon DYRK1A phosphorylation (e.g., Tau, PI3K / AKt, APP, PSI, ASF, RCAN-1, NF AT, p53, ASK1 / JNK1, SIRT1, GluN2A and other NMDA receptors). The invention also relates to the use of compounds for sensitizing cells to additional agent(s), such as agents known to be effective in the treatment of neurodegenerative disorders.

[0065] In certain embodiments, the compounds are used as DYRK protein degraders (see, Valazquez, et al, 2019 Molecular Neurobiology71-12).

[0066] The compounds of the invention are useful for the treatment, amelioration, or prevention of disorders associated with DYRK1A activity (e.g., AD. DS. Parkinson’s disease. Huntington’s disease, diabetes (e.g., any form or type of diabetes, including type 1 or type 2), glioblastoma), such as those responsive to DYRK1 A activity7inhibition.

[0067] In certain embodiments, the compounds can be used to treat, ameliorate, or prevent cancer that is associated with DYRK1 A activity (e.g.. glioblastoma, prostate cancer).

[0068] In certain embodiments, the compounds can be used to treat, ameliorate, or prevent autoimmune diseases.

[0069] In certain embodiments, the compounds can be used to treat, ameliorate, or prevent inflammatory7disorders (e.g., airway inflammation).

[0070] In certain embodiments, the compounds can be used to treat, ameliorate, or prevent diabetes (e.g., any type or form of diabetes, including type-1 and type-2).

[0071] The invention also provides pharmaceutical compositions comprising the compounds of the invention in a pharmaceutically acceptable carrier.

[0072] In certain embodiments, the present invention provides methods for administering an effective amount of a compound of the invention and one or more additional therapeutic agents useful in treating a disorder associated with DYRK1 activity. Such additional therapeutic agents may be useful in treating neurological, autoimmune, inflammatory, metabolic, or neoplastic disorders.

[0073] In some embodiments, the additional therapeutic agent is useful in treating a neurodegenerative disease (e.g., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Down syndrome, or a related cognitive or motor disorder). Suitable neurodegenerative disease agents include, but are not limited to, cholinesterase inhibitors (e.g., donepezil, rivastigmine. galantamine, tacrine), NMDA receptor antagonists (e.g., memantine), -secretase (BACE) inhibitors (e.g.. verubecestat, lanabecestat, elenbecestat), y-secretase modulators (e.g., semagacestat, avagacestat), anti-amyloid monoclonal antibodies (e.g., aducanumab, lecanemab, donanemab, bapineuzumab, solanezumab), tau aggregation inhibitors (e g., hydromethylthionine, TRxO237), dopaminergic agents (e.g., levodopa / carbidopa, ropinirole, pramipexole, rotigotine), MAO-B inhibitors (e.g., selegiline, rasagiline, safinamide), COMT inhibitors (e.g.. entacapone, tolcapone, opicapone), adenosine A2A receptor antagonists (e.g., istradefylline), VMAT2 inhibitors (e.g., tetrabenazine, deutetrabenazine), antisense oligonucleotides (e.g., tominersen), and GABA-A antagonists (e.g., pentylenetetrazole, RO4938581).

[0074] In some embodiments, the additional therapeutic agent is useful in treating an autoimmune disease. Suitable agents include, but are not limited to, corticosteroids and immunosuppressants (e g., prednisone, methylprednisolone, dexamethasone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus) and biologic agents such as TNF-a inhibitors (e.g., infliximab, etanercept, adalimumab, golimumab, certolizumab pegol), IL-1 inhibitors (e.g., anakinra, canakinumab, rilonacept), IL-6 pathway inhibitors (e.g., tocilizumab, sarilumab), IL- 17 or IL-23 inhibitors (e.g., secukinumab, ixekizumab, ustekinumab, guselkumab, risankizumab), B-cell modulators (e.g., rituximab, ocrelizumab, belimumab), T-cell costimulation blockers (e.g., abatacept), integrin antagonists (e.g., natalizumab, vedolizumab), and JAK inhibitors (e.g., tofacitinib, baricitinib, upadacitinib, ruxolitinib).

[0075] In some embodiments, the additional therapeutic agent is useful in treating an inflammatory disorder. Exemplary anti-inflammatory agents include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, meloxicam). corticosteroids (e.g., hydrocortisone, prednisone, prednisolone, dexamethasone, budesonide, fluticasone), cytokine or chemokine inhibitors (e g., maraviroc, apremilast, roflumilast), antioxidants and redox modulators (e.g., N-acetylcysteine, vitamin E, curcumin, resveratrol), and agents for specific inflammatory conditions (e.g., inflammatory’ bowel disease, psoriasis, atopic dermatitis, or asthma).

[0076] In some embodiments, the additional therapeutic agent is useful in treating diabetes (any form or type of diabetes, including type 1 or type 2). Suitable antidiabetic agents include, but are not limited to, insulin formulations (e.g., insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin degludec, regular human insulin, NPH insulin); insulin secretagogues (e.g., glipizide, glyburide, glimepiride, repaglinide, nateglinide); insulin sensitizers (e.g.. metformin, pioglitazone, rosiglitazone); incretin-based agents (e.g., GLP-1 receptor agonists such as exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, efpeglenatide; and DPP-4 inhibitors such as sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin); SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin); a-glucosidase inhibitors (e.g., acarbose, miglitol, voglibose); amylin analogs (e.g., pramlintide): bile acid sequestrants (e.g., colesevelam); dopamine D₂ agonists (e.g., bromocriptine); GLP-1 receptor agonists (e.g., exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, efpeglenatide); and GLP-1 / GIP dual agonists (e.g., tirzepatide, LY3437943, mazdutide [IBI362], retatrutide, VK2735, CT-388, HRS9531).

[0077] In some embodiments, the additional therapeutic agent is useful in treating cancer (e.g., glioblastoma, prostate cancer, or any cancer associated with DYRK1 A or DYRK1B activity). Exemplary anticancer agents include, but are not limited to, alkylating agents (e.g., temozolomide, cyclophosphamide, ifosfamide, melphalan, carmustine, lomustine, dacarbazine), antimetabolites (e.g., methotrexate, pemetrexed. 5-fluorouracil, capecitabine, gemcitabine, cytarabine, cladribine), platinum-based agents (e.g.. cisplatin, carboplatin, oxaliplatin), microtubule-targeting agents (e.g., paclitaxel, docetaxel, nab-paclitaxel, vincristine, vinblastine, vinorelbine), topoisomerase inhibitors (e.g., irinotecan, topotecan, etoposide, doxorubicin, daunorubicin, mitoxantrone), and targeted therapies including tyrosine kinase inhibitors (e.g., imatinib, erlotinib, gefitinib, osimertinib, lapatinib, sorafenib, sunitinib, pazopanib, lenvatinib, regorafenib, cabozantinib, dasatinib, nilotinib), mTOR inhibitors (e.g., everolimus, temsirolimus), CDK inhibitors (e g., palbociclib, ribociclib, abemaciclib), MEK / ERK pathway inhibitors (e.g., trametinib, selumetinib, cobimetinib, binimetinib), PI3K / AKT pathway inhibitors (e.g.. alpelisib, capivasertib, buparlisib), PARP inhibitors (e.g., olaparib, niraparib, rucaparib, talazoparib), and proteasome inhibitors (e.g.. bortezomib, carfilzomib. ixazomib). Additional agents may include immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab, atezolizumab, durvalumab, ipilimumab, tremelimumab), anti-angiogenic agents (e.g., bevacizumab, ramucirumab, aflibercept), hormonal or androgen-targeted therapies (e.g., enzalutamide, abiraterone, apalutamide, tamoxifen, fulvestrant, aromatase inhibitors), DNA damage response modulators (e.g., ATR, ATM, CHK.1 / 2, or WEE1 inhibitors), epigenetic modulators (e.g., vorinostat, panobinostat, romidepsin, azacitidine, decitabine), and immunomodulatory agents (e.g., lenalidomide, pomalidomide, thalidomide).

[0078] In some embodiments, the additional therapeutic agent may be selected from an analgesic, an anti-spasmodic, an antioxidant, a mitochondrial enhancer, a neurotrophic factor mimetic, a small-molecule anti-oxidative stress agent, or a metabolic regulator (e.g., acetaminophen, gabapentin, baclofen, N-acetylcysteine. coenzyme Q10, idebenone, minocycline, edaravone, metformin, pioglitazone, or a GLP-1 receptor agonist).

[0079] These and other embodiments are encompassed within the scope of the invention and may be administered sequentially or concurrently with the compound of the invention, either in the same pharmaceutical composition or in separate dosage forms.

[0080] The invention also provides kits comprising a compound of the invention and instructions for administering the compound to an animal. The kits may optionally contain other therapeutic agents, e.g., agents useful in treating neurodegenerative disorders, diabetes (e.g., any form or type of diabetes, including type 1 or type 2), and / or anticancer agents.

[0081] The additional therapeutic agents may include, but are not limited to, agents for treating neurodegenerative, autoimmune, inflammatory, metabolic, or neoplastic diseases.

[0082] In some embodiments, the kit comprises agents useful for treating neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Down syndrome, or related cognitive or motor disorders). Exemplary neurodegenerative agents include cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, tacrine), NMD A receptor antagonists (e.g., memantine), -secretase (BACE) inhibitors (e.g., verubecestat, lanabecestat, elenbecestat), y-secretase modulators (e.g., semagacestat, avagacestat), anti-amyloid monoclonal antibodies (e g., aducanumab, lecanemab, donanemab, bapineuzumab, solanezumab), tau aggregation inhibitors (e.g., hydromethylthionine, TRxO237), dopaminergic agents (e.g., levodopa / carbidopa, ropinirole, pramipexole, rotigotine), MAO-B inhibitors (e g., selegiline, rasagiline, safinamide), COMT inhibitors (e.g., entacapone, tolcapone, opicapone), adenosine A2A receptor antagonists (e.g.. istradefylline), VMAT2 inhibitors (e.g., tetrabenazine, deutetrabenazine), antisense oligonucleotides (e.g., tominersen), and GABA-A antagonists (e.g.. pentylenetetrazole, RO4938581).

[0083] In some embodiments, the kit comprises agents useful for treating autoimmune diseases, including, but not limited to, corticosteroids and immunosuppressants (e.g., prednisone, methylprednisolone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus) and biologic agents such as TNF-a inhibitors (e.g., infliximab, adalimumab, etanercept), IL-1 inhibitors (e.g., anakinra, canakinumab, rilonacept), IL-6 pathway inhibitors (e.g., tocilizumab, sarilumab), IL-17 or IL-23 inhibitors (e.g., secukinumab, ixekizumab, ustekinumab, guselkumab, risankizumab), B-cell modulators (e.g., rituximab, ocrelizumab, belimumab), T-cell costimulation blockers (e.g.. abatacept). integrin antagonists (e.g., natalizumab, vedolizumab), and JAK inhibitors (e.g., tofacitinib, baricitinib, upadacitinib. ruxolitinib).

[0084] In some embodiments, the kit includes agents useful for treating inflammatory disorders. Exemplary7anti-inflammatory agents include non-steroidal anti-inflammatory7drugs (NSAIDs) (e.g., ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, meloxicam), corticosteroids (e.g., hydrocortisone, prednisone, dexamethasone, budesonide, fluticasone), cytokine or chemokine inhibitors (e.g., maraviroc, apremilast, roflumilast), antioxidants and redox modulators (e.g., N-acetylcysteine, vitamin E, curcumin, resveratrol), and agents for specific inflammatory7diseases (e.g., infliximab, adalimumab, vedolizumab, ustekinumab, dupilumab).

[0085] In certain embodiments, the kit comprises agents useful for treating diabetes (e g., any form or type of diabetes, including type 1 or type 2). Exemplary antidiabetic agents include insulin formulations (e.g., insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin degludec), insulin secretagogues (e.g., glipizide, glyburide, repaglinide, nateglinide), insulin sensitizers (e.g., metfonnin, pioglitazone, rosiglitazone), incretin-based agents (e.g., GLP-1 receptor agonists such as exenatide, liraglutide, semaglutide, dulaglutide. lixisenatide; and DPP-4 inhibitors such as sitagliptin, linagliptin, saxagliptin), SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin, canagliflozin, ertugliflozin), and GLP-1 / GIP dual agonists (e.g., tirzepatide, LY3437943, mazdutide [IBI362], retatrutide, VK2735, CT-388, HRS9531).

[0086] In additional embodiments, the kit comprises agents useful for treating cancer (e.g., glioblastoma, prostate cancer, or any cancer associated with DYRK1 A or DYRK.1B activity). Exemplary anticancer agents include alkylating agents (e.g., temozolomide, cyclophosphamide), antimetabolites (e.g., 5-fluorouracil, gemcitabine), platinum-based agents (e.g., cisplatin, carboplatin, oxaliplatin), microtubule-targeting agents (e.g.. paclitaxel, docetaxel), topoisomerase inhibitors (e.g.. etoposide, doxorubicin), tyrosine kinase inhibitors (e.g., imatinib. erlotinib, sunitinib), mTOR inhibitors (e.g., everolimus), CDK inhibitors (e.g., palbociclib, abemaciclib), PI3K / AKT pathway inhibitors (e.g., alpelisib), PARP inhibitors (e.g., olaparib), and immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab, atezolizumab).

[0087] In certain embodiments, the components of the kit are packaged together or separately and are provided with instructions for use. The kit may be configured to enable sequential or concurrent administration of the compound of the invention and the one or more additional therapeutic agents, either in the same or in separate pharmaceutical compositions.

[0088] In certain embodiments, the invention provides pharmaceutical compositions comprising a compound of the invention and one or more additional therapeutic agents useful in treating a disorder associated with DYRK1 activity. Such compositions may further include one or more pharmaceutically acceptable carriers, excipients, or diluents, and may be formulated for simultaneous, sequential, or separate administration of the compound and the additional therapeutic agent. The compositions may be provided as a single co-formulated dosage form or as a multi-component combination packaged for concurrent use.

[0089] In some embodiments, the disorder associated with DYRK1 activity is Alzheimer's disease, Down syndrome, Huntington’s disease, Parkinson’s disease, an autoimmune disease, an inflammatory disorder (e.g., airway inflammation), diabetes (e.g., any form or type of diabetes, including ty pe 1 or type 2), or a cancer (e.g., glioblastoma, prostate cancer, or any cancer associated with aberrant DYRK1A or DYRK1B activity).

[0090] In certain embodiments, the one or more additional therapeutic agents are selected from agents useful for treating neurodegenerative diseases, autoimmune diseases, inflammatory disorders, diabetes, or cancers. Exemplary neurodegenerative disease agents include cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, tacrine), NMDA receptor antagonists (e.g.. memantine), -secretase (BACE) inhibitors (e.g., verubecestat, lanabecestat, elenbecestat), y-secretase modulators (e.g., semagacestat, avagacestat), anti-amyloid monoclonal antibodies (e.g., aducanumab, lecanemab, donanemab, bapineuzumab, solanezumab), tau aggregation inhibitors (e g., hydromethylthionine, TRxO237), dopaminergic agents (e.g., levodopa / carbidopa, ropinirole, pramipexole, rotigotine), MAO-B inhibitors (e.g., selegiline, rasagiline, safinamide), COMT inhibitors (e.g., entacapone, tolcapone, opicapone), adenosine A2A receptor antagonists (e.g., istradefylline), VMAT2 inhibitors (e g., tetrabenazine, deutetrabenazine), antisense oligonucleotides (e.g., tominersen), and GABA-A antagonists (e.g., pentylenetetrazole, RO4938581).

[0091] In some embodiments, the additional therapeutic agent is useful in treating an autoimmune disease and may include corticosteroids or immunosuppressants (e g., prednisone, methylprednisolone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus) or biologic agents (e.g., TNF-a inhibitors such as infliximab, adalimumab. etanercept; IL-1 inhibitors such as anakinra. canakinumab, rilonacept; IL-6 pathway inhibitors such as tocilizumab, sarilumab; IL-17 / IL-23 inhibitors such as secukinumab, ixekizumab, ustekinumab, guselkumab, risankizumab; B-cell modulators such as rituximab, ocrelizumab, belimumab; T-cell costimulation blockers such as abatacept; integrin antagonists such as natalizumab. vedolizumab; and JAK inhibitors such as tofacitinib, baricitinib. upadacitinib. ruxolitinib). In additional embodiments, the composition comprises an agent useful for treating an inflammatory disorder. Suitable agents include non-steroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, meloxicam), corticosteroids (e g., hydrocortisone, dexamethasone, budesonide, fluticasone), cytokine or chemokine inhibitors (e.g., maraviroc, apremilast, roflumilast), antioxidants and redox modulators (e.g., N-acetylcysteine, vitamin E, curcumin. resveratrol), and agents for inflammatory bowel disease, psoriasis, or asthma (e.g., infliximab, adalimumab, vedolizumab, ustekinumab, dupilumab, montelukast).

[0092] In certain embodiments, the composition further includes an antidiabetic agent useful for treating diabetes (e.g., type 1 or type 2). Exemplary antidiabetic agents include insulin formulations (e.g., insulin lispro, insulin aspart, insulin glargine, insulin detemir. insulin degludec), insulin secretagogues (e.g., glipizide, glyburide, repaglinide, nateglinide), insulin sensitizers (e.g., metformin, pioglitazone, rosiglitazone), incretin-based agents (e.g., GLP-1 receptor agonists such as exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, efpeglenatide; and DPP-4 inhibitors such as sitagliptin, saxagliptin. linagliptin. alogliptin, vildagliptin), SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), a-glucosidase inhibitors (e.g., acarbose, miglitol, voglibose), amylin analogs (e.g., pramlintide), bile acid sequestrants (e.g., colesevelam), and dopamine D2agonists (e.g., bromocriptine). In further embodiments, the additional therapeutic agent comprises a GLP-1 receptor agonist (e.g., exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, efpeglenatide) or a GLP-1 / G1P dual agonist (e.g., tirzepatide, LY3437943, mazdutide [IBI362], retatrutide, VK2735, CT-388, HRS9531).

[0093] In other embodiments, the composition comprises an anticancer agent (e.g., glioblastoma, prostate cancer, or cancers associated with DYRK1 A or DYRK1B activity). Suitable agents include alkylating agents (e.g., temozolomide, cyclophosphamide, ifosfamide), antimetabolites (e.g., 5-fluorouracil, gemcitabine), platinum-based agents (e.g., cisplatin, carboplatin, oxaliplatin), microtubule-targeting agents (e.g., paclitaxel, docetaxel), topoisomerase inhibitors (e.g., etoposide, doxorubicin), tyrosine kinase inhibitors (e.g., imatinib. erlotinib, sunitinib), mTOR inhibitors (e.g., everolimus), CDK inhibitors (e.g., palbociclib, abemaciclib), PI3K / AKT pathway inhibitors (e.g., alpelisib), PARP inhibitors (e.g., olaparib), and immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab, atezolizumab).

[0094] In some embodiments, the pharmaceutical composition is formulated with pharmaceutically acceptable carriers, excipients, or diluents, and may be provided in any suitable dosage form, including oral, parenteral, or subcutaneous formulations, or as sustained-release, liposomal, or nanoparticle-based preparations. In certain embodiments, the compound of the invention and the additional therapeutic agent are co-formulated within a single dosage unit, whereas in other embodiments they are provided in separate dosage forms configured for sequential or concurrent administration.

[0095] In certain embodiments, the invention provides pharmaceutical compositions comprising a compound of the invention and a GLP-1 pathway modulator. The GLP-1 pathway modulator may be a glucagon-like peptide-1 (GLP-1) receptor agonist or a dual GLP-l / glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. The composition may further include one or more pharmaceutically acceptable carriers, excipients, or diluents, and may be formulated for simultaneous, sequential, or separate administration of the compound and the GLP-1 pathway modulator.

[0096] In some embodiments, the GLP-1 receptor agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, or efpeglenatide. These agents act by mimicking the incretin hormone GLP-1 to enhance glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, and improve glycemic control, thereby complementing the activity of DYRK1 -modulating compounds that regulate 0-cell proliferation and insulin signaling.

[0097] In other embodiments, the GLP-l / GIP dual agonist is selected from tirzepatide, LY3437943. mazdutide (1B1362), retatrutide, VK2735, CT-388, or HRS9531. Such agents exhibit combined GLP-1 and GIP receptor agonism to potentiate glucose-dependent insulin release, improve insulin sensitivity, and promote weight loss, thereby synergizing with DYRK1 inhibition to enhance metabolic regulation and 0-cell function.

[0098] In some embodiments, the compound of the invention and the GLP-1 pathway modulator are co-formulated in a single dosage form, such as a tablet, capsule, or injectable preparation. In other embodiments, the components are provided in separate dosage forms configured for sequential or concurrent administration. The compositions may be formulated for oral, parenteral, or subcutaneous delivery, and may be presented as sustained-release, liposomal, or nanoparticle-based preparations to achieve controlled release and optimized pharmacokinetics.

[0099] These combination compositions are useful for treating disorders associated with DYRK1 activity7, including metabolic diseases such as diabetes (e.g., type 1 or type 2), obesity, insulin resistance, and related complications. In some embodiments, the compositions are further useful for improving glycemic control, reducing insulin dependence, promoting P-cell regeneration, or enhancing glucose tolerance in patients in need thereof.

[0100] DETAILED DESCRIPTION OF THE INVENTION DYRK1A is a member of the DYRK family containing 5 kinases (DYRK1 A, DYRK1B, DYRK2, DYRK3 and DYRK4). DYRKs belong to the CMGC group of proline-directed kinases, which also includes cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs) and CDC2-like kinases (CLKs). While the signaling pathways of CDK and MAPK families have been extensively studied, much less is known on how DYRKs and CLKs are linked to other proteins and various physiological or pathological processes.

[0101] The DYRK1 A gene is located on chromosome 21 (21 q22.2), a region known as the Down-Syndrome Critical Region (DSCR) (see, e.g., Hammerle et al., 2011 Development 138, 2543-2554). The under- or over-expression of the Dyrkla gene in mammals or of its orthologous gene minibrain (mnb) in Drosophila causes severe retardation of central nervous system development and maturation. At the molecular level, DYRK1 A phosphorylates the nuclear factor of activated T cells (NF AT), counteracting the effect of calcium signaling and maintaining inactive NF AT (see, e.g., Arron et al., 2006 Nature 411, 595-600). DYRK1 A has been identified as a negative regulator of the cell cycle that promotes the switch to a quiescent state or differentiation (see, e.g., Chen et al., 2013 Mol. Cell 52, 87-100). In malignant cells, DYRK1A promotes survival via inhibition of pro-apoptotic proteins (see, e.g., Guo et al., 2010 J. Bio. Chem. 285, 13223-13232; Seifert et al., 2008 FEBS J. 275, 6268-6280).

[0102] Currently, treatment options for cognitive deficiencies associated with AD and DS are extremely limited and represent a major, extremely significant unmet therapeutic need. The DYRK 1 A inhibitors of the present invention provide a new avenue for pharmaceutical intervention of mental impairment associated w ith AD and other neurodegenerative diseases, and address a critical unmet medical need and significantly changing treatment paradigm for AD.

[0103] Experiments conducted during the course of developing embodiments for the present invention designed, synthesized and biologically evaluated compounds having a 6,5-heterocyclic structure (e.g., compounds having a imidazo-pyridine structure, or compounds having a pyridinyl-purine structure) as inhibitors of the dual specificity tyrosine phosphorylation regulated kinase-lA (DYRK1A). and their potential for use as therapeutics against AD and other disorders related to DYRK-1A activity (e.g., DS, other neuropathology, cancer (e.g., glioblastoma, prostate cancer), diabetes, cognitive enhancement). Many of such compounds exhibit activity against dual specificity tyrosine phosphorylation regulated kinase-lB (DYRK1B) and exhibit activity against other kinases implicated in a variety' of disease states (e.g., dual specificity' protein kinase CLK1 (Clk-1). The DYRK1B gene is not as ubiquitous as the DYRK1 A gene and is found in the testis and muscle. DYRK1B plays roles in survival of certain cancer cells and myoblast differentiation.

