Mitochondrial complex i inhibitors

Abstract

In some embodiments, this document provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof; and a method of improving mitochondrial biogenesis and mitochondria function, and increasing autophagy in a subject in need thereof, comprising administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt thereof, or of the pharmaceutical composition.

Description

[0001] Attorney Docket No. 07039-2355WO1 / 2024-258

[0002] MITOCHONDRIAL COMPLEX I INHIBITORS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application Serial No. 63 / 746,026, filed on January 16, 2025. The disclosure of the prior application is considered part of the disclosure of this application, and is incorporated in its entirety into this application.

[0004] FEDERALLY SPONSORED RESEARCH

[0005] This invention was made with government support under NS11377, awarded by the National Institutes of Health. The government has certain rights in the invention.

[0006] TECHNICAL FIELD

[0007] This application in one embodiment relates to methods and materials for improving mitochondrial biogenesis and / or mitochondria function as well as methods and materials for increasing autophagy in a subject in need thereof. This application in one embodiment relates to methods and materials for activating protection against oxidative stress and mitochondrial biogenesis.

[0008] BACKGROUND

[0009] Despite recent FDA approval of anti-amyloid antibodies for Alzheimer's Disease (AD), strategies that target early molecular mechanisms and could delay or change the disease trajectory are still needed. While the underlying mechanisms of AD are complex, mounting data suggests that abnormal energy homeostasis is at the heart of the neuronal dysfunction, which gradually leads to the loss of cognitive abilities and neurodegeneration. Mitochondria are essential for the energy supply to support neuronal functions. Recent studies identified multiple abnormalities associated with mitochondrial dynamics and function, evident at the very early stages of AD that preclude the development of amyloid plaques and neurofibrillary tangles (1. Cunnane, S. C., et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing, Nat Rev Drug Discov 19, 609-633 (2020); Trushina. E.. et al. Defects in Mitochondrial Dynamics and Metabolomic SignaturesAttorney Docket No. 07039-2355WO1 / 2024-258

[0010] of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease, PLoS One 7 (2012); Trushina, E., Dutta, T., Persson, X. M., Mielke. M. M. & Petersen, R. C. Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer's disease using metabolomics, PLoS One 8, e63644 (2013); Chang, R., et al. Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease, Alzheimers Dement 19. 518-531 (2023)); Gao et al..

[0011] Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy. Alzheimers Dement. 2025 Aug;21(8):e70519. doi: 10.1002 / alz.70519.. Compelling data suggests that mitochondria are signaling organelles involved in the regulation of multiple cellular functions, such as maintenance of cellular bioenergetics, genomic stability, redox state, ion homeostasis, lipid and heme biosynthesis, innate immune surveillance, active stress responses, which ultimately determine the fate of the cell (Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging, Cell 153, 1194- 1217 (2013); Friedman, J. R. & Nunnari, J. Mitochondrial form and function. Nature 505, 335-343 (2014)). The improved ability of mitochondria to work under stress conditions have been shown to reduce oxidative stress, improve energy homeostasis and neuronal survival in models of chronological aging and neurodegenerative diseases (Grimm, M.O., Mett, J., Grimm, H. S. & Hartmann, T. APP Function and Lipids: A Bidirectional Link, Front Mol Neurosci 10, 63 (2017); Chandel, N. S. Evolution of Mitochondria as Signaling Organelles, Cell Metab 22, 204-206 (2015); Michel, S., et al. Crosstalk between mitochondrial (dys)function and mitochondrial abundance. J Cell Physiol 227, 2297-2310 (2012)).

[0012] There is a need for the development of strategies to improve mitochondrial dynamics and function in order to delay the onset of age-related diseases, including AD (Trushina, E., Nguyen, T. K. O. & Trushin, S. Modulation of Mitochondrial Function as a

[0013] Therapeutic Strategy for Neurodegenerative Diseases. J Prev Alzheimers Dis 10, 675-685 (2023); Flannery, P. J. & Trushina, E. Mitochondrial Dysfunction in Alzheimer’s Disease and Progress in Mitochondria-Targeted Therapeutics, Current Behavioral Neuroscience Reports 6, 88-102 (2019)).Attorney Docket No. 07039-2355WO1 / 2024-258

[0014] SUMMARY

[0015] In some embodiments, this document provides a compound of Formula (I):

[0016]

[0017] or a pharmaceutically acceptable salt thereof, wherein the R- and X-groups and L, A, m and n are as described herein.

[0018] In some embodiments, this document provides a pharmaceutical composition comprising any one or more of the compounds as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0019] In some embodiments, the following uses of, or treatments with, the compounds are disclosed. In each case, the use or treatment comprises administering to a subject an effective amount of any one or more of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0020] 1. Neurodegenerative diseases and metabolic diseases.

[0021] In one embodiment, one or more compounds described herein can be used to reduce cell death and / or multiple cellular dysfunctions associated with Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Restless Legs Syndrome, Niemann-Pick Disease, Epilepsy, Huntington’s Disease, Multiple Sclerosis, Beta-propeller protein-associated neurodegeneration (BP AN); Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, Stroke, Cockayne syndrome, Ataxia telangiectasia, diabetes. Mucopolysaccharidosis (MPS) type III, Familial dysautonomia, and Niemann-Pick Type C; diseases related to aging; and mitochondrial diseases such as Disorders of pyruvate carboxylase and pyruvate dehydrogenase complex. Leigh syndrome. Barth syndrome, and Disorders of mitochondrial depletion, Mitochondrial fatty acid oxidation disorders, and Primary carnitine deficiency.

[0022] In one embodiment, one or more compounds described herein can be used to treat schizophrenia or mood disorders.Attorney Docket No. 07039-2355WO1 / 2024-258

[0023] 2. In one embodiment, one or more compounds described herein can be used to alleviate human conditions associated with oxidative stress, including hypoxia-reperfusion. In one embodiment, one or more compounds described herein can be used in tissue transplantation (e.g., kidneys, heart and other organs) as an additive to the perfusion or preservation media to preserve tissues. In one embodiment, one or more compounds described herein can be used as a cryoprotective agent(s) for preservation of human organoids and other cells during freezing / thaw cycle(s), to reduce oxidative stress and / or to increase NADPH due to compound treatment, and / or to provide protection against X ray irradiation-induced tissue damage during cancer therapy. In one embodiment, one or more compounds described herein can be used to reduce or prevent UV radiation damage during sun exposure, can be used in cosmetics, and / or can be used in the treatment of skin conditions associated with wounds, psoriasis, and other skin diseases.

[0024] 3. In one embodiment, one or more compounds described herein can be used to reduce inflammation in diseases such as polycystic kidney disease and rheumatoid arthritis, and other conditions with inflammatory phenotype.

[0025] 4. In one embodiment, one or more compounds described herein can be used in anti-aging therapy to reverse multiple aspects of aging such as inflammation, oxidative stress, metabolic dysfunction and increase mitochondrial function and energy homeostasis in brain and periphery, including increased NAD+ levels. In one embodiment, one or more compounds described herein can be used to reduce senescence cell burden in tissues. In one embodiment a compound is useful in regenerative treatment to promote neurogenesis.

[0026] 5. In one embodiment, one or more compounds described herein can be used to treat cancer, e.g., by supporting TREG and CAR-T cells function.

[0027] 6. In one embodiment, one or more compounds described herein can be used in combinatory therapy in conjunction with other drugs (e.g., amyloid beta monoclonal antibodies) to promote mitochondrial function to support brain cell regeneration.

[0028] 7. In one embodiment, one or more compounds described herein can be used in in vitro fertilization (IVF) as an additive to culture media to promote early embryonic development.Attorney Docket No. 07039-2355WO1 / 2024-258

[0029] In some embodiments, this document provides a method of improving mitochondrial biogenesis and mitochondria function, and increasing autophagy in a subject in need thereof, comprising administering to the subject an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0030] In some embodiments, this document provides a method of activating protection against oxidative stress and mitochondrial biogenesis in a subject in need thereof, comprising administering to the subject an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0031] In some embodiments, this document provides a method of inhibiting mitochondrial complex I (mtCI) in a subject in need thereof, comprising administering to the subject an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0032] In some embodiments, this document provides a method of treating age-related neurovegetative diseases in a subject in need thereof, comprising administering to the subject an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0033] In some embodiments, this document provides a method of protecting against amyloid beta and phospho Tau toxicity in a subject in need thereof, comprising administering to the subject an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0034] In some embodiments, this document provides a method of improving glutathione and NADPH levels in a subject in need thereof, comprising administering to the subject an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0035] In some embodiments, this document provides a method of protecting against oxidative stress in a subject in need thereof, comprising administering to the subject an effective amount of any one of the compounds as described herein, or aAttorney Docket No. 07039-2355WO1 / 2024-258

[0036] pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0037] In some embodiments, this document provides a method of protecting an embryo from oxidative stress, such as oxidative stress associated with culturing early embryos in the lab, comprising treating an embryo culture medium with an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0038] In some embodiments, this document provides a method of inhibiting mitochondrial complex I (mtCI), comprising contacting a cell expressing mtCI with an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, this document provides a method of protecting against amyloid beta toxicity, comprising contacting a cell expressing amyloid beta with an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, this document provides a method of treating or preventing a disease or condition responsive to inhibition of mtCI in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. In some embodiments, the disease or condition is selected from a neurodegenerative disease; a disease related to aging, and a mitochondrial disease.

[0041] In some embodiments, this document provides a method of treating or preventing a disease or condition responsive to protection against amyloid beta toxicity in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. In some embodiments, the disease or condition is selected from a neurodegenerative disease; a disease related to aging, and a mitochondrial disease.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art toAttorney Docket No. 07039-2355WO1 / 2024-258

[0043] which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the present application will be apparent from the following detailed description, and from the claims.

[0044] BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1. Treatment with C273 shortens embryonic cell division, enhancing the progression of embryonic development. A. A schematic diagram illustrates each step of the embryonic cell division. B-H. Embryoscope slides were prepared using media with and without C273 (5 nM and 15 nM). The embryoscope and time-lapse systems captured images every 10 - 20 minutes. The time taken for cell division represents the stage duration. The durations of embryonic cell cycles (B-E) and embryonic stage development (F-H) were analyzed. Each dot represents an individual single-cell embryo, with a total of 34 embryos per group. Data are expressed as mean± SEM (n = 3). Statistics: one-way ANOVA and Tukey's multiple comparisons test. *P < 0.05, **P < 0.01, ***p < 0.001.

[0046] Figure 2. C273 protects embryonic development against oxidative stress. A. Experimental design to assess the effect of oxidative stress (cumene treatment) on embryonic survival and the protective effect of C273 treatment against cumene-induced cell death. B. Cumene treatment (8 mM) caused complete embryo loss, which was rescued by C273 treatment (15 mM). C, D. C273 treatment supports embryonic development to the morula and blastocyst stages in the presence of cumene treatment. Each dot represents an individual single-cell embryo. Data are expressed as mean ± SEM (n = 3). Statistics: one-way ANOVA and Tukey's multiple comparisons test, *P < 0.05, **P < 0.01, ***P < 0.001.

[0047] Figure 3. C273 protects MC65 neuroblastoma cells against Ap toxicity. A.

[0048] Protection against Ap toxicity in MC65 cells that conditionally express human Ap. ApAttorney Docket No. 07039-2355WO1 / 2024-258

[0049] (-) cells do not express Af> and are used as a cytotoxicity' control. Ap (+) cells express A and die within 72 hours unless rescued by neuroprotective compounds. Cell survival was measured using Promega CellTiter-Glo 2.0, and Ap (-) vehicle values were used to determine cell survival. The EC50 was calculated using GraphPad Prism with nonlinear fit - log (inhibitor) vs. response (four parameters). B. Western blot analysis in MC65 cells demonstrates that C273 treatment activates neuroprotective mechanisms.

[0050] Figure 4. Treatment with C273 increases levels of NADPH and Glutathione in MC65 cells suggesting strong protection against Aβ-induced oxidative stress. A. NADPH levels in MC65 cells. Ap (-) and Ap (+) MC65 cells were treated with C273 for 48 hours, and NADPH levels were measured with Promega NADP / NADPH-Glo assay. B. Total glutathione levels were measured in MC65 Ap (-) and Ap (+) cells treated with C273 for 48 hours using Promega GSH-Glo assay. C. Treatment with C273 protected MC65 cells against oxidative stress induced by H2O2treatment. LD50 was determined with GraphPad Prism nonlinear fit-log(inhibitor) vs. response (four parameters).

[0051] Figure 5. Treatment with C273 increases NADH levels in MC65 cells without Ap toxicity. NADH levels in Ap (-) MC65 cells after 72-hour treatment with C273. Mitochondrial complex I inhibition with C273 increases cellular NADH levels in control cells demonstrating target engagement. NADH levels were measured with Promega NAD / NADH-Glo assay. EC50 was determined with GraphPad Prism nonlinear fit- log(inhibitor) vs. response (four parameters).

[0052] Figure 6. Treatment with C273 partially inhibits mitochondrial complex I (mtCI) and increases lactate levels without inducing cytotoxicity at therapeutically relevant concentrations, indicating good safety margins. A. C273 mildly inhibits mtCI enzymatic activity in isolated mitochondria. Wild-type (WT) mouse brain mitochondria were isolated and treated with C273. Mitochondrial complex I enzymatic activity was measured as NADH oxidation, monitored by absorbance at 340 nm over time. B. Extracellular lactate levels in HEPG2 cells were measured after 48 hours of C273 treatment using the Promega Lactate-Glo assay. CellAttorney Docket No. 07039-2355WO1 / 2024-258

[0053] viability was assessed using the Promega CellTiter-Glo 2.0 assay. C. EC50 values were determined using GraphPad Prism with nonlinear fit - log(inhibitor) vs. response (four parameters).

[0054] Figure 7. ADMET characterization of C273. C273 demonstrates excellent drug-like properties in metabolic stability in liver microsomes, the blood brain barrier (BBB) penetration. CYP inhibition, hERG inhibition, DMPK solubility, and PPB. Assays were performed by the CRO Pharmaron.

[0055] Figure 8. The PK study for C273 demonstrates excellent bioavailability via intended oral administration. (A) Plasma and (B) brain levels of C273 were measured after 3 mg / kg IV injection or 25 mg / kg PO treatment. PK study and calculation of PK parameters were done by the CRO Jubilant Biosystems.

[0056] Figure 9. Translational biomarkers for C273 efficacy. A. Activation of AMPK in WT mice was observed 24 hours after gavage with 25 mg / kg of the tool compound CP2. Blood was collected and pooled from 3 mice per group, followed by the isolation of peripheral blood mononuclear cells (PBMCs). Western blot analysis was performed to determine activation of mechanisms of action (MoA). B. Human donor PBMCs treated with 1 pM CP2 showed activation of the same mechanisms as in mouse brain tissue, as confirmed by Western blot analysis. This suggests that PBMCs can be used to determine target engagement and activation of MoA using C273 as well.

[0057] Figure 10. The diagram of a 384-well plate with the designation of serial dilution for each compound.

[0058] Figure 11. Diagram of 96 well plate with final concentration of compound.

[0059] Figure 12. A Western blot analysis with specific antibodies indicates activation of neuroprotective mechanisms associated with the efficacy of complex I inhibitors in human PBMCs. P-AMPKa, AMPK activation; CI - CV, antibodiesAttorney Docket No. 07039-2355WO1 / 2024-258

[0060] against OXPHOS complexes I-V; actin, loading control; Veh, vehicle; CP2, DI, D2, C273, mitochondrial complex I inhibitors; MF, metformin.

[0061] Figure 13. C273 protects MC65 cells against Aβ toxicity (Tet OFF, blue line) with EC₅₀ 12.9 nM. Pretreatment with rotenone, which blocks access of C273 to the binding site on complex I, eliminates C273 efficacy (red line).

[0062] Figure 14. Mitochondrial complex I inhibitors CP2 and C273 decrease NF-κB activation induced by IL-1β and TNF-α in HEK293 cells.

[0063] Figure 15. Preliminary toxicology for C273 administration in wild-type mice. Histopathological assessment of heart and liver tissue failed to demonstrate any toxicity associated with C273 administration. Treatment with C273 did not affect body weight gain and locomotor activity in these mice. All mice were females, n = 5 mice / group.

[0064] Figure 16 shows the results of a hERG inhibition in Dofetilide radioligand binding assay for C273 (Pharmaron CRO). IC50 was generated in GraphPad Prism 10. The green box indicates the range of C273 EC50 in the MC65 Tet OFF assay (protection against Ap toxicity).

[0065] Figure 17A-F. Treatment with C458 reduces the levels of Aβ and p-Tau T181 in iPSC-derived organoids from patients with sporadic AD,

[0066] DETAILED DESCRIPTION

[0067]

[0068] Attorney Docket No. 07039-2355WO1 / 2024-258

[0069] In some embodiments, this document provides a compound of Formula (I):

[0070] X27\

[0071] m

[0072]

[0073] (I),

[0074] or a pharmaceutically acceptable salt thereof, wherein:

[0075] (Rbn

[0076] A

[0077]

[0078] is Ci-Ce alkyl or;

[0079] Ar is phenyl or 6-membered heteroaryl having one or two ring heteroatoms atoms each independently selected from O, S andN;

[0080] n = 0-5;

[0081] each R1is independently selected from CN, NO2, C(O)ORal, ORal, NRclRdl, Cy1, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with CN, C(O)ORal, ORal, NRclRdl, or Cy2;

[0082] X1is absent, O. NR2or CR3R4;

[0083] X2is N or CR3;

[0084] m = 0 or 1;

[0085] R2, R3, R4, R5, R6and R7are each independently selected from H, Cy3, C(=O)Cy3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rbl, C(O)NRclRdl, C(O)ORal, S(O)2Rbl, and S(O)2NRclRdl, wherein said C1-6 alkyl is optionally substituted with Cy4, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, or NRclRdl;

[0086] or R5and R6taken together with atoms connecting them form a 4, 5, 6, 7- or 8- carbocyclic or heterocyclic ring

[0087] or 2 R7taken together with the atoms connecting them form a 5, 6, or 7-cycloaliphatic or heterocycloaliphatic ring;

[0088] or 2 R7bonded to the same carbon atom form C=O;

[0089] X3=N or CR3;

[0090] L = Co-Cg alkylene optionally substituted with 1-6 R7;Attorney Docket No. 07039-2355WO1 / 2024-258

[0091] R10is a 5-10-membered carbocycle or 5-10-membered heterocycle or NR8R9;

[0092] R8and R9are each independently selected from H, Cy5, C(=O)Cy5, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rbl, C(O)NRclRdl, C(O)ORal, S(O)2Rbl, S(O)2NRclRdl,

[0093] wherein said C1-6 alkyl is optionally substituted with Cy6, CN. NO2, ORal, C(O)Rbl. C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0. orNRclRdl

[0094] wherein said R105-10-membered carbocycle OR 5-10-membered heterocycle is optionally substituted with Cy7-C1-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =O, or NRclRdl;

[0095] each Rblis independently selected from C1-3 alkyl, C1-3 haloalkyl, Cy8, Cy8-Ci- 3 alkylene, NRc2Rd2-Ci-3 alkylene, C(O)ORa2-Ci-3 alkylene, and ORa2-Ci-3 alkylene;

[0096] each Ral, Rcland Rdlis independently selected from H, C1-3 alkyl, C1-3 haloalkyl, Cy9, Cy9-Ci-3 alkylene, NRc2Rd2-Ci-3 alkylene, C(O)ORa2-Ci-3 alkylene, and ORa2-Ci-3 alkylene;

[0097] Cy1, Cy2, Cy3. Cy4, Cy5, Cy6, Cy7’ Cy8and Cy9are each independently selected from Ce-io aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl such as 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy; each RCyis independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, S(O)2Rb2, and S(O)2NRc2Rd2; wherein said C1-6 alkyl is optionally substituted with CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, S(O)2Rb2, or S(O)2NRc2Rd2;

[0098] each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, and C1-4 haloalkyl; and

[0099] each Rb2is independently selected from C1-6 alkyl and C 1-4 haloalkyl;

[0100] In some embodiments, A is C1-C6 alkyl. In some embodiments, A is

[0101]

[0102] In some embodiments, Ar is phenyl;Attorney Docket No. 07039-2355WO1 / 2024-258

[0103] In some embodiments, X1is O. In some embodiments, X1is CR3R4. In some embodiments, X1is CH2. In some embodiments, X1is absent.

[0104] In some embodiments, R1is CH3. In some embodiments, R1is CF3.

[0105] In some embodiments,

[0106]

[0107] In some embodiments, R9is H and R8is C1-6 alkyl optionally substituted with Cy6. In some embodiments, Cy6is 5-14 membered heteroaryl such as 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from RCy. In some embodiments, Cy6is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from RCy. In some embodiments, Cy6is pyridinyl optionally substituted with RCy. In some embodiments, Cy6is 4-pyridinyl optionally substituted with RCy. In some embodiments, Cy6is quinolinyl optionally substituted with RCy. In some embodiments, Cy6is 3 -pyridinyl optionally substituted with RCy. In some embodiments, Cy6is 2-pyridinyl optionally substituted with RCy. In some embodiments, Cy6is pyrimidinyl optionally substituted with RCy. In some embodiments, Cy6is THP optionally substituted with RCy. In some embodiments, Cy6is THF optionally substituted with RCy. In some embodiments, Cy6is morpholino optionally substituted with RCy.

[0108] In some embodiments, R10is a 5-6-membered heterocycle wherein an N atom is connected to L. In some embodiments, R10is a 5-10-membered heterocycle. In some embodiments, R10is a 5-10-membered heterocycloalkyl. In some embodiments, R10is a 5-10-membered heteroaryl. In some embodiments, R10is l,3-dihydro-2H-pyrrolo[3,4-c]pyridine. In some embodiments, R10is py ridinyl. In some embodiments, R10is 4-pyridinyl. In some embodiments, R10is 3-pyridinyl. In someAttorney Docket No. 07039-2355WO1 / 2024-258

[0109] embodiments, R10is 2-pyridinyl. In some embodiments, R10is pyrimidinyl. In some embodiments, R10is THP. In some embodiments, R10is THF. In some embodiments, R10is morpholino. In each case R10is optionally substituted with Cy7-Ci-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =O, or NRclRdl.

[0110] In some embodiments, the compound of Formula (I) is a compound of Formula (IA):

[0111]

[0112] wherein

[0113] X1is O, CH2, or absent;

[0114] m is 0 or 1;

[0115] R3and R6are each H; or R3and R6taken together with atoms connecting them form a 4, 5, 6, 7- or 8- carbocyclic or heterocyclic ring;

[0116] L = is C2-C3alkylene optionally substituted with methyl;

[0117] R10is a 5-10-membered heterocycle or NHR9, optionally substituted as defined in Formula (I),

[0118] and

[0119] R1and R9are defined as in Formula I.

[0120] In some embodiments of the compound of Formula (IA), X1is O.

[0121] In some embodiments of the compound of Formula (IA), m is 0.

[0122] In some embodiments of the compound of Formula (IA), mis 1.

[0123] In some embodiments of the compound of Formula (IA), R10is a 5-10-membered heterocycloalkyl optionally substituted as defined in Formula (I).

[0124] In some embodiments of the compound of Formula (IA), R10is a 5-10-membered heteroaryl optionally substituted as defined in Formula (I).

[0125] In some embodiments of the compound of Formula (IA), R10is NHC1-6 alkyl substituted with 5-10 heterocycloalkyl optionally substituted as defined in Formula (I).

[0126] In some embodiments of the compound of Formula (IA), R10is NHC1-6 alkyl substituted with 5-10 heteroaryl optionally substituted as defined in Formula (I).Attorney Docket No. 07039-2355WO1 / 2024-258

[0127] In some embodiments of the compound of Formula (IA), R10is NHCI-6 alky l substituted with pyridinyl N-oxide optionally substituted as defined in Formula (I). In some embodiments of the compound of Formula (IA), R10is NHCI-6 alkyl substituted with pyridinyl optionally substituted with RCy.

[0128] In some embodiments of the compound of Formula (IA), R10is morpholino optionally substituted with RCy.

[0129] Compounds of Formula (II)

[0130] In some embodiments, this document provides a compound of Formula (II):

[0131]

[0132] (II),

[0133] or a pharmaceutically acceptable salt thereof, wherein:

[0134] Ar is phenyl or 6-membered heteroaryl having one or two ring heteroatoms atoms each independently selected from O, S andN;

[0135] n = 0-5;

[0136] each R1is independently selected from CN, NO2, C(O)ORal, ORal, NRclRdl, Cy1, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with CN, C(O)ORal, ORal, NRclRdl, or Cy2;

[0137] X1is absent, O, NR2or CR3R4;

[0138] X2is N or CR3;

[0139] m = 0 or 1;

[0140] R2, R3, R4, and R7are each independently selected from H, Cy3, C(=O)Cy3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rbl, C(O)NRclRdl, C(O)ORal, S(O)2Rbl, and S(O)2NRclRdl, wherein said C1-6 alkyl is optionally substituted with Cy4, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, or NRclRdl;

[0141] or R5and R6taken together with atoms connecting them form a 4, 5, 6, 7- or 8- carbocyclic or heterocyclic ringAttorney Docket No. 07039-2355WO1 / 2024-258

[0142] or 2 R7taken together with the atoms connecting them form a 5, 6, or 7-cycloaliphatic or heterocycloaliphatic ring;

[0143] or 2 R7bonded to the same carbon atom form C=O;

[0144] X3=N or CR3;

[0145] L = C(O), or C(R7)2;

[0146] R10is a 5-10-membered carbocycle or 5-10-membered heterocycle or NR8R9;

[0147] R8and R9are each independently selected from H, Cy5, C(=O)Cy5, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rbl, C(O)NRclRdl, C(O)ORal, S(O)2Rbl, S(O)2NRclRdl,

[0148] wherein said C1-6 alkyl is optionally substituted with Cy6, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =O, or NRclRdl

[0149] wherein said R105-10-membered carbocycle OR 5-10-membered heterocycle is optionally substituted with Cy7-C1-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =O, or NRclRdl;

[0150] each Rblis independently selected from C1-3 alkyl, C1-3 haloalkyl, Cy8, Cy8-Ci-3 alkylene, NRc2Rd2-Ci-3 alkylene, C(O)ORa2-Ci-3 alkylene, and ORa2-Ci-3 alkylene;

[0151] each Ral, Rcland Rdlis independently selected from H, C1-3 alkyl, C1-3 haloalkyl, Cy9, Cy9-Ci-3 alkylene, NRc2Rd2-Ci-3 alkylene, C(O)ORa2-Ci-3 alkylene, and ORa2-Ci-3 alkylene;

[0152] Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7, Cy8and Cy9are each independently selected from Ce-io aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl such as 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy; each RCyis independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, S(O)2Rb2, and S(O)2NRc2Rd2; wherein said C1-6 alkyl is optionally substituted with CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, S(O)2Rb2, or S(O)2NRc2Rd2;

[0153] each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, and C 1-4 haloalkyl; and

[0154] each Rb2is independently selected from C1-6 alkyl and C1-4 haloalkyl.Attorney Docket No. 07039-2355WO1 / 2024-258

[0155] In some embodiments, this document provides a compound selected from the group consisting of the following compounds:

[0156] 2-((R)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-l -amine;

[0157] N-methyl-3-(pyridin-4-yl)-N-(3-(m-tolyloxy)phenyl)propan amide;

[0158] (S)-N-(pyridin-4-ylmethyl)-l-((R)-3-(m-tolyloxy)piperidin-l-y l)propan-2-amine;

[0159] (R)-N 1 -methyl -N2-(pyridin-4-ylmethyl)-N 1 -(3 -(m-tolyloxy)phenyl)propane-1,2-diamine;

[0160] 1-(pyridin-4-yl)-N-((4-(m-tolyloxy)quinolin-8-yl)methyl)methanamine; (S)-2-((pyridin-4-ylmethyl)amino)-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one;

[0161] (S)-4-((3-(4-(m-tolyl oxy )piperidin-l-yl)pyrrolidin-l-yl)methyl)pyri dine; N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)acetamide;

[0162] N-(Pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propanamide;

[0163] (S)-N-((2-fluoropyridin-4-yl)methyl)-l-(4-(m-tolyloxy)piperidm-l-yl)propan-2-amine;

[0164] (S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;

[0165] 2-((S)-l-((lR,3S.5S)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-2-yl)-2,3-dihydro-lH-pyrrolo[3,4-c]pyridine;

[0166] (S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-(4-(p-tolyloxy)piperidin-l-y l)propan-2-amine;

[0167] (S)-4-(l -(4-phenoxypiperidin-l -yl)propan-2-yl)morpholine;

[0168] 3-(pyridin-4-yl)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one;

[0169] (S)-N, N-dimethyl-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;

[0170] 2-(pyridin-4-ylmethyl)-8-(m-tolyloxy)-l,2,3,4-tetrahydroisoquinoline;

[0171] (S)-1-(4-benzylpiperazin-1-yl)-N-(pyridin-4-ylmethyl)propan-2-amine•4HCl (S)-l-(4-Benzylpiperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine;

[0172] 4-(3-methylbenzyl)-1-(3-(tetrahydro-2H-pyran-4-yl)propyl)piperidine;

[0173] 4-((S)-l-((lR,5S)-3-(3-methylbenzyl)-3,8-diazabicyclo[3.2. l]octan-8-yl)propan-2-yl)morpholine;Attorney Docket No. 07039-2355WO1 / 2024-258

[0174] N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propan-l-amine;

[0175] N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-l -amine; N-(pyridin-4-ylmethyl)-2-(4-(m-tolyloxy)piperidin-l-yl)propan-l -amine; N-methyl-N-(3-(pyridin-4-yl)propyl)-3-(m-tolyloxy)aniline;

[0176] N-(pyridin-4-ylmethyl)-2-((R)-3-(m-tolyloxy)piperidin-l-yl)propan-l-amine; N-methyl-N-(2-(pyridin-4-yl)ethyl)-3-(m-tolyloxy)aniline;

[0177] 2-(pyridin-4-ylmethyl)-6-(m-tolyloxy)-l,2,3,4-tetrahydroisoquinoline;

[0178] N-methyl-2-(pyridin-4-yl)-N-(3-(m-tolyloxy)phenyl)acetamide;

[0179] N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-l -amine; N-(pyridin-4-ylmethyl)-2-((lR,3r,5S)-3-(m-tolyloxy)-8-azabicy clo [3.2.1 ] octan-8-y l)propan- 1 -amine;

[0180] (S)-N-(pyridin-4-ylmethyl)-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-2-amine;

[0181] (S)-3-((pyridin-4-ylmethyl)amino)-1-(3-(m-tolyloxy)piperidin-l-yl)propan-l-one;

[0182] (S)-N-(pyridin-4-ylmethyl)-3-(3-(m-tolyloxy)piperidin-1-yl)propan-1-amine; (S)-3-(pyridin-4-yl)-l-(3-(m-tolyloxy)piperidin-l-yl)propan-l-one;

[0183] 1 -(pyridin-4-yl)-N-((7 -(m-toly loxy )naphthalen- 1 -y l)methyl)methanamine; (S)-4-(3-(3-(m-tolyloxy)piperidin-l-yl)propyl)pyridine;