[0104] Moreover, the DYRK1A inhibitors of the present invention can be used for treating other cellular pathways involved in mental impairment and neurodegenerative dementia. Specifically, the DYRK1 A inhibitors of the present invention can be used for inhibiting DYRK1 A activated PI3K / Akt signaling, a pathway largely involved in neuronal development, grow th, and survival. The DYRK1 A inhibitors of the present invention DYRK1A can be used for inhibiting DYRK1A stimulated ASK1 / JNK1 activity, thereby inducing neuronal death and apoptosis. In addition, the DYRK1 A inhibitors of the present invention DYRK1 A can be used to inhibit DYRK1A phosphorylation of p53 during embryonic brain development, thereby preventing neuronal proliferation alteration. The DYRK1A inhibitors of the present invention can be used to inhibit DYRK1 A phosphorylation of synaptic proteins Amph 1, Dynamin 1, and Synaptojanin, involved in the regulation of endocytosis, thereby retaining synaptic plasticity’ through preventing alteration of the number, size, and morphology of dendritic spines. The DYRK1 A inhibitors of the present invention can be used to inhibit presenilin 1 (the catalytic sub-unit of y-secretase). The DYRK1A inhibitors of the present invention can be used to inhibit DYRK2 activity'. The DYRK1A inhibitors of the present invention can be used to inhibit DYRK1B activity. The DYRK1A inhibitors of the present invention can be used to inhibit CMGC / CLK kinase activity. The DYRK1 A inhibitors of the present invention can be used to inhibit CLK2 activity'. The DYRK1A inhibitors of the present invention can be used to inhibit CLK3 activity. The DYRK1 A inhibitors of the present invention can be used to inhibit CLK4 activity.

[0105] As such, the present invention addresses the need for effective therapies for AD and DS by providing potent and selective DYRK1 A inhibitors able to permeate the blood-brain barrier (BBB) and elicit on-mechanism therapeutic responses in AD animal models.

[0106] Accordingly, the invention relates to anew class of small-molecules having a 6,5-heterocyclic structure (e.g., compounds having a imidazo-pyridine structure, or compounds having a pyridinyl-purine structure) which function as inhibitors of DYRK1 A, DYRK1B, and Clk-1, and are useful as therapeutics for the treatment of Alzheimer's disease, Down syndrome, diabetes (e.g., any form or type of diabetes, including type 1 or type 2), autoimmune diseases, inflammatory disorders (e.g., airway inflammation), cancer (e.g., glioblastoma, prostate cancer), and other diseases.

[0107] The CDC2-like kinase (CLK) family contains four isoforms which are important in regulating the function of the spliceosome complex (see, e.g., Fedorov et al, Chem Biol. 201 1; 18(1): 67-76). This complex, comprised of small nuclear RNAs (snRNA) and a large number of associated proteins, regulates the splicing of pre-mRNAs to give mature protein-encoding mR As. CLK1 is known to regulate the activity of the spliceosome via phosphorylation of the constituent serine-arginine-rich (SR) proteins (see, e.g.. Bullock et al, Structure. 2009;17(3):352-62). By controlling the activity of the spliceosome in this way. many genes are able express more than one mRNA leading to diversity in the translated proteins. The alternative protein iso forms transcribed from the same gene will often have different activities and physiological functions. Deregulation of alternative splicing has been linked to cancer, where a number of cancer-related proteins are known to be alternatively spliced (see, e.g., Druillennec et al, J Nucleic Acids. 2012:2012:639062). An example of an alternatively spliced protein in cancer is Cyclin DI, important for the progression of cancer cells through the cell cycle (see, e.g., Wang et al, Cancer Res. 2008;68(14):5628-38).

[0108] Alternative splicing regulated by CLK1 has also been described to play a role in neurodegenerative diseases, including Alzheimer's and Parkinson's, via phosphorylation of the SR proteins of the spliceosome (see, e.g., Jain et al, Curr Drug Targets. 2014;15(5):539-50). In the case of Alzheimer's, CLK1 is know n to regulate the alternative splicing of the microtubule-associated protein TAU leading to an imbalance between TAU iso forms which is sufficient to cause neurodegeneration and dementia (see, e g., Liu et al. Mol Neurodegener. 2008:3:8).

[0109] In the treatment of both cancer and neurological disease, there is thus undoubtedly an urgent need for compounds which potently inhibit the DYRK1 and CLK1 kinases whilst not affecting other closely-related kinases. The compounds described herein address this need. In a particular embodiment, compounds encompassed within Formula I:

[0110]

[0111] g pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0112] Formulas I and II are independently not limited to a particular chemical moiety for X, Y, Rl, R2, R3, R4, and R5. In some embodiments, the particular chemical moiety for X, Y, Rl, R2, R3. R4, and R5 independently include any chemical moiety that permits the resulting compound to inhibit DYRK1A activity. In some embodiments, the particular chemical moiety for X, Y, Rl, R2, R3, R4, and R5 independently include any chemical moiety’ that permits the resulting compound to inhibit one or more of: DYRK1A related PI3K / Akt signaling; DYRK1A related tau phosphorylation; DYRK1A related NF AT phosphorylation; DYRK1 A related ASK1 / JNK1 pathway activation; DYRK1 A related p53 phosphorylation; DYRK1A related Amph 1 phosphorylation; DYRK1A related Dynamin 1 phosphorylation; DYRK1 A related Synaptojanin phosphorylation; DYRK1 A related presenilin 1 (the catalytic sub-unit of y-secretase) activity; DYRK1A related amyloid precursor protein phosphorylation: DYRK1A related SIRT1 activation; DYRK2 activity; DYRK1B activity; CMGC / CLK kinase activity; CLK.2 activity; CLK3 activity; and CLK4 activity.

[0113] In some embodiments, X and Y are each independently selected from either C or N. For example, in some embodiments, X and Y are each C and the resulting formulas are represented

[0114]

[0115] example, in some embodiments, X and Y are each N and the resulting formulas are represented

[0116]

[0117] some embodiments, X is C and Y is N or X is N and Y is C and the resulting formulas are

[0118]

[0119] In some embodiments, R1 is selected from hydrogen,

[0120]

[0121]

[0122]

[0123]

[0124] In some embodiments, R1 is heterocycle chemical moiety comprising a hydrogen-bond acceptor (e.g., morpholine).

[0125]

[0126] In some embodiments, R2 is selected from Hydrogen, F, Cl, CH3, CN (5), and OCH3

[0127]

[0128] In some embodiments,. R2 is either hydrogen or halogen (e.g., F, Cl, Br, I).

[0129]

[0130] In some embodiments. R3 is selected from Hydrogen. F, Cl, CH3. CN (§), and OCH3

[0131]

[0132] In some embodiments,. R3 is either hydrogen or halogen (e.g., F, Cl, Br, I).

[0133] In some embodiments, X and Y are C and R1 combines with R2 such that the resulting

[0134]

[0135] In some embodiments, X and Y are C and R1 combines with R3 such that the resulting

[0136]

[0137] In some embodiments, R4 is selected from Hydrogen, NH2 or CH3. For example, in 5 some embodiments, R4 is H and the resulting formula is represented by

[0138]

[0139] example, in some embodiments, R4 is NH2 and the resulting formula is represented by

[0140]

[0141] some embodiments, R5 is H and the resulting formula is represented by

[0142]

[0143] some embodiments, R5 is CH3 and the resulting formula is represented by

[0144]

[0145] in some embodiments, R5 is NH2 and the resulting formula is represented by

[0146]

[0147] In some embodiments, R4 is H and R5 is H, and the resulting formula is represented by

[0148]

[0149] embodiments, R4 is CH3 and R5 is CH3, and the resulting formula is represented by

[0150]

[0151] embodiments, R4 is NH2 and R5 is NH2, and the resulting formula is represented by

[0152]

[0153] 1.

[0154] The invention further provides processes for preparing any of the compounds of the present invention.

[0155] In some embodiments, the compositions and methods of the present invention are used to treat diseased cells, tissues, organs, or pathological conditions and / or disease states in an animal (e.g., a mammalian patient including, but not limited to, humans and veterinary’ animals). In this regard, various diseases and pathologies are amenable to treatment or prophylaxis using the present methods and compositions. A non-limiting exemplary list of these diseases and conditions includes, but is not limited to, Alzheimer’s disease, Down syndrome. Huntington’s disease, Parkinson’s disease, autoimmune diseases, cancer (e.g., glioblastoma, prostate cancer, any type of cancer related to DYRK1A and / or DYRK1B activity)), inflammatory disorders (e.g., airway inflammation), diabetes (e.g., any type or form of diabetes, including tye-1 and type-2), and any neurodegenerative disorder related to DYRK.1A activity.

[0156] Some embodiments of the present invention provide methods for administering an effective amount of a compound of the invention and at least one additional therapeutic agent (including, but not limited to, any agent useful in treating Alzheimer's disease, Down syndrome. Huntington's disease, Parkinson's disease, autoimmune diseases, cancer (e.g., glioblastoma, prostate cancer, any type of cancer related to DYRK1A and / or DYRK1B activity )), inflammatory disorders (e.g., airway inflammation), diabetes (e.g., any ty pe or form of diabetes, including tye-1 and type-2), and any neurodegenerative disorder related to DYRK1 A activity'.

[0157] Such additional therapeutic agents include, but are not limited to, agents useful for the treatment of neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease.

[0158] Huntington’s disease, Down syndrome, or related cognitive or motor disorders). Exemplary neurodegenerative disease agents include, but are not limited to, cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, tacrine), NMDA receptor antagonists (e.g.. memantine), - secretase (BACE) inhibitors (e.g., verubecestat, lanabecestat, elenbecestat), y-secretase modulators (e.g.. semagacestat, avagacestat), anti-amyloid monoclonal antibodies (e.g., aducanumab, lecanemab, donanemab, bapineuzumab, solanezumab), tau aggregation inhibitors (e.g., hydromethylthionine, TRxO237), dopaminergic agents (e.g., levodopa / carbidopa, ropinirole, pramipexole, rotigotine), MAO-B inhibitors (e.g., selegiline, rasagiline, safinamide), COMT inhibitors (e.g., entacapone, tolcapone, opicapone), adenosine A2A receptor antagonists (e.g., istradefylline), VMAT2 inhibitors (e.g., tetrabenazine, deutetrabenazine), antisense oligonucleotides (e.g., tominersen), and GABA-A antagonists (e.g., pentylenetetrazole, RO4938581). Additional examples include, but are not limited to, neuroprotective and antiinflammatory agents (e.g., ibuprofen, naproxen, curcumin, resveratrol, selegiline, minocycline, riluzole). mitochondrial and metabolic modulators (e.g., pioglitazone, metformin, coenzyme Q10, nicotinamide riboside, creatine, rapamycin), and neurotrophic or synaptic modulators (e.g., epigallocatechin gallate, fluoxetine, GDNF, neurturin, dopaminergic stem-cell preparations).

[0159] Such additional therapeutic agents include, but are not limited to, agents useful for the treatment of autoimmune diseases. Exemplary additional therapeutic agents for treating autoimmune diseases include, but are not limited to, corticosteroids and immunosuppressants (e.g., prednisone, methylprednisolone, dexamethasone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus) and biologic agents (e.g., TNF-a inhibitors such as infliximab, etanercept, adalimumab, golimumab, certolizumab pegol; IL-1 inhibitors such as anakinra, canakinumab. rilonacept; IL-6 pathway inhibitors such as tocilizumab, sarilumab; IL-17 / IL-23 inhibitors such as secukinumab, ixekizumab, ustekinumab, guselkumab, risankizumab; B-cell modulators such as rituximab, ocrelizumab, belimumab; T-cell costimulation blockers such as abatacept; integrin antagonists such as natalizumab and vedolizumab; and JAK inhibitors such as tofacitinib, baricitinib, upadacitinib, and ruxolitinib). Disease-specific agents include, but are not limited to, interferon-P, glatiramer acetate, fingolimod, siponimod, ozanimod, dimethyl fumarate, natalizumab, and ocrelizumab for multiple sclerosis; methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, TNF or JAK inhibitors for rheumatoid arthritis; belimumab, anifrolumab, hydroxychloroquine, and azathioprine for systemic lupus erythematosus; and insulin, teplizumab, and anti-CD3 antibodies for type 1 diabetes.

[0160] Such additional therapeutic agents include, but are not limited to, agents useful for the treatment of inflammatory diseases. Exemplary additional therapeutic agents for treating inflammatory diseases include, but are not limited to, non-steroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, meloxicam, etodolac, ketoprofen), corticosteroids (e.g., hydrocortisone, prednisone, prednisolone, dexamethasone, budesonide, fluticasone), cytokine or chemokine inhibitors (e.g., maraviroc, apremilast, roflumilast), antioxidants and redox modulators (e.g., N-acetylcysteine. vitamin E, curcumin, resveratrol), and agents for specific inflammatory disorders including, but not limited to, inflammatory bowel disease (e.g., infliximab, adalimumab, vedolizumab. ustekinumab, mesalamine, azathioprine), psoriasis or atopic dermatitis (e.g., methotrexate, cyclosporine, acitretin, secukinumab, ixekizumab, ustekinumab, dupilumab), and asthma or allergic inflammation (e.g., montel ukast, zafirlukast, omalizumab, mepolizumab, reslizumab, 02-agonists).

[0161] Such additional therapeutic agents include, but are not limited to, agents useful for the treatment of diabetes (e g., any form or type of diabetes, including type 1 or type 2). Exemplary additional therapeutic agents for treating diabetes include, but are not limited to, insulin formulations (e.g., insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin degludec, regular human insulin, NPH insulin); insulin secretagogues (e.g.. sulfonylureas such as glipizide, glyburide, glimepiride; and meglitinides such as repaglinide, nateglinide); insulin sensitizers (e.g., biguanides such as metformin; and thiazolidinediones such as pioglitazone, rosiglitazone); incretin-based agents (e.g., GLP-1 receptor agonists such as exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide; and DPP-4 inhibitors such as sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin); SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin); a-glucosidase inhibitors (e.g., acarbose, miglitol, voglibose); amylin analogs (e.g., pramlintide); bile acid sequestrants (e.g., colesevelam); and dopamine D2agonists (e.g., bromocriptine).

[0162] Additional therapeutic agents include, but are not limited to, weight-loss or metabolic modulators (e.g., orlistat, metformin, GLP-1 / GIP dual agonists such as tirzepatide, LY3437943, mazdutide [IBI362], retatrutide, VK2735, CT-388, and HRS9531), lipid-lowering agents (e.g., statins, fibrates, ezetimibe), and antihypertensives (e.g., ACE inhibitors, angiotensin receptor blockers) that may be co-administered to manage comorbidities commonly associated with diabetes. In certain embodiments, the compound of the invention may also be co-administered with therapeutic agents that promote 0-cell regeneration or survival (e.g., DYRK1 A inhibitors, harmine analogs, GABA, GLP-1 analogs) or agents that modulate insulin resistance and glucose uptake (e.g., metformin, thiazolidinediones, adiponectin agonists). Such additional therapeutic agents include, but are not limited to, agents useful for the treatment of cancer (e.g., glioblastoma, prostate cancer). Exemplary additional therapeutic agents for treating cancer (e.g., glioblastoma, prostate cancer) include, but are not limited to, alkylating agents (e.g., temozolomide, cyclophosphamide, ifosfamide, melphalan, carmustine, lomustine, dacarbazine); antimetabolites (e.g., methotrexate, pemetrexed, 5-fluorouracil, capecitabine. gemcitabine, cytarabine, cladribine); platinum-based agents (e.g.. cisplatin, carboplatin, oxaliplatin); microtubule-targeting agents (e.g., paclitaxel, docetaxel, nab-paclitaxel, vincristine, vinblastine, vinorelbine); topoisomerase inhibitors (e.g., irinotecan, topotecan, etoposide, doxorubicin, daunorubicin, mitoxantrone); and DNA intercalating or crosslinking agents (e g., actinomycin D, mitomycin C, bleomycin). Additional agents for treating cancer include, but are not limited to. targeted therapies such as tyrosine kinase inhibitors (e.g., imatinib, erlotinib, gefitinib, osimertinib, lapatinib, sorafenib, sunitinib, pazopanib, lenvatinib, regorafenib, cabozantinib, dasatinib, nilotinib), mTOR inhibitors (e.g., everolimus, temsirolimus), CDK inhibitors (e.g., palbociclib, ribociclib, abemaciclib), MEK / ERK pathway inhibitors (e.g.. trametinib. selumetinib, cobimetinib, binimetinib), PI3K / AKT pathway inhibitors (e.g., alpelisib, capivasertib, buparlisib), PARP inhibitors (e.g., olaparib, niraparib, rucaparib, talazoparib), and proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib).

[0163] In some embodiments, the compound of the invention may be co-administered with immune checkpoint inhibitors (e.g., anti-PD-1 antibodies such as nivolumab, pembrolizumab; anti-PD-Ll antibodies such as atezolizumab, durvalumab, avelumab; and anti-CTLA-4 antibodies such as ipilimumab, tremelimumab), anti-angiogenic agents (e.g., bevacizumab, ramucirumab, aflibercept), or hormonal or androgen-targeted therapies (e.g., enzalutamide, abiraterone, apalutamide, darolutamide, leuprolide, degarelix. fulvestrant, tamoxifen, aromatase inhibitors such as anastrozole, letrozole. exemestane). Additional combination partners include DNA damage response modulators (e.g., ATR, ATM, CHK. I / 2, or WEE1 inhibitors), epigenetic modulators (e.g., histone deacetylase inhibitors such as vorinostat, panobinostat, romidepsin; and DNMT inhibitors such as azacitidine, decitabine), and immunomodulatory agents (e.g., lenalidomide, pomalidomide, thalidomide).

[0164] In further embodiments, the compound of the invention may be co-administered with radiation therapy, adoptive cell therapy, cancer vaccines, or antibody-drug conjugates (e.g., trastuzumab-emtansine, brentuximab vedotin, sacituzumab govitecan). In certain embodiments, the compound of the invention is co-administered with agents targeting the DYRK1 A or DYRK1B pathway, cell-cycle regulators (e.g., cyclin D / CDK complexes), or downstream transcriptional and metabolic effectors associated with aberrant DYRK kinase signaling.

[0165] In some embodiments, the compound of the invention may further be co-administered with additional therapeutic agents including, but not limited to, analgesics or anti-spasmodics (e.g., acetaminophen, gabapentin, baclofen), antioxidants or mitochondrial enhancers (e.g., N-acetylcysteine, coenzyme Q10, idebenone), neurotrophic factors or mimetics (e.g., BDNF or NGF modulators), small-molecule anti-oxidative stress or anti-inflammatory agents (e.g., minocycline, edaravone), or metabolic regulators (e.g., metformin, pioglitazone, GLP-1 receptor agonists).

[0166] These and other additional therapeutic agents may be administered sequentially or concurrently with the compound of the invention, in the same or in separate pharmaceutical compositions.

[0167] Compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount which is effective to achieve its intended purpose. While individual needs vary’, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 50 mg / kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for disorders responsive to induction of apoptosis. In one embodiment, about 0.01 to about 25 mg / kg is orally administered to treat, ameliorate, or prevent such disorders. For intramuscular injection, the dose is generally about one-half of the oral dose. For example, a suitable intramuscular dose would be about 0.0025 to about 25 mg / kg, or from about 0.01 to about 5 mg / kg.

[0168] The unit oral dose may comprise from about 0.01 to about 1000 mg, for example, about 0.1 to about 100 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets or capsules each containing from about 0.1 to about 10 mg, conveniently about 0.25 to 50 mg of the compound or its solvates.

[0169] In atopical formulation, the compound may be present at a concentration of about 0.01 to 100 mg per gram of carrier. In a one embodiment, the compound is present at a concentration of about 0.07-1.0 mg / ml, for example, about 0.1-0.5 mg / ml, and in one embodiment, about 0.4 mg / ml.

[0170] In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. The preparations, particularly those preparations which can be administered orally or topically and which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound(s), together with the excipient.

[0171] The pharmaceutical compositions of the invention may be administered to any patient which may experience the beneficial effects of the compounds of the invention. Foremost among such patients are mammals, e g., humans, although the invention is not intended to be so limited. Other patients include veterinary’ animals (cows, sheep, pigs, horses, dogs, cats and the like).

[0172] The compounds and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0173] The pharmaceutical preparations of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, drageemaking, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.

[0174] Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dyestuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

[0175] Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are in one embodiment dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

[0176] Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0177] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene gly col-400. Aqueous injection suspensions may' contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and / or dextran. Optionally, the suspension may also contain stabilizers. The topical compositions of this invention are formulated in one embodiment as oils, creams, lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C12). The carriers may be those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in U. S. Pat. Nos. 3,989,816 and 4,444,762; each herein incorporated by reference in its entirety.

[0178] Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight. Lotions may be conveniently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.

[0179] One of ordinary skill in the art will readily recognize that the foregoing represents merely a detailed description of certain preferred embodiments of the present invention. Various modifications and alterations of the compositions and methods described above can readily be achieved using expertise available in the art and are within the scope of the invention.

[0180] The invention also provides kits comprising a compound of the invention and instructions for administering the compound to an animal. The kits may optionally contain other therapeutic agents, e.g., agents useful in treating neurodegenerative disorders, diabetes (e.g., any form or type of diabetes, including type 1 or type 2), and / or anticancer agents.

[0181] The additional therapeutic agents may include, but are not limited to, agents for treating neurodegenerative, autoimmune, inflammatory, metabolic, or neoplastic diseases.

[0182] In some embodiments, the kit comprises agents useful for treating neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Down syndrome, or related cognitive or motor disorders). Exemplary neurodegenerative agents include cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, tacrine), NMD A receptor antagonists (e.g., memantine), -secretase (BACE) inhibitors (e.g., verubecestat, lanabecestat, elenbecestat), y-secretase modulators (e.g., semagacestat, avagacestat), anti-amyloid monoclonal antibodies (e.g., aducanumab, lecanemab, donanemab, bapineuzumab, solanezumab), tau aggregation inhibitors (e.g., hydromethylthionine. TRxO237). dopaminergic agents (e.g.. levodopa / carbidopa, ropinirole, pramipexole, rotigotine), MAO-B inhibitors (e.g., selegiline, rasagiline, safinamide), COMT inhibitors (e.g., entacapone. tolcapone, opicapone). adenosine A2A receptor antagonists (e g., istradefylline), VMAT2 inhibitors (e g., tetrabenazine, deutetrabenazine), antisense oligonucleotides (e.g., tominersen), and GABA-A antagonists (e.g., pentylenetetrazole, RO4938581).

[0183] In some embodiments, the kit comprises agents useful for treating autoimmune diseases, including, but not limited to, corticosteroids and immunosuppressants (e.g., prednisone, methylprednisolone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus) and biologic agents such as TNF-a inhibitors (e.g., infliximab, adalimumab, etanercept), IL-1 inhibitors (e.g., anakinra, canakinumab, rilonacept), IL-6 pathway inhibitors (e.g., tocilizumab, sarilumab), IL- 17 or IL-23 inhibitors (e.g., secukinumab, ixekizumab, ustekinumab, guselkumab, risankizumab), B-cell modulators (e.g., rituximab, ocrelizumab, belimumab), T-cell costimulation blockers (e.g., abatacept), integrin antagonists (e.g., natalizumab, vedolizumab), and JAK inhibitors (e.g., tofacitinib, baricitinib, upadacitinib. ruxolitinib).

[0184] In some embodiments, the kit includes agents useful for treating inflammatory disorders. Exemplary anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, meloxicam), corticosteroids (e.g., hydrocortisone, prednisone, dexamethasone, budesonide, fluticasone), cytokine or chemokine inhibitors (e.g., maraviroc, apremilast, roflumilast), antioxidants and redox modulators (e g., N-acetylcysteine, vitamin E, curcumin, resveratrol), and agents for specific inflammatory diseases (e.g., infliximab, adalimumab, vedolizumab, ustekinumab, dupilumab).

[0185] In certain embodiments, the kit comprises agents useful for treating diabetes (e g., any form or type of diabetes, including type 1 or type 2). Exemplary antidiabetic agents include insulin formulations (e.g., insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin degludec), insulin secretagogues (e.g., glipizide, glyburide, repaglinide, nateglinide), insulin sensitizers (e.g., metformin, pioglitazone, rosiglitazone), incretin-based agents (e.g., GLP-1 receptor agonists such as exenatide, liraglutide, semaglutide, dulaglutide. lixisenatide; and DPP-4 inhibitors such as sitagliptin, linagliptin, saxagliptin), SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin, canagliflozin, ertugliflozin), and GLP-1 / GIP dual agonists (e.g., tirzepatide, LY3437943, mazdutide [IBI362], retatrutide, VK2735, CT-388, HRS9531).

[0186] In additional embodiments, the kit comprises agents useful for treating cancer (e.g., glioblastoma, prostate cancer, or any cancer associated with DYRK1 A or DYRK1B activity). Exemplary anticancer agents include alkylating agents (e.g., temozolomide, cyclophosphamide), antimetabolites (e.g.. 5-fluorouracil. gemcitabine), platinum-based agents (e.g.. cisplatin, carboplatin, oxaliplatin), microtubule-targeting agents (e g., paclitaxel, docetaxel), topoisomerase inhibitors (e.g., etoposide, doxorubicin), tyrosine kinase inhibitors (e.g., imatinib, erlotinib, sunitinib), mTOR inhibitors (e.g., everolimus), CDK inhibitors (e.g., palbociclib, abemaciclib), PI3K / AKT pathway inhibitors (e.g., alpelisib), PARP inhibitors (e.g., olaparib), and immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab, atezolizumab).

[0187] In certain embodiments, the components of the kit are packaged together or separately and are provided with instructions for use. The kit may be configured to enable sequential or concurrent administration of the compound of the invention and the one or more additional therapeutic agents, either in the same or in separate pharmaceutical compositions.

[0188] In certain embodiments, the invention provides pharmaceutical compositions comprising a compound of the invention and one or more additional therapeutic agents useful in treating a disorder associated with DYRK1 activity. Such compositions may further include one or more pharmaceutically acceptable carriers, excipients, or diluents, and may be formulated for simultaneous, sequential, or separate administration of the compound and the additional therapeutic agent. The compositions may be provided as a single co-formulated dosage form or as a multi-component combination packaged for concurrent use.

[0189] In some embodiments, the disorder associated with DYRK1 activity is Alzheimer’s disease, Down syndrome, Huntington’s disease, Parkinson’s disease, an autoimmune disease, an inflammatory disorder (e.g., airway inflammation), diabetes (e.g., any form or type of diabetes, including type 1 or type 2), or a cancer (e.g., glioblastoma, prostate cancer, or any cancer associated with aberrant DYRK1A or DYRK1B activity).

[0190] In certain embodiments, the one or more additional therapeutic agents are selected from agents useful for treating neurodegenerative diseases, autoimmune diseases, inflammatory disorders, diabetes, or cancers. Exemplary neurodegenerative disease agents include cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, tacrine), NMD A receptor antagonists (e.g.. memantine), -secretase (BACE) inhibitors (e.g., verubecestat, lanabecestat, elenbecestat), y-secretase modulators (e.g., semagacestat, avagacestat), anti-amyloid monoclonal antibodies (e.g., aducanumab, lecanemab, donanemab, bapineuzumab, solanezumab), tau aggregation inhibitors (e.g., hydromethylthionine, TRxO237), dopaminergic agents (e.g., levodopa / carbidopa, ropinirole, pramipexole, rotigotine), MAO-B inhibitors (e.g., selegiline, rasagiline, safinamide), COMT inhibitors (e.g., entacapone. tolcapone, opicapone). adenosine A2A receptor antagonists (e.g.. istradefylline), VMAT2 inhibitors (e.g., tetrabenazine, deutetrabenazine), antisense oligonucleotides (e.g., tominersen), and GABA-A antagonists (e.g.. pentylenetetrazole, RO4938581).

[0191] In some embodiments, the additional therapeutic agent is useful in treating an autoimmune disease and may include corticosteroids or immunosuppressants (e.g., prednisone, methylprednisolone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus) or biologic agents (e.g., TNF-a inhibitors such as infliximab, adalimumab, etanercept; IL-1 inhibitors such as anakinra, canakinumab, rilonacept; IL-6 pathway inhibitors such as tocilizumab, sarilumab; IL-17 / IL-23 inhibitors such as secukinumab, ixekizumab, ustekinumab, guselkumab, risankizumab; B-cell modulators such as rituximab, ocrelizumab, belimumab; T-cell costimulation blockers such as abatacept; integrin antagonists such as natalizumab, vedolizumab; and JAK inhibitors such as tofacitinib, baricitinib, upadacitinib, ruxolitinib).

[0192] In additional embodiments, the composition comprises an agent useful for treating an inflammatory’ disorder. Suitable agents include non-steroidal anti-inflammatory’ drugs (e.g., ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, meloxicam), corticosteroids (e.g., hydrocortisone, dexamethasone, budesonide, fluticasone), cytokine or chemokine inhibitors (e.g., maraviroc, apremilast, roflumilast), antioxidants and redox modulators (e.g., N-acetylcysteine, vitamin E, curcumin. resveratrol), and agents for inflammatory bowel disease, psoriasis, or asthma (e.g., infliximab, adalimumab, vedolizumab, ustekinumab, dupilumab, montelukast).

[0193] In certain embodiments, the composition further includes an antidiabetic agent useful for treating diabetes (e.g., type 1 or type 2). Exemplary antidiabetic agents include insulin formulations (e.g., insulin lispro, insulin aspart, insulin glargine, insulin detemir. insulin degludec), insulin secretagogues (e g., glipizide, glyburide, repaglinide, nateglinide), insulin sensitizers (e.g., metformin, pioglitazone, rosiglitazone), incretin-based agents (e.g., GLP-1 receptor agonists such as exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, efpeglenatide; and DPP-4 inhibitors such as sitagliptin, saxagliptin. linagliptin, alogliptin, vildagliptin), SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), a-glucosidase inhibitors (e.g., acarbose, miglitol, voglibose), amylin analogs (e.g., pramlintide), bile acid sequestrants (e.g., colesevelam), and dopamine D2agonists (e.g., bromocriptine). In further embodiments, the additional therapeutic agent comprises a GLP-1 receptor agonist (e.g., exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, efpeglenatide) or a GLP-l / GIP dual agonist (e.g., tirzepatide, LY3437943, mazdutide [IBI362], retatrutide, VK2735, CT-388, HRS9531).

[0194] In other embodiments, the composition comprises an anticancer agent (e g., glioblastoma, prostate cancer, or cancers associated with DYRK1 A or DYRK1B activity). Suitable agents include alkylating agents (e.g., temozolomide, cyclophosphamide, ifosfamide), antimetabolites (e.g.. 5-fluorouracil, gemcitabine), platinum-based agents (e.g.. cisplatin, carboplatin, oxaliplatin), microtubule-targeting agents (e.g., paclitaxel, docetaxel), topoisomerase inhibitors (e.g., etoposide, doxorubicin), tyrosine kinase inhibitors (e.g., imatinib, erlotinib, sunitinib), mTOR inhibitors (e.g., everolimus), CDK inhibitors (e.g., palbociclib, abemaciclib), PI3K / AKT pathway inhibitors (e.g., alpelisib), PARP inhibitors (e.g., olaparib), and immune checkpoint inhibitors (e.g.. pembrolizumab, nivolumab, atezolizumab).

[0195] In some embodiments, the pharmaceutical composition is formulated with pharmaceutically acceptable carriers, excipients, or diluents, and may be provided in any suitable dosage form, including oral, parenteral, or subcutaneous formulations, or as sustained-release, liposomal, or nanoparticle-based preparations. In certain embodiments, the compound of the invention and the additional therapeutic agent are co-formulated within a single dosage unit, whereas in other embodiments they are provided in separate dosage forms configured for sequential or concurrent administration.

[0196] In certain embodiments, the invention provides pharmaceutical compositions comprising a compound of the invention and a GLP-1 pathway modulator. The GLP-1 pathway modulator may be a glucagon-like peptide-1 (GLP-1) receptor agonist or a dual GLP-l / glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. The composition may further include one or more pharmaceutically acceptable carriers, excipients, or diluents, and may be formulated for simultaneous, sequential, or separate administration of the compound and the GLP-1 pathway modulator.

[0197] In some embodiments, the GLP-1 receptor agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, or efpeglenatide. These agents act by mimicking the incretin hormone GLP-1 to enhance glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, and improve glycemic control, thereby complementing the activity of DYRK1 -modulating compounds that regulate 0-cell proliferation and insulin signaling.

[0198] In other embodiments, the GLP-l / GIP dual agonist is selected from tirzepatide, LY3437943, mazdutide (IBI362), retatrutide, VK2735, CT-388, or HRS9531. Such agents exhibit combined GLP-1 and GIP receptor agonism to potentiate glucose-dependent insulin release, improve insulin sensitivity’, and promote weight loss, thereby synergizing with DYRK1 inhibition to enhance metabolic regulation and f>-cell function.

[0199] In some embodiments, the compound of the invention and the GLP-1 pathway modulator are co-formulated in a single dosage form, such as a tablet, capsule, or injectable preparation. In other embodiments, the components are provided in separate dosage forms configured for sequential or concurrent administration. The compositions may be formulated for oral, parenteral, or subcutaneous delivery, and may be presented as sustained-release, liposomal, or nanoparticle-based preparations to achieve controlled release and optimized pharmacokinetics.

[0200] These combination compositions are useful for treating disorders associated with DYRK1 activity, including metabolic diseases such as diabetes (e.g.. type I or type 2). obesity, insulin resistance, and related complications. In some embodiments, the compositions are further useful for improving glycemic control, reducing insulin dependence, promoting β-cell regeneration, or enhancing glucose tolerance in patients in need thereof.

[0201] EXAMPLES

[0202] The following examples are illustrative, but not limiting, of the compounds, compositions, and methods of the present invention. Other suitable modifications and adaptations of the variety’ of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.

[0203] Example I.

[0204] Table 1 includes the results of affinity testing of the compounds of the present invention with DYRK1A (DYRK1A Affinity Key (+++ KD O.lnM to lOOnM, ++ lOOnM to luM (KD: dissociation constant))).

[0205]

[0206]

[0207]

[0208]

[0209] Example II.

[0210] This example provides synthesis and characterization information for compounds of the present invention.

[0211] General Scheme 1:

[0212]

[0213] In General Scheme 1 the aniline building block A is prepared via a SNAT reaction between a secondary amine and activated fluoro-aryl B to afford the nitro derivative C, followed by a Bechamp reduction. The aniline D then undergoes a Buchwald amination-cyclo-condensation reaction to produce final product F. (X = CH or N, Y = CH or N, Q = CH, N, O, S).

[0214] General Scheme 2:

[0215]

[0216] In General Scheme 2 the aniline building block D is prepared via SxAr reaction followed by a copper-catalyzed Ullman amination on H. (X = CH or N, Y = CH or N, Q = CH, N, O. S).

[0217] General Scheme 3:

[0218]

[0219] In General Scheme 3 the nitro intermediate J is prepared via a S\ Ar reaction of I with D. A Bechamp reduction afford an aniline, which undergoes a cyclocondensation reaction to afford M. This is followed by a Suzuki cross coupling to produce final product L. (X = CH or N, Y = CH orN, Z = CH or N, Q = CH, N, O, S).

[0220] Step 1, General Scheme 1

[0221]

[0222] l-(2,6-difluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine, la.

[0223]

[0224] K.2CO3 (801 mg, 5.79 mmol), l-(oxetan-3- yl)piperazine (336 mg, 2.36 mmol), and DMF (2.15 mL) were stirred in a sealed 20 mL microwave vial that had previously been purged with argon for 15 minutes. l,2,3-trifluoro-5-nitrobenzene (0.25 mL, 2.146 mmol), was then injected and the vial heated at 120 C for 40 minutes. Upon cooling, the reaction mixture is washed with water (3 x 100 mL), filtered, and then washed with hexanes, affording l-(2,6-difluoro-4- nitrophenyl)-4- (oxetan-3-yl)piperazine, la, as a beige powder (470 mg, 1.570 mmol, 73% yield).XH NMR (CDC13) 5: 7.74 (d, J = 9.9 Hz, 2H), 4.66 (dt, J = 18.4, 6.4 Hz, 4H), 3.57 (p, J = 6.4 Hz, 1H), 3.47 - 3.39 (m. 4H), 2.50 - 2.43 (m, 4H).19F NMR (CDC13) 5: -117.58 (d, J = 9.0 Hz).

[0225] Step 2, General Scheme 1

[0226]

[0227] 3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-l-yl)aniline, lb.

[0228]

[0229] l-(2,6-difluoro-4-nitrophenyl)-4-(oxetan-3- yljpiperazine, la, (400 mg. 1.34 mmol), iron (373 mg, 6.68 mmol), and ammonium chloride (143 mg, 2.62 mmol), were added stirred in a sealed 20 mL microwave vial that had previously been purged with argon for 15 minutes. Degassed EtOH: H2O (3.34 mL:3.34 mL, 1:1 v / v) was then injected and the vial heated for 0.5 h at 110 °C in an oil bath. Upon cooling, the reaction mixture was diluted with EtOAc, filtered through celite, transferred to a separator}’ funnel and 10% NaOH was added. The aqueous layer was extracted with EtOAc (20 mL) and the organic layer washed with brine (20 mL) and dried with Na2SO4. The solvent was evaporated in vacuo, redissolved in DCM, dry -loaded onto silica and chromatographed on a 12g silica column, (DCM / MeOH, 0-5%), to afford 3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-l- yljaniline, lb, as ayellow powder (190 mg, 0.706 mmol, 53% yield, 5% MeOH in DCM). 'H NMR (CDC13) 5: 6.17 (d, J = 10.7 Hz, 2H), 4.76 - 4.63 (m, 4H), 3.73 (s, 2H), 3.57 (p, J = 6.5 Hz, 1H), 3.15 (t, J = 4.8 Hz, 4H), 2.49 - 2.42 (m, 4H).19F NMR (CDC13) 5: -119.22 (d. J = 10.4 Hz).

[0230] Step 3, General Scheme 1

[0231]

[0232] 4-(3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)-2-methyl-3 / / -imidazo[4,5-b\ pyridin-5-yl)pyridin-2-amine, 1.

[0233]

[0234] 3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-l- yl)aniline, lb, (75 mg, 0.28 mmol, 1 eq.), tert-butyl (5-acetamido-6-chloro-[2,4'-bipyridin]-2'-yl)(tert-butoxycarbonyl)carbamate (110 mg, 0.31 mmol, 1.1 eq.), Pd2(dba)3 (3.8 mg, 4.2 pmol, 0.015 eq.), XPhos (11 mg, 22 pmol, 0.08 eq.), K3PO4 (180 mg, 0.84 mmol, 3 eq.), and f-BuOH (0.7 mL, 0.4 M) were stirred in a sealed 5 mL microwave vial under argon at 110 °C for 18 hours. The reaction mixture was cooled, diluted with DCM. fdtered through celite, concentrated in vacuo, and dry -loaded onto silica gel and purified on a 12 g column (DCM / MeOH, 0-8%), to afford 4-(3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)-2-methyl-3H-imidazo[4,5- / ?]pyridin5-yl)pyridin-2-amine, 1, as a light green semi-solid (16 mg, 0.034 mmol, 12% yield, 8% MeOH in DCM). 'H NMR (CDC13) 5: 8.11 (d, J = 5.5 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.26 (dd, J = 5.6, 1.5 Hz. 1H), 7.18 (s, 1H), 7.05 (d, J = 9.1 Hz, 2H), 4.86 (bs, 2H), 4.72 (p, J = 6.4 Hz, 4H), 3.63 (p. J = 6.4 Hz, 1H), 3.45 - 3.38 (m, 4H), 2.64 (s, 3H), 2.58 - 2.50 (m, 4H).19F NMR (CDC13) 5: -117.76 (d, J = 8.9 Hz).

[0235] Step 1, General Scheme 2

[0236]

[0237] 4-(5-broino-3-chloropyridin-2-yl)thiomorpholine 1,1-dioxide, 2a.

[0238]

[0239] K2CO3 (1.182 g, 8.55 mmol), 5-bromo-3- chloro-2-fluoropyridine (600 mg, 2.85 mmol), and thiomorpholine 1,1-dioxide (424 mg, 3.14 mmol) in DMF (3 mL) were stirred in a sealed micro wave vial under argon at 65 °C for 45 hours. Upon cooling, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (20 mL). The organic layer was washed with brine (20 mL) and then dried with Na2SC>4. The solvent was evaporated in vacuo and the crude product washed with warm hexane. The suspension was cooled, and filtered to afford 4-(5-bromo-3- chloropyridin-2-yl)thiomorpholine 1,1-dioxide, 2a, as a tan powder (220 mg, 0.676 mmol, 24% yield). 'H NMR (CDC13) 5: 8.24 (d, J = 2.2 Hz, 1H). 7.81 (d, J = 2.2 Hz, 1H), 4.00 - 3.85 (m, 4H), 3.22 (dd, J = 6.6, 4.2 Hz, 4H).13C NMR (CDC13) 8: 155.26, 146.72, 141.29, 122.78, 113.29, 51.57, 47.53.

[0240] Step 2, General Scheme 2

[0241]

[0242] jV-Methyl-2-pyrrolidone (1.024 mL), 4-(5- bromo-3-chloropyridin-2-yl)thiomorpholine 1,1-dioxide, 2a, (200 mg, 0.614 mmol), 28% NH4OH (1.11 mL, 7.99 mmol), and C112O (8.79 mg, 0.061 mmol) were stirred in a sealed 5 mL microwave vial at 70 C for 18 hours. Upon cooling, the reaction mixture was partitioned between water (10 rnL) and ether (20 mL). The organic layer was washed with brine (20 mL), and then dried with Na2SOr. The solvent was evaporated in vacuo and the crude product was washed with warm hexane. The suspension was cooled, and filtered, to afford 4- (5-amino-3-chloropyridin-2-yl)thiomorpholine 1,1-dioxide, 2b, as a dark tan powder (47 mg, 0.18 mmol, 29% yield).JH NMR (CDC13) 5: 7.71 (d, J = 2.6 Hz, 1H), 7.08 (d, J = 2.6 Hz, 1H), 3.80 - 3.72 (m, 4H), 3.64 (bs, 2H), 3.29 - 3.19 (m, 4H).13C NMR (CDC13) 5: 149.14, 139.85, 132.79, 125.44, 123.72, 51.61, 48.28.

[0243] 4-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3 / / -imidazo[4,5- / >|pyridin-3-yl)-3-chloropyridin-2-yl)thiomorpholine 1,1-dioxide, 2.

[0244]

[0245] Compound 2 was prepared in a similar manner as depicted in Step 3, General Scheme 1 utilizing aniline 2b. 4-(5-(5-(2-aminopyridin-4-yl)-2-methyl-377-imidazo[4,5-Z>]pyridin-3-yl)-3-chloropyridin-2- yl)thiomorpholine 1,1-dioxide, 2, a green semi-solid (12 mg, 0.026 mmol, 16% yield, 6% MeOH in DCM). 'H NMR (CDC13) 5: 8.38 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 5.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.24 (dd, J = 5.5, 1.5 Hz, 1H), 7.16 - 7.14 (m, 1H), 4.75 (bs, 2H), 4.18 - 4.04 (m, 4H). 3.37 - 3.27 (m, 4H), 2.67 (s, 3H).19F NMR (CDC13) 5: -125.07 (d. J = 12.8 Hz).

[0246] 4-(3-(5-fluoro-6-morpholinopyridin-3-yl)-2-methyl-3 / / -imidazo[4,5-Z>]pyridin-5-yl)pyridin-2- amine, 3.

[0247] 4-(5-bromo-3-fluoropyridin-2-yl)morpholine, 3a.

[0248] Br

[0249] Com 0pound 3a was prepared in a similar manner as depicted in Step 1, General Scheme 2. 4-(5-bromo-3-fluoropyridin-2- yl)morpholine, 3a, as a white powder (515 mg, 1.972 mmol, 85% yield). 'H NMR (CDC13) 5: 8.07 (dd, J = 2.0, 1.0 Hz, 1H), 7.40 (dd, J = 12.1, 2.0 Hz, 1H), 3.89 - 3.80 (m, 4H), 3.53 - 3.44 (m, 4H).19F NMR (CDC13) 5: -125.20 (d, J = 11.9 Hz).

[0250] 5-fluoro-6-morpholinopyridin-3- amine, 3b.

[0251]

[0252] Compound 3b was prepared in a similar manner as depicted in Step 2, General Scheme 2. 5-fluoro-6- morpholinopyridin-3-amine.3b. as a tan powder (268 mg, 1.359 mmol, 79% yield). 'H NMR (CDC13) 8: 7.59 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 13.2, 2.4 Hz, 1H), 3.89 - 3.81 (m, 4H), 3.56 (bs, 2H), 3.29 - 3.23 (m, 4H).19F NMR (CDC13) 8: -128.52 (d, J = 13.4 Hz).

[0253] 4-(3-(5-fluoro-6-morpholinopyridin-3-yl)-2-methyl-3H-imidazo[4,5-Z>]pyridin-5-yl)pyridin-2- amine, 3.

[0254]

[0255] Compound 3 was prepared in a similar manner as depicted in Step 3, General Scheme 1 utilizing aniline 3b. 4-(3-(5-fluoro-6-morpholinopyridin3-yl)-2-methyl-37 / -imidazo[4,5-6]pyridin-5-yl)pyridin-2-amine, 3, as a tan powder (50 mg, 0.123 mmol, 41% yield, 7% MeOH in DCM). 'H NMR (CDC13) 6: 8.14 (s, 1H), 8.10 (d, J = 5.5 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 13.0 Hz, 1H), 7.20 (d, J = 4.9 Hz, 1H), 7.13 (s, 1H), 4.65 (bs, 2H), 3.92 -3.80 (m, 4H), 3.65 (t, J = 4.7 Hz, 4H), 2.61 (s, 3H).19F NMR (CDC13) 8: -126.07 (d, J = 13.1 Hz).

[0256] 4-(5-(5-(2-aminopyridin-4-yl)-2-methyl-37 / -imidazo[4,5-6]pyridin-3-yl)-3-fluoropyridin-2-yl)thiomorpholine 1,1 -dioxide, 4.

[0257] 4-(5-bromo-3-fluoropyridin-2-yl)thiomorpholine 1,1-dioxide, 4a.

[0258]

[0259] Compound 4a was prepared in a similar manner as depicted in Step 1, General Scheme 2. 4-(5-bromo-3- fluoropyridin-2-yl)thiomorpholine 1,1-dioxide, 4a, as a white powder (270 mg, 0.873 mmol, 28% yield). ^NMR^DCB) 5: 8.10 (dd, J = 2.0. 1.0 Hz, 1H), 7.49 (dd, J = 11.9, 2.0 Hz. 1H), 4.13 - 4.05 (m.4H), 3.19 - 3.11 (m, 4H).19F NMR (CDC13) 6: -124.33 (d, J = 12.1 Hz).

[0260] 4-(5-amino-3-fluoropyridin-2-yl)thiomorpholine 1,1-dioxide, 4b.

[0261]

[0262] Compound 4b was prepared in a similar manner as depicted in Step 2, General Scheme 2. 4- (5-amino-3-fluoropyridin-2-yl)thiomorpholine 1,1-dioxide, 4b, as a white powder (70 mg, 0.285 mmol, 33% yield). 'H NMR (CDC13) 5: 7.57 (dd, J = 2.4. 0.9 Hz, 1H), 6.79 (dd, J = 13.2, 2.4 Hz. 1H), 3.94 - 3.86 (m. 4H), 3.62 (bs, 2H). 3.21 - 3.13 (m, 4H).19F NMR (CDC13) 5: - 127.65 (d, J = 13.3 Hz).

[0263] 4-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3 / / -imidazo[4,5- / >|pyridin-3-yl)-3-fluoropyridin-2-yl)thiomorpholine 1,1-dioxide, 4.

[0264]

[0265] Compound 4 was prepared in a similar manner as depicted in Step 3, General Scheme 1 utilizing aniline 4b. 4-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3 / 7-imidazo[4,5-6]pyridin-3-yl)-3- fluoropyridin-2- yl)thiomorpholine 1,1-dioxide, 4, as a tan semi-solid (31 mg, 0.068 mmol, 25% yield, 6% MeOH in DCM). 'H NMR (CDC13) 6: 8.21 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 5.7 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 12.9 Hz, 1H), 7.30 - 7.20 (m, 2H), 5.22 (s, 2H), 4.43 - 4.23 (m, 4H), 3.32 - 3.23 (m, 4H), 2.67 (s, 3H).19F NMR (CDC13) 5: -125.07 (d, J = 12.9 Hz)

[0266] 4-(3-(4-(( lR,4*S)-2-oxa-5-azabicyclo[2.2.1 ]heptan-5-yl)-3-fluorophenyl)-2-methyl-3 / 7-imidazo |4,5-Z>] pyridin-5-yl)pyridin-2-amine, 5.