[0184] (R)-2-((pyridin-4-ylmethyl)amino)-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one;

[0185] (R)-N-(pyridin-4-ylmethyl)-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-2-amine;

[0186] (S)-2-((pyridin-4-ylmethyl)amino)-l-(3-(m-tolyloxy)piperidin-l-yl)ethanone; (S)-N-(pyridin-4-ylmethyl)-2-(3-(m-tolyloxy)piperidin-1-yl)ethanamine; (lR,5S)-8-(3-(pyridin-4-yl)propyl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane; 2-((pyridin-4-ylmethyl)amino)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1 ]octan-8-yl)ethanone;

[0187] (3S,3'S)-1'-(pyridin-4-ylmethyl)-3-(m-tolyloxy)-1,3'-bipyrrolidine;

[0188] 3-((pyridin-4-ylmethyl)amino)-1-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-l-one;

[0189] N-(pyridin-4-ylmethyl)-2-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)ethanamine;Attorney Docket No. 07039-2355WO1 / 2024-258

[0190] (2R)-2-((pyridin-4-ylmethyl)amino)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-l-one;

[0191] N-(pyridin-4-ylmethyl)-3-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-amine;

[0192] (2S)-2-((pyridin-4-ylmethyl)amino)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one;

[0193] (R)-4-((3-(4-(m-tolyloxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine; (S)-4-((3-(m-tolyloxy)pyrrolidin-l-yl)methyl)pyridine;

[0194] 4-(((S)-3-((S)-3-(m-tolyloxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine; 4-(((S)-3-((R)-3-(m-tolyloxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine; ((2R)-N-(pyridin-4-ylmethyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0195] (2S)-N-(pyridin-4-ylmethyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0196] (S)-4-((3-(3-(m-tolyloxy)pyrrolidin-1-yl)azetidin-1-yl)methyl)pyridine;

[0197] N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)ethanamine;

[0198] (S)-4-((3-(3-(m-tolyloxy)pyrrolidin-l-yl)azeti din-1 -yl)methyl)pyri dine;

[0199] 2-methyl-N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propanamide; (S)-2-((pyridin-4-ylmethyl)amino)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-l-one;

[0200] 2-methyl-N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propan-l-amine;

[0201] (R)-2-((pyridin-4-ylmethyl)amino)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-l-one;

[0202] (S)-N-(pyridin-4-ylmethyl)-1-(4-(m-tolyloxy)piperidin-1-yl)propan-2-amine; (R)-N-(pyridin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine; (R)-N-methyl-N-(pyridin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;

[0203] N-(2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propyl)isonicotinamide;

[0204] (lR)-N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)cyclopentanamine;

[0205] (lS)-N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)cyclopentanamine;Attorney Docket No. 07039-2355WO1 / 2024-258

[0206] N-methyl-N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-y l)propan- 1 -amine;

[0207] 4-(((R)-2-(((S)-3-(m-tolyloxy)pyrrolidin-l-yl)methyl)pyrrolidin-l-yl)methyl)pyridine;

[0208] N-isopropyl-N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-y l)propan- 1 -amine;

[0209] 4-(((S)-2-(((S)-3-(m-tolyloxy)pyrrolidin-l-yl)methyl)pyrrolidin-l-yl)methyl)pyridine;

[0210] (2S)-N-(furan-3-ylmethyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0211] (2S)-N-(4-fluorobenzyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0212] (2S)-N-((2-fluoropyridin-4-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0213] N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propanamide hydrochloride;

[0214] 1-(pyridin-4-yl)-N-(((lR,3S)-3-(m-tolyloxy)cyclohexyl)methyl)meth an amine; 2-(pyridin-4-yl)-N-(((lR,3S)-3-(m-tolyloxy)cyclohexyl)methyl)ethanamine; 4-(l-(((lR,3S)-3-(m-tolyloxy)cyclohexyl)methyl)pyrrolidin-3-yl)pyridine; 4-((3-(4-(3-(trifluoromethyl)phenoxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine;

[0215] 4-((3-(4-phenoxypiperi din-1 -yl)pyrrolidin-l-yl)methyl)pyri dine;

[0216] (lR,3r,5S)-8-(l-benzyl-lH-pyrrol-3-yl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane;

[0217] 4-(( 3 -(4-( 3 -(trifluoromethy l)phenoxy )piperidin- 1 -yl)- 1 H-py rrol- 1 -yl)methyl)pyridine;

[0218] 4-((3-(4-phenoxypiperidin-l-yl)-lH-pyrrol-l-yl)methyl)pyridine;

[0219] (S)-4-((4-(3-(m-tolyl oxy )pyrrolidin-l-yl)piperidin-l-yl)methyl)pyri dine; (lR,3r,5S)-8-(l-(pyridin-4-ylmethyl)piperidin-4-yl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane;

[0220] (2S)-N-((2-methoxypyridin-4-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0221] (3S)-l'-benzyl-3-(m-tolyloxy)-l,3'-bipyrrolidine;Attorney Docket No. 07039-2355WO1 / 2024-258

[0222] 4-((3-(4-(3-(trifluoromethoxy)phenoxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine;

[0223] 4-((3-(4-(3,5-difluorophenoxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine; (2S)-N, N-dimethyl-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octan-8-y l)propan-2-amine;

[0224] (2S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0225] 4-((3-(4-methoxypiperi din-1 -yl)pyrrolidin-l-yl)methyl)pyri dine;

[0226] (2S)-N-(4-methoxybenzyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0227] (S)-l-(4-benzylpiperazin-l-yl)-N-((2-methylpyridin-4-yl)methyl)propan-2-amine»4HCl

[0228] 3-((l-(l-(pyridin-4-ylmethyl)pyrrolidin-3-yl)piperidin-4-yl)oxy)-5-(trifluoromethyl)pyridine;

[0229] (2S)-N-(pyridin-3-ylmethyl)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0230] (2S)-N-((2-methylpyridin-4-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0231] (S)-l-(4-(3-methylbenzyl)piperazin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine»4HCl

[0232] (S)-l-(4-(3-methylbenzyl)piperazin-l-yl)-N-((2-methylpyridin-4-yl)methyl)propan-2-amine*4HCl

[0233] (S)-l-(4-(3-methylbenzyl)piperazin-l-yl)-N-(pyridin-3-ylmethyl)propan-2-amine»4HCl

[0234] (S)-N-(pyridin-4-ylmethyl)-l -(4-(3-(trifluoromethyl)phenoxy)piperi din-1 -y l)propan-2-amine;

[0235] (S)-l-(4-(3, 5-difluorophenoxy)piperi din-1 -yl)-N-(pyridin-4-ylmethyl)propan-2-amine;

[0236] (S)-N-(pyridin-4-ylmethyl)-l-(4-(3-(tri fluoromethoxy )phenoxy)piperi din- 1-yl)propan-2-amine;

[0237] (S)-l-(4-phenoxypiperi din-1 -yl)-N-(pyridin-4-ylmethyl)propan-2-amine; (S)-N-(quinolin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;Attorney Docket No. 07039-2355WO1 / 2024-258

[0238] (S)-l-(4-(3-methylbenzyl)piperazin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;

[0239] (S)-N-(pyridin-4-ylmethyl)-l-(4-(3-(trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine*4HCl

[0240] (S)-N-((2-methylpyridin-4-yl)methyl)-l-(4-(3- (trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine’4HCl

[0241] (S)-N-(pyridin-3-ylmethyl)-l-(4-(3-(trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine*4HCl

[0242] (S)-6-(((l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyrimidine-2,4(lH,3H)-dione;

[0243] (S)-4-(((l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridin-2(lH)-one;

[0244] (S)-5-(((l-(4-(m-tolyloxy)piperi din-1 -yl)propan-2-yl)amino)methyl)pyridin-2(lH)-one;

[0245] (S)-4-(((l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridine 1 -oxi de;

[0246] (S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-(4-(3- (trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine;

[0247] (2S)-N-((tetrahydrofuran-3-yl)methyl)-l-(4-(3-(trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine;

[0248] 4-((((2S)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-2-yl)amino)methyl)pyridin-2(lH)-one;

[0249] (2S)-N-((tetrahydrofuran-3-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicy clo [3.2.1 ] octan-8-y l)propan-2-amine;

[0250] 5-((((2S)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)amino)methyl)pyridin-2(1H)-one;

[0251] (S)-l-(4-(tert-butoxy)piperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine 4-((2S)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)morpholine

[0252] (2S)-N-(quinolin-4-ylmethyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;

[0253] N-((2S)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-2-yl)tetrahydro-2H-pyran-4-amine;Attorney Docket No. 07039-2355WO1 / 2024-258

[0254] (S)-l-(4-benzylpiperidin-l-yl)-N-((2-methylpyridin-4-yl)methyl)propan-2-amine;

[0255] (S)-l-(4-benzylpiperidin-l-yl)-N-(pyridin-3-ylmethyl)propan-2-amine;

[0256] (S)-l-(4-(3-chlorophenoxy)piperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;

[0257] (S)-l-(4-(4-chlorophenoxy)piperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;

[0258] (S)-l-(4-(3-chlorophenoxy)piperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine;

[0259] (S)-l-(4-benzylpiperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;

[0260] (S)-l-(4-benzylpiperidin-l-yl)-N-(quinolin-4-ylmethyl)propan-2-amine; (S)-l-(4-(3-isopropylphenoxy)piperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;

[0261] (S)-l-(4-(3-isopropylphenoxy)piperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine;

[0262] (S)-N-(pyridazin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;

[0263] (S)-l-(4-phenylpiperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine;

[0264] (S)-N-((2-methylpyridin-4-yl)methyl)-l-(4-phenylpiperidin-l-yl)propan-2-amine;

[0265] (S)-l-(4-phenylpiperidin-l-yl)-N-(pyridin-3-ylmethyl)propan-2-amine;

[0266] (S)-l-(4-((5-fluoropyridin-3-yl)oxy)piperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;

[0267] 4-phenoxy-l-(3-(tetrahydro-2H-pyran-4-yl)propyl)piperidine;

[0268] (S)-l-(4-Phenylpiperidin-l-yl)-N-(quinolin-4-ylmethyl)propan-2-amine; (S)-l-(4-phenylpiperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;

[0269] (2S)- 1 -(4-phenylpiperidin- 1 -yl)-N-((tetrahydrofuran-3-y l)methyl)propan-2-amine;

[0270] (lR,5S)-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3-(m-tolyloxy)-8-azabicy clo [3.2.1 ] octane;Attorney Docket No. 07039-2355WO1 / 2024-258

[0271] 4-(3-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propyl)morpholine;

[0272] (lR,5S)-8-(3-(tetrahydro-2H-pyran-4-yl)propyl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane;

[0273] (S)-4-(l-(4-(3-methylbenzyl)piperidin-l-yl)propan-2-yl)morpholine;

[0274] l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-4-(3-(trifluoromethyl)phenoxy)piperidine;

[0275] (S)-N-(pyrimidin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;

[0276] (S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-2-amine;

[0277] (S)-N-(pyridin-4-ylmethyl)-l-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-2-amine;

[0278] 4-(3-methylbenzyl)-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperidine;

[0279] 4-(3-(4-(3-methylbenzyl)piperidin-l-yl)propyl)morpholine;

[0280] l-(3-(tetrahydro-2H-pyran-4-yl)propyl)-4-(m-tolyl)piperidine;

[0281] (S)-4-(l-(4-(m-tolyl)piperidin-l-yl)propan-2-yl)morpholine;

[0282] 4-(3-(4-(m-tolyl)piperidin-l-yl)propyl)morpholine;

[0283] l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-4-(m-tolyl)piperidine;

[0284] 4-(3 -(4-( 3 -(trifluoromethyl)phenoxy )piperidin- 1 -y l)propyl)morpholine;

[0285] (S)-N-(quinolin-4-ylmethyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine; (S)-N-(pyridin-4-ylmethyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine; (S)-N-((2-methylpyridin-4-yl)methyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine;

[0286] (S)-N-(pyridin-3-ylmethyl)-l-(4-(m-tolyl)pipendin-l-yl)propan-2-amine; (S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l -(4-(m-tolyl)piperi din-1 -y l)propan-2-amine;

[0287] (2S)-N-((tetrahydrofuran-3-yl)methyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine;

[0288] and

[0289] (S)-l-((lR,5S)-3-(3-methylbenzyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(quinolin-4-ylmethyl)propan-2-amine;

[0290] or a pharmaceutically acceptable salt thereof.Attorney Docket No. 07039-2355WO1 / 2024-258

[0291] Pharmaceutically acceptable salts

[0292] In some embodiments, a salt of a compound described herein is formed between an acid and a basic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, a compound described herein can be a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of a compound described herein include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acry late, formate, isobuty rate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-1,6-dioate. benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, or those formed with organic acids such as maleic acid. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of a compound described herein include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxylsubstituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine:Attorney Docket No. 07039-2355WO1 / 2024-258

[0293] pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), such as N, N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. In some embodiments, the compounds of this disclosure, or pharmaceutically acceptable salts thereof, are substantially isolated. In some embodiments where the compound disclosed herein is dibasic or tribasic, pharmaceutically acceptable salts include disalts or tr-salts of the compound, such as, for example, a di-salt or tri-salt of an inorganic acid such as, for example, hydrochloric acid, hydrobromic acid, or hydroiodic acid, or of an organic acids such as, for example, para-toluenesulfonic acid, salicylic acid, ascorbic acid, besylic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, para-bromophenylsulfonic acid, carbonic acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.

[0294] In some cases, a compound described herein can have asymmetric centers. Compounds containing an asymmetrically substituted atom can be in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials, for example by chiral chromatography. All forms, including enantiomers, diastereomers, racemic mixtures, scalemic mixtures, as well as mixtures of diastereomers, are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specified.

[0295] Methods of making therapeutic compounds

[0296] Compounds described herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. A person skilled in the art knows how to select and implement appropriate synthetic protocols and appreciates that the processes described are not the exclusive means by which compounds provided herein may be synthesized, and that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds described herein.

[0297] Suitable synthetic methods of starting materials, intermediates and products may be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012);Attorney Docket No. 07039-2355WO1 / 2024-258

[0298] Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky. et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations / / (Elsevier, 2ndEdition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6thEd. (Wiley, 2007); and Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

[0299] The reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

[0300] Preparation of the compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in P G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4thEd., Wiley & Sons, Inc., New York (2006).

[0301] Methods of using therapeutic compounds

[0302] In some embodiments, this document provides a method of improving mitochondrial biogenesis and mitochondria function, and / or increasing autophagy in a subject in need thereof, comprising administering to the subject an effective amount of any one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0303] In some embodiments, this document provides a method of inhibiting mitochondrial complex I (mtCI) in a subject in need thereof, comprisingAttorney Docket No. 07039-2355WO1 / 2024-258

[0304] administering to the subject an effective amount of any one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0305] In some embodiments, this document provides a method of treating age-related neurovegetative diseases in a subject in need thereof, comprising administering to the subject an effective amount of any one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0306] In some embodiments, this document provides a method of treating neurodegenerative diseases such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Restless Legs Syndrome, Niemann-Pick Disease, Epilepsy, Huntington’s Disease, Multiple Sclerosis, Beta-propeller protein-associated neurodegeneration (BP AN); Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, Stroke, Cockayne syndrome, Ataxia telangiectasia, diabetes. Mucopolysaccharidosis (MPS) type III, Familial dysautonomia, and Niemann-Pick Type C; diseases related to aging; and mitochondrial diseases such as Disorders of pyruvate carboxylase and pyruvate dehydrogenase complex, Leigh syndrome, Barth syndrome, and Disorders of mitochondrial depletion, Mitochondrial fatty acid oxidation disorders, and Primary carnitine deficiency, in a subject in need thereof, comprising administering to the subj ect an effective amount of any one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0307] In some embodiments, this document provides a method of treating schizophrenia or mood disorders.