[0267] (17?,4 )-5-(2-fluoro-4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane, 5a.

[0268]

[0269] Compound 5a was prepared in a similar manner as depicted in Step 1, General Scheme 1.

[0270] (17?,4S)-5-(2-fluoro-4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane, 5a, as a yellow-orange powder (600 mg, 2.52 mmol, 92% yield). 'H NMR (CDC13) 8: 7.91 (ddd, J = 9.0, 2.6, 0.7 Hz, 1H), 7.86 (dd, J = 13.9, 2.6 Hz, 1H), 6.55 (t, J = 8.9 Hz, 1H), 4.81 - 4.74 (m, 1H), 4.72 - 4.67 (m, 1H), 3.98 - 3.87 (m, 2H), 3.71 (d, J = 10.2 Hz, 1H). 3.42 (d, J = 10.2 Hz, 1H), 2.05 - 2.02 (m. 2H).19F NMR (CDC13) 8: -127.15 (t, J = 11.4 Hz).

[0271] 4-((lR,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-fluoroaniIine, 5b.

[0272]

[0273] Compound 5b was prepared in a similar manner as depicted in Step 2, General Scheme 1. 4-((17?.45)-2-oxa-5-azabicyclo[2.2. l]heptan-5-yl)-3-fluoroaniline, 5b, as a pink solid (370 mg. 1.777 mmol, 64% yield, 5% MeOH in DCM). ’H NMR (CDC13) 8: 6.54 (t, J = 9.1 Hz, 1H), 6.46 (d, J = 14.4 Hz, 1H), 6.40 (d, J = 7.9 Hz, 1H), 4.60 - 4.54 (m, 1H), 4.36 - 4.30 (m, 1H), 4.02 (d, J = 7.6 Hz, 1H), 3.81 (d, J = 7.6 Hz, 1H), 3.64 - 3.08 (m, 4H), 2.01 (d, J = 9.7 Hz, 1H), 1.89 (d, J = 9.7 Hz, 1H).19F NMR (CDC13) 8: -124.45 (t, J = 12.3 Hz).

[0274] 4-(3-(4-((17?,4*5)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-fluorophenyl)-2-methyl-3 / / -iinidazo [4,5-Z»] pyridin-5-yl)pyridin-2-amine, 5.

[0275]

[0276] Compound 5 was prepared in a similar manner as depicted in Step 3. General Scheme 1 utilizing aniline 5b. 4-(3-(4-((17?,4S’)-2-oxa-5-azabicyclo[2.2. l]heptan-5-yl)-3-fluorophenyl)-2-methyl-3#-imidazo[4,5-6]pyridin-5-yl)pyridin-2-amine, 5, as a green semi-solid (32 mg, 0.077 mmol, 27% yield, 6% MeOH in DCM). ’H NMR (CDC13) 5: 8.10 (d, J = 5.5 Hz, 1H), 8.04 (d, J = 8.3 Hz. 1H), 7.71 (d. J = 8.3 Hz. 1H), 7.24 (d. J = 5.5 Hz. 1H), 7.20 - 7.05 (m, 3H), 6.77 (t, J = 9.1 Hz, 1H), 4.92 - 4.42 (m, 4H), 4.10 (d, J = 7.7 Hz, 1H), 3.93 (d, J = 7.6 Hz, 1H), 3.76 (d, J = 9.8 Hz, 1H), 3.38 (d, J = 9.8 Hz, 1H), 2.59 (s, 3H), 2.11 - 1.96 (m, 2H).19F NMR (CDC13) 5: - 125.20 (t, J = 11.6 Hz).

[0277] 4-(3-(3-fluoro-4-((3a7?,6aN)- tetrahydro- LH-furo [3,4-c] pyrrol-5(3 / / )-yl)phenyl)-2-methyl- 3 / / -imidazo|4,5- / >]pyridiii-5-yl)pyridin-2-amine, 6.

[0278] (3a / ?,6a5')-5-(2-fluoro-4-nitrophenyl)hexahydro-17 / -furo[3,4-c| pyrrole, 6a.

[0279]

[0280] Compound 6a was prepared in a similar manner as depicted in Step 1, General Scheme 1.

[0281] (3a / ?,6aS)-5-(2-fluoro-4-nitrophenyl)hexahydro-H7-furo[3,4-c]pyrrole, 6a, as a yellow powder (215 mg. 0.852 mmol. 77% yield). 'H NMR (CDC13) 5: 7.93 (dd, J = 9.0, 2.6 Hz, 1H). 7.88 (dd. J = 14.1, 2.6 Hz, 1H), 6.61 (t, J = 8.9 Hz, 1H), 4.07 - 3.91 (m, 2H), 3.84 - 3.68 (m, 4H), 3.57 -3.47 (m, 2H), 3.16 - 3.02 (m, 2H).19F NMR (CDC13) 5: -124.78 (t, J = 12.2 Hz).

[0282] 3-fluoro-4-((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)aniline, 6b.

[0283]

[0284] Compound 6b was prepared in a similar manner as depicted in Step 2, General Scheme 1. 3-fluoro-4-((3a / C6aS)-tetrahydro-l / / -furo[3.4-c]pyrrol-5(3 / f)- yl)aniline.6b. as a gray solid (130 mg, 0.585 mmol, 69% yield). ’H NMR (CDC13) 5: 6.68 (t, J = 9.0 Hz, 1H), 6.45 (dd, J = 14.0, 2.6 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 3.99 - 3.93 (m, 2H), 3.66 (dd, J = 8.9, 3.9 Hz, 2H), 3.53 (bs, 2H), 3.31 - 3.21 (m, 2H), 3.05 (d, J = 8.9 Hz, 2H), 3.02 - 2.90 (m, 2H).19F NMR (CDC13) 5: -121.26 (t, J = 12.8 Hz).

[0285] 4-(3-(3-fluoro-4-((3a7?,6aN)-tetrahydro-LH-furo[3,4-c]pyrrol-5(31 / )-yl)phenyl)-2-methyl-37 / -imidazo[4,5- / >]pyridin-5-yl)pyridin-2-amine, 6.

[0286]

[0287] Compound 6 was prepared in a similar manner as depicted in Step 3, General Scheme 1 utilizing aniline 6b. 4-(3-(3-fluoro-4-((3a / ?,6aS)-tetrahydro- 177-furo[3,4-c]pyrrol-5(3 / / )-yl)phenyl)-2-methyl-3 / / -imidazo|4.5-6|pyridin-5-yl)pvridin-2-amine. 6, as a green semi-solid (38 mg, 0.088 mmol, 32% yield, 6% MeOH in DCM). ‘H NMR (CDC13) 5: 8.07 (d, J = 5.4 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.20 (dd, J = 5.4, 1.5 Hz, 1H), 7.17 - 7.05 (m, 3H), 6.86 (t, J = 8.9 Hz, 1H), 4.73 (bs, 2H), 4.05 - 3.94 (m, 2H), 3.70 (dd, J = 8.9, 3.7 Hz, 2H), 3.56 - 3.48 (m. 2H), 3.41 - 3.30 (m, 2H), 3.09 - 2.95 (m, 2H), 2.56 (s, 3H).19F NMR (CDC13) 5: -121.12 (t, J = 13.3 Hz).

[0288] 4-(4-(5-(2-aminopyridin-4-yl)-2-methyl-3 / / -imidazo[4,5- / >|pyridin-3-yl)-2-fluorophenyl)morpholin-2-one, 7.

[0289] 4-(2-fluoro-4-nitrophenyl)morpholin-2-one, 7a.

[0290]

[0291] Compound 7a was prepared in a similar manner as depicted in Step 1, General Scheme 1. 4-(2-fluoro-4-nitrophenyl)morpholin-2-one, 7a, as a dark brown powder (360 mg, 1.499 mmol, 69% yield). ‘HNMR (CDC13) 5: 8.14 - 8.01 (m, 2H), 7.55 (dd, J = 8.7, 7.3 Hz, 1H), 4.38 (s, 2H), 4.09 (t, J = 5.1 Hz, 2H), 3.80 (t, J = 5.1 Hz, 2H).19F NMR (CDC13) 5: -114.00 (t, J = 8.6 Hz).

[0292] 4-(4-amino-2-fluorophenyl)morpholin-2-one, 7b.

[0293]

[0294] Compound 7b was prepared in a similar manner as depicted in Step 2, General Scheme 1. 4-(4-amino-2-fluorophenyl)morpholin-2-one, 7b, as a red powder (103 mg, 0.490 mmol, 40% yield). 'H NMR (CDC13) 6: 7.04 (t. J = 8.3 Hz. 1H), 6.50 - 6.42 (m, 2H), 4.36 (s, 2H), 4.03 (t, J = 5.4 Hz, 2H), 3.88 (bs, 2H), 3.67 (t, J = 5.4 Hz, 2H).19F NMR (CDC13) 5: -121.20 (t, J = 11.7 Hz).

[0295] 4-(4-(5-(2-aminopyridin-4-yl)-2-methyl-3 / / -imidazo[4,5- / >|pyridin-3-yl)-2-fluorophenyl)morpholin-2-one, 7.

[0296]

[0297] Compound 7 was prepared in a similar manner as depicted in Step 3, General Scheme 1 utilizing aniline 7b. 4-(4-(5-(2-aminopyridin-4-yl)-2-methyl-377-imidazo[4,5-Z?]pyridin-3-yl)-2-fluorophenyl)morpholin-2-one, 7b, as a green semi-solid (19 mg, 0.045 mmol, 16% yield, 5% MeOH in DCM). ’H NMR (CDC13) 5: 8.11 (d, J = 5.5 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H). 7.75 (d, J = 8.3 Hz, 1H), 7.58 (t, J = 8.2 Hz, 1H), 7.46 - 7.34 (m, 2H), 7.23 (dd, J = 5.5, 1.5 Hz, 1H), 7.16 (s. 1H), 4.79 (bs, 2H), 4.44 (s, 2H), 4.13 (t, J = 5.0 Hz, 2H), 3.86 (t, J = 5.0 Hz, 2H), 2.67 (s, 3H).19F NMR (CDC13) 5: -116.42 (1, J = 9.1 Hz).

[0298] 4-(2-methyl-3-(2-morpholinopyrimidin-5-yl)-31f-imidazo[4,5-Z>]pyridin-5-yl)pyridin-2-amine, 8.

[0299] 4-(5-nitropyrimidin-2-yl)morpholine, 8a.

[0300]

[0301] Compound 8a was prepared in a similar manner as depicted in Step 1, General Scheme 1. 4-(5-nitropyrimidin-2-yl)morpholine, 8a, as a yellow powder (705 mg, 3.35 mmol, 76% yield). 'H NMR (DMSO) 5: 9.12 (s, 2H), 3.92 (t, J = 4.9 Hz, 4H), 3.70 (t, J = 4.9 Hz, 4H).13C NMR (DMSO) 5: 161.43, 155.50, 133.85, 66.27, 45.02.

[0302] 2-morpholinopyrimidin-5-amine, 8b.

[0303]

[0304] Compound 8b was prepared in a similar manner as depicted in Step 2, General Scheme 1. 2-morpholinopyrimi din-5 -amine, 8b, as a red powder (305 mg, 1.69 mmol. 59% yield). 'H NMR (DMSO) 5: 7.92 (s, 2H), 4.65 (s, 2H), 3.64 (t, J = 5.0 Hz, 4H), 3.46 (t, J = 4.9 Hz, 4H).13C NMR (DMSO) 5: 156.40, 144.43, 135.23, 66.44, 45.53.

[0305] 4-(2-methyl-3-(2-morpholinopyrimidin-5-yl)-37 / -imidazo[4,5-b]pyridin-5-yl)pyridin-2-amine, 8.

[0306]

[0307] Compound 8 was prepared in a similar manner as depicted in Step 3, General Scheme 1 utilizing aniline 8b. 4-(2-methyl-3-(2-morpholinopyrimidin-5-yl)-3 / / -imidazo[4,5-6]pyridin-5-yl)pyridin-2-amine, 8. as a green semi-solid (10 mg, 0.026 mmol, 9% yield, 6% MeOH in DCM). 'H NMR (CDC13) 8: 8.45 (s, 2H), 8.13 - 8.04 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.26 (dd, J = 5.6, 1.5 Hz, 1H), 7.21 (s, 1H), 4.93 (bs, 2H), 3.96 (t, J = 5.6 Hz, 4H), 3.85 (t, J = 5.6 Hz, 4H), 2.63 (s, 3H).

[0308] 13C NMR (CDC13) 8: 160.86, 158.60, 156.06, 154.53. 149.20, 149.08, 148.84, 146.97, 135.27, 127.22. 119.38, 116.64, 111.90, 106.47, 66.75, 44.44. 15.07.

[0309] 4-(3-(6-((17?,4*’)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-chloropyridin-3-yl)-2-methyl-3 / -imid azo [ 4,5- b ] py ridin-5-yl)py ridin-2-amine, 9.

[0310] (l / ?,4N)-5-(5-biomo-3-chloropyiidin-2-yl)-2-oxa-5-azabicyclo|2.2.1 [heptane, 9a.

[0311]

[0312] Compound 9a was prepared in a similar manner as depicted in Step 1, General Scheme 2.

[0313] (17?,4S)-5-(5- bromo-3-chloropyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane, 9a, as a white powder (495 mg, 1.710 mmol, 72% yield). 'HNMR (CDC13) 8: 8.07 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 4.87 (d, J = 1.8 Hz, 1H), 4.66 - 4.60 (m, 1H), 4.09 (d, J = 7.7 Hz, 1H), 3.94 - 3.86 (m, 2H), 3.49 (d, J = 10.2 Hz. 1H), 1.97 - 1.92 (m. 2H).13C NMR (CDC13) 8: 153.97, 145.95, 140.62, 117.74, 107.65, 76.64, 72.90, 59.46, 59.22, 35.67.

[0314] 6-((17?,4N)-2-oxa-5- azabicyclo [2.2.1] heptan-5-yl)-5-chloropy ridin-3-amine, 9b.

[0315]

[0316] Compound 9b was prepared in a similar manner as depicted in Step 2, General Scheme 2. 6-((17?,4<. S’)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-chloropyridin-3-amine, 9b, as a red semi-solid (340 mg, 1.507 mmol, 97% yield).JHNMR(CDC13) 8: 7.61 (d, J = 2.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 4.60 (d, J = 32.3 Hz, 2H), 4.11 (d, J = 7.6 Hz, 1H), 3.84 (dd, J = 7.6, 1.8 Hz, 1H), 3.75 (dd, J = 10.0. 1.8 Hz, 1H), 3.40 (bs, 2H), 3.39 - 3.32 (m, 1H), 1.94 - 1.81 (m, 2H).13C NMR (CDC13) 8: 149.47, 136.10, 132.33, 127.14, 119.25, 76.93, 72.74, 59.42, 59.33, 35.76. 4-(3-(6-((17?,- / 5)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-chloropyridin-3-yl)-2-methyl-3 / 7-imidazo [4,5-6] pyridin-5-yl)pyridin-2-amine, 9.

[0317]

[0318] Compound 9 was prepared in a similar manner as depicted in Step 3, General Scheme 1 utilizing aniline 9b. 4-(3-(6-((17?,4< S)-2-oxa-5-azabicyclo[2.2. l]heptan-5-yl)-5-chloropyridin-3-yl)-2-methyl-3 / / -miidazo|4.5-6|pyridin-5-yl)pyridin-2-amine. 9, as a green semi-solid (5 mg, 0.012 mmol, 4% yield, 6% MeOH in DCM). 'H NMR (CDC13) 5: 8.17 (d, J = 2.3 Hz, 1H), 8.12 - 8.06 (m, 2H), 7.76 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.28 - 7.22 (m, 2H), 5.11 - 4.93 (m, 3H), 4.71 (s, 1H), 4.21 (d, J = 7.6 Hz, 1H), 4.06 (dd, J = 10.2, 1.6 Hz, 1H), 3.99 (dd, J = 7.7, 1.7 Hz. 1H), 3.69 (d. J = 10.4 Hz, 1H), 2.63 (s, 3H). 2.06 - 2.00 (m, 2H).

[0319] Step 1, General Scheme 3

[0320]

[0321] 3-fluoro-4-morpholinoaniline (3.24 g, 16.50 mmol). NaHCOs (3.05 g, 36.3 mmol), and EtOH (11.00 mL) were stirred for 5 minutes in a 20 mL microwave vial. 2,4-Dichloro-5- nitropyrimidine (3.2 g, 16.50 mmol) was added and the sealed vial stirred at 25 °C for 48 hours. The mixture was vented, filtered, and the precipitated product was washed with cold EtOH (30 mL), H2O (30 mL), and hexanes (30 mL) to afford 2-chloro-A-(3-fluoro-4-morpholinophenyl)-5- nitropyrimidin-4-amine, 10a, as a red solid (5.43 g, 15.35 mmol, 93% yield). 'H NMR (DMSO) 5: 10.38 (bs, 1H), 9.02 (s, 1H), 7.33 (d, J = 14.3 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.05 (t, J = 9.8 Hz, 1H). 3.75 (t. J = 4.3 Hz, 4H), 3.02 (t, J = 4.3 Hz, 4H).

[0322] Step 2, General Scheme 3

[0323]

[0324] 10a 10b

[0325] 4-(4-(2-chloro-8-methyl-9 / / -purin-9-yl)-2-fluorophenyl (morpholine, 10b.

[0326]

[0327] 2-chloro-A-(3-fluoro-4- morpholinophenyl)-5-nitropyrimidin-4-amine, 10a, (2.10 g, 5.94 mmol), iron (2.65 g, 47.5 mmol), and ammonium chloride (1.27 g, 23.75 mmol) were stirred in a sealed microwave vial under argon. Degassed AcOH (18 mL) was then injected and stirred at 110 °C for 1 hour in an oil bath. Upon cooling, the reaction mixture was diluted with EtOAc, solids filtered through celite, and concentrated in vacuo and used immediately in Step 2B. The crude product from Step 1A was dissolved in AcOH (17 mL), gently warmed, and pipetted into a 20 mL microwave vial. AC2O (1.68 mL, 17.81 mmol) was injected, and the sealed microwave vial under argon was heated at 170 °C for 1 hour then 25 C for 48 hours. Upon cooling, the reaction mixture was poured into a 500 mL RBF and azeotroped with toluene repeatedly. DCM was added followed by 7M NHs in MeOH (10 mL) with subsequent concentration in vacuo. The crude freebase was concentrated / dry loaded onto silica with DCM and purified on a 40g silica column (DCM) to afford 4-(4-(2-chloro-8-methyl-9 / 7-purin-9-yl)-2- fluorophenyl)morpholine.

[0328] 10b, as a white powder (105 mg, 0.302 mmol. 5% yield, 100% DCM) 'H NMR (CDC13) 6: 8.86 (s, 1H), 7.10 (s, 2H), 7.15 - 7.04 (m, 1H), 3.89 (t, J = 5.7 Hz, 4H), 3.19 (t, J = 5.7 Hz, 4H), 2.56 (s, 3H).19F NMR (CDC13) S: -118.59 (dd, J = 13.0, 6.7 Hz).

[0329] Step 3, General Scheme 3

[0330]

[0331] 4-(4-(2-chloro-8-methyl-97 -purin-9-yl)-2- fluorophenyl)morpholine, 10b, (50 mg, 0.144 mmol), / e / 7-butyl (4-(4,4,5,5-rerramethyll,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (51 mg, 0.158 mmol), PdCb(dppf) (11.60 mg, 0.016 mmol), and K3PO4, (73 mg, 0.345 mmol) were stirred in a sealed microwave vial under argon. Degassed dioxane: H2O (0.46 mL:0.12 mL, 4:1 v / v) was injected and stirred at 125 °C for 65 minutes in an oil bath. The reaction mixture was cooled, 37% cone. HC1 (0.6 mL, 50 equiv.) was added, stirred for 1 hour and basified with 10% NaOH. The crude product was partitioned between EtOAc (20 mL) and water (10 mL). The organic layer was washed with 10% NaOH and brine, dried over Na2SO4, concentrated in vacuo, dry loaded onto silica gel and purified on a 12g silica gel column (DCM / MeOH, 0-6%), to afford 4-(9-(3-fluoro-4-morpholinophenyl)-8-methyl-9 -purin-2-yl)pyridin-2-amine, 10, as an opaque semisolid (7 mg, 0.017 mmol, 12% yield, 6% MeOH in DCM). 'H NMR (CDC13) 5: 9.17 (s, 1H), 8.60 (s, 1H), 8.22 (s, 1H), 7.28 - 7.16 (m, 4H), 4.00 - 3.88 (m, 6H), 3.31 (t, J = 5.0 Hz, 4H), 2.69 (s, 3H).19F NMR (CDC13) 5: -118.67 (dd, J = 12.0, 9.0 Hz). 4-(3-(6-((1R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-fluoropyridin-3-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-amine, 11.

[0332] (1R,4S)-5-(5-bromo-3-fluoropyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane, IIa.

[0333]

[0334] Compound Ila was prepared in a similar manner as depicted in Step 1, General Scheme 2. (1R,4S)-5-(5-bromo-3-fluoropyridin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane. IIa, as a green oil (634 mg, 2.32 mmol, 82% yield). ’H NMR (CDC13) 5: 7.90 (dd, J = 2.0, 1.1 Hz, 1H), 7.26 (dd, J = 11.9, 2.0 Hz, 1H), 4.85 - 4.79 (m, 1H), 4.62 - 4.55 (m, 1H), 3.90 (d, J = 7.6 Hz, 1H), 3.82 (dd, J = 7.6, 1.6 Hz, 1H), 3.63 (ddd, J = 10.4, 3.5, 1.6 Hz, 1H), 3.48 (ddd, J = 10.4, 4.3, 1.0 Hz, 1H), 1.92 - 1.86 (m. 2H).19F NMR (CDC13) 5: -131.76 (dt, J = 12.0, 4.0 Hz).

[0335] 6-((17?,45)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-fluoropyridin-3-amine, 11b.

[0336]

[0337] Compound 11b was prepared in a similar manner as depicted in Step 2, General Scheme 2. 6-((1R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-fluoropyridin-3-amine, 11b, as a red oil (160 mg, 0.765 mmol, 52% yield). H NMR (CDC13) 5: 7.52 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 13.4, 2.4 Hz, 1H), 4.75 - 4.69 (m, 1H), 4.61 - 4.56 (m, 1H), 4.00 (d, J = 7.6 Hz, 1H), 3.86 (dd, J = 7.6, 1.7 Hz, 1H), 3.64 (d, J = 10.2 Hz, 1H), 3.45 (dd, J = 10.1, 3.9 Hz, 1H), 3.36 (bs, 2H), 1.99 -1.85 (m, 2H).19F NMR (CDC13) 5: -133.18 (dt, J= 14.1, 3.0 Hz).

[0338] 4-(3-(6-((1R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-fluoropyridin-3-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-amine, 11.

[0339]

[0340] Compound 11 was prepared in a similar manner as depicted in Step 3, General Scheme 1 utilizing aniline 11b. 4-(3-(6-((1R,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-fluoropyridin-3-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-amine, 11, as a green semi-solid (22 mg, 0.053 mmol, 19% yield, 5% MeOH in DCM). ’H NMR (CDC13) 5: 8.13 - 8.03 (m, 3H), 7.75 (d, J = 8.3 Hz. 1H), 7.38 (dd, J = 12.6, 2.2 Hz, 1H). 7.26 (dd. J = 5.6. 1.5 Hz, 1H), 7.21 (s. 1H), 5.10 - 5.04 (m, 1H), 4.93 (bs, 2H), 4.77 - 4.72 (m, 1H), 4.11 (d, J = 7.6 Hz, 1H), 3.98 (dd, J = 7.6, 1.5 Hz, 1H), 3.84 (d, J = 11.4 Hz, 1H), 3.73 (dd, J = 10.5, 4.2 Hz, 1H), 2.63 (s, 3H), 2.07 - 2.02 (m, 2H). 19F NMR (CDC13) 5: -133.12 (dt, J = 2.6, 4.0 Hz).