[0308] In some embodiments, this document provides a method of protecting against amyloid beta toxicity in a subject in need thereof, comprising administering to the subject an effective amount of any one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0309] In some embodiments, this document provides a method of improving glutathione and NADPH levels in a subject in need thereof, comprising administering to the subject an effective amount of any one or more of the compounds describedAttorney Docket No. 07039-2355WO1 / 2024-258

[0310] herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0311] In some embodiments, this document provides a method of protecting against oxidative stress in a subject in need thereof, comprising administering to the subject an effective amount of any one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0312] In some embodiments, this document provides a method of protecting an embryo from oxidative stress, such as oxidative stress associated with culturing early embryos in the lab, comprising treating an embryo culture medium with an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0313] In some embodiments, this document provides a method of inhibiting mitochondrial complex I, comprising contacting a cell expressing mtCI with an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, this document provides a method of protecting against amyloid beta toxicity, comprising contacting a cell expressing amyloid beta with an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, this document provides a method of treating or preventing a disease or condition responsive to inhibition of mtCI in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. In some embodiments, the disease or condition is selected from a neurodegenerative disease; a disease related to aging, and a mitochondrial disease.

[0316] In some embodiments, this document provides a method of treating or preventing a disease or condition responsive to protection against amyloid beta toxicity in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. In some embodiments, the disease or condition isAttorney Docket No. 07039-2355WO1 / 2024-258

[0317] selected from a neurodegenerative disease; a disease related to aging, and a mitochondrial disease.

[0318] In some embodiments, this document provides a method of protecting an embryo from oxidative stress, such as oxidative stress associated with culturing early embryos in the lab, comprising treating an embryo culture medium with an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0319] In some embodiments, the disease or condition is a CNS disorder, such as a neurodegenerative disease. Examples of such diseases include Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy body dementia, Parkinson’s Disease, Restless Legs Syndrome, Niemann-Pick Disease, Epilepsy, Huntington’s Disease, Multiple Sclerosis, Beta-propeller protein-associated neurodegeneration (BP AN); Chronic Traumatic Encephalopathy, Traumatic Brain Injury. Tumor, Stroke, Cockayne syndrome, Ataxia telangiectasia, diabetes. Mucopolysaccharidosis (MPS) type III, Familial dysautonomia, and Niemann-Pick Type C.

[0320] In some embodiments, the disease or condition is a disease related to aging. In some embodiments, the disease or condition is a mitochondrial disease, such as Disorders of pyruvate carboxylase and pyruvate dehydrogenase complex. Leigh syndrome, Barth syndrome, and Disorders of mitochondrial depletion, Mitochondrial fatty acid oxidation disorders, and Primary carnitine deficiency

[0321] Pharmaceutical compositions and formulations

[0322] The present application also provides pharmaceutical compositions comprising an effective amount of a compound of as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The carrier(s) and excipient(s) are “acceptable” in the sense of beingAttorney Docket No. 07039-2355WO1 / 2024-258

[0323] compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

[0324] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-poly oxypropylene-block polymers, polyethylene glycol, and wool fat.

[0325] The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients. The contemplated compositions may contain 0.001%-100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients.

[0326] Routes of administration and dosage forms

[0327] The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intraarterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal. intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary. intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral,Attorney Docket No. 07039-2355WO1 / 2024-258

[0328] parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal.

[0329] Compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy. Lippincot Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0330] In some embodiments, any one of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in aAttorney Docket No. 07039-2355WO1 / 2024-258

[0331] capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0332] Compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, ater, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables. as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[0333] The pharmaceutical compositions of the present application may be administered in the form of suppositories for rectal administration. TheseAttorney Docket No. 07039-2355WO1 / 2024-258

[0334] compositions can be prepared by mixing a compound of the present application with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0335] The pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, U. S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11:1-18, 2000.

[0336] The topical compositions of this document can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and / or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of the pharmaceutical compositions of the present application is especially useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / detergent cleansing agents, penetration enhancers, and thickeners.

[0337] The compounds and therapeutic agents of the present application may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings andAttorney Docket No. 07039-2355WO1 / 2024-258

[0338] the general preparation of coated implantable devices are known in the art and are exemplified in U. S. Patent Nos. 6,099.562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.

[0339] According to another embodiment, the present application provides an implantable drug release device impregnated with or containing a compound or a therapeutic agent, or a composition comprising a compound of the present application or a therapeutic agent, such that said compound or therapeutic agent is released from said device and is therapeutically active.

[0340] Dosages and regimens

[0341] In the pharmaceutical compositions of the present application, a compound as described herein is present in an effective amount (e.g., a therapeutically effective amount). Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.

[0342] In some embodiments, an effective amount of a compound as described herein can range, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5Attorney Docket No. 07039-2355WO1 / 2024-258

[0343] mg / kg; from about 0.1 mg / kg to about 2 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; or from about 0.1 mg / kg to about 0.5 mg / kg). In some embodiments, an effective amount of a compound as described herein is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg.

[0344] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, twice daily, thrice daily) or non-daily basis (e.g.. every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month).

[0345] Kits

[0346] The present invention also includes pharmaceutical kits useful, for example, in the treatment of disorders, diseases and conditions referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of this document. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. The kit may optionally include an additional therapeutic agent in a suitable amount or dosage.

[0347] Definitions

[0348] At various places in the present specification, substituents of compounds of the present application are disclosed in groups or in ranges. It is specifically intended that various embodiments of the present application include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0349] As used herein, the term "‘about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).

[0350] As used herein, the term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures named or depicted. Compounds herein identified by name or structure as one particularAttorney Docket No. 07039-2355WO1 / 2024-258

[0351] tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0352] As used herein, the term "tautomer" refers to compounds which are capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound.

[0353] As used herein, the term "isomer" refers to structural, geometric and stereo isomers.

[0354] Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbon atoms. Examples include C1-4. C1-6, and the like.

[0355] As used herein, the phrase "‘optionally substituted’’ means unsubstituted or substituted. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency.

[0356] As used herein, the term " Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alky l moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertbutyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0357] As used herein, the term “Cn-mhaloalkyr, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+ 1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0358] As used herein, “Cn-malkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-Attorney Docket No. 07039-2355WO1 / 2024-258

[0359] butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0360] As used herein, “Cn-malkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0361] As used herein, the term “Cn-malkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons.

[0362] Examples of alkylene groups include, but are not limited to, ethan- 1,1 -diyl, ethan-1,2-diyl, propan-1,1, -diyl, propan- 1,3-diyl, propan- 1,2-diyl, butan-l,4-diyl, butan-1,3-diyl, butan- 1.2 -diyl, 2-methyl-propan-l,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0363] As used herein, the term “Cn-malkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0364] As used herein. “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0365] As used herein, the term “amino” refers to a group of formula –NH2.

[0366] As used herein, the term " Cn-malkylamino” refers to a group of

[0367] formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g.. N-(n-butyl)amino and N-(tert-butyl)amino), and the like.

[0368] As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula -N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbonAttorney Docket No. 07039-2355WO1 / 2024-258

[0369] atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0370] As used herein, the term " Cn-m alkoxy carbonyl” refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxy carbonyl groups include, but are not limited to, methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxy carbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl). and the like.

[0371] As used herein, the term “Cn-m alkylcarbonyl” refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, but are not limited to, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl and tert-butylcarbonyl), and the like.

[0372] As used herein, the term " Cn-m alkylcarbonylamino” refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0373] As used herein, the term “Cn-m alkylsulfonylamino” refers to a group of formula -NHS(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0374] As used herein, the term ‘‘aminosulfonyl” refers to a group of

[0375] formula -S(O)2NH2.

[0376] As used herein, the term “Cn-malkylaminosulfonyl” refers to a group of formula -S(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0377] As used herein, the term “di(Cn-malkyl)aminosulfonyl” refers to a group of formula -S(O)2N(alkyl)2. wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0378] As used herein, the term '‘aminosulfonylamino” refers to a group of formula -NHS(O)2NH2.Attorney Docket No. 07039-2355WO1 / 2024-258

[0379] As used herein, the term “Cn-malkylaminosulfonylamino” refers to a group of formula -NHS(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0380] As used herein, the term “di(Cn-m alkyl)aminosulfonylamino” refers to a group of formula -NHS(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0381] As used herein, the term '‘aminocarbonylamino” employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2.

[0382] As used herein, the term “Cn-m alkylaminocarbonylamino” refers to a group of formula -NHC(O)NH( alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0383] As used herein, the term “di(Cn-malkyl)aminocarbonylamino” refers to a group of formula -NHC(O)N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0384] As used herein, the term “carbamyl” to a group of formula -C(O)NH2.

[0385] As used herein, the term “Cn-m alkylcarbamyl” refers to a group of formula -C(O)-NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0386] As used herein, the term “di(Cn-m-alkyl)carbamyl” refers to a group of formula -C(O)N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0387] As used herein, the term "thio” refers to a group of formula -SH.

[0388] As used herein, the term “Cn-malkylthio” refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0389] As used herein, the term “Cn-malkylsulfinyl” refers to a group of formula -S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.Attorney Docket No. 07039-2355WO1 / 2024-258

[0390] As used herein, the term “Cn-malkylsulfonyl” refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0391] As used herein, the term ‘‘carbonyl”, employed alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O).

[0392] As used herein, the term “carboxy” refers to a -C(O)OH group.

[0393] As used herein, the term “cyano-Ci-3 alkyl” refers to a group of formula -(C1-3 alkyl ene)-CN.

[0394] As used herein, the term “HO-C1-3 alkyl” refers to a group of formula -(C1-3 alkylene)-OH.

[0395] As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br.

[0396] As used herein, “carbocyclyl” or “carbocycle” refers to a monocyclic or polycyclic carbon ring system. Included in carbocyclyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10-membered groups. Carbocyclyl groups can also include spirocycles. Ring-forming carbon atoms can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). In some embodiments, the carbocyclyl group contains 0 to 3 double bonds. In some embodiments, the carbocyclyl group contains 0 to 2 double bonds. In some embodiments, the carbocyclyl is a monocyclic or bicyclic 4-10 membered carbocyclyl. In some embodiments, the carbocyclyl is a monocyclic 4-6 membered carbocyclyl. In some embodiments, the carbocyclyl is a monocyclic or bicyclic 4-10 membered carbocyclyl. groups include aryl groups and cycloalkyl groups.

[0397] As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term " Cn-maryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphtyl.

[0398] As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2. 3 or 4 fused rings) groups and spirocycles. Ring-Attorney Docket No. 07039-2355WO1 / 2024-258

[0399] forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0400] As used herein, “heterocyclyl’' or ‘"heterocycle” refers to a monocyclic or polycyclic ring system having one or more ring-forming heteroatoms selected from O. N, or S. Included in heterocyclyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclyl groups. Heterocyclyl groups can also include spirocycles. Ring-forming carbon atoms and heteroatoms of a heterocyclyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocyclyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocyclyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclyl group contains 0 to 2 double bonds. In some embodiments, the heterocyclyl is a monocyclic 4-6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocyclyl is a monocyclic or bicyclic 4-10 membered heterocyclyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. Hetrocyclyl groups include heteroaryl groups and heterocycloalkyl groups.

[0401] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3. or 4 heteroatomAttorney Docket No. 07039-2355WO1 / 2024-258

[0402] ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a fivemembered or six-membereted heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary' five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six -membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

[0403] As used herein, “heterocycloalky 1” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N. or S. Included in heterocycloalkyl are monocyclic 4-. 5-, 6-, 7-, 8-. 9- or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydro thienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S). or S(O)2. etc.). The heterocycloalkyl group can be attached through a ringforming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e.,Attorney Docket No. 07039-2355WO1 / 2024-258

[0404] having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

[0405] At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.

[0406] As used herein, the term "oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=O), or attached to a heteroatom forming a sulfoxide or sulfone group.

[0407] As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0408] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system, an in vivo system, or an ex vivo system. For example, “contacting” the particulate guanylyl cyclase receptor A with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having particulate guanylyl cyclase receptor A, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the particulate guanylyl cyclase receptor A.

[0409] As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, otherAttorney Docket No. 07039-2355WO1 / 2024-258

[0410] rodents, rabbits, dogs, cats, swine, catle, sheep, horses, or primates, and most preferably humans.

[0411] As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0412] As used herein the term “treating” or “treatment” refers to 1 ) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0413] As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring.

[0414] EXAMPLES

[0415] Example 1 - synthetic examples

[0416] The following compounds were prepared according to the procedures disclosed herein:

[0417] ID Name MS (m / z)

[0418] [M+H]+C508 [(4-pyridyl)methyl]{2-t(R)-3-(m- 326 toly loxy)- 1 -py rroli dinyl] propyl } amine«2HCl

[0419]

[0420] Attorney Docket No. 07039-2355WO1 / 2024-258

[0421] N-methyl-3-(pyridin-4-yl)-N-(3-(m- [M+H]+C696

[0422] tolyloxy)phenyl)propanamide*HCl 347 (1S)-jV-(pyridin-4-ylmethyl)-l-((7?)-3-(m- [M+H]+C697

[0423] tolyloxy)piperidin-l-yl)propan-2-amine*2HCl 340 (R)-N1-methyl-N2-(pyridin-4-ylmethyl)-N1-(3-(m-tolyloxy)phenyl)propane-1,2- 362 di amine* 2HC1

[0424] 1 -(pyridin-4-yl)-jV-((4-( / n- [M+H]+C764 tolyloxy)quinolin-8- 356 yl)methyl)methanamine*2HCl

[0425] (S)-2-((pyridin-4-ylmethyl)amino)-1- [M+H]+C762 ((S)-3-( / w -tolyloxy )piperi din-l-yl)propan-l- 354 one*HCl

[0426] (S)-4-((3-(4-(m-tolyloxy)piperidin-l- [M+H]+C939

[0427] yl)pyrrolidin- 1 -yl)methyl)pyridine*2HCl 352 A-(pyridin-4-ylmethyl)-2-(5-(m- [M+H]+C042

[0428] tolyloxy)pyridin-3-yl)acetamide*2HCl 334 A-(Pyridin-4-ylmethyl)-2-(5-(m- [M+H]+C616

[0429] tolyloxy)pyridin-3-yl)propanamide*HCl 348 (S)-N-((2-fluoropyridin-4-yl)methyl)-1- [M+H]+C125 (4-(m-tolyloxy)piperidin-l-yl)propan-2- 358 amine*3HCl

[0430] (S)-N-((tetrahydro-2H-pyran-4- [M+H]+C234 yl)methyl)-l -(4-( / n-tolyloxy)piperidin-l - 347 yl)propan-2-amine*2HCl

[0431] 2-((< S)-l-((lA,3S.5< S’)-3-(m-tolyloxy)-8- [M+H]1C438 azabicyclo[3.2.1]octan-8-yl)propan-2-yl)-2,3- 378 dihydro-1H-pyrrolo[3,4-c]pyridine•2HCl

[0432] (S)-A-((tetrahydro-27 / -pyran-4- [M+H]+C480 yl)methyl)-1-(4-(p-tolyloxy)piperidin-1- 347 yl)propan-2-amine*2HCl

[0433] (S)-4-(l -(4-phenoxypiperidin-l - [M+H]+C558

[0434] yl)propan-2-yl)morpholine*2HCl 305

[0435]

[0436] Attorney Docket No. 07039-2355WO1 / 2024-258

[0437] 3-(pyridin-4-yl)-l-((17?,55)-3-(m- [M+H]+C903 tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan- 351 l-one*HCl