[0341] 6-(2-methyl-5-(2-methylpyridin-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]oxazol-2(3H)-one, 12.

[0342] 6-((6-chloro-3-nitropyridin-2-yl)amino)benzo[d]oxazol-2(3H)-one, 12a.

[0343]

[0344] 6-aminobenzo[d]oxazol-2(3H)-one (518 mg, 1 eq., 3.45 mmol), sodium bicarbonate (290 mg, 1 eq., 3.45 mmol), and EtOH (1.75 mL, 0.2M) were stirred for 5 minutes. 2,6-dichloro-3-nitropyridine (666 mg, 1 eq.. 3.45 mmol) was then added and stirred at 110 °C for 20 mins in a microwave reactor. The reaction mixture was then stirred at 25 °C for 18 hours, placed in freezer, filtered, and the precipitated product was washed with cold EtOH, H2O, and hexanes, to afford 6-((6-chloro-3-nitropyridin-2-yl)amino)benzo[d]oxazol-2(3H)-one, 12a, (1.0 g, 3.3 mmol, 95 %) as a red-brown solid. *H NMR (500 MHz, DMSO) 5 11.80 (s, 1H), 10.12 (s, 1H), 8.53 (d, J= 8.6 Hz, 1H), 7.59 (d, J= 2.0 Hz, 1H), 7.29 (dd, J= 8.4, 2.0 Hz, 1H), 7.15 - 7.06 (m, 1H), 6.99 (d, J= 8.6 Hz, 1H).13C NMR (126 MHz, DMSO) 5 155.01. 154.73. 149.97, 143.53, 139.28. 132.45, 128.25, 128.16, 120.12, 114.29. 109.85, 106.61, 40.50, 40.42, 40.33. 40.26, 40.16, 40.00. 39.92, 39.83, 39.66, 39.49.

[0345] 6-(2-methyl-5-(2-methylpyridin-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]oxazol-2(3H)-one, 12.

[0346]

[0347] 6-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]oxazol-2(3H)-one, 12a, (0.100 g, 1 eq.. 333 pmol), 2-methyl-4-(4.4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridine (79 mg. 1.1 eq., 366 pmol)), 1, 1 '-Bis (diphenylphosphino)ferrocene-palladium(II) dichloride (19.5 mg, 0.08 eq., 26.6 pmol) and sodium bicarbonate (112 mg, 4.0 Eq, 1.33 mmol) was stirred in a sealed microwave vial under argon. Degassed dioxane: H2O (1.52 mL:0.38 mL, 4:1 v / v)(0.1M) was injected and stirred at 160 °C for 25 minutes in a microwave reactor. The reaction mixture was cooled, diluted with DCM / MeOH. filtered through celite. concentrated in vacuo, dry loaded onto silica gel, and purified on a 12g silica gel column (DCM / MeOH, 0-20%), to afford 6-(2-methyl-5-(2-methylpyridin-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]oxazol-2(3H)-one, 12, (0.0295 g, 82.5 pmol, 25 %) as a brown solid.1H NMR (500 MHz, DMSO) 5 11.98 (s, 1H), 8.49 (d, J = 5.3 Hz. 1H), 8.16 (d. J= 8.3 Hz. 1H), 8.01 (d. J= 8.3 Hz. 1H), 7.81 (d. J= 1.7 Hz. 1H), 7.74 (dd, J = 5.2. 1.7 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.41 (dd, J= 8.2, 2.0 Hz, 1H), 7.34 (d, J= 8.2 Hz, 1H), 2.50 (s, 5H).13C NMR (126 MHz, DMSO) 8 158.93, 155.54, 154.97, 150.01, 149.55, 148.12, 146.60, 143.90, 135.32, 131.37, 128.65, 127.30, 124.03, 120.32, 118.49, 116.71, 110.49, 110.13. 40.50, 40.43, 40.33, 40.26, 40.17, 40.09, 40.00, 39.92, 39.83. 39.67, 39.50, 24.70, 15.40.

[0348] 4-(4-(5-(2-aminopyridin-4-yl)-2-methyl-3E / -imidazo[4,5-6]pyridin-3-yI)-2-chloi’ophenyljthiomoipholine 1,1-dioxide, 13.

[0349] 4-(2-chloro-4-nitrophenyl)thiomorpholine 1,1-dioxide, 13a.

[0350]

[0351] Compound 13a was prepared in a similar manner as Step 1, General Scheme 1. 4-(2-chloro-4-nitrophenyl)thiomorpholine 1,1-dioxide, 13a, (0.94 g, 3.2 mmol, 52 %) as a yellow solid. 'H NMR (500 MHz, DMSO) 5 8.28 (dd, J= 2.7, 1.5 Hz, 1H), 8.16 (dt, J= 8.9, 1.8 Hz, 1H), 7.44 (d, 9.0 Hz, 1H), 3.65 - 3.59 (m, 4H), 3.34 (dd, J= 5.5, 2.8 Hz, 4H).13C NMR (126 MHz, DMSO) 6 154.14, 142.79, 127.30. 126.29. 126.22, 124.99, 124.48, 124.07. 122.54. 51.82, 49.71, 40.50, 40.43, 40.33, 40.26, 40.17, 40.09, 40.00, 39.92, 39.83, 39.67, 39.50.

[0352] 4-(4-amino-2-chlorophenyl)thiomorpholine 1,1-dioxide, 13b.

[0353]

[0354] Compound 13b was prepared in a similar manner as Step 2. General Scheme 1. 4-(4-amino-2- chlorophenyl)thiomorpholine 1,1-dioxide, 13b, was used in the next step without further purification and characterization.

[0355] 4-(2-chloro-4-((6-chloro-3-nitropyridin-2-yl)amino)phenyl)thiomorpholine 1,1-dioxide, 13c.

[0356]

[0357] Compound 13c was prepared in a similar manner as Step 1, General Scheme 3 utilizing aniline 13b. 4-(2-chloro-4-((6-chloro-3-nitropyridin-2-yl)amino)phenyl)thiomorpholine 1,1-dioxide, 13c, (0.51 g, 1.2 mmol, 39%) as a brown solid. This intermediate was used without further characterization. 4-(2-chloro-4-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)thiomorpholine 1,1-dioxide, 13d.

[0358]

[0359] Compound 13d was prepared in a similar manner as Step 2, General Scheme 3. 4-(2-chloro-4-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)thiomorpholine 1,1-dioxide, 13d, (0.118 g, 288 pmol, 25 %) as a white solid. 'H NMR (500 MHz, DMSO) δ8.09 (d, J= 8.3 Hz, 1H), 7.78 (d, J= 2.3 Hz, 1H), 7.57 - 7.48 (m, 2H), 7.36 (d, J= 8.3 Hz, 1H), 3.56 (dd, J= 7.6, 2.9 Hz, 4H), 3.34 (s, 4H), 2.46 (s, 3H).13C NMR (126 MHz, DMSO) 5 154.52, 149.06, 148.51, 143.91, 133.92, 130.23, 129.85, 129.64, 128.53, 127.93, 123.31, 118.87, 55.39, 52.15, 50.16, 40.60, 40.50, 40.42, 40.33, 40.26, 40.17, 40.09, 40.00, 39.93, 39.83, 39.67, 39.50, 15.18.

[0360] 4-(4-(5-(2-aminopyridin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-chlorophenyl)thiomorpholine 1,1-dioxide, 13.

[0361]

[0362] Compound 13 was prepared in a similar manner as Step 3, General Scheme 3. 4-(4-(5-(2-aminopyridin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-chlorophenyl)thiomorpholine 1,1-dioxide, 13, (0.041 g, 87 pmol, 36 %) as a brown solid. 'H NMR (500 MHz, DMSO) 58.12 (d, J= 8.3 Hz, 1H), 7.97 (d, J= 5.4 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.60 (dd, J= 8.5, 2.4 Hz, 1H).

[0363] 7.52 (d, J= 8.5 Hz, 1H). 7.05 (dd. J= 5.4. 1.6 Hz, 1H), 7.00 (d. J= 1.6 Hz, 1H). 5.97 (d. J = 1.6 Hz, 2H), 3.61 - 3.55 (m, 4H), 3.36 (t, J = 5.2 Hz, 4H), 2.50 (s, 3H).13C NMR (126 MHz, DMSO) 5 149.22, 148.86, 147.37, 135.03, 130.81, 129.78, 128.43, 127.86, 127.25, 123.13, 110.13. 105.30, 52.18, 50.21, 40.50, 40.43, 40.34. 40.26, 40.17, 40.09, 40.00, 39.84, 39.67, 39.50, 15.46.

[0364] 4-(2,6-dichloro-4-nitrophenyl)morpholine, 14a.

[0365]

[0366] Compound 14a was prepared in a similar manner as Step 1, General Scheme 1. 4-(2,6-dichloro-4-nitrophenyl)morpholine. 14a, (1.33 g, 4.80 mmol. 84 %) as a yellow solid.XH NMR (500 MHz, DMSO) 58.26 (s, 2H), 3.77 - 3.71 (m, 4H), 3.31 - 3.25 (m, 4H).13C NMR (126 MHz, DMSO) 5 150.51, 143.35, 132.74, 125.35, 67.23, 50.57, 40.49, 40.41, 40.32, 40.25, 40.15, 40.08, 39.99, 39.91, 39.82, 39.65, 39.49.

[0367] 3,5-dichloro-4-morpholinoaniline, 14b.

[0368]

[0369] Compound 14b was prepared in a similar manner as Step 2, General Scheme 1. 3,5-dichloro-4-morpholinoaniline. 14b, (1.4 g, 5.8 mmol. 99 %) as a tan solid was used in the next step without further purification or characterization.

[0370] 6-chloro-2V-(3,5-dichloro-4-morpholinophenyl)-3-nitropyridin-2-amine, 14c.

[0371]

[0372] Compound 14c was prepared in a similar manner as Step 1, General Scheme 3 utilizing aniline 14b. 6-chloro- / V-(3.5-dichloro-4-morpholinophenyl)-3-nilropyridin-2-amine. 14c. (0.66 g. 1.6 mmol, 28 %) as an orange solid. This intermediate was used without further characterization.

[0373] 4-(2,6-dichloro-4-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)morpholine, 14d.

[0374]

[0375] Compound 14d was prepared in a similar manner as Step 2, General Scheme 3. 4-(2,6-dichloro-4-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)morpholine (0.375 g, 943 pmol, 59 %) as a white solid. 'H NMR (500 MHz, DMSO) 88.10 (d, J= 8.3 Hz, 1H), 7.81 (s, 2H), 7.38 (d, J= 8.3 Hz, 1H), 3.79 - 3.73 (m, 4H), 3.28 - 3.23 (m, 4H), 2.48 (s, 3H).13C NMR (126 MHz, DMSO) 8 134.63, 129.23, 67.42, 50.04, 40.50, 40.42, 40.33, 40.25, 40.16, 40.08, 40.00, 39.83, 39.66, 39.50. 15.19.

[0376] 4-(3-(3,5-dichloro-4-morpholinophenyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-amine, 14.

[0377]

[0378] Compound 14 was prepared in a similar manner as Step 3, General Scheme 3. 4-(3-(3,5-dichloro-4-morpholinophenyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-amine, 14, (33 mg, 72 pmol, 29 %) as a tan solid. 'H NMR (500 MHz, DMSO) 8 8.17 (dd, J= 8.3, 5.0 Hz, 1H), 8.03 (d, J= 5.4 Hz, 1H), 7.90 (s, 2H), 7.87 (d, J= 8.1 Hz, 1H), 7.10 (dd, J= 5.4, 1.5 Hz, 1H), 7.05 (dd, J= 5.0, 1.5 Hz, 1H), 6.04 (d, J= 5.3 Hz, 2H), 3.83 (t,.7 = 4,5 Hz, 4H), 3.32 (t, J = 4.6 Hz. 4H), 2.57 (s, 3H).13C NMR (126 MHz, DMSO) 8 160.87, 148.90, 144.84, 135.02. 134.47. 132.41, 129.13, 127.36, 116.64, 110.13. 105.35, 67.43, 50.15, 40.50, 40.43, 40.34, 40.26, 40.17. 40.09, 40.00, 39.83, 39.67, 39.50, 15.46.

[0379] 4-(3-(3-fluoro-4-(1,4-oxazepan-4-yl)phenyl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-2-amine, 15.

[0380] 4-(2-fluoro-4-nitrophenyl)-l,4-oxazepane, 15a.

[0381]

[0382] Compound 15a was prepared in a similar manner as Step 1, General Scheme 1. 4-(2-fluoro-4-nitrophenyl)-l,4-oxazepane (110 mg, 458 pmol, 46 %) as an orange powder. LCMS: 241 [M + H]+.

[0383] 3-fluoro-4-(l,4-oxazepan-4-yl)aniline, 15b.

[0384]

[0385] 4-(2-fluoro-4-nitrophenyl)-l,4-oxazepane (110 mg, 1 eq., 458 pmol), iron (128 mg, 5 eq., 2.29 mmol), ammonium chloride (49 mg, 2 eq., 916 pmol), and 2.5 mL of a 3:1 ethanol water solution were stirred in a sealed microwave vial at reflux for 16 hours. After the reaction was complete the reaction mixture was diluted with 100 mL of ethyl acetate and filtered through a thick pad of celite and concentrated in vacuo. The resulting crude product was purified via column chromatography (DCM / MeOH 0-5%) to afford 3-fluoro-4-(l,4-oxazepan-4-yl)aniline, 15b, (83 mg, 0.39 mmol, 86 %). LCMS: 211 [M + H]+.

[0386] 6-chloro-N-(3-fluoro-4-(1,4-oxazepan-4-yl)phenyl)-3-nitropyridin-2-amine, 15c.

[0387]

[0388] 3-fluoro-4-(l,4-oxazepan-4-yl)aniline (350 mg, 1 eq., 1.67 mmol), 2,6-dichloro-3-nitropyridine (322 mg, 1 eq., 1.66 mmol), DIPEA (259 mg, 348 pL, 1.2 eq., 2.00 mmol), and 1,4-Dioxane (2 mL) were stirred in a sealed microwave vial at 180 °C for 15 minutes in a microwave reactor. The reaction mixture was concentrated in vacuo and purified via column chromatography (DCM / MeOH 0-5%) to afford 6-chloro-N-(3-fluoro-4-(1,4-oxazepan-4-yl)phenyl)-3-nitropyridin-2-amine, 15c, (347 mg, 946 pmol, 57 %) LCMS: 367 [M + H]+.

[0389] 6-chloro-N2-(3-fluoro-4-(1,4-oxazepan-4-yl)phenyl)pyridine-2,3-diamine, 15d.

[0390]

[0391] 6-chloro-N-(3-fluoro-4-(1,4-oxazepan-4-yl)phenyl)-3-nitropyridin-2-amine, 15c, (760 mg, 1 eq., 2.07 mmol), iron (579 mg. 5 eq.. 10.4 mmol), and ammonia hydrochloride (222 mg, 2 eq., 4.14 mmol) were added to a round bottom flask. Water (3.45 mL) and EtOH (10.4 mL) were added and stirred at reflux overnight. Upon cooling, the reaction mixture pH was adjusted to 9 and filtered through a thick pad of celite. The filter cake was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The crude product was partitioned between ethyl acetate (50 mL) and washed with water (3 x 75 mL). The organic layer was then dried with sodium sulfate, filtered, and concentrated in vacuo. The crude product was then suspended in a 20% EtOAc: Hexane solution (lOOmL) and passed through a silica plug, and washed with an additional portion of 20% EtOAc: Hexane solution. The filtrate was then concentrated in vacuo to afford 6-chloro-N2-(3-fluoro-4-(1,4-oxazepan-4-yl)phenyl)pyridine-2,3-diamine, 15d. (350 mg, 1.04 mmol, 50 %). LCMS: 337 [M + H]+. 4-(4-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluorophenyl)-1,4-oxazepane, 15e.

[0392]

[0393] 6-chloro-N2-(3-fluoro-4-(1,4-oxazepan-4-yl)phenyl)pyridine-2,3-diamine, 15d, (698 mg, 1 eq., 2.07 mmol) is added to a solution of triethyl orthoacetate (3.36 g, 3.80 mL, 10 eq., 20.7 mmol) and acetic acid (373 mg, 356 pL, 3 eq., 6.22 mmol) in a microwave vial and stirred at 120 °C for 24 hours. The crude reaction solution was concentrated in vacuo. The crude product was then partitioned in dichloromethane (100 mL) and w ater and washed with a 10% NaOH aqueous solution (3x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified via column chromatography (DCM / MeOH 0-5%) to afford 4-(4-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluorophenyl)-1,4-oxazepane, 15e, (126 mg, 349 pmol, 17 %). LCMS: 361 [M + H]+.

[0394] 4-(3-(3-fkioi’o-4-(l,4-oxazepan-4-yl)phenyl)-2-methyl-3 / / -imidazo[4,5-6|pyiidin-5-yl)pyridin-2-amine, 15.

[0395]

[0396] Compound 15 was prepared in a similar manner as Step 3, General Scheme 3. 4-(3-(3-fluoro-4-(1,4-oxazepan-4-yl)phenyl)-2-methyl-377-imidazo[4,5-6]pyridin-5-yl)pyridin-2-amine, 15, (10 mg, 24 pmol, 22 %) as a white solid. LCMS: 419 [M + H]+. 'H NMR (CDC13) 5: 8.00 (m. 2H), 7.71 (d, 1H), 7.27 (s, 1H), 7.22 (s, 1H), 7.16-7.10 (m, 2H), 7.02 (t, 1H), 3.93 - 3.88 (m, 4H), 3.61-3.58 (m, 4H), 2.59 (s, 3H), 2.15-2.08 (m, 2H).

[0397] 6-(5-(2-aminopyridin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]oxazol-2(3H)-one, 16.

[0398]

[0399] Compound 16 was prepared in similar manner as compound 12. 6-(5-(2-aminopyridin-4-yl)-2-methyl-3 7-imidazo[4,5-6]pyridin-3-yl)benzo[<7]oxazol-2(3 / 7)-one, 16, (32 mg, 90 pmol, 27 %) as a brown solid..1H NMR (500 MHz, DMSO) 5 11.98 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.82 (d, J= 8.3 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.39 (dd, J= 8.2, 2.0 Hz, 1H), 7.33 (d, J= 8.2 Hz, 1H), 7.05 (dd, J= 5.4, 1.6 Hz, 1H), 7.00 (d, J= 1.7 Hz, 1H), 5.97 (s, 2H), 2.49 (s, 3H).13C NMR (126 MHz, DMSO) 5 160.87, 149.07, 148.81, 135.00, 124.10, 116.29, 110.51, 110.19, 110.08, 105.23, 40.50, 40.42, 40.33, 40.26, 40.17, 40.09, 40.00, 39.92, 39.83, 39.67, 39.50, 15.37.

[0400] 4-(3-(5-fliioro-6-(4-methoxypiperi(lin-l-yl)pyri(lin-3-yl)-2-methyl-3 / / -imidazo|4,5- Z>]pyridin-5-yl)pyridin-2-amine, 17.

[0401] 6-chloro-7V-(5-fluoro-6-(4-methoxypiperidin-l-yl)pyridin-3-yl)-3-nitropyridin-2-amine, 17a.

[0402]

[0403] Compound 17a was prepared in a similar manner as Step 1, General Scheme 3. 6-chloro-7V-(5-fluoro-6-(4-methoxypiperidin-l-yl)pyridin-3-yl)-3-nitropyridin-2-amine, 17a, (64 mg, 0.17 mmol, 48 %). 'H NMR (500 MHz, CDC13) 5 10.09 (s, 1H). 8.46 (d, J= 8.6 Hz, 1H). 8.16 (d, J = 2.3 Hz, 1H), 7.77 (dd, J= 13.9, 2.3 Hz, 1H), 6.82 (d, J= 8.6 Hz, 1H), 3.86 (d, J= 13.2 Hz, 2H), 3.42 (s, 1H), 3.40 (s, 3H), 3.17 (td, J= 10.5, 5.7 Hz, 2H), 2.02 (d, J= 12.5 Hz, 2H), 1.70 (qd, J = 10.9, 3.7 Hz, 2H). LCMS: 382 [M + H]+. 5-chloro-3-(5-fluoro-6-(4-methoxypiperidin-l-yl)pyridin-3-yl)-2-methyl-3 / f-imidazo[4,5-b\ pyridine, 17b.

[0404]

[0405] Compound 17b was prepared in a similar manner as Step 2, General Scheme 3. 5-chloro-3-(5-fluoro-6-(4-methoxypiperidin-l -yl)pyridin-3-yl)-2-methyl-3H-imidazo[4,5-Zi]pyridine, 17b, (36 mg, 96 pmol, 57 %) as a brown semi solid. 'H NMR (500 MHz, CDCk) 8 8.02 (dd, J= 2.2, 1.0 Hz, 1H), 7.94 (d, J= 8.3 Hz, 1H), 7.30 (dd, J= 12.9, 2.2 Hz, 1H), 7.26 (s, 1H), 4.02 - 3.95 (m, 2H), 3.48 (tt, J= 8.0, 3.8 Hz, 1H), 3.41 (s. 3H), 3.33 (ddd, J= 12.9, 9.2, 3.2 Hz, 2H). 2.54 (s, 3H), 2.03 (ddt, J= 13.2, 6.7, 3.6 Hz, 2H), 1.72 (tdd, J= 12.7, 8.6, 3.7 Hz, 2H).13C NMR (126 MHz, CDCh) 6 153.78, 149.87, 149.58, 148.25, 147.50, 145.40, 141.01, 140.97, 133.57, 129.03, 122.43, 122.26, 121.51, 119.19, 77.27, 77.02, 76.77, 76.05, 55.67, 44.87, 44.82, 30.82, 14.98. LCMS: 376 [M + H]+.

[0406] 4-(3-(5-fluoro-6-(4-inethoxypiperidin-l-yl)pyridin-3-yl)-2-methyl-3 / / -imidazo[4,5- Z>|pyridin-5-yl)pyridin-2-amine, 17.

[0407]

[0408] Compound 17 was prepared in a similar manner as Step 3, General Scheme 3. 4-(3-(5-fluoro-6-(4-melhoxypiperidin-l-yl)pyridin-3-yl)-2-methyl-377-imidazo[4,5- j]pyridin-5-yl)pyridin-2-amine, 17, (5.6 mg, 13 pmol, 14 %) as a white solid. 'H NMR (500 MHz, DMSO) 58.32 - 8.24 (m, 1H), 8.11 (d, J = 8.3 Hz, 1H), 8.00 - 7.90 (m, 2H), 7.81 (d, J= 8.3 Hz, 1H), 7.05 (dd, J = 5.4, 1.6 Hz, 1H). 7.01 (d, J= 1.7 Hz, 1H). 5.99 (s.2H), 3.89 (dt, J= 13.6, 4.5 Hz, 2H). 3.46 (it, J= 8.3, 3.8 Hz, 1H), 3.30 (s, 3H), 3.26 (dt, J= 11.6, 2.8 Hz, 2H), 2.49 (d, J= 2.0 Hz, 3H), 1.99 (dq, J= 7.7, 4.2 Hz, 2H), 1.57 (dtd, J= 12.7, 8.9, 3.6 Hz, 2H).13C NMR (126 MHz, DMSO) 5 160.41, 154.79, 148.98, 148.90, 148.83, 148.79, 148.39, 146.85, 141.59, 141.56, 134.57. 126.80, 123.40, 123.23, 122.68, 122.66. 116.02, 109.64, 104.81, 75.32, 54.95, 44.66, 44.61, 40.11, 40.02, 39.95, 39.86, 39.78, 39.69, 39.61, 39.52, 39.36, 39.19, 39.02, 30.50, 14.79. LCMS: 434 [M + H]+.

[0409]

[0410] In a 24 mL microwave vial were added 2,3-difluoro-5-nitropyridine (1.00 g, 6.25 mmol, 1.0 eq) and potassium carbonate (2.16 g, 15.6 mmol, 2.5 eq). DMF (20.8 mL) was added, followed by pyrrolidine (489 mg, 6.87 mmol, 1.1 eq). The reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded 3-fluoro-5-nitro-2-(pyrrolidin-l-yl)pyridine (1.10 g, 5.21 mmol, 83%) as a solid.

[0411]

[0412] NMR (500 MHz, CDCh) 5 8.82 (s, 1H), 7.85 (dd. J = 12.9, 2.2 Hz. 1H), 3.75 (t, J = 6.3 Hz, 4H), 1.98 (d, J = 6.4 Hz, 4H).13C NMR (126 MHz, CDCk) 5 150.44 (d, J = 8.6 Hz), 145.71, 143.65, 141.77 (d, J = 3.5 Hz), 133.57, 117.10, 116.92, 49.05, 25.20.19F NMR (471 MHz, CDCh) 5 -135.21.

[0413]

[0414] In a 24 mL microwave vial were added 3-fluoro-5-nitro-2-(pyrrolidin-l-yl)pyridine (1.10 g, 5.21 mmol, 1.0 eq), iron powder (873 mg, 15.6 mmol, 3.0 eq), and ammonium chloride (1.39 g. 26.0 mmol, 5.0 eq). A 3:1 mixture of methanol / water (MeOH, 9.6 mL; FLO, 2.9 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and evaporated to dryness. The resulting solid was directly loaded onto silica and purified by flash column chromatography (Teledyne ISCO™ system) to afford 5-fluoro-6-(pyrrolidiii-l-yl)pyridiii-3-amine (224 mg, 1.24 mmol, 24%) as a solid.3H NMR (500 MHz, CDCL) 57.50 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 13.8, 2.4 Hz, 1H), 3.48 (tt, J = 4.2, 2.7 Hz, 4H), 3.25 (s, 2H), 1.99-1.80 (m, 4H).13C NMR (126 MHz, CDCL) 5 149.19. 147.16, 142.85 (d, J = 9.4 Hz), 133.70 (d, J = 3.2 Hz), 129.60 (d, J = 4.7 Hz), 112.73 (d, J = 20.6 Hz), 48.37, 25.17 (d, J = 2.2 Hz).19F NMR (471 MHz, CDCL) 5 -133.57.

[0415]

[0416] In a 24 mL microwave vial were added 5-fluoro-6-(pyrrolidin-1-yl)pyridin-3-amine (516 mg, 2.85 mmol, 1.0 eq), 2,6-dichloro-3-nitropyridine (550 mg, 2.85 mmol, 1.0 eq), and sodium bicarbonate (479 mg, 5.70 mmol, 2.0 eq). Ethanol (2.85 mL) was added, and the reaction mixture was heated at 110 °C for 1 h, ensuring to vent with a needle when necessary. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded 6-chloro-N-(5-fluoro-6-(pyrrolidin-l-yl)pyridin-3-yl)-3-nitropyridin-2-amine (520 mg, 1.54 mmol, 54%) as a solid.3H NMR (500 MHz, CDCL) 59.98 (s, 1H). 8.41 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.59 (dd, J = 14.2, 2.2 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 3.63 (h, J = 2.9 Hz, 4H), 2.07-1.86 (m, 4H).13C NMR (126 MHz, CDCL) 5 156.62, 149.74, 14744. 146.01 (d, J = 9.0 Hz), 145.41, 137.91, 136.97, 127.01, 122.73 (d, J = 3.0 Hz), 118.65, 118.48. 113.95, 48.30 (d, J = 5.3 Hz), 25.34 (d, J = 2.3 Hz).19F NMR (471 MHz, CDCL) 5 -134.12.

[0417]

[0418] Stepl:

[0419] In a 24 mL microwave vial were added 6-chloro-N-(5-fluoro-6-(pyrrolidin-l-yl)pyridin-3-yl)-3-nitropyridin-2-amine (520 mg, 1.54 mmol, 1.0 eq), iron powder (516 mg. 9.24 mmol, 6.0 eq), and ammonium chloride (329 mg, 6.16 mmol. 4.0 eq). Acetic acid (3.85 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, and filtered over Celite (x2). The filtrate was concentrated to dryness and used directly in the next step without further purification.

[0420] Step2:

[0421] The crude residue from Step 1 was transferred to a 12 mL micro wave vial, followed by addition of acetic acid (5.13 mL). Acetic anhydride (472 mg, 4.62 mmol, 3.0 eq) was added, and the mixture was heated at 150 °C for 4 h. Upon completion (monitored by TLC). the reaction was cooled to room temperature, diluted with water, and quenched with saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with saturated NaCl, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (Teledyne ISCO™ system) to afford 5-chloro-3-(5-fluoro-6-(pyrrolidin-l-yl)pyridin-3-yl)-2-methyl-3H-imidazo[4,5-b]pyridine (309 mg, 0.924 mmol, 60%).^ NMR (500 MHz, CDCh) 57.96 (dd, J = 2.2, 1.1 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.26-7.21 (m, 2H), 3.73 (h, J = 3.0 Hz, 4H), 2.55 (s, 3H), 2.03-1.99 (m, 4H).13C NMR (126 MHz, CDCL) 5 154.10, 148.44, 148.30 (d, J = 8.3 Hz), 147.51. 145.45, 145.23, 141.36, 141.33, 133.55. 128.87, 121.26 (d, J = 19.9 Hz), 118.96. 118.20 (d, J = 2.3 Hz). 48.38 (d. J = 5.5 Hz), 25.35 (d, J = 2.3 Hz), 14.94.19F NMR (471 MHz, CDCL) 5 —133.58.

[0422]

[0423] In a 24 mL microwave vial equipped with a stir bar were added potassium phosphate (144 mg, 678 pmol, 3.0 eq), 6-chloro-N-(l -methyl- lH-imidazol-2-yl)-3-nitropyridin-2-amine (75.0 mg, 226 pmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (54.7 mg, 249 pmol, 1.1 eq), and Pd(dppf)C12 (8.27 mg, 11.3 pmol, 0.05 eq). The vial was sealed and purged with argon. A 4:1 mixture of dioxane / water (dioxane, 723 pL; water, 181 pL) was then added, and the reaction mixture was heated at 85 °C for 5 h. Upon completion (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and stirred with Celite for 5 min. The slurry w as fdtered through a Celite pad, and the filter cake was washed with ethyl acetate (2 x 20 mL). The combined filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with w ater (3 x 25 mL), followed by a wash with saturated NaCl solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by alumina flash column chromatography (Teledyne ISCO™ system) to afford 2-(2-methyI-3-(quinoxalin-6-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyridin-4-amine (14.0 mg, 16%).1H NMR (500 MHz, CDCL) 5 8.20 (d, J = 5.4 Hz, 1H), 8.13-8.08 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.41-7.35 (m, 1H), 7.30 (d, J = 5.4 Hz, 1H), 7.24 (s, 1H). 4.67 (s, 2H), 3.83 (dt, J = 6.9, 3.4 Hz, 4H), 2.67 (s, 3H), 2.25-2.00 (m, 4H).13C NMR (126 MHz, CDCL) 5 159.01, 154.76, 149.29 (d, J = 2.0 Hz), 148.45, 148.36, 147.97, 147.50, 145.45, 141.32 (d, J = 4.4 Hz), 134.98, 126.96, 121.37 (d, J = 20.0 Hz), 118.85, 116.35, 112.07, 106.15, 48.41 (d, J = 5.5 Hz), 25.38 (d, J = 2.3 Hz), 15.16.19F NMR (471 MHz, CDCL) 5 -133.87.

[0424]

[0425] In a 24 mL microwave vial were added 2,3-difluoro-5-nitropyridine (1.00 g, 6.25 mmol, 1.0 eq) and potassium carbonate (2.16 g, 15.6 mmol, 2.5 eq). DMF (20.8 mL) was added, followed by pyrrolidine (480 mg, 6.56 mmol, 1.05 eq). The reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded N, N-diethyl-3-fluoro-5-nitropyridin-2-amine (1.33 g, 5.37 mmol, 86%) as a solid. 'H NMR (500 MHz, Chloroform-d) 5 8.83 (t. J = 1.8 Hz. 1H), 7.88 (dd, J = 14.0, 2.3 Hz, 1H), 3.64 (qd, J = 7.0, 2.0 Hz, 4H), 1.24 (t, J = 7.1 Hz, 6H).13C NMR (126 MHz, Chloroform-d) 5 150.84 (d, J = 6.0 Hz), 145.74, 143.67, 141.39 (d, J = 3.6 Hz), 118.08 (d, J = 24.7 Hz), 45.05 (d, J = 6.8 Hz), 13.76 (d, J = 1.8 Hz).19F NMR (471 MHz, Chloroform-d) 5 -132.48.

[0426] NH2

[0427] n

[0428] N2, N2-diethyl-3-fluoropyridine-2.5-diamine

[0429] In a 24 mL microwave vial were added N, N-diethyl-3-fluoro-5-nitropyridin-2-amine (950 mg, 4.46 mmol, 1.0 eq), iron powder (2.49 g, 44.6 mmol, 10.0 eq), and ammonium chloride (2.38g, 44.6 mmol, 10.0 eq). A 1:1 mixture of ethanol / water (EtOH, 11.1 mL; ELO, 11.1 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, filtered through celite, and evaporated to dryness. The resulting solid N2, N2-diethyl-3-fluoropyridine-2,5-diamine was directly used in the next reaction without further purification or characterization.

[0430]

[0431] In a 24 mL microwave vial were added N2, N2-diethyl-3-fluoropyridine-2,5-diamine (546 mg, 2.98 mmol, 1.0 eq), 2,6-dichloro-3-nitropyridine (575 mg, 2.98 mmol, 1.0 eq), and sodium bicarbonate (501 mg, 5.96 mmol, 2.0 eq). Ethanol (2.98 mL) was added, and the reaction mixture was heated at 110 °C for 1 h, ensuring to vent with a needle when necessary. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded N5-(6-chloro-3-nitropyridin-2-yl)-N2, N2-diethyI-3-fluoropyridine-2,5-diamine (360 mg, 1.07 mmol, 36%) as a solid. 'H NMR (500 MHz, Chloroform-d) δ 10.01 (s, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.06 (dd, J = 2.3, 1.1 Hz, 1H), 7.64 (dd, J = 14.9, 2.4 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 3.50 (qd, J = 7.0, 1.6 Hz.4H), 1.19 (t, J = 7.0 Hz, 6H).13C NMR (126 MHz, Chloroform-d) 8 156.59, 149.56, 148.17, 146.33 (d, J = 6.8 Hz), 146.13, 137.93, 136.52 (d, J = 4.6 Hz), 127.04, 124.66 - 123.58 (m), 118.93, 118.75, 114.01, 44.04 (d, J = 5.6 Hz), 13.81.19F NMR (471 MHz, Chloroform-d) 8 -130.33.

[0432]

[0433] Stepl:

[0434] In a 24 mL microwave vial were added N5-(6-chloro-3-nitropyridin-2-yl)-N2, N2-diethyl-3-fluoropyridine-2.5 -diamine (360 mg, 1.06 mmol, 1.0 eq), iron powder (355 mg, 6.36 mmol, 6.0 eq), and ammonium chloride (227 mg, 4.24 mmol, 4.0 eq). Acetic acid (2.65 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, and filtered over Celite (x2). The filtrate was concentrated to dryness and used directly in the next step without further purification.

[0435] Step2:

[0436] The crude residue from Step 1 was transferred to a 12 mL micro wave vial, followed by addition of acetic acid (3.55 mL). Acetic anhydride (326 mg, 3.20 mmol, 3.0 eq) was added, and the mixture was heated at 150 °C for 4 h. Upon completion (monitored by TLC). the reaction was cooled to room temperature, diluted with water, and quenched with saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with saturated NaCl, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (Teledyne ISCO™ system) to afford 5-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-N, N-diethyl-3- fluoropyridin-2-amine (100 mg, 299 pmol, 28%).1HNMR (500 MHz, Chloroform-d) 57.96 (t, J = 1.7 Hz. 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 5.5 Hz, 1H), 7.24 (d, J = 2.7 Hz, 1H), 3.60 (it, J = 7.1, 4.3 Hz, 4H), 2.54 (s, 3H), 1.27 (t, J = 7.0 Hz, 6H).13C NMR (126 MHz, Chloroform-d) δ 154.13, 148.61, 148.41, 145.23, 141.09 (d, J = 4.3 Hz), 133.60, 128.92, 122.13, 121.96, 119.00, 118.74, 44.18 (d, J = 6.1 Hz), 15.00, 13.87.19F NMR (471 MHz, Chloroform-d) δ -130.41.

[0437]

[0438] In a 24 mL micro wave vial equipped with a stir bar were added potassium phosphate (95.4 mg, 449 pmol, 3.0 eq), 6-chloro-N-(l-methyl-lH-imidazol-2-yl)-3-nitropyridin-2-amine (50 mg. 150 pmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (36.3 mg, 165 pmol, 1.1 eq), and Pd(dppf)C12 (5.4 mg, 7.49 pmol, 0.05 eq). The vial was sealed and purged with argon. A 4:1 mixture of dioxane / water (dioxane, 479 pL; water, 120 pL) was then added, and the reaction mixture was heated at 85 °C for 5 h. Upon completion (monitored by TLC). the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and stirred with Celite for 5 min. The slurry was fdtered through a Celite pad, and the filter cake was washed with ethyl acetate (2 x 20 mL). The combined filtrate w as concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water (3 x 25 mL), followed by a wash with saturated NaCl solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by alumina flash column chromatography (Teledyne ISCO™ system) to afford 5-(5-(2-aminopyridin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-N, N-diethyl-3-fluoropyridin-2-amine (25.0 mg, 64.5 pmol, 43%). ‘HNMR (500 MHz, Chloroform-d) 8 8.20 (d, J = 5.5 Hz, 1H), 8.14 - 8.11 (m, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 13.9, 2.2 Hz, 1H), 7.31 (dd, J = 5.5, 1.5 Hz, 1H), 7.24 (s, 1H), 4.70 (s, 2H), 3.71 (qd, J = 7.0, 1.8 Hz, 4H), 2.68 (s, 3H), 1.37 (t, J = 7.0 Hz, 6H),13C NMR (126 MHz, Chloroform-d) δ 158.95, 154.75, 149.33, 149.23, 148.57, 148.35 (d, J = 6.2 Hz), 148.24. 147.84, 145.78, 141.01 (d. J = 4.4 Hz), 135.02, 127.01, 122.18. 122.00, 119.45, 116.44, 112.13. 106.22, 44.16 (d, J = 6.0 Hz), 15.24, 13.92.19F NMR (471 MHz. Chloroform-d) 5 -130.58.

[0439]

[0440] In a 24 mL microwave vial were added 2,3-difluoro-5-nitropyridine (1.10 g, 6.25 mmol, 1.0 eq) and potassium carbonate (2.16 g, 15.6 mmol, 2.5 eq). DMF (20.8 mL) was added, followed by 3,3-difluoroazetidine hydrochloride (850 mg, 6.56 mmol, 1.05 eq). The reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The resulting solid was collected by fdtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded 2-(3,3-difluoroazetidin-l-yl)-3-fluoro-5-nitropyridine (1.38 g, 5.93 mmol, 95%) as a solid. 'H NMR (500 MHz, Chloroform-d) δ 8.86 (d, J = 2.2 Hz, 1H), 7.98 (dd, J = 11.1, 2.2 Hz, 1H), 4.65 (td, J = 11.8, 2.0 Hz, 4H).13C NMR (126 MHz, Chloroform-d) δ 150.96, 146.65, 144.59, 141.27 (d, J = 4.5 Hz), 136.23. 117.51 (d, J = 19.8 Hz), 115.99 (d, J = 3.6 Hz), 63.70 - 63.05 (m).19F NMR (471 MHz, Chloroform-d) δ -99.98, -138.86.

[0441]

[0442] In a 24 mL microwave vial were added 2-(3,3-difluoroazetidin-l-yl)-3-fluoro-5-nitropyridine (1.30 g, 5.58 mmol, 1.0 eq), iron powder (3.11 g, 55.8 mmol, 10.0 eq), and ammonium chloride (2.98g, 55.8 mmol. 10.0 eq). A 3:1 mixture of ethanol / water (EtOH, 20.9 mL; H2O, 6.9 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and evaporated to dryness. The resulting solid was directly loaded onto silica and purified by flash column chromatography (Teledyne ISCO™ system) to afford 6-(3,3-difluoroazetidin-l-yl)-5-fluoropyridin-3-amine (914 mg, 4.51 mmol, 81%) as a solid. ‘HNMR (500 MHz, Chloroform-d) 87.48 (dd, J = 2.4, 0.8 Hz, 1H), 6.71 (dd, J = 12.4, 2.4 Hz, 1H), 4.30 (td, J = 12.2, 1.7 Hz, 4H), 3.29 (s, 2H). ‘3CNMR (126 MHz, Chloroform-d) 5 150.10, 148.07, 142.32 (d. J = 11.5 Hz). 137.22 (d, J = 3.3 Hz). 129.37 (d, J = 4.9 Hz). 119.21 (d, J = 2.6 Hz). 117.04 (d, J = 2.4 Hz). 114.87 (d, J = 2.7 Hz). 111.90 (d, J = 18.5 Hz), 62.73 (id, J = 25.7, 2.1 Hz).19FNMR (471 MHz, Chloroform-d) 5 -99.16, -136.27.

[0443]

[0444] In a 24 mL microwave vial were added 6-(3,3-difluoroazetidin-l-yl)-5-fluoropyridin-3-amine (662 mg, 3.26 mmol, 1.0 eq), 2,6-dichloro-3-nitropyridine (630 mg, 3.26 mmol, 1.0 eq), and sodium bicarbonate (548 mg, 6.53 mmol, 2.0 eq). Ethanol (3.26 mL) was added, and the reaction mixture was heated at 110 °C for 1 h, ensuring to vent with a needle when necessary. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne IS CO™ system) afforded 6-chloro-N-(6-(3,3-difluoroazetidin-l-yl)-5-fluoropyridin-3-yl)-3-nitropyridin-2-amine (550 mg, 1.53 mmol, 47%) as a solid. 'HNMR (500 MHz, Chloroform-d) 5 10.05 (s, 1H), 8.44 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 12.7, 2.2 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 4.47 (td, J = 12.2, 1.8 Hz, 4H)..13CNMR (126 MHz, Chloroform-d) 5 156.52, 149.39, 148.61, 146.58. 146.24, 137.97, 136.80 (d. J = 5.0 Hz), 127.32, 126.66 (d, J = 3.1 Hz), 118.42 (d, J = 19.6 Hz), 116.78, 114.60, 62.92 (d, J = 2.2 Hz).19FNMR (471 MHz, Chloroform-d) 5 -99.40, -136.35.

[0445]

[0446] Stepl:

[0447] In a 24 mL microwave vial were added 6-chloro-N-(6-(3,3-difluoroazetidin-l-yl)-5-fluoropyridin-3-yl)-3-nitropyridin-2-amine (550 mg, 1.53 mmol, 1.0 eq), iron powder (512 mg, 9.17 mmol, 6.0 eq), and ammonium chloride (327 mg, 6.12 mmol, 4.0 eq). Acetic acid (3.82 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC). the mixture was cooled to room temperature, diluted with EtOAc, and filtered over Celite (x2). The filtrate was concentrated to dryness and used directly in the next step without further purification.

[0448] Step2:

[0449] The crude residue from Step 1 was transferred to a 12 mL microwave vial, followed by addition of acetic acid (5.10 mL). Acetic anhydride (468 mg, 4.59 mmol, 3.0 eq) was added, and the mixture was heated at 150 °C for 4 h. Upon completion (monitored by TLC), the reaction was cooled to room temperature, diluted with water, and quenched with saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with saturated NaCl, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (Teledyne ISCO™ system) to afford 5-chloro-3-(6-(3,3-difluoroazetidin-l-yl)-5-fluoropyridin-3-yl)-2-methyl-3H-imidazo [4, 5-b] pyridine (100 mg, 299 pmol, 28%). 'HNMR (500 MHz, Chloroform-d) 5 8.00 (dd, J = 2.1. 0.8 Hz. 1H), 7.91 (d. J = 8.3 Hz. 1H), 7.33 (dd, J = 11.2, 2.1 Hz, 1H). 7.27 -7.19 (m, 1H), 4.55 (td. J = 12.1, 1.9 Hz. 4H), 2.52 (s, 3H).13CNMR (126 MHz, Chloroform-d) 5 153.56, 149.05, 148.59, 148.18, 146.52, 145.42, 141.57 (d, J = 5.0 Hz), 133.56, 129.12, 122.03 (d, J = 2.3 Hz), 121.87, 121.73, 119.30, 63.05 (td, J = 27.4, 2.3 Hz), 14.98.19FNMR (471 MHz, Chloroform-d) 5 -99.53, -135.83.

[0450]

[0451] In a 24 mL micro wave vial equipped with a stir bar were added potassium phosphate (95.4 mg, 449 pmol, 3.0 eq), 5-chloro-3-(6-(3,3-difluoroazetidin-l-yl)-5-fluoropyridin-3-yl)-2-methyl-3H- imidazo[4,5-b]pyridine (53 mg, 150 pmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (36.3 mg, 165 pmol. 1.1 eq), and Pd(dppf)C12 (5.4 mg, 7.49 pmol, 0.05 eq). The vial was sealed and purged with argon. A 4:1 mixture of dioxane / water (dioxane, 479 pL; water, 120 pL) was then added, and the reaction mixture was heated at 85 °C for 5 h. Upon completion (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and stirred with Celite for 5 min. The slurry was filtered through a Celite pad, and the filter cake was washed with ethyl acetate (2 x 20 mL). The combined filtrate w as concentrated under reduced pressure, and the residue w as dissolved in ethyl acetate, washed with water (3 x 25 mL), followed by a wash with saturated NaCl solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by alumina flash column chromatography (Teledyne ISCO™ system) to afford 4-(3-(6-(3,3-difluoroazetidin- 1 -yl)-5-fluoropyridin-3-yl)-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl)pyridin-2-amine (25.0 mg, 64.5 pmol, 43%).1HNMR (500 MHz, Chloroform-d) 58.22 -8.15 (m, 2H), 8.13 (dd, J = 8.3, 2.0 Hz, 1H), 7.81 (dd, J = 8.5, 2.0 Hz, 1H), 7.53 (dt, J = 11.3, 2.2 Hz. 1H), 7.30 (d. J = 5.4 Hz. 1H), 7.24 (s, 1H), 4.69 (td. J = 11.9, 1.9 Hz. 6H), 2.68 (d, J = 2.2 Hz, 3H)13CNMR (126 MHz, Chloroform-d) 5 158.74, 154.34, 149.21, 149.02, 148.60, 148.54, 147.39, 146.48, 141.53 (d, J = 4.9 Hz), 135.03, 127.23, 122.54 (d, J = 2.3 Hz), 121.87, 121.73, 116.69, 116.57, 111.87, 106.36, 63.55 - 62.39 (m), 15.18.19FNMR (471 MHz, Chloroform-d) 5 -99.53, -136.22.

[0452]

[0453] In a 24 mL microwave vial were added 2,3-difluoro-5-nitropyridine (1.10 g, 6.25 mmol, 1.0 eq) and potassium carbonate (2.37 g, 17.2 mmol, 2.5 eq). DMF (20.8 mL) was added, followed by (R)-3-pyrrolidinol (629 mg, 7.22 mmol, 1.05 eq). The reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture w as cooled to room temperature and diluted with water. The resulting solid w as collected by filtration, w ashed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded (R)-l-(3-fluoro-5-nitropyridin-2-yI)pyrroIidin-3-ol (1.38 g, 6.04 mmol, 88%) as a solid. 'HNMR (500 MHz, Chloroform-d) 58.82 (q, J = 1.3 Hz, 1H), 7.88 (dd, J = 12.7, 2.4 Hz, 1H), 4.62 (q, J = 3.1 Hz, 1H), 3.93 (dt, J = 8.4, 4.3 Hz, 2H), 3.84 (d, J = 2.9 Hz, 2H), 2.09 (dq, J = 7.8, 3.5 Hz, 2H), 1.93 (d, J = 2.9 Hz, 1H).13CNMR (126 MHz, Chloroform-d) 5 150.52 (d, J = 8.4 Hz), 145.82, 143.76, 141.64 (d, J = 3.6 Hz), 133.91 (d, J = 2.2 Hz), 117.21 (d, J = 22.6 Hz), 57.19 (d, J = 5.3 Hz), 46.76 (d, J = 6.0 Hz).19FNMR (471 MHz, Chloroform-d) 5 -135.31.