[0438] (, S')-AGV-di methyl- 1 -(4-(m- [M+H]+C663

[0439] tolyloxy)piperidin-l-yl)propan-2-amine*2HCl 277 2-(pyridin-4-ylmethyl)-8-(m-tolyloxy)- [M+H]+C664

[0440] l,2,3,4-tetrahydroisoquinoline*2HCl 331 (S)-l-(4-benzylpiperazin-l-yl)-jV- [M+H]+C065

[0441] (pyridin-4-ylmethyl)propan-2-amine*4HCl 325 (S’)- 1 -(4-Benzylpiperidin- 1 -yl)-A- [M+H]+C477

[0442] (pyridin-4-ylmethyl)propan-2-amine*3HCl 324 4-(3-methylbenzyl)-1-(3-(tetrahydro- [M+H]+C598

[0443] 2H-pyran-4-yl)propyl)piperidine•HCl 316 4-((S)-1-((1R,5S)-3-(3-methylbenzyl)- [M+H]+C705 3,8-diazabicyclo[3.2. l]octan-8-yl)propan-2- 344 yl)morpholine*2HCl

[0444] N-(pyridin-4-ylmethyl)-2-(5-(m- [M+H]+C390

[0445] tolyloxy)pyridin-3-yl)propan-l -amine* 2H Cl 334 N-(pyridin-4-ylmethyl)-2-((S)-3-(m- [M+H]+C509

[0446] tolyloxy)pyrrolidin-l -yl)propan-l -amine* 2HC1 326

[0447] 7V-(pyridin-4-ylmethyl)-2-(4-(m- [M+H]+C510

[0448] tolyloxy)piperidin-l-yl)propan-1-amine•2HCl 340 N-methyl-N-(3-(pyridin-4-yl)propyl)-3- [M+H]+C698

[0449] (m-tolyloxy)aniline*2HCl 333 N-(pyridin-4-ylmethyl)-2-((R)-3-(m- [M+H]+C699

[0450] tolyloxy)piperidin-l-yl)propan-1-amine•2HCl 340 N-methyl-N-(2-(pyridin-4-yl)ethyl)-3- [M+H]+C700

[0451] (m-tolyloxy)aniline*2HCl 319 2-(pyridin-4-ylmethyl)-6-( / M-tolyloxy)- [M+H]+C701

[0452] l,2?3.4-tetahydroisoquinoline*HCl 331 N-methyl-2-(pyridin-4-yl)-N-(3-(m- [M+H]+C702

[0453] tolyloxy)phenyl)acetamide*HCl 333

[0454]

[0455] Attorney Docket No. 07039-2355WO1 / 2024-258

[0456] N-(pyridin-4-ylmethyl)-2-((S)-3-(m-

[0457] tolyloxy)piperidin-l-yl)propan-1-amine•2HCl 340. N-(pyridin-4-ylmethyl)-2-((1R,3r,5S)-3- [M+H]+C2704 ( / ?7-tolyloxy)-8-azabicyclo|3.2. l |octan-8- 366 yl)propan-1-amine•2HCl

[0458] (S)-A-(pyridin-4-ylmethyl)-l-((S)-3-(m- [M+H]+C763

[0459] tolyloxy)piperidin-l-yl)propan-2-amine*2HCl 340 (5)-3-((pyridin-4-ylmethyl)amino)-1-(3- [M+H]+C828

[0460] (m-tolyloxy)piperidin-l-yl)propan-l-one*HCl 354 (S)-N-(pyridin-4-ylmethyl)-3-(3-(m- [M+H]+C829

[0461] tolyl oxy)piperidin- 1 -yl)propan- 1 -amine*2HCl 340

[0462] (5)-3-(pyridin-4-yl)-l-(3-(m- [M+H]+C830

[0463] tolyloxy )piperidin- 1 -y l)propan- 1 -one’HCl 325 1-(pyridin-4-yl)-N-((7-(m- [M+H]+C831 tolyloxy)naphthalen-l - 355 yl)methyl)methanamine»HCl

[0464] (S)-4-(3-(3-(m-tolyloxy)piperidin-1- [M+H]+C832

[0465] yl)propyl)pyridine*HCl 340 (R)-2-((pyridin-4-ylmethyl)amino)-1-((S)-3-(m-tolyloxy)piperidin-1-yl)propan-1- 354 one*2HCl

[0466] (R)-N-(pyridin-4-ylmethyl)-1-((S)-3-(m- [M+H]+C852

[0467] tolyloxy)piperidin-l-yl)propan-2-amine*2HCl 354 (S)-2-((pyridin-4-ylmethyl)amino)-1-(3- [M+H]+C853

[0468] ( / w-tolyloxy)piperidin-l-yl)ethanone*HCl 340 (S)-N-(pyridin-4-ylmethyl)-2-(3-(m- [M+H]+C854

[0469] tolyloxy)piperidin-l-yl)ethanamine*2HCl 326 (1R,5S)-8-(3-(pyridin-4-yl)propyl)-3-(m- [M+H]+C904

[0470] toly loxy )-8-azabicy clo [3.2.1 ] octane*HCl 337 2-((pyridin-4-ylmethyl)amino)-1-((1R,5S)-3-(m-tolyloxy)-8- 366 azabicyclo[3.2.1]octan-8-yl)ethanone»2HCl

[0471]

[0472] Attorney Docket No. 07039-2355WO1 / 2024-258

[0473] (3< S’,3'< S)-r-(pyridin-4-ylmethyl)-3-(m- [M+H]+C940

[0474] tolyloxy)-l,3'-bipyrrolidine*2HCl 338 3-((pyridin-4-ylmethyl)amino)-1- [M+H]+C969 (( 17?, 5S)-3-(m -tolyloxy )-8- 380 azabicyclo[3.2. l]octan-8-yl)propan-l-one*2HCl

[0475] N-(pyridin-4-ylmethyl)-2-((1R,5S)-3-(m- [M+H]+C970 tolyloxy)-8-azabicyclo[3.2.1]octan-8- 352 yl)ethanamine»2HCl

[0476] (2R)-2-((pyridin-4-ylmethyl)amino)-1-((1R,5S)-3-(m-tolyloxy)-8- 380 azabicyclo[3.2.1]octan-8-yl)propan-l-one»2HCl

[0477] N-(pyridin-4-ylmethyl)-3-((1R,5S)-3-(m- [M+H]+C987 tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan- 366 l-amine’SHCl

[0478] (2S)-2-((pyridin-4-ylmethyl)amino)- 1 - [M+H]+C988 ((17?,55)-3-( / n-tolyloxy)-8- 380 azabicyclo[3.2. l]octan-8-yl)propan-l-one*2HCl

[0479] (R)-4-((3-(4-(m-tolyloxy)piperidin-1- [M+H]+C989

[0480] yl)pyrrolidin-l-yl)methyl)pyridine»2HCl 352 (S)-4-((3-(m-tolyloxy)pyrrolidin-1- [M+H]+C990

[0481] yl)methy l)py ridine«HCl 269 4-(((S)-3-((S)-3-(m-tolyloxy)piperidin-1- [M+H]+C991

[0482] yl)pyrrolidin-l-yl)methyl)pyridine»2HCl 352 4-(((S)-3-((R)-3-(m-tolyloxy)piperidin- [M+H]+C992

[0483] l-yl)pyrrolidin-l-yl)methyl)pyridine*2HCl 352 ((2R)-N-(pyridin-4-ylmethyl)-1-((1R,5S)-3-(m-tolyloxy)-8- [M+H]+C040

[0484] azabicyclo[3.2.1]octan-8-yl)propan-2- 366 amine*3HCl

[0485] (2S)-N-(pyridin-4-ylmethyl)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine•2HCl

[0486]

[0487] Attorney Docket No. 07039-2355WO1 / 2024-258

[0488] (S)-4-((3-(3-(m-tolyloxy)pyrrolidin-1- [M+H]+C043

[0489] y l)azetidin- 1 -y l)methy l)py ri di ne*2HCI 338 N-(pyridin-4-ylmethyl)-2-(5-(m- [M+H]+C044

[0490] tolyloxy)pyridin-3-yl)ethanamine*2HCl 320 (S)-4-((3-(3-(m-tolyloxy)pyrrolidin-1- [M+H]+C045

[0491] y l)azetidin- 1 -y l)methy l)py ri di ne*2HCI 324 2-methyl-A-(pyridin-4-ylmethyl)-2-(5- [M+H]+C617

[0492] (m-tolyloxy)pyridin-3-yl)propanamide*HCl 362 (S)-2-((pyridin-4-ylmethyl)amino)-1-(4- [M+H]+C618

[0493] (m-tolyloxy)piperidin-l-yl)propan-l-one*2HCl 354 2-methyl-A-(pyridin-4-ylmethyl)-2-(5- [M+H]+C619

[0494] (m-tolyloxy)pyridin-3-yl)propan-l -amine* 2HC1 348 (R)-2-((pyridin-4-ylmethyl)amino)-1-(4- [M+H]+C660

[0495] (m-tolyloxy)piperidin-l-yl)propan-l-one*2HCl 354 (S)-N-(pyridin-4-ylmethyl)-1-(4-(m- [M+H]+C661

[0496] tolyloxy)piperidin-l-yl)propan-2-amine*2HCl 340 (R)-N-(pyridin-4-ylmethyl)-1-(4-(m- [M+H]+C662

[0497] tolyloxy)piperidin-l-yl)propan-2-amine*3HCl 340 (R)-N-methyl-N-(pyridin-4-ylmethyl)-1-(4-(m-tolyloxy)piperidin-1-yl)propan-2- 354 amine*3HCl

[0498] JV-(2-( (< S)-3 -(m-tolyloxy )py rroli din- 1 - [M+H]+C3703

[0499] yl)propyl)isonicotinamide*HCl 340 (1R)-N-(pyridin-4-ylmethyl)-2-((S)-3- [M+H]+C3704 (m-tolyloxy)pyrrolidin-l - 352 yl)cyclopentanamine*2HCl

[0500] (1S)-N-(pyridin-4-ylmethyl)-2-((S)-3- [M+H]+C847 (m-toly loxy )py rrol i din- 1 - 352 yl)cyclopentanamine*2HCl

[0501] N-methyl-N-(pyridin-4-ylmethyl)-2-((S)- [M+H]+C848 3-(m-tolyloxy)pyrrolidin-l-yl)propan-l- 340 amine*3HCl

[0502]

[0503] Attorney Docket No. 07039-2355WO1 / 2024-258

[0504] 4-(((7?)-2-(((< S)-3-( / n-tolyloxy)pyrrolidin- [M+H]+C877 1 -y l)methyl)pyrrolidin- 1 - 352 yl)methyl)pyridine»3HCl

[0505] A-isopropyl-; V-(pyridin-4-ylmethyl)-2- [M+H]+C878 ((< S)-3-(m-toly 1 oxy)py rrolidin- 1 -y l)propan- 1 - 368 amine»3HCl

[0506] 4-(((S)-2-(((5)-3-(w-tolyloxy)pyrrolidin- [M+H]+C879 1 -yl)methyl)pyrrolidin- 1 - 352 yl)methyl)pyridine*3HCl

[0507] (2X)-AL(furan-3-yl methyl)- 1 -(( 1 R,5S)-3- [M+H]+C890 ( / w-tolyloxy)-8-azabicyclo[3.2.1]octan-8- 355 yl)propan-2-amine»2HCl

[0508] (2< S)-A-(4-fluorobenzyl)-l-((17?,5<5’)-3- [M+H]+C891 (m-tolyloxy)-8-azabicyclo[3.2. l]octan-8- 383 yl)propan-2-amine»2HCl

[0509] (21S)-A-((2-fluoropyridin-4-yl)methyl)-l- ((17?,5S)-3-( / w-tolyloxy)-8- [M+H]+C892

[0510] azabicyclo[3.2.1]octan-8-yl)propan-2- 384 amine»2HCl

[0511] A-(pyridin-4-ylmethyl)-2-(5-(m- [M+H]+C893 tolyloxy)pyridin-3-yl)propanamide

[0512] 339 hydrochloride’HCl

[0513] l-(pyridin-4-yl)-A-(((lA,3iS’)-3-(m- [M+H]+C894

[0514] tolyloxy)cyclohexyl)methyl)methanamine»2HCl 311

[0515] 2-(pyridin-4-yl)-7V-(((17?,3S)-3-(»7- [M+H]+C895

[0516] tolyloxy)cyclohexyl)methyl)ethanamine*2HCl 325

[0517] 4-(l-(((17?,3S)-3-(m- [M+H]+C896 tolyloxy)cyclohexyl)methyl)pyrrolidin-3- 351 yl)pyridine*2HCl

[0518] 4-((3-(4-(3- [M+H]+C897 (trifluoromethyl)phenoxy)piperidin- 1 - 406 yl)pyrrolidin- 1 -yl)methyl)pyridine»2HCl

[0519]

[0520] Attorney Docket No. 07039-2355WO1 / 2024-258

[0521] 4-((3-(4-phenoxypiperi din-1 - [M+H]+C898

[0522] yl)pyrrolidin- 1 -y l)methy l)py ri dine*2HCI 338 (17?,3r,5lS)-8-(l-benzyl-lH-pyrrol-3-yl)- [M+H]+C934

[0523] 3-(m-tolyloxy)-8-azabicyclo[3.2. l]octane*HCl 373

[0524] 4-((3-(4-(3- [M+H]+C935 (trifluoromethyl)phenoxy)piperidin- 1 -yl)- 1H- 402 py rrol - 1 -y 1 )methy 1 )py ri dine* 2HC1

[0525] 4-((3-(4-phenoxypiperidin-l-yl)-lH- [M+H]+C936

[0526] pyrrol-l-yl)methyl)pyridine*2HCl 334 (X) -4-( (4-( 3 -(m -tolyloxy )py rroli din- 1 - [M+H]+C937

[0527] yl)piperidin-l-yl)methyl)pyridine*2HCl 352

[0528] (17?,3r,5S)-8-(l-(pyridin-4- [M+H]+C3938 ylmethyl)piperidin-4-yl)-3-(7M-tolyloxy)-8- 392 azabicyclo[3.2.1]octane*2HCl

[0529] (2S)-jV-((2-methoxypyridin-4- yl)methyl)-l-((17?,51S)-3-(m-tolyloxy)-8- [M+H]+C976

[0530] azabicyclo[3.2.1]octan-8-yl)propan-2- 396 amine*2HCl

[0531] (3S)-r-benzj’l-3-(m-tolyloxy)-l,3'- [M+H]+C977

[0532] bipyrrolidine*2HCl 337 4-((3-(4-(3- [M+H]+C978 (trifluoromethoxy )phenoxy )piperidin- 1 - 422 yl)pyrrolidin-l-yl)methyl)pyridine*2HCl

[0533] 4-((3-(4-(3,5-difluorophenoxy)piperidin- [M+H]+C979

[0534] l-yl)pyrrolidin-l-yl)methyl)pyridine*2HCl 374 (2S)-A, JV-dimethyl- 1 -(( 17?, 5S)-3-(m- [M+H]+C980 tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan- 303 2-amine*2HCl

[0535] (2, S')-A-((tetrahydro-2 / / -pyran-4- yl)methyl)- 1 -(( 1 A,5S)-3-(m-tolyloxy )-8- [M+H]+C008

[0536] azabicy clo[3.2.1] octan-8-yl)propan-2- 373 amine*2HCl

[0537]

[0538] Attorney Docket No. 07039-2355WO1 / 2024-258

[0539] 4-((3-(4-methoxypiperi din-1 - [M+H]+C009

[0540] yl)pyrrolidin- 1 -y l)methy l)py ri dine*2HCI 276 (2S')-A-(4-metho\\ benzyl)-l-((l / ?.5S')-3- [M+H]+C038 (m-tolyloxy)-8-azabicyclo[3.2.1]octan-8- 395 yl)propan-2-amine*2HCl