[0454]

[0455] In a 24 mL microwave vial were added (R)-l-(3-fluoro-5-nitropyridin-2-yl)pyrrolidin-3-ol (1.0 g, 4.40 mmol, 1.0 eq), iron powder (2.46 g, 44.0 mmol, 10.0 eq), and ammonium chloride (2.35 g, 44.0 mmol, 10.0 eq). A 3: 1 mixture of ethanol / water (EtOH, 16.5 mL; H? O, 5.5 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, filtered through celite and evaporated to dryness. The resulting solid (R)-l-(5-amino-3-fluoropyridin-2-yl)pyrrolidin-3-ol was directly used in the next reaction without further purification or characterization.

[0456]

[0457] In a 24 mL microwave vial were added (R)-l-(5-amino-3-fluoropyridin-2-yl)pyrrolidin-3-ol (510 mg, 2.46 mmol, 1.0 eq), 2,6-dichloro-3-nitropyridine (475 mg, 2.46 mmol, 1.0 eq), and sodium bicarbonate (455 mg, 5.41 mmol, 2.2 eq). Ethanol (2.46mL) was added, and the reaction mixture was heated at 110 °C for 1 h, ensuring to vent with a needle when necessary. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded (R)-l-(5-((6-chloro-3-nitropyridin-2-yl)amino)-3-fluoropyridin-2-yl)pyrrolidin-3-ol (550 mg, 1.55 mmol. 63%) as a solid. 'HNMR (500 MHz, Chloroform-d) 5 10.05 (s, 1H), 8.44 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 12.7, 2.2 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 4.47 (td, J = 12.2, 1.8 Hz, 4H).13CNMR (126 MHz, Chloroform-d) 5 156.52, 149.39, 148.61, 146.58, 146.24, 137.97, 136.80 (d, J = 5.0 Hz), 127.32, 126.66 (d, J = 3.1 Hz), 118.42 (d. J = 19.6 Hz). 116.78, 114.60, 62.92 (d, J = 2.2 Hz).19FNMR (471 MHz, Chloroform-d) 5 -99.40, -136.35.

[0458]

[0459] Stepl:

[0460] In a 24 mL micro wave vial were added (R)-l-(5-((6-chloro-3-nitropyridin-2-yl)amino)-3-fluoropyridin-2-yl)pyrrolidin-3-ol (278 mg, 786 pmol, 1.0 eq), iron powder (263 mg, 4.72 mmol, 6.0 eq), and ammonium chloride (168 mg, 3.14 mmol, 4.0 eq). Acetic acid (1.96 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, and filtered over Celite (x2). The filtrate was concentrated to dryness and used directly in the next step without further purification.

[0461] Step2:

[0462] The crude residue from Step 1 was transferred to a 12 mL micro wave vial, followed by addition of acetic acid (1.97 mL). Acetic anhydride (241 mg, 2.36 mmol, 3.0 eq) was added, and the mixture was heated at 150 °C for 4 h. Upon completion (monitored by TLC), the reaction was cooled to room temperature, diluted with water, and quenched with saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc. and the combined organic extracts were washed with saturated NaCl, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (Teledyne ISCO™ system) to afford (R)-l-(5-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-yl acetate (150 mg, 386 umol. 49%). 'HNMR (500 MHz, Chloroform-t / ) 5 7.97 (dd. J= 2.1. 1.1 Hz, 1H), 7.92 (d. J= 8.3 Hz, 1H), 7.28 - 7.26 (m. 1H), 7.22 (s, 1H), 5.43 (q, J= 3.2 Hz, 1H), 3.97 - 3.77 (m, 5H), 2.53 (s, 3H), 2.20 (tq, J= 5.8, 3.5, 2.7 Hz, 2H), 2.09 (s,

[0463]

[0464] In a 24 mL microwave vial equipped with a stir bar were added potassium phosphate (109.4 mg, 515 pmol, 3.0 eq), (R)-l-(5-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-yl acetate (67 mg. 171 pmol, 1.0 eq). 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (41.6 mg, 189 pmol, 1.1 eq), and Pd(dppf)C12 (6.2 mg, 8.59 pmol, 0.05 eq). The vial was sealed and purged with argon. A 4:1 mixture of dioxane / water (dioxane, 687 pL; water, 171 pL) was then added, and the reaction mixture was heated at 85 °C for 5 h. Upon completion (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and stirred with Celite for 5 min. The slurry was filtered through a Celite pad, and the filter cake was washed with ethyl acetate (2 x 20 mL). The combined filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water (3 x 25 mL), followed by a wash with saturated NaCl solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by alumina flash column chromatography (Teledyne ISCO™ system) to afford (R)-l-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3H-imidazo [4,5-b] pyridin-3-yl)-3-fhioropyridin-2-yl)pyrrolidin-3-yl acetate (50.0 mg, 110 pmol, 65%). 'HNMR (400 MHz, Chloroform-c / ) 58.10 (d. J= 5.4 Hz), 8.06 - 8.00 (m), 7.69 (d, J= 8.3 Hz). 7.33 (dd, J= 12.9, 2.1 Hz), 7.20 (dd, J= 5.5, 1.5 Hz), 7.12, 5.44 (q, J= 3.9 Hz), 4.54, 4.03 - 3.80 (m), 2.57, 2.21 (td, J= 7.9, 4.1 Hz), 2.08.13CNMR (126 MHz, Chloroform- ) 5 170.72, 156.15, 155.87, 151.76, 149.32, 147.65 (d, J= 8.1 Hz), 146.61, 141.40, 139.18, 135.90, 127.25, 121.52 (d, J= 19.2 Hz). 119.28, 117.10, 111.23, 108.72, 73.21, 54.12, 46.31, 31.02. 29.72, 21.27,

[0465] 15.22.19FNMR (471 MHz, Chloro form-t / ) 6 -133.79

[0466]

[0467] In a 12 mL microwave vial were added (R)-l-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3H-irmdazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-yl acetate (44 mg, 98 pmol, 1.0 eq). A 3:1 mixture of THF / methanol (THF, 351 pL; methanol, 117 pL) was then added, followed by Lithium Hydroxide (3.8 mg, 157 pmol, 1.6 eq, IM). The reaction mixture was stirred at 25 °C for 1 h. Upon completion (monitored by TLC), the mixture quenched with saturated ammonium chloride solution and the aqueous layer was extracted with EtOAc. and the combined organic extracts were washed with saturated NaCl, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (Teledyne ISCO™ system) to afford (R)-l-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-ol(24 mg, 59 pmol, 60%).

[0468] 1HNMR (500 MHz, DMSO-ds) 58.16 (t, J= 1.6 Hz, 1H), 8.11 (d, J= 8.3 Hz, 1H), 7.97 (d, J = 5.4 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.81 (d, J= 1.6 Hz, 1H), 7.07 (dd, J= 5.5, 1.6 Hz, 1H), 7.04 (s, 1H), 6.06 (s, 2H), 5.06 (s, 1H), 4.41 (dp, J= 4.7, 2.2 Hz, 1H), 3.75 (td, J= 6.5, 5.1, 2.5 Hz, 2H), 3.63 - 3.55 (m, 1H), 2.49 (s, 3H), 2.01 (dtd, J= 13.2, 8.9, 4.4 Hz, 1H), 1.92 (q, J= 6.5, 5.2 Hz. 1H).13CNMR (126 MHz. DMSO-t / e) 5 160.78. 155.54, 149.64, 149.02, 148.60, 147.72 (d, J = 8.0 Hz), 147.43, 147.15, 145.11, 142.40 (d, J= 4.2 Hz), 135.03, 127.16, 122.72 (d,.7= 19.8 Hz), 119.61 (d,.7= 2.7 Hz), 116.35, 110.05, 105.28, 69.22 (d, J= 2.3 Hz), 56.99 (d, J= 5.1 Hz), 46.62 (d, J= 4.9 Hz), 33.56, 15.19.19FNMR (471 MHz, DMSO-cfc) 5 -135.20.

[0469]

[0470] In a 24 mL microwave vial were added 2,3-difluoro-5-nitropyridine (1.5 g, 8.49 mmol, 1.0 eq) and potassium carbonate (2.93 g, 21.24 mmol, 2.5 eq). DMF (20.8 mL) was added, followed by (S)-3-pyrrolidinol (777 mg, 8.922 mmol, 1.05 eq). The reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded (S)-l-(3-fluoro-5-nitropyridin-2-yl)pyrrolidin-3-ol (1.53 g, 6.73 mmol, 79%) as a solid. 'HNMR (500 MHz, Chloroform- ) 5 8.94 - 8.75 (m, 1H), 7.88 (dd, J = 12.8, 2.3 Hz, 1H), 4.84 - 4.50 (m, 1H), 3.93 (qd, J= 8.5, 4.9 Hz, 2H), 3.85 (d, J= 2.8 Hz, 2H), 2.09 (td, J= 7.9, 3.5 Hz, 2H), 1.84 (s, 1H).13CNMR (126 MHz, Chloroform- ) 5 150.52 (d, J = 8.7 Hz), 145.82, 143.76, 141.64 (d, J= 3.7 Hz), 133.94, 117.31, 117.13, 57.21, 46.75 (d, J = 6.2 Hz).19FNMR (471 MHz, Chloroform- ) 5 -135.34.

[0471]

[0472] In a 24 mL microwave vial were added (S)-l-(3-fluoro-5-nitropyridin-2-yl)pyrrolidin-3-ol (1.53 g, 6.73 mmol, 1.0 eq), iron powder (3.76 g, 67.3 mmol, 10.0 eq), and ammonium chloride (3.60 g, 67.3 mmol, 10.0 eq). A 3: 1 mixture of ethanol / water (EtOH, 25.3 mL; H? O, 8.42 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and evaporated to dry ness. The resulting solid was directly loaded onto silica and purified by flash column chromatography (Teledyne ISCO™ system) to afford (S)-l-(5-amino-3-fluoropyridin-2-yl)pyrrolidin-3-ol (520 mg. 2.64 mmol, 39%) as a solid.XHNMR (500 MHz, DMSO- 6) 57.39 (t, J= 1.7 Hz, 1H), 6.78 (dd, J = 14.8, 2.3 Hz, 1H), 4.85 (d, J= 3.6 Hz, 1H), 4.71 (s, 2H), 4.30 (tt, J= 5.2, 2.8 Hz, 1H), 3.56 -3.42 (m, 2H), 3.36 (ddt, J= 7.9, 4.1, 1.8 Hz, 1H), 3.22 (dt, J= 10.7, 2.8 Hz, 1H), 1.96 - 1.87 (m, 1H), 1.77 (ddt, J= 11.3, 7.1, 3.6 Hz. 1H).13CNMR (126 MHz, DMSO-J6) 5 149.27, 147.27, 140.47 (d, J= 9.3 Hz). 137.90 (d, J = 3.7 Hz). 128.64 (d, J = 4.3 Hz). 111.23 (d, J = 19.9 Hz).

[0473] 69.53 (d, J = 2.1 Hz), 57.33 (d, J= 4.2 Hz), 46.72 (d, J = 4.0 Hz), 33.88.19FNMR (471 MHz, DMSO- 6) 3 -134.75.

[0474]

[0475] In a 24 mL micro wave vial were added (S)-l-(5-amino-3-fluoropyri din-2 -yl)pyrrolidin-3-ol (520 mg, 2.64 mmol, 1.05 eq), 2,6-dichloro-3-nitropyridine (485 mg, 2.51 mmol, 1.0 eq), and sodium bicarbonate (422 mg, 5.03 mmol, 2.0 eq). Ethanol (2.51 mL) was added, and the reaction mixture was heated at 110 °C for 1 h, ensuring to vent with a needle when necessary. Upon completion (monitored by TLC), the mixture w as cooled to room temperature and diluted with water. The resulting solid was collected by filtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded (S)- 1 -(5-((6-chloro-3-nitropyridin-2-yl)amino)-3-fluoropyridin-2-yl)pyrrolidin-3-ol (521 mg, 1.47 mmol, 59%) as a solid.1HNMR (500 MHz, DMSO-cfc) 5 10.03 (s, 1H), 8.51 (d,.7= 8.6 Hz, 1H), 8.07 (q, J = 2.9, 1.6 Hz, 1H), 7.65 (ddd, J = 14.7, 4.7, 2.2 Hz. 1H), 6.96 (d. J= 8.7 Hz. 1H), 4.97 (d. J= 3.5 Hz. 1H), 4.36 (tt. J= 5.0, 2.6 Hz, 1H). 3.65 (dddt, J= 14.6, 7.9, 6.0, 2.8 Hz, 3H), 3.46 (ddt, J= 11.4, 3.6, 1.7 Hz, 1H), 1.97 (dtt, J= 17.4, 8.7, 4.4 Hz, 1H), 1.92 - 1.83 (m, 1H).13CNMR (126 MHz, DMSO-6) 5 154.86, 150.32, 146.92, 145.58, 144.90, 139.25, 128.08, 123.93 (d, J= 2.8 Hz), 120.52 (d, J = 20.5 Hz), 114.07, 69.30 (d, J= 2.3 Hz), 56.92 (d, J= 4.8 Hz), 46.48 (d, J= 4.6 Hz), 33.63.19FNMR (471 MHz, DMSO-O 5 -136.04.

[0476]

[0477] Stepl:

[0478] In a 24 mL microwave vial were added (S)-l-(5-((6-chloro-3-nitropyridin-2-yl)amino)-3- fluoropyridin-2-yl)pyrrolidin-3-ol (531 mg, 1.5 mmol, 1.0 eq), iron powder (503 mg. 9.01 mmol, 6.0 eq), and ammonium chloride (321 mg, 6.0 mmol, 4.0 eq). Acetic acid (3.75 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, and filtered over Celite (x2). The filtrate was concentrated to dry ness and used directly in the next step without further purification.

[0479] Step2:

[0480] The crude residue from Step 1 was transferred to a 12 mL micro wave vial, followed by addition of acetic acid (1.97 mL). Acetic anhydride (460 mg, 4.50 mmol, 425 pL 3.0 eq) was added, and the mixture was heated at 150 °C for 4 h. Upon completion (monitored by TLC), the reaction was cooled to room temperature, diluted with water, and quenched with saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with saturated NaCl, dried over sodium sulfate, filtered, and concentrated to dry ness. The crude product was purified by flash column chromatography (Teledyne ISCO™ system) to afford (S)-l-(5-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-yl acetate (150 mg, 386 pmol, 49%). ’HNMR (500 MHz, Chloroform-d) 5 7.96 (dd, J= 2.1, 1.0 Hz, 1H), 7.92 (d, J= 8.3 Hz, 1H), 7.25 - 7.21 (m, 1H), 5.49 - 5.34 (m, 1H), 4.00 - 3.74 (m, 4H), 2.52 (s, 3H), 2.20 (qd, J= 5.7, 4.9, 2.6 Hz, 2H), 2.08 (s, 3H).13CNMR (126 MHz, Chloroforme d 170.73, 153.95, 148.39, 147.91 (d, J= 8.3 Hz), 147.58, 145.52, 145.30. 141.42 (d, J = 4.4 Hz), 133.53, 128.96, 121.59 (d, J= 19.8 Hz), 119.08, 73.21 (d, J = 2.6 Hz), 54.15 (d, J= 5.9 Hz), 46.27 (d, J = 5.7 Hz), 30.98 (d, J= 2.3 Hz), 21.24, 14.93.19FNMR (471 MHz, Chloroform-t / ) 5 -133.75.

[0481]

[0482] In a 24 mL microwave vial equipped with a stir bar were added potassium phosphate (613 mg, 2.89 mol, 3.0 eq), (S)-l-(5-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-yl acetate (375 mg, 962 pmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (233 mg, 1.06 mmol, 1.1 eq), and Pd(dppf)C12 (35.2 mg. 48.1 pmol, 0.05 eq). The vial was sealed and purged with argon. A 4:1 mixture of dioxane / water (dioxane. 3.85 mL: water, 962 pL) was then added, and the reaction mixture was heated at 85 °C for 5 h. Upon completion (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and stirred with Celite for 5 min. The slurry was filtered through a Celite pad, and the filter cake was washed with ethyl acetate (2 x 20 mL). The combined filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water (3 x 25 mL), followed by a wash with saturated NaCl solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by alumina flash column chromatography (Teledyne ISCO™ system) to afford (S)-l-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-yl acetate (200.0 mg. 447 pmol, 47%). 'HNMR (400 MHz. Chloroform-t / ) 58.12 (d,.7 = 5.5 Hz), 8.07 - 8.03 (m), 7.72 (d, J = 8.3 Hz), 7.36 (dd,.7= 12.9, 2.2 Hz), 7.22 (dd, J= 5.4, 1.5 Hz), 7.15, 5.46 (q, J= 4.0 Hz), 4.61, 4.05 - 3.80 (m), 2.60, 2.23 (ddd, J= 8.8. 6.4, 3.7 Hz), 2.10.13CNMR (101 MHz, Chlorolorm-c / ) 5 170.81, 159.07, 154.68, 149.46. 149.30, 148.55, 148.41, 147.63 (d, J= 8.3 Hz), 145.35. 141.44 (d, J= 4.4 Hz). 135.06, 127.14, 121.75 (d, J= 19.9 Hz), 119.81, 116.55, 112.18, 106.25, 73.34, 54.24, 46.37 (d, J= 5.6 Hz), 31.10, 21.35, 15.27.19FNMR (376 MHz, Chloroform- ) 5 -133.94 (dt, J= 13.0, 2.7 Hz).

[0483]

[0484] In a 12 mL microwave vial were added (S)-l-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3H-irrridazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-yl acetate (371 mg, 829 pmol, 1.0 eq). A 3:1 mixture of THF / methanol (THF, 2.96 mL; methanol, 987 pL) was then added, followed by Lithium Hydroxide (31.8 mg, 1.33 mmol, 1.6 eq, IM). The reaction mixture w as stirred at 25 °C for 1 h. Upon completion (monitored by TLC), the mixture quenched with saturated ammonium chloride solution and the aqueous layer was extracted with EtOAc, and the combined organic extracts were w ashed with saturated NaCl, dried over sodium sulfate, filtered, and concentrated to drymess. The crude product was purified by flash column chromatography (Teledyne ISCO™ system) to afford (S)-l-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3H- imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-ol(132 mg, 326 pmol. 39%).

[0485] ‘HNMR (400 MHz, DMSO-J6) 58.11 (d, J= 2.0 Hz), 8.06 (d. J= 8.3 Hz), 7.92 (d, J= 5.3 Hz), 7.82 - 7.73 (m), 7.01 (dd, J= 5.3, 1.7 Hz), 6.98, 5.98, 5.20 (d, J= 56.4 Hz), 4.36 (qd, J= 4.3, 2.8, 2.1 Hz), 3.74 - 3.65 (m), 3.57 - 3.49 (m), 2.44, 2.02 - 1.81 (m).13CNMR (101 MHz, DMSO- 6) 5 160.98, 155.58, 149.71, 149.16, 148.92, 147.38, 144.92, 142.46, 135.07, 127.24, 122.70. 119.68, 116.40, 110.09, 105.25, 69.27, 57.09. 46.71, 33.62. 26.10, 15.26.19FNMR (376 MHz, DMSO-r / 6) 5 -135.11 (d, J = 13.8 Hz).

[0486]

[0487] In a 100 mL rbf equipped with a stir bar were added 2-chloro-3 -fl uoro-5 -nitropyridine (2.0 g, 11.3 mmol, 1.0 eq), PdzDbas (1.04 g, 1.13 mmol, 0.1 eq), xantphos (983 mg, 1.70 mmol, 0.15 eq), cesium carbonate (7.38 g, 22.7 mmol. 2 eq). The vial was sealed and purged with argon. Then 1,4-Dioxane (56.6 mL) was added, followed by pyrrolidine-2-one(1.16 g, 13.6 mmol, 1.03 mL, 1.2 eq) and the reaction mixture was heated at 110 °C for 6 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The slurry was filtered through a celite pad, and the filter cake was washed with ethyl acetate (2 x 20 mL). The combined filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water (3 x 25 mL), followed by a wash with saturated NaCl solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by alumina flash column chromatography (Teledyne ISCO™ system) to afford l-(3-fluoro-5-nitropyridin-2-yl)pyrrolidin-2-one (1.3 g, 5.7 mmol, 50%).1HNMR (500 MHz, Chloroform- ) 59.07 (d,.7= 2.3 Hz, 1H), 8.25 (dd,.7= 9.0, 2.3 Hz, 1H), 4.03 (t,.7= 7.0 Hz, 2H), 2.63 (t, J= 8.0 Hz, 2H), 2.30 - 2.22 (m, 2H).13CNMR (126 MHz, Chloroform- ) 5 173.72, 151.65, 149.50, 145.78 (d, J= 12.8 Hz), 141.79, 139.39 (d, J= 5.0 Hz), 120.47 (d, J = 23.0 Hz). 47.90, 31.72, 18.98.19FNMR (471 MHz, Chloroform-J) 5 -115.12.

[0488]

[0489] In a 24 mL microwave vial were added l-(3-fluoro-5-nitropyridin-2-yl)pyrrolidin-2-one (2.0 g, 8.88 mmol, 1.0 eq), iron powder (4.96 g, 88.8 mmol, 10.0 eq), and ammonium chloride (4.75 g, 88.8 mmol, 10.0 eq). A 3:1 mixture of ethanol / water (EtOH, 33.3 mL; ELO, 11.1 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and evaporated to dryness. The resulting solid was directly loaded onto silica and purified by flash column chromatography (Teledyne ISCO™ system) to afford l-(5-amino-3-fluoropyridin-2-yl)pyrrolidin-2-one (238 mg, 1.22 mmol, 14%).1HNMR (500 MHz, Chloroform- ) 57.64 (d, J= 2.5 Hz, 1H), 6.68 (dd, J= 11.0, 2.5 Hz, 1H), 4.06 (s, 2H), 3.82 (t, J= 7.0 Hz, 2H), 2.53 (t, J= 8.1 Hz, 2H), 2.18 (p, J= 7.6 Hz, 2H).13CNMR (126 MHz, Chloroform- ) 5 174.83, 154.85. 152.79, 144.24 (d, J= 5.9 Hz), 131.08 (d, J= 3.9 Hz), 130.30 (d, J= 14.3 Hz), 110.31 (d, J= 21.1 Hz), 48.48, 31.35, 18.90.19FNMR (471 MHz, Chloroform- ) 8 -124.53.

[0490]

[0491] In a 24 mL micro wave vial were added l-(5-amino-3-fluoropyri din-2 -yl)pyrrolidin-2-one (223 mg, 1.1 mmol, 1.1 eq). 2,6-dichloro-3-nitropyridine (200 mg. 1.04 mmol, 1.0 eq), and sodium bicarbonate (174 mg, 2.07 mmol, 2.0 eq). Ethanol (1.3 mL) was added, and the reaction mixture was heated at 110 °C for 1 h, ensuring to vent with a needle when necessary. Upon completion (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration, washed with cold water, and dried to afford the crude product. Purification by flash column chromatography (Teledyne ISCO™ system) afforded 1-(5-((6-chloro-3-nitropyridin-2-yl)amino)-3-fluoropyridin-2-yl)pyrrolidin-2-one (250 mg, 711 pmol, 69%) as a sohd^NMR (500 MHz, Chloroform-J) 8 10.31 (s, 1H), 8.49 (d, J= 8.6 Hz. 1H), 8.39 (d. J= 2.3 Hz. 1H), 8.23 (dd, J= 11.2, 2.4 Hz, 1H), 6.92 (d,.7= 8.6 Hz, 1H), 3.97 (t, J = 7.0 Hz, 2H), 2.60 (t. J= 8.1 Hz. 2H), 2.32 - 2.18 (m, 2H).13CNMR (126 MHz, Chloroforme d 174.13. 156.38, 153.31, 151.22, 148.65, 138.00. 136.54 (d, J= 4.5 Hz). 133.80 (d,.7= 5.3 Hz), 127.84, 118.32 (d, J= 23.1 Hz), 115.61, 48.01, 31.56, 19.05.19FNMR (471 MHz, Chloroform- ) 5 -119.94.

[0492]

[0493] Stepl:

[0494] In a 24 mL microwave vial were added (S)-l-(5-((6-chloro-3-nitropyridin-2-yl)amino)-3-fluoropyridin-2-yl)pyrrolidin-3-ol (194 mg, 552 pmol, 1.0 eq), iron powder (185 mg, 3.31 mmol, 6.0 eq), and ammonium chloride (118 mg, 2.2 mmol, 4.0 eq). Acetic acid (1.38 mL) was added, and the reaction mixture was heated at 110 °C for 1 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature, diluted with EtOAc, and fdtered over Celite (x2). The filtrate was concentrated to dryness and used directly in the next step without further purification.

[0495] Step2:

[0496] The crude residue from Step 1 was transferred to a 12 mL micro wave vial, followed by addition of acetic acid (1.83 mL). Acetic anhydride (168 mg, 1.65 mmol, 156 pL 3.0 eq) was added, and the mixture w as heated at 150 °C for 4 h. Upon completion (monitored by TLC), the reaction was cooled to room temperature, diluted with water, and quenched with saturated sodium bicarbonate solution. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with saturated NaCl, dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (Teledyne ISCO™ system) to afford l-(5-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-2-one (136 mg, 394 pmol, 71%). *HNMR (500 MHz, Chloroform-t / ) 5 8.31 (d. J = 2.2 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 9.4, 2.3 Hz, 1H), 7.28 - 7.20 (m, 1H), 4.02 (t, J= 7.0 Hz, 2H), 2.61 (t, J= 8.0 Hz, 2H), 2.54 (s, 3H), 2.31 - 2.21 (m, 3H).13CNMR (126 MHz, Chloroform-J) 6 174.03, 153.01, 152.93, 150.88, 147.77, 145.62, 141.69 (d, J= 4.7 Hz), 141.29 (d, J= 13.0 Hz), 133.65, 129.34. 124.15 (d, J= 20.2 Hz), 119.67.47.93, 31.68. 19.07, 15.22.19FNMR (471 MHz, Chloroform-

[0497]

[0498]

[0499] In a 24 mL microw ave vial equipped with a stir bar were added potassium phosphate (92 mg, 430 pmol, 3.0 eq), (S)-l-(5-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-3-yl acetate (50 mg, 140 pmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (35 mg, 160 pmol, 1.1 eq), and Pd(dppf)C12 (5.3 mg, 7.2 pmol, 0.05 eq). The vial was sealed and purged with argon. A 4:1 mixture of dioxane / water (dioxane. 3.85 mL: water, 962 pL) was then added, and the reaction mixture was heated at 85 °C for 5 h. Upon completion (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and stirred with Celite for 5 min. The slurry was filtered through a Celite pad, and the filter cake was w ashed with ethyl acetate (2 x 20 mL). The combined filtrate w as concentrated under reduced pressure, and the residue w as dissolved in ethyl acetate, washed with water (3 x 25 mL). followed by a wash with saturated NaCl solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue w as purified by alumina flash column chromatography (Teledyne ISCO™ system) to afford l-(5-(5-(2-aminopyridin-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoropyridin-2-yl)pyrrolidin-2-one (22 mg. 55 pmol. 38%).1HNMR (400 MHz. Chloroform-d) 5 8.43 (d, J= 2.1 Hz), 8.07 (dd, J= 18.0, 6.8 Hz), 7.73 (dd, J= 9.2, 2.5 Hz), 7.16 (d, J = 5.4 Hz), 7.10, 4.61, 4.08 (t, J= 7.0 Hz), 2.64 (d, J= 14.3 Hz), 2.29 (p, J= 7.5 Hz).19FNMR (471 MHz, Chloroform-c / ) 5 -117.44.

[0500] INCORPORATION BY REFERENCE

[0501] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. The following references are herein incorporated by reference in their entireties: EQUIVALENTS

[0502] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

What Is Claimed Is:

1. A compound encompassed within Formula(Formula I) or Formula(Formula II), including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof,wherein each of Rl, R2, R3, R4, R5, X, and Y independently include any chemical moiety that permits the resulting compound to inhibit DYRK1 A activity.

2. The compound of Claim 1, wherein each of Rl, R2, R3, R4, R5, X, and Y independently include any chemical moiety that permits the resulting compound to inhibit one or more of:DYRK1A related PI3K / Akt signaling;DYRK1 A related tau phosphorylation;DYRK1 A related NF AT phosphorylation;DYRK1A related ASK1 / JNK1 pathway activation;DYRK1A related p53 phosphory lation;DYRK1A related Amph 1 phosphorylation;DYRK1 A related Dynamin 1 phosphorylation;DYRK1A related Synaptojanin phosphory lation;DYRK1A related presenillin 1 (the catalytic sub-unit of y-secretase) activity;DYRK1 A related Amyloid precursor protein phosphorylation;DYRK1A related SIRT1 activation;DYRK2 activity;DYRK1B activity;CMGC / CLK kinase activity;CLK2 activity;CLK3 activity; andCLK4 activity'.

3. The compound of Claim 1, wherein X and Y are each independently selected from either C orN.

4. The compound of Claim 1. wherein X and Y are each C and the resulting formulas are5. The compound of Claim 1, wherein X and Y are each N and the resulting formulas are6. The compound of Claim 1, wherein X is C and Y is N or X is N and Y is C and the resulting formulas are representedThe compound of Claim 1, wherein Rl is selected from handwherein R7 is selected from:

8. The compound of Claim 1. wherein R1 is a heterocycle chemical moiety comprising a hydrogen-bond acceptor (e.g., morpholine).

9. The compound of Claim 1, wherein R2 is selected from Hydrogen, F, Cl, CH3, CN10. The compound of Claim 1, wherein R2 is either hydrogen or halogen (e.g., F, CL Br, I).

11. The compound of Claim 1, wherein R3 is selected from Hydrogen, F, Cl, CH3, CN12. The compound of Claim 1. wherein R3 is either hydrogen or halogen (e.g., F. Cl. Br. I).

13. The compound of Claim 1, wherein X and Y are C and R1 combines with R2 such that14. The compound of Claim 1, wherein X and Y are C and R1 combines with R3 such thatthe resulting formulas are represented15. The compound of Claim 1, wherein R4 is selected from Hydrogen, NH2 or CH3.

16. The compound of Claim 1. wherein R5 is selected from Hydrogen, NH2 or CH3.

17. The compound of Claim 1,wherein R4 is H and R5 is H, and the resulting formula is represented bywherein R4 is H and R5 is CH3, and the resulting formula is represented bywherein R4 is CH3 and R5 is NH2, and the resulting formula is represented byNH2 and R5 is CH3, and the resulting formula is represented by18. The compound of Claim 1, wherein said compound is selected from the group of compounds recited in Table 1.

19. A pharmaceutical composition comprising a compound of Claim 1.

20. A method of treating, ameliorating, or preventing a disorder related to DYRK1A activity in a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of Claim 19.

21. The method of Claim 20, wherein said disorder related to DYRK1 A activity is Alzheimer's disease, Down syndrome, Huntington’s disease, Parkinson’s disease, an autoimmune disease, an inflammatory disorder (e.g., airway inflammation), diabetes (e.g., any type or form of diabetes, including type-1 and type-2), or cancer (e.g., glioblastoma, prostate cancer).

22. The method of Claim 21, wherein said patient is a human patient.

23. The method of Claim 21, further comprising administering to said patient one or more additional agents for treating Alzheimer’s disease, Down syndrome, Huntington’s disease, Parkinson’s disease, autoimmune disease, an inflammatory disorder (e.g., airway inflammation), diabetes (e.g., any type or form of diabetes, including type-1 and type-2), or cancer (e.g.. glioblastoma, prostate cancer).

24. The method of Claim 23, w herein the additional therapeutic agent is selected from a cholinesterase inhibitor, an NMDA receptor antagonist, a -secretase (BACE) inhibitor, a y-secretase modulator, an anti-amyloid monoclonal antibody, a tau aggregation inhibitor, a dopaminergic agent, a MAO-B inhibitor, a COMT inhibitor, an adenosine A2A receptor antagonist, a VMAT2 inhibitor, an antisense oligonucleotide, or a GABA-A antagonist.

25. The method of Claim 24, wherein the additional therapeutic agent is selected from donepezil, nvastigmine, galantamine, memantine, verubecestat, lanabecestat, elenbecestat, aducanumab, lecanemab, donanemab, hydromethylthionine, levodopa / carbidopa, pramipexole, selegiline, rasagiline, entacapone, istradefylline, tetrabenazine, tominersen, orpentylenetetrazole.

26. The method of Claim 23. wherein the additional therapeutic agent is useful in treating an autoimmune disease.

27. The method of Claim 26, wherein the additional therapeutic agent is selected from a corticosteroid, an immunosuppressant, a TNF-a inhibitor, an IL-1 inhibitor, an IL-6 pathway inhibitor, an IL- 17 or IL-23 inhibitor, a B-cell modulator, a T-cell costimulation blocker, an integrin antagonist, or a JAK. inhibitor.

28. The method of Claim 27, wherein the additional therapeutic agent is selected from prednisone, methotrexate, cyclophosphamide, azathioprine, cyclosporine, tacrolimus, infliximab, adalimumab. tocilizumab, secukinumab, rituximab, abatacept, natalizumab, tofacitinib, or baricitinib.

29. The method of Claim 23, wherein the additional therapeutic agent is useful in treating an inflammatory’ disorder.

30. The method of Claim 29, wherein the additional therapeutic agent is selected from a nonsteroidal anti-inflammatory' drug (NSAID), a corticosteroid, a cytokine or chemokine inhibitor, an antioxidant, or a redox modulator.

31. The method of Claim 30, wherein the additional therapeutic agent is selected from ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, hydrocortisone, dexamethasone, budesonide, fluticasone, maraviroc, apremilast, roflumilast, N-acetylcysteine, vitamin E, cur cumin, or resveratrol.

32. The method of Claim 23, wherein the additional therapeutic agent is useful in treating diabetes (any form or type of diabetes, including type 1 or ty pe 2).

33. The method of Claim 32, wherein the additional therapeutic agent is selected from an insulin formulation, an insulin secretagogue, an insulin sensitizer, an incretin-based agent, an SGLT2 inhibitor, an a-glucosidase inhibitor, an amylin analog, a bile acid sequestrant, or a dopamine D2 agonist.

34. The method of Claim 33. wherein the additional therapeutic agent is selected from insulin lispro, insulin aspart. insulin glargine, metformin, pioglitazone, exenatide, liraglutide, semaglutide, dulaglutide, sitagliptin, empagliflozin, acarbose, pramlintide, colesevelam, or bromocriptine.

35. The method of Claim 32, wherein the additional therapeutic agent is a GLP-1 receptor agonist selected from exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, or efpeglenatide.

36. The method of Claim 32, wherein the additional therapeutic agent is a GLP-l / GIP dual agonist selected from tirzepatide, LY3437943, mazdutide (IBI362). retatrutide. VK2735, CT-388, or HRS9531.

37. The method of Claim 23, wherein the additional therapeutic agent is useful in treating cancer (e.g., glioblastoma, prostate cancer, or any cancer associated with DYRK1 A or DYRK1B activity).

38. The method of Claim 37, wherein the additional therapeutic agent is selected from an alkylating agent, an antimetabolite, a platinum-based agent, a microtubule-targeting agent, a topoisomerase inhibitor, a tyrosine kinase inhibitor, an mTOR inhibitor, a CDK inhibitor, a MEK / ERK pathway inhibitor, a PI3K / AKT pathway inhibitor, a PARP inhibitor, or a proteasome inhibitor.

39. The method of Claim 38, wherein the additional therapeutic agent is selected from temozolomide, cisplatin, paclitaxel, docetaxel, etoposide, doxorubicin, imatinib, erlotinib, sorafenib, sunitinib, everolimus, palbociclib, trametinib, alpelisib, olaparib, or bortezomib.

40. The method of Claim 37. wherein the additional therapeutic agent is selected from an immune checkpoint inhibitor, an anti-angiogenic agent, a hormonal or androgen-targeted therapy, a DNA damage response modulator, an epigenetic modulator, or an immunomodulatory agent.

41. The method of Claim 40. wherein the additional therapeutic agent is selected from pembrolizumab, nivolumab. atezolizumab, bevacizumab, abiraterone, tamoxifen, olaparib. vorinostat, azacitidine, or lenalidomide.

42. The method of Claim 23, wherein the additional therapeutic agent is selected from an analgesic, an anti-spasmodic, an antioxidant, a mitochondrial enhancer, a neurotrophic factor mimetic, a small-molecule anti-oxidative stress agent, or a metabolic regulator.

43. The method of Claim 42, wherein the additional therapeutic agent is selected from acetaminophen, gabapentin, baclofen, N-acetylcysteine. coenzyme Q10, idebenone, minocycline, edaravone. metformin, pioglitazone. or a GLP-1 receptor agonist.

44. A kit comprising a compound of Claim 1 and instructions for administering said compound to a patient having a disorder related to DYRK1 activity.

45. The kit of Claim 44, wherein the disorder related to DYRK1 activity is Alzheimer’s disease, Down syndrome, Huntington’s disease, Parkinson’s disease, autoimmune disease, an inflammatory disorder (e.g., airw ay inflammation), diabetes (e.g., any ty pe or form of diabetes, including type-1 and type-2), or cancer (e.g., glioblastoma, prostate cancer).

46. The kit of Claim 44, further comprising one or more agents for treating Alzheimer’s disease, Down syndrome, Huntington's disease, Parkinson’s disease, autoimmune disease, an inflammatory disorder (e.g., airw ay inflammation), diabetes (e.g.. any type or form of diabetes, including type-1 and type-2), or cancer (e.g., glioblastoma, prostate cancer).

47. The kit of Claim 46, wherein the one or more additional therapeutic agents are selected from:(a) agents useful for treating neurodegenerative diseases, including, but not limited to, cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, tacnne), NMD A receptor antagonists (e.g., memantine), 0-secretase (BACE) inhibitors (e.g., verubecestat, lanabecestat, elenbecestat), y-secretase modulators (e.g., semagacestat, avagacestat), antiamyloid monoclonal antibodies (e g., aducanumab, lecanemab, donanemab, bapineuzumab, solanezumab), tau aggregation inhibitors (e.g., hydromethylthionine, TRxO237), dopaminergicagents (e.g., levodopa / carbidopa, ropinirole, pramipexole, rotigotine), MAO-B inhibitors (e.g., selegiline, rasagiline, safinamide). COMT inhibitors (e.g., entacapone, tolcapone, opicapone), adenosine A2A receptor antagonists (e g., istradefylline), VMAT2 inhibitors (e.g., tetrabenazine, deutetrabenazine), antisense oligonucleotides (e.g., tominersen), and GABA-A antagonists (e.g., pentylenetetrazole, RO4938581);(b) agents useful for treating autoimmune diseases, including, but not limited to, corticosteroids and immunosuppressants (e.g., prednisone, methylprednisolone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus) and biologic agents (e.g., TNF-a inhibitors such as infliximab, adalimumab, etanercept; IL-1 inhibitors such as anakinra, canakinumab, rilonacept; IL-6 pathway inhibitors such as tocilizumab, sarilumab; IL-17 / IL-23 inhibitors such as secukinumab. ixekizumab, ustekinumab, guselkumab, risankizumab; B-cell modulators such as rituximab, ocrelizumab, belimumab; T-cell costimulation blockers such as abatacept; integrin antagonists such as natalizumab, vedolizumab; and JAK inhibitors such as tofacitinib, baricitinib, upadacitinib, ruxolitinib);(c) agents useful for treating inflammatory disorders, including, but not limited to, non-steroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, meloxicam), corticosteroids (e.g., hydrocortisone, prednisone, dexamethasone, budesonide, fluticasone), cytokine or chemokine inhibitors (e.g., maraviroc, apremilast, roflumilast), antioxidants and redox modulators (e.g., N-acetylcysteine. vitamin E, curcumin, resveratrol), and agents for specific inflammatory diseases (e.g., infliximab, adalimumab, vedolizumab, ustekinumab, dupilumab);(d) agents useful for treating diabetes (e.g., any form or type of diabetes, including type 1 or type 2), including, but not limited to, insulin formulations (e.g., insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin degludec), insulin secretagogues (e.g., glipizide, glyburide, repaglinide, nateglinide), insulin sensitizers (e.g., metformin, pioglitazone, rosiglitazone), incretin-based agents (e.g., GLP-1 receptor agonists such as exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide; and DPP-4 inhibitors such as sitagliptin, linagliptin, saxagliptin), SGLT2 inhibitors (e.g.. empagliflozin, dapagliflozin, canagliflozin, ertugliflozin), and GLP-1 / GIP dual agonists (e.g., tirzepatide, LY3437943, mazdutide [IBI362], retatrutide, VK2735, CT-388, HRS9531); and(e) agents useful for treating cancer (e.g., glioblastoma, prostate cancer, or any cancer associated with DYRK1 A or DYRK1B activity), including, but not limited to, alkylating agents (e.g., temozolomide, cyclophosphamide), antimetabolites (e.g., 5 -fluorouracil,gemcitabine), platinum-based agents (e.g.. cisplatin, carboplatin, oxaliplatin), microtubuletargeting agents (e.g., paclitaxel, docetaxel), topoisomerase inhibitors (e.g.. etoposide, doxorubicin), tyrosine kinase inhibitors (e.g., imatinib, erlotinib, sunitinib), mTOR inhibitors (e.g., everolimus), CDK inhibitors (e.g., palbociclib, abemaciclib), PI3K / AKT pathway inhibitors (e.g., alpelisib), PARP inhibitors (e.g., olaparib), and immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab, atezolizumab).

48. A method for inhibiting DYRK1 A related activity in a subject, comprising administering to the subject a compound of Claim 1.

49. The method of Claim 48, wherein administration of the compound results in inhibition of one or more DYRK1 A related activities in the subject:DYRK1A related PI3K / Akt signaling;DYRK1 A related tau phosphorylation;DYRK1 A related NF AT phosphorylation;DYRK1A related ASK1 / JNK1 pathway activation;DYRK1A related p53 phosphorylation;DYRK1A related Amph 1 phosphorylation;DYRK1 A related Dynamin 1 phosphorylation;DYRK1A related Synaptojamn phosphorylation;DYRK1A related presenilin 1 (the catalytic sub-unit of y-secretase) activity7;DYRK1 A related Amyloid precursor protein phosphorylation;DYRK1A related SIRT1 activation.

50. The method of Claim 48, wherein the subject is human subject suffering from or at risk for developing a disorder related to DYRK1 A activity7.

51. The method of Claim 50, wherein the disorder related to DYRK1A activity is Alzheimer’s disease, Down syndrome, Huntington’s disease, Parkinson’s disease, autoimmune disease, an inflammatory disorder (e.g., airway inflammation), diabetes (e.g., any type or form of diabetes, including type-1 and type-2), or cancer (e.g., glioblastoma).

52. A pharmaceutical composition comprising a compound according to Claim 1 and one or more additional therapeutic agents useful in treating a disorder associated with DYRK1 activity.

53. The pharmaceutical composition of Claim 52, wherein the disorder associated with DYRK1 activity is Alzheimer's disease, Down syndrome, Huntington’s disease, Parkinson’s disease, an autoimmune disease, an inflammatory disorder (e.g., airway inflammation), diabetes (e.g., any form or type of diabetes, including type 1 or type 2), or a cancer (e.g., glioblastoma, prostate cancer).

54. The pharmaceutical composition of Claim 52, wherein the one or more additional therapeutic agents are selected from agents useful for treating neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Down syndrome, or related cognitive or motor disorders), autoimmune diseases, inflammatory disorders, diabetes (e.g., type 1 or type 2), or cancers (e.g., glioblastoma, prostate cancer, or cancers associated with DYRK1A or DYRK1B activity).

55. The pharmaceutical composition of Claim 54, wherein the additional therapeutic agent is selected from:(a) a cholinesterase inhibitor (e.g., donepezil, rivastigmine, galantamine, tacrine); an NMDA receptor antagonist (e.g., memantine); a P-secretase (BACE) inhibitor (e.g., verubecestat, lanabecestat, elenbecestat); a y-secretase modulator (e.g., semagacestat, avagacestat); an anti-amyloid monoclonal antibody (e.g., aducanumab, lecanemab, donanemab, bapineuzumab, solanezumab); atau aggregation inhibitor (e.g., hydromethylthionine, TRxO237); a dopaminergic agent (e.g., levodopa / carbidopa. ropinirole, pramipexole. rotigotine); aMAO-B inhibitor (e.g., selegiline, rasagiline, safinamide); a COMT inhibitor (e.g., entacapone, tolcapone, opicapone); an adenosine A2A receptor antagonist (e.g., istradefylline); a VMAT2 inhibitor (e.g., tetrabenazine, deutetrabenazine); an antisense oligonucleotide (e.g., tominersen); or a GABA-A antagonist (e.g., pentylenetetrazole, RO4938581);(b) a corticosteroid or immunosuppressant (e.g., prednisone, methylprednisolone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, sirolimus); a biologic agent (e.g., a TNF-a inhibitor, IL-1 inhibitor, IL-6 pathway inhibitor, IL-17 / IL-23 inhibitor, B-cell modulator. T-cell costimulation blocker, integrin antagonist, or JAK inhibitor);(c) an anti-inflammatory agent (e.g., a non-steroidal anti-inflammatory drug such as ibuprofen, naproxen, diclofenac, indomethacin, celecoxib, or meloxicam: a corticosteroid such as hydrocortisone, dexamethasone, budesonide, or fluticasone; or a cytokine or chemokine inhibitor such as maraviroc, apremilast, or roflumilast);(d) an antidiabetic agent (e.g., an insulin formulation, insulin secretagogue, insulin sensitizer, incretin-based agent, SGLT2 inhibitor, a-glucosidase inhibitor, amylin analog, bile acid sequestrant, dopamine D? agonist, GLP-1 receptor agonist [e.g., exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide], or GLP-l / GIP dual agonist [e.g., tirzepatide, LY3437943, mazdutide (IBI362), retatrutide, VK2735, CT-388, HRS9531]); and(e) an anticancer agent (e.g., an alkylating agent such as temozolomide or cyclophosphamide; an antimetabolite such as 5 -fluorouracil or gemcitabine; a platinum agent such as cisplatin or carboplatin; a microtubule-targeting agent such as paclitaxel or docetaxel; a topoisomerase inhibitor such as etoposide or doxorubicin; a tyrosine kinase inhibitor such as imatinib or erlotinib; an mTOR inhibitor such as everolimus; a CDK inhibitor such as palbociclib or abemaciclib; a PARP inhibitor such as olaparib; or an immune checkpoint inhibitor such as pembrolizumab or nivolumab).

56. The pharmaceutical composition of any of Claims 52-55, further comprising a pharmaceutically acceptable carrier, excipient, or diluent.

57. The pharmaceutical composition of any of Claims 52-56, wherein the compound and the one or more additional therapeutic agents are co-formulated in a single dosage form.

58. The pharmaceutical composition of any of Claims 52-56. wherein the compound and the one or more additional therapeutic agents are provided in separate dosage forms for sequential or concurrent administration.

59. A pharmaceutical composition comprising a compound according to Claim 1 and a GLP-1 pathway modulator selected from a GLP-1 receptor agonist or a GLP-l / GIP dual agonist, together with one or more pharmaceutically acceptable carriers, excipients, or diluents.

60. The pharmaceutical composition of Claim 59, wherein the GLP-1 receptor agonist is selected from exenatide, liraglutide, semaglutide, dulaglutide. lixisenatide, or efpeglenatide.

61. The pharmaceutical composition of Claim 59, wherein the GLP-l / GIP dual agonist is selected from tirzepatide, LY3437943, mazdutide (IBI362), retatrutide, VK2735, CT-388, or HRS9531.

62. The pharmaceutical composition of any of Claims 59-61, wherein the compound according to Claim 1 and the GLP-1 pathway modulator are co-formulated in a single dosage form or provided in separate dosage forms for sequential or concurrent administration.

63. The pharmaceutical composition of any of Claims 59-62, wherein the composition is formulated for oral, parenteral, or subcutaneous administration, or as a sustained-release or liposomal formulation.

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