[0541] (S')- 1 -(4-benzy Ipiperazin- 1 -yl ) -N-( ( 2- [M+H]+C066 methylpyridin-4-yl)methyl)propan-2- 339 amine»4HCl

[0542] 3-((l -(1 -(pyridin-4-ylmethyl)pyrrolidin- [M+H]+C067 3-yl)piperidin-4-yl)oxy)-5- 407 (trifluoromethyl)pyridine»3HCl

[0543] (2S)-7V-(py ridin-3 -ylmethy 1)- 1 -(( 17?, 5S)- [M+H]+C068 3-( / w-tolyloxy)-8-azabicyclo[3.2.1]octan-8- 366 yl)propan-2-amine»3HCl

[0544] (2S')-A-((2-methylpyndin-4-yl)methyl)- l-((17?,5S)-3-(m-tolyloxy)-8- [M+H]+C117

[0545] azabicyclo[3.2.1]octan-8-yl)propan-2- 380 amine»2HCl

[0546] (S)-l-(4-(3-methylbenzyl)piperazin-l- [M+H]+C118 yl)- / V-(pyridin-4-ylmethyl)propan-2- 339 amine*4HCl

[0547] (S)-l-(4-(3-methylbenzyl)piperazin-l- [M+H]+C119 yl)-A-((2-methylpyridin-4-yl)methyl)propan-2- 353 amine»4HCl

[0548] (S)-l-(4-(3-methylbenzyl)piperazin-l- [M+H]+C120 yl)-JV-(pyridin-3-ylmethyl)propan-2- 339 amine»4HCl

[0549] (S’)-A-(pyridin-4-ylmethyl)-l-(4-(3- [M+H]+C121 (trifluoromethyl)phenoxy)piperidin-l- 394 yl)propan-2-amine*3HCl

[0550] (S)-l-(4-(3,5-difluorophenoxy)pipendin- [M+H]+C122 l-yl)-2V-(pyridin-4-ylmethyl)propan-2- 362 amine*3HCl

[0551]

[0552] Attorney Docket No. 07039-2355WO1 / 2024-258

[0553] (< S)-A-(pyridin-4-ylmethyl)-l-(4-(3- [M+H]+C123 (trifluoromethoxy )phenoxy)piperidin- 1 - 410 yl)propan-2-amine»3HCl

[0554] (S)-l-(4-phenoxypiperidin-l-yl)-jV- [M+H]+C124

[0555] (pyridin-4-ylmethyl)propan-2-amine*3HCl 326 (S)-JV-(quinolin-4-y Imethyl)- 1 -(4-(m- [M+H]+C126

[0556] tolyloxy)piperidin-l-yl)propan-2-amine*3HCl 390 (S)-l-(4-(3-methylbenzyl)piperazin-l- [M+H]+C229 yl)-2V-((tetrahydro-27 / -pyran-4- 346 yl)methyl)propan-2-amine»3HCl

[0557] (5yA-(pyridin-4-ylmethyl)-l-(4-(3- [M+H]+C230 (trifluoromethyl)benzy l)piperazin-l-yl)propan- 393 2-amine,4HCl

[0558] GS')- / V-((2-methy 1 py ndin-4-y Ijmethy 1)- 1 - [M+H]+C231 (4-(3-(tifluoromethyl)benzyl)piperazin-l- 407 yl)propan-2-amine»4HCl

[0559] (< S)-A-(pyridin-3-ylmethyl)-l-(4-(3- [M+H]+C232 (trifluoromethyl)benzyl)piperazin-l-yl)propan- 393 2-amine,4HCl

[0560] (S)-6-(((l-(4-( / w-tolyloxy)piperidin-l- [M+H]+C233 yl)propan-2-yl)amino)methyl)pyrimidine- 373 2.4(177.377)-dione«2HCl

[0561] (S)-4-(((l-(4-(m-tolyloxy)piperidin-l- [M+H]+C271 yl)propan-2-yl)amino)methyl)pyridin-2(177)- 356 one*2HCl

[0562] (S)-5-(((l-(4-(m-tolyloxy)piperi din-1 - [M+H]+C272 yl)propan-2-yl)amino)methyl)pyridin-2(l / / )- 356 one*2HCI

[0563] (S)-4-((( 1 -(4-(m-tolyloxy)piperi din-1 - [M+H]+C273 yl)propan-2-yl)amino)methyl)pyridine 1- 356 oxide»3HCl

[0564] (. S)-A-((tetrahydro-277-pyran-4- [M+H]+C274

[0565] yl)methyl)-l -(4-(3 - 400

[0566]

[0567] Attorney Docket No. 07039-2355WO1 / 2024-258

[0568] (trifl uoromethyl)benzyl)piperazin-l-yl)propan- 2-amine,3HCl

[0569] (21S)-jV-((tetrahydrofuran-3-yl)methyl)- [M+H]+C275 1 -(4-(3 -(trifl uoromethyl) benzyl) pi perazin- 1 - 386 yl)propan-2-amine*3HCl

[0570] 4-((((2S)-l-((17?.5S)-3-( / n-tolyloxy)-8- [M+H]+C298 azabicyclo[3.2.1 ] octan-8-yl)propan-2- 382 yl)amino)methyl)pyridin-2(177)-one»2HCl

[0571] (2< S)-jV-((tetrahydrofuran-3-yl)methyl)- l-((17?,5< S)-3-(m-tolyloxy)-8- [M+H]+C299

[0572] azabicy clo[3.2.1] octan-8-y l)propan-2- 359 amine»2HCl

[0573] 5-((((25)-l-((17?,55)-3-(7n-tolyloxy)-8- [M+H]+C300 azabicy clo[3.2.1] octan-8-yl)propan-2- 382 yl)amino)methyl)pyridin-2(17 / )-one»2HCl

[0574] (S)-l -(4-(ter / -butoxy)piperidin-l -y 1 )-A- [M+H]+C301

[0575] (pyridin-4-ylmethyl)propan-2-amine 306 4-((2< S)- 1 -(( 1 / ?.55')-3-( / «-toly 1 oxy )-8- [M+H]+C439 azabicy clo[3.2.1] octan-8-yl)propan-2- 345 yl)morpholine

[0576] (2. S')- / V-(quinol in-4-y Imethy 1 )- 1 - (( lA.5S)-3 -(m -tolyloxy )-8- [M+H]+C440

[0577] azabicy clo[3.2.1] octan-8-yl)propan-2- 416 amine»2HCl

[0578] A-((25)-l-((17?,5S)-3-(m-tolyloxy)-8- [M+H]+C476 azabicyclo[3.2.1]octan-8-yl)propan-2- 359 yl)tetrahydro-2 / 7-pyran-4-amine*2HCl

[0579] (5)-l-(4-benzylpiperidin-l-yl)-jV-((2- [M+H]+C478 methylpyridin-4-yl)methyl)propan-2- 338 amine*3HCl

[0580] (S)-l -(4-benzylpiperi din-1 -yl)-JV- [M+H]+C479

[0581] (py ri di n-3 -yl methyl )propan-2-ami n e* 3 HC1 324

[0582]

[0583] Attorney Docket No. 07039-2355WO1 / 2024-258

[0584] (< S)-l-(4-(3-chlorophenoxy)piperidin-l- [M+H]+C481 yl)- / V-((tetrahydro-27 / -pyran-4- 367 yl)methyl)propan-2-amine»2HCl

[0585] (S)-l-(4-(4-chlorophenoxy)piperidin-l- [M+H]+C482 yl)-2V-((tetrahydro-27 / -pyran-4- 367 yl)methyl)propan-2-amine»2HCl

[0586] (5)- 1 -(4-(3-chl orophenoxy )piperidin-l - [M+H]+C483 yl)- / V-(pyridin-4-ylmethyl)propan-2- 360 amine*2HCl

[0587] (5)- 1 -(4-benzylpiperidin-l -yl)-JV- [M+H]+C489 ((tetrahydro-2 / / -pyran-4-yl)methyl)propan-2- 331 amine»2HCl

[0588] (5)-l -(4-benzy Ipiperi din-1 -yl)-7V- [M+H]+C490

[0589] (quinolin-4-ylmethyl)propan-2-amine»3HCl 374 (S)-l-(4-(3-isopropylphenoxy)piperidin- [M+H]+C529 1 -yl)-jV-((tetrahydro-277-pyran-4- 375 yl)methyl)propan-2-amine*2HCl

[0590] (S)-l-(4-(3-isopropylphenoxy)piperidin- [M+H]+C530 l-yl)-jV-(pyridin-4-ylmethyl)propan-2- 368 amine»2HCl

[0591] (, S')-A'-(py ridazi n-4-y Imethy 1)- 1 -(4-(m- [M+H]+C531

[0592] tolyloxy)piperidin-l-yl)propan-2-amine*2HCl 341

[0593] (S)-l -(4-phenylpiperi din-1 -yl)-jV- [M+H]+C532

[0594] (pyridi n-4-yl methyl )propan-2-amine«3HCI 310 (5')- / V-((2-methy 1 py ri di n-4-y 1 Jmethy 1 )- 1 - [M+H]+C533

[0595] (4-phenylpiperidin-l-yl)propan-2-amine»3HCl 324

[0596] (S)-l -(4-phenylpiperi din-1 -yl)-jV- [M+H]+C534

[0597] (pyridi n-3-yl methyl )propan-2-amine«3HCI 310

[0598] (S)- 1 -(4-((5-fluoropy ridin-3 - [M+H]+C557 yl)oxy)piperidin-l-yl)-A-((tetrahydro-277- 352 pyran-4-yl)methyl)propan-2-amine*2HCl

[0599] 4-phenoxy- 1 -(3 -(tetrahy dro-277-py ran-4- [M+H]+C559

[0600] yl)propyl)piperidine«2HCl 304

[0601]

[0602] Attorney Docket No. 07039-2355WO1 / 2024-258

[0603] (S)-l-(4-Phenylpiperidin-l-yl)-JV- [M+H]+C560

[0604] (quinolin-4-ylmethyl)propan-2-amine»3HCl 360 (A)-l -(4-phenylpiperidin-l -yl)-jV- [M+H]+C561 ((tetrahydro-27 / -pyran-4-yl)methyl)propan-2- 317 amine*2HCl

[0605] (2S)-1 -(4-phenylpiperi din-1 -yl)-jV- [M+H]+C562 ((tetrahydrofuran-3-yl)methyl)propan-2- 303 amine»2HCl

[0606] (17?,5S)-8-(2-(tetrahydro-277-pyran-4- [M+H]+C563 yl)ethyl)-3-(m-tolyloxy)-8- 330 azabicy clo [3.2.1 ] octane»HCl

[0607] 4-(3-((17?,5S)-3-( / w-tolyloxy)-8- [M+H]+C564 azabicyclo[3.2.1]octan-8- 345 yl)propyl)morpholine»2HCl

[0608] (17?,5> S)-8-(3-(tetrahydro-227-pyran-4- [M+H]+C597 yl)propyl)-3-( / w-tolyloxy)-8- 344 azabicy clo [3.2.1 ] octane*HCl

[0609] (S)-4-( 1 -(4-(3 -methylbenzy l)piperidin- 1 - [M+H]+C599

[0610] y 1) propan -2-yl )morphol ine* 2HC1 317 l-(2-(tetrahydro-277-pyran-4-yl)ethyl)-4- [M+H]+C600

[0611] (3-(trifluoromethyl)phenoxy)piperidine«2HCl 358 GS')- / V-(py rimi din-4-y Imethy 1)- 1 -(4-(m- [M+H]+C601

[0612] tolyloxy)piperidin-l-yl)propan-2-amine*2HCl 341

[0613] (S)-N-((tetrahydro-2H-pyran-4- [M+H]+C602 yl)methyl)-l-((< S)-3-( / w-tolyloxy)pyrrolidin-l- 333 yl)propan-2-amine»2HCl

[0614] (S)-A-(pyridin-4-ylmethyl)-l-((5)-3-(m- [M+H]+C603

[0615] tolyloxy)pyrrolidin-l-yl)propan-2-amine»2HCl 326 4-(3-methylbenzyl)-l-(2-(tetrahydro- [M+H]+C628

[0616] 27 / -pyran-4-yl)ethyl)piperidine»HCl 302 4-(3-(4-(3-methylbenzyl)piperi din-1 - [M+H]+C629

[0617] yl)propyl)morpholine»2HCl 317

[0618]

[0619] Attorney Docket No. 07039-2355WO1 / 2024-258

[0620] l-(3-(tetrahydro-2H-pyran-4-yl)propyl)- [M+H]+C644

[0621] 4-(m-tolyl)piperidine*2HCl 302 (1S’)-4-(l-(4-(m-tolyl)piperidin-l- [M+H]+C645

[0622] yl)propan-2-yl)morpholine’2HCl 303 4-(3-(4-(m-toly l)pi peridi n-1- [M+H]+C646

[0623] yl)propyl)morpholine»2HCl 303 l-(2-(tetrahydro-277-pyran-4-yl)ethyl)-4- [M+H]+C672

[0624] ( / n-tolyl)piperidine’HCl 288

[0625] 4-(3-(4-(3- [M+H]+C673 (trifluoromethyl)phenoxy)piperidin- 1 - 373 yl)propyl)morpholine»2HCl

[0626] (N)-JV-(quinolin-4-ylmethyl)-l-(4-(7?7- [M+H]+C4703

[0627] tolyl)piperidin- 1 -y l)propan-2-amine*2HCl 374 (S)-7V-(pyridin-4-ylmethyl)-l-(4-(m- [M+H]+C4704

[0628] tolyl)piperidin-l-yl)propan-2-amine»3HCl 324 GS')- / V-((2-methy Ipy ridin-4-yl)methy 1)- 1 - [M+H]+C733 (4-(m-toly l)pi peridi n-l-yl)propan-2- 338 amine»3HCl

[0629] (S)-A-(pyridin-3-ylmethyl)-l-(4-(»2- [M+H]+C734

[0630] tolyl)piperidin-l-yl)propan-2-amine»3HCl 324 (S)-2V-((tetrahy dro-27 / -py ran-4- [M+H]+C735 yl)methyl)-l-(4-(m-tolyl)piperidin-l-yl)propan- 331 2-amine,2HCl

[0631] (25)-N-((tetrahydrofuran-3-yl)methyl)- [M+H]+C736 l-(4-(m-tolyl)piperidin-l-yl)propan-2- 317 amine»2HCl

[0632] (5)-l-((17?,5S)-3-(3-methylbenzyd)-3,8- [M+H]+C771 diazabicyclo[3.2.1]octan-8-yl)-jV-(quinolin-4- 415 ylmethyl)propan-2-amine*3HCl

[0633]

[0634] Scheme 1: Preparation of C508-AQ-001Attorney Docket No. 07039-2355WO1 / 2024-258

[0635]

[0636] Method A: Preparation of ( / ?)-ter / -Butyl 3-( / n-Tolyloxy)pyrrolidine-l-carboxylate.

[0637] d N

[0638]

[0639] i"

[0640] Boc

[0641] To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2.50 g, 13.4 mmol) in tetrahydrofuran (60 mL) was added triphenylphosphine (4.20 g, 16.0 mmol) and the reaction cooled to 0°C in an ice / water bath. m-Cresol (1.44 g, 13.4 mmol) was then added followed by dropwise addition of diisopropylazodicarboxylate (2.62 mL, 13.4 mmol). The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, the reaction was diluted with ethyl acetate and the organics were washed with 1 N aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (120g RediSepRF Gold column, 0-25% ethyl acetate / heptanes) to provide (R)-tert-butyl 3-(m-tolyloxy)pyrrolidine-1-carboxylate (2.95 g, 80%) as a white solid: ESI MS m / z 222 [M-t-Bu+H]+, [C12H15NO3+ H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[0642] Method B: Preparation of (R)-3-(m-Tolyloxy)pyrrolidine.

[0643]

[0644] To a solution of (R)-tert-butyl 3-(m-tolyloxy)pyrrolidine-1-carboxylate (2.95 g, 10.6 mmol) in methylene chloride (25 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (8.14 mL, 106 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, saturated sodium bicarbonate was added (75 mL) slowly to pH~10 and the organics extracted with methylene chloride (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography ((80g RediSepRF HP Gold column, 0-25% ethyl acetate / heptanes) to provide (R)-3-(m-tolyloxy)pyrrolidine (1.91 g, quantitative): ESI MS m / z 178 [C11H15NO + H]+

[0645] Method C: Preparation of tert- Butyl (2-((?)-3-(»t-Tolyloxy)pyrrolidin-l-yl)propyl)carbamate.

[0646]

[0647] To a solution of (R)-3-(m-tolyloxy)pyrrolidine (0.23 g, 1.3 mmol) in anhydrous acetonitrile (6 mL) was added the tert-butyl (2-oxopropyl)carbamate (0.27 g, 1.59 mmol) followed by the sodium triacetoxyborohydride (0.33 g, 1.6 mmol) and the reaction stirred at room temperature overnight. In the morning, the reaction was quenched with saturated sodium bicarbonate solution (25 mL) and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, 0-25% ethyl acetate / heptanes), methylene chloride to 80% ethyl acetate / methylene chloride) to provide tert-butyl (2-Attorney Docket No. 07039-2355WO1 / 2024-258

[0648] ((A)-3-( / w-tolyloxy)pyrrolidin-l-yl)propyl)carbamate (0.33 g, 74%): ESI MS m / z 335 [C19H30N2O3 + H]+

[0649] Method D: Preparation of 2-((?)-3-(» / -Tolyloxy)pyrrolidin-l-yl)propan-l-amine.

[0650]

[0651] To a solution of tert-butyl (2-((A)-3-(m-tolyloxy)pyrrolidin-l-yl)propyl) carbamate (0.32 g, 0.95 mmol) in methylene chloride (3 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (0.73 mL, 9.58 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, 2 g of SCX-2 resin was added and stirred for 10 minutes. The resin was then filtered and washed with methanol (5 mL x 2). The product was eluted off the resin using 2 N ammonium hydroxide in acetonitrile (2 x 5 mL) and the filtrate concentrated in vacuo to provide 2-((A)-3-(m-tolyloxy)pyrrolidin-l -yl)propan-l -amine (0.17 g, 69%): ESI MS m / z 235 [C14H22N2O + H]+

[0652] Method E: Preparation of 2-((7?)-3-( / n-Tolyloxy)pyrrolidin-l-yl)propan-l-amine«2HCl (C508-AQ-001).

[0653]

[0654] To a solution of 2-(( / ?)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-l -amine (0.16 g, 0.68 mmol) in methylene chloride (10 mL) was added isonicotinaldehyde (0.07 g, 0.68 mmol) and magnesium sulfate (0.82 g, 6.8 mmol). The reaction was then stirred at room temperature overnight. In the morning, the reaction was filtered through diatomaceous earth and washed through with methylene chloride (x 3). The filtrateAttorney Docket No. 07039-2355WO1 / 2024-258

[0655] was concentrated in vacuo and redissolved in methanol (10 mL). Sodium borohydride (52 mg, 1.36 mmol) was then added and the reaction stirred at room temperature for 3 hours. The solvent was then reduced to about 2 mL in vacuo and 1: 1 saturated sodium bicarbonate: brine added (10 mL) and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (12g RediSepRF Gold column, methylene chloride to 15% methanol / methylene chloride) provided 2-(( / )-3-( / «-tolyloxy)pyrrolidin-l-yl)propan-l-amine which was diluted with acetonitrile and concentrated twice, then diluted again with acetonitrile, 1 N aqueous hydrochloric acid was added and the mixture lyophilized overnight to give 2-((R)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-l-amine»2HCl (C508-AQ-001) as a white solid (0.02 g, 10%): ESI MS m / z 326 [C20H27N3O + H]+

[0656]

[0657] Attorney Docket No. 07039-2355WO1 / 2024-258

[0658]

[0659] NHBoc

[0660] To a solution of tert-butyl (3-hydroxyphenyl)carbamate (1.00 g, 4.77 mmol) in 1,4-di oxane (20 mL), degassing under nitrogen, was added l-iodo-3 -methylbenzene (1.25 g, 5.73 mmol), dimethylglycine»HCl (50 mg, 0.38 mmol) and cesium carbonate (3.11 g, 9.55 mmol). Copper (I) iodide (18 mg, 0.09 mmol) was then added and the reaction placed in a pre-heated oil bath at 90 °C with stirring overnight. In the morning, the reaction was allowed to cool to room temperature and 10% citric acid solution (10 mL) added to pH~6. The organics were then extracted with ethyl acetate (x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (40g RediSepRF Gold column, 0-25% ethyl acetate / heptanes) to provide tert- Butyl (3-im-tolyloxy (phenyl (carbamate (0.51 g, 35%): ESI MS m / z 300 [C18H21NO3 + H]+

[0661] Method G: Preparation of / V-Methyl-3-( / n-tolyloxy)aniline.

[0662]

[0663] To a solution of tert-butyl (3-(m-tolyloxy)phenyl)carbamate (0.50 g, 1.7 mmol) in tetrahydrofuran (12 mL) was added lithium aluminum hydride (1 M in diethyl ether, 5.00 mL, 5.01 mmol) slowly over 5 minutes. After this time, the reaction was placed in a pre-heated oil bath and stirred at 65 °C for 5 hours. After this time, the reaction was allowed to cool to room temperature and diluted with ethyl acetate (12 mL). Water was then added (5 mL), with stirring, followed by 2 N aqueous sodium hydroxide solution (10 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to provide crude / V-methyl-3-(m-tolyloxy)aniline (0.40 g, >100%): ESI MS m / z 214 [C14H15NO + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[0664] Method H: Preparation of A'-methyl-3-(pyridin-4-yl)- / V-(3-( / H-tolyloxy)phenyl)propanamide»HCl (C696-AQ-001)

[0665]

[0666] To a solution of N-methy 1-3 -(m-tolyloxy)ani line (0.10 g, 0.47 mmol) in dimethylformamide (3 mL) was added 3-(pyridin-4-yl)propanoic acid (0.08 g, 0.56 mmol) followed by diisopropylethylamine (0.16 mL, 0.94 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 0.45 mL, 0.07 mmol). The reaction was stirred at room temperature overnight. In the morning, the reaction was quenched with saturated sodium bicarbonate solution (5 mL) and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, methylene chloride to 90% ethyl acetate / methylene chloride) to provide A-methyl-3-(pyridin-4-yl)-A-(3-(m-tolyloxy)phenyl)propanamide which was diluted with acetonitrile and concentrated twice, then diluted again with acetonitrile, 1 N aqueous hydrochloric acid was added and the mixture lyophilized overnight to give A-methyl-3-(pyridin-4-yl)-A-(3-(m-tolyloxy)phenyl)propanamide»HCl (C696-AQ-001) as a white solid (0.10 g, 55%): ESI MS m / z 347 [C22H22N2O2 + H]+

[0667] Scheme 3: Preparation of C697-AQ-001Attorney Docket No. 07039-2355WO1 / 2024-258

[0668]

[0669] o

[0670] N

[0671]

[0672] H

[0673] (?)-3-( / n-Tolyloxy)piperidine was prepared via Method A and Method B using starting materials (S)-piperidin-3-ol and m-cresol: ESI MS m / z 192 [C12H17NO

[0674] Method I: Preparation of tert-Butyl ((5)-l-Oxo-l-((7?)-3-(wi-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate.

[0675]

[0676] To a solution of (7?)-3-( / w-tolyloxy)piperidine (150 mg, 0.78 mmol) in dimethylformamide (4 mL) was added (5')-2-(( / e / 7-butoxycarbonyl)amino)propanoic acid (178 mg, 0.94 mmol) and diisopropylethylamine (273 pL, 1.57 mmol).

[0677] Propylphosphonic anhydride (50% in ethyl acetate, 178 pL, 1.18 mmol) was then added and the reaction stirred at room temperature overnight. In the morning, theAttorney Docket No. 07039-2355WO1 / 2024-258

[0678] reaction was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (x 3). The combined organics were washed with water (10 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, methylene chloride to 70% ethyl acetate / methylene chloride) to provide tert-butyl ((S)-l-oxo-l-((A)-3-( / w-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate (180 mg, 63%)

[0679] Method D: Preparation of (A)-2-Amino-l-(( / ?)-3-(m-tolyloxy)piperidin-l-yl)propan- 1-one.

[0680]

[0681] To a solution of tert-butyl ((, S)-l-oxo-l-(( / ?)-3-(m-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate (180 mg, 0.50 mmol) in methylene chloride (3 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (380 pL, 4.97 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, 1 g of SCX-2 resin was added and stirred for 10 minutes. The resin was then filtered and washed with methanol (5 mL x 2). The product was eluted off the resin using 2 N ammonium hydroxide in acetonitrile (2 x 10 mL) and the filtrate concentrated in vacuo to provide (b’)-2-amino-l-(( )-3-( / w-tolyloxy)piperidin-l-yl)propan-l-one (85 mg, 65%): ESI MS m. z 263 [C15H22N2O2 + H]+

[0682] Method J: Preparation of (A)-2-((Pyridin-4-ylmethyl)ainino)-l-(( / ?)-3-( / n-tolyloxy)piperidin- l-yl)propan- 1-one.

[0683]

[0684] To a solution of (5)-2-amino-l-(( )-3-(m-tolyloxy)piperidin-l-yl)propan-l-one (80 mg, 0.30 mmol) in methylene chloride (4 mL) was added the isonicotinaldehyde (39 mg, 0.36 mmol) followed by magnesium sulfate (367 mg, 3.05Attorney Docket No. 07039-2355WO1 / 2024-258

[0685] mmol) and the reaction stirred at room temperature overnight. In the morning, the reaction was filtered through diatomaceous earth, and washed through with methylene chloride (x 3). The filtrate was concentrated in vacuo and redissolved in methanol (5 mL). Sodium borohydride (23 mg, 0.61 mmol) was added and the reaction stirred at room temperature for 3 hours. After this time, the reaction was concentrated in vacuo and saturated sodium bicarbonate solution (3 mL) added. The organics were extracted with ethyl acetate (x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, methylene chloride to 50% CMA (80% methylene chloride, 18% methanol, 2% ammonium hydroxide):methylene chloride to provide (< S)-2-((pyridin-4-ylmethyl)amino)-l-((A)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one (66 mg, 62%): ESI MS m / z 354 [C21H27N3O2 + H]+

[0686] Method K: Preparation of (5')- / V-(Pyridin-4-ylmethyl)-l-(( / ?)-3-( / ?i-tolyloxy)piperidin-l-yl)propan-2-amine»2HCl (C697-AQ-001)

[0687]

[0688] To a solution of (S)-2-((pyridin-4-ylmethyl)amino)-l-((7?)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one (62 mg, 0.17 mmol) in tetrahydro furan (2 mL) was added borane dimethylsulfide complex (88 pL, 0.87 mmol) and the reaction placed in a pre-heated oil bath at 65 °C for 4 hours. The reaction was then cooled to 0 °C in an ice / water bath, methanol (1 mL) added and the reaction stirred at room temperature for 1 hour. 1 N hydrogen chloride in diethyl ether (1 mL) was added and the reaction re-heated to 65 °C for 1 hour. After this time, the reaction was allowed to cool, methanol (10 mL) was added, and the reaction mixture was concentrated in vacuo. Methanol (10 mL) was again added and the reaction concentrated in vacuo and placed on a high-vac line overnight. In the morning, 1 N aqueous sodium hydroxide was added and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, methylene chloride to 20% methanol / methylene chloride) to provide (S)-A-(pyridin-4-ylmethyl)-l-(( )-3-(m-tolyloxy)piperidin-l-yl)propan-2-amine which was diluted withAttorney Docket No. 07039-2355WO1 / 2024-258

[0689] acetonitrile and concentrated twice, then diluted again with acetonitrile, 1 N aqueous hydrochloric acid was added and the mixture lyophilized overnight to give (S)-N-(pyridin-4-ylmethyl)-l-((7?)-3-(m-tolyloxy)piperidin-l-yl)propan-2-amine»2HCl (C697-AQ-001) as a white solid (42 mg, 58%): ESI MS m / z 340 [C21H29N3O + H]+

[0690] Scheme 4: Preparation of C761-AQ-001

[0691]

[0692] Method F: Preparation of / ert-Butyl (3-(m-Tolyloxy)phenyl)carbamate.

[0693]

[0694] To a solution of tert-butyl (3-hydroxyphenyl)carbamate (1.00 g. 4.77 mmol) in 1,4-dioxane (20 mL), degassing under nitrogen, was added l-iodo-3 -methylbenzene (1.25 g, 5.73 mmol), dimethylglycine»HCl (50 mg, 0.38 mmol) and cesium carbonate (3.11 g, 9.55 mmol). Copper (I) iodide (18 mg, 0.09 mmol) was then added and the reaction placed in a pre-heated oil bath at 90 °C with stirring overnight. In the morning, the reaction was allowed to cool to room temperature and 10% citric acid solution (10 mL) added to pH~6. The organics were then extracted with ethyl acetate (x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (40g RediSepRF Gold column, 0-25% ethyl acetate / heptanes) to provide tert-butyl (3-(m-tolyloxy)phenyl)carbamate (0.51 g, 35%): ESI MS m / z 300 [C18H21NO3 + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[0695] Method G: Preparation of N-Methyl-3-( / n-tolyloxy)aniline.

[0696]

[0697] To a solution of tert-butyl (3-(m-tolyloxy)phenyl)carbamate (0.50 g, 1.67 mmol) in tetrahydrofuran (12 mL) was added lithium aluminum hydride (1 M in diethyl ether, 5.00 mL, 5.01 mmol) slowly over 5 minutes. After this time, the reaction was placed in a pre-heated oil bath and stirred at 65 °C for 5 hours. After this time, the reaction was allowed to cool to room temperature and diluted with ethyl acetate (12 mL). Water was then added (5 mL), with stirring, followed by 2 N aqueous sodium hydroxide solution (10 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to provide crude A-methyl-3-(m-tolyloxy)aniline (0.40 g, >100%): ESI MS m / z 214 [C14H15NO + H]+

[0698] Method H: Preparation of ( / ?)- / <? / ' / - Butyl (l-(Methyl(3-(»i-tolyloxy)phenyl)amino)-l-oxopropan-2-yl)carbamate

[0699]

[0700] O

[0701] To a solution of A-methy 1-3 -(m -tolyloxy )aniline (0.10 g, 0.47 mmol) in dimethylformamide (3 mL) was added (7?)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.11 g, 0.56 mmol) followed by diisopropylethylamine (0.16 mL, 0.94 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 0.45 mL, 0.07 mmol). The reaction was stirred at room temperature overnight. In the morning, the reaction was quenched with saturated sodium bicarbonate solution (5 mL) and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodiumAttorney Docket No. 07039-2355WO1 / 2024-258

[0702] sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, methylene chloride to 20% ethyl acetate / methylene chloride) to provide (R)-tert-buty (l-(methyl(3-( / «-tolyloxy)phenyl)amino)-l-oxopropan-2-yl)carbamate (0.06 g, 34%): ESI MS m / z 385 [C22H28N2O4 + H]+

[0703] Method D: Preparation of ( / ?)-2-Aniino- / V-methyl- / V-(3-( / n-tolyloxy)phenyl)propanamide.

[0704]

[0705] O

[0706] To a solution of (?)-terZ-butyl (l-(methyl(3-(m-tolyloxy)phenyl)amino)-l-oxopropan-2-yl)carbamate (0.06 g, 0.15 mmol) in methylene chloride (3 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (0.12 mL, 1.56 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, 1.0 g of SCX-2 resin was added and stirred for 10 minutes. The resin was then filtered and washed with methanol (5 mL x 2). The product was eluted off the resin using 2 N ammonium hydroxide in methanol (2 x 5 mL) and the filtrate concentrated in vacuo to provide (R)-2-amino-N-methyl-N-(3-(m-tolyloxy)phenyl)propanamide (0.04 g, quantitative): ESI MS m / z 285 [C17H20N2O2 + H]+

[0707] Method J: Preparation of (7?)-A-Methyl-2-((pyridin-4-ylinethyl)amino)-7V- (3-(m-tolyloxy)phenyl)propanamide.

[0708]

[0709] Attorney Docket No. 07039-2355WO1 / 2024-258

[0710] To a solution of (R)-2-amino-N-methyl-N-(3-(m-tolyloxy)phenyl)propanamide (0.04 g, 0.15 mmol) in methylene chloride (10 mL) was added isonicotinaldehyde (0.02 g, 0.15 mmol) and magnesium sulfate (0.19 g, 1.6 mmol). The reaction was then stirred at room temperature overnight. In the morning, the reaction w as filtered through diatomaceous earth and washed through with methylene chloride (x 3). The filtrate was concentrated in vacuo and redissolved in methanol (10 mL). Sodium borohydride (52 mg, 1.36 mmol) was then added and the reaction stirred at room temperature for 3 hours. The solvent was then reduced to about 2 mL in vacuo and 1: 1 saturated sodium bicarbonate: brine added (10 mL) and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (12g RediSepRF Gold column, methylene chloride to 10% methanol / methylene chloride) provided (R)-N-methyl-2-((pyridin-4-ylmethyl)amino)-N-(3-(m-tolyloxy)phenyl)propanamide (0.04 g, 64%): ESI MS m / z 376 [C23H25N3O2 + H]+

[0711] Method K: Preparation of ( / ?)- / Vl-Methyl-A‘-(pyridin-4-ylmethyl)-A'1-(3-(fli-tolyloxy)phenyl)propane-l,2-diamine»2HCl (C761-AQ-001)

[0712] . O

[0713] •2HCI

[0714] N

[0715] H

[0716]

[0717] To a solution of (R)-N-methyl-2-((pyridin-4-ylmethyl)amino)-N-(3-(m-tolyloxy)phenyl)propanamide (0.04 g, 0.10 mmol) in tetrahydrofuran (2 mL) was added borane dimethylsulfide complex (0.06 mL, 0.50 mmol) and the reaction placed in a pre-heated oil bath at 65 °C for 4 hours. The reaction was then cooled to 0 °C in an ice / water bath, methanol (1 mL) added and the reaction stirred at room temperature for 1 hour. 1 N hydrogen chloride in diethyl ether (1 mL) was added and the reaction re-heated to 65 °C for 1 hour. After this time, the reaction was allowed to cool and methanol (10 mL) added and the reaction concentrated in vacuo. Methanol (10 mL) was again added and the reaction concentrated in vacuo and placed on a high-vac line overnight. In the morning, 1 N aqueous sodium hydroxide was added and the organicsAttorney Docket No. 07039-2355WO1 / 2024-258

[0718] extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, methylene chloride to 7% methanol / methylene chloride) to provide (R)-N1-methyl-N2-(pyridin-4-ylmethyl)-N1-(3-(m-tolyloxy)phenyl)propane-1,2-diamine which was diluted with acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous hydrochloric acid was added and the mixture lyophilized overnight to give ( / )-A'-methvl-; V2-(pyridin-4-ylmethyl)-A1-(3-(»?-tolyloxy)phenyl)propane-L2-diamine’2HCl (C761-AQ-001) as a white solid (0.03 g, 85%): ESI MS m / z 362 [C23H27N3O + H]+

[0719] Scheme 5: Preparation of C764-AQ-001

[0720]

[0721] Method L: Preparation of 8-Bromo-4-( / n-tolyloxy)quinoline.

[0722]

[0723] To a solution of 8-bromo-4-chloroquinoline (0.50 g, 2.1 mmol) in dimethylformamide (7 mL) was added cesium carbonate (1.67 g, 5.15 mmol) and m-cresol (0.27 g, 2.5 mmol). The reaction was placed in a pre-heated oil bath at 90 °C and stirred for 3 hours. After this time, the reaction was allowed to cool to room temperature and stirred overnight. In the morning, the reaction was diluted with water (25 mL) and the organics were then extracted with ethyl acetate (x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentratedAttorney Docket No. 07039-2355WO1 / 2024-258

[0724] in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, hexanes to 80% methylene chloride / hexanes) to provide 8-bromo-4-(m-tolyloxy)quinoline (0.50 g, 88%): ESI MS m / z 315 [CieHnBrNO + H]+

[0725] Method M: Preparation of 4-( / n-Tolyloxy)quinoline-8-carbonitrile.

[0726]

[0727] To a solution of 8-bromo-4-( / w-tolyloxy)quinoline (0.50 g, 1.6 mmol) in dimethylformamide (8 mL) in a 20 mL micro wave vial, degassing with nitrogen, was added zinc cyanide (0.28 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.18 g, 0.15 mmol). The reaction was sealed and stirred with microwave heating for 30 minutes at 150 °C. After this time, the reaction mixture was allowed to cool and diluted with saturated sodium bicarbonate solution (10 mL). The organics w ere extracted with ethyl acetate (x 3), combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, hexanes to 50% ethyl acetate / hexanes) to provide 4-(m-tolyloxy)quinoline-8-carbonitrile (0.30 g, 63%): ESI MS m / z 261 [C17H12N2O + H]+

[0728] Method N: Preparation of Ze / t-Butyl ((4-( / n-Tolyloxy)quinolin-8-yl)methyl)carbamate.

[0729]

[0730] BocHN

[0731] To a solution of 4-(m-tolyloxy)quinoline-8-carbonitrile (0.29 g, 1.1 mmol) in methanol (9 mL), under nitrogen atmosphere at 0 °C (ice / water bath), was added di-tert-butyl dicarbonate (0.48 g, 2.2 mmol) followed by nickel (II) chloride hexahydrate (0.03 g, 0.11 mmol). Sodium borohydride (0.29 g, 7.8 mmol) was then addedAttorney Docket No. 07039-2355WO1 / 2024-258

[0732] portionwise over 30 minutes, the ice bath removed and the reaction stirred at room temperature for 2 hours. Diethylene triamine (0.11 g, 1.11 mmol) was then added and the reaction stirred for 30 minutes. The reaction was then concentrated in vacuo, taken up in ethyl acetate (30 mL) and washed with saturated sodium bicarbonate solution (25 mL x 2). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, hexanes to 50% ethyl acetate / hexanes) to provide terf-butyl ((4-(m-tolyloxy)quinolin-8-yl)methyl)carbamate (0.40 g, quantitative): ESI MS m / z 365 [C22H24N2O3 + H]+

[0733] Method B: Preparation of (4-(w / -Tolyloxy)quinolin-8-yl)methanamine.

[0734]

[0735] To a solution of tert-butyl ((4-(m-tolyloxy)quinolin-8-yl)methyl)carbamate (0.40 g, 1.09 mmol) in methylene chloride (5 mL), at 0 °C in an ice / water bath, w as added trifluoroacetic acid (0.84 mL, 10.9 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, saturated sodium bicarbonate was added (75 mL) slowly to pH~10 and the organics extracted with methylene chloride (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, methylene chloride to 50% CMA (80% chloroform, 18% methanol, 2% ammonium hydroxide):methylene chloride) to provide ((4-(m-tolyloxy)quinolin-8-yl)methanamine (0.10 g, 34%): ESI MS m / z 265 [C17H16N2O + H]+

[0736] Method E: Preparation of l-(Pyridin-4-yl)-7V-((4-( / n-tolyloxy)quinolin-8-yl)methyl)methanamine»2HCl (C764-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[0737]

[0738] To a solution of ((4-(m-tolyloxy)quinolin-8-yl)methanamine (0.03 g, 0.13

[0739] mmol) in methylene chloride (3 mL) was added isoni cotinaldehyde (0.02 g, 0.13

[0740] mmol) and magnesium sulfate (0.16 g, 1.4 mmol). The reaction was then stirred at

[0741] room temperature overnight. In the morning, the reaction was filtered through

[0742] diatomaceous earth and washed through with methylene chloride (x 3). The filtrate

[0743] was concentrated in vacuo and redissolved in methanol (10 mL). Sodium borohydride

[0744] (10 mg, 0.27 mmol) was then added and the reaction stirred at room temperature for 3

[0745] hours. The solvent was then reduced to about 2 mL in vacuo and 1: 1 saturated sodium

[0746] bicarbonate: brine added (10 mL) and the organics extracted with ethyl acetate (x 3).

[0747] The combined organics were dried over sodium sulfate, filtered and concentrated in

[0748] vacuo. Purification by column chromatography (12g RediSepRF Gold column,

[0749] methylene chloride to 10% methanol / methylene chloride) provided 1-(pyridin-4-yl)-N-((4-(m-tolyloxy)quinolin-8-yl)methyl)methanamine which was diluted with

[0750] acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous

[0751] hydrochloric acid was added and the mixture lyophilized overnight to give 1-(pyridin-4-yl)-N-((4-(m-tolyloxy)quinolin-8-yl)methyl)methanamine•2HCl (C764-AQ-001) as

[0752] a white solid (0.04 g, 81%): ESI MS m / z 356 [C23H21N3O + H]+

[0753]

[0754] Attorney Docket No. 07039-2355WO1 / 2024-258

[0755] N

[0756]

[0757] H

[0758] (S)-3-(m-Tolyloxy)piperidine was prepared via Method A and Method B using starting materials (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate and m-cresol: ESI MS m / z 191 [C12H17NO + H]+

[0759] Method I: Preparation of tert-Butyl ((A)-1-OXO-1-((A)-3-(MI-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate.

[0760]

[0761] To a solution of (S)-3-(m-Tolyloxy)piperidine (270 mg, 1.41 mmol) in dimethylformamide (4 mL) was added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (321 mg, 1.69 mmol) and diisopropylethylamine (0.49 mL, 2.8 mmol).

[0762] Propylphosphonic anhydride (50% in ethyl acetate, 1.34 mL, 2.12 mmol) was then added and the reaction stirred at room temperature overnight. In the morning, the reaction was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (x 3). The combined organics were washed with water (10 mL) and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, methylene chloride to 70% ethyl acetate / methylene chloride) to provide tert-butyl ((S)-l-oxo-l-((S)-3-( / w-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate (509 mg, 99%): ESI MS m / z 363 [C20H30N2O4 + H]+

[0763] Method D: Preparation of GS')-2-Aniino-l-((5')-3-( / n-tolyloxy)piperidin-l-yl)propan- 1-one.Attorney Docket No. 07039-2355WO1 / 2024-258

[0764]

[0765] To a solution of tert- butyl ((S)-l-oxo-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate (500 mg, 1.38 mmol) in methylene chloride (5 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (1.05 mL, 13.8 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, 4 g of SCX-2 resin was added and stirred for 10 minutes. The resin was then filtered and washed with methanol (10 mL x 2). The product was eluted off the resin using 2 N ammonium hydroxide in acetonitrile (2 x 10 mL) and the filtrate concentrated in vacuo to provide (S)-2-amino-1-((S)-3-(m-tolyloxy)piperidin-1-yl)propan-1-one (280 mg, 78%): ESI MS m / z 263 [C15H22N2O2+ H]+

[0766] Method E: Preparation of GV)-2-((Pyridin-4-ylmethyl)amino)-l-(GS')-3-( / n-tolyloxy)piperidin-l-yl)propan-l-one»HCl (C762-AQ-001)

[0767]

[0768] To a solution of (S)-2-amino-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one (140 mg, 0.53 mmol) in methylene chloride (5 mL) was added the isonicotinaldehyde (50 mg, 0.53 mmol) followed by magnesium sulfate (642 mg, 5.34 mmol) and the reaction stirred at room temperature overnight. In the morning, the reaction was filtered through diatomaceous earth, and washed through with methylene chloride (x 3). The filtrate was concentrated in vacuo and redissolved in methanol (5 mL).

[0769] Sodium borohydride (41 mg, 1.06 mmol) was added and the reaction stirred at room temperature for 3 hours. After this time, the reaction was concentrated in vacuo and saturated sodium bicarbonate solution (20 mL) added. The organics were extractedAttorney Docket No. 07039-2355WO1 / 2024-258

[0770] with ethyl acetate (x 3), dried over sodium sulfate, filtered and concentrated in vacuo.

[0771] The crude residue was purified by column chromatography (24g RediSepRF Gold

[0772] column, methylene chloride to 7% methanol / methylene chloride to provide (S)-2-((pyridin-4-ylmethyl)amino)-l-((5)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one which

[0773] was diluted with acetonitrile and concentrated twice, then diluted again with

[0774] acetonitrile. 1 N Aqueous hydrochloric acid was added and the mixture lyophilized

[0775] overnight to give (<S’)-2-((pyridin-4-ylmethyl)amino)-l-(( )-3-(m-tolyloxy)piperidin-l-yl)propan-l-one»HCl (C762-AQ-001 (152 mg, 73%): ESI MS m / z 354 [C21H27N3O2 +

[0776] H]+

[0777]

[0778] Method O: Preparation of ( / ?)- r / -Butyl 3-((Methylsulfonyl)oxy)pyrrolidine-l-carboxylate.

[0779] OMs

[0780]

[0781] N

[0782] i

[0783] Boc

[0784] A solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.00 g, 5.34

[0785] mmol) in methylene chloride (20 mL) was cooled to 0°C in an ice / water bath.

[0786] Triethylamine (1.45 mL, 10.6 mmol) was added followed by dropwise addition of

[0787] methane sulfonyl chloride (0.45 mL, 5.9 mmol). The reaction was then left to stir

[0788] overnight (do not remove ice / water bath, let it melt). In the morning, the reaction was

[0789] diluted with methylene chloride and the organics washed with water (20 mL), 1 N

[0790] aqueous hydrogen chloride (20 mL), saturated sodium bicarbonate solution (20 mL)

[0791] and brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The

[0792] crude residue w as used in the next step without further purification (1.42 g, 100%).Attorney Docket No. 07039-2355WO1 / 2024-258

[0793] Preparation of 4-( / n-Tolyloxy)piperidine.

[0794] O

[0795] N

[0796]

[0797] H

[0798] 4-(m-Tolyloxy)piperidine was prepared via Method A and Method B using starting materials tert-butyl 4-hydroxypiperidine-1-carboxylate and m-cresol: ESI MS m / z 192 [C12H17NO + H]+

[0799] Method P: Preparation of (A')- / e / r-Butyl 3-(4-( / w-Tolyloxy)piperidin-l-yl)pyrrolidine-l-carboxylate.

[0800]

[0801] To a solution of 4-(m-tolyloxy)piperidine (0.20 g, 1.0 mmol) in dimethylformamide (4 mL) was added diisopropylethylamine (0.55 mL, 3.1 mmol) followed by the (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (0.33 g, 1.3 mmol) and the reaction placed in a pre-heated oil bath at 80 °C and stirred overnight. In the morning, the reaction was diluted with ethyl acetate (50 mL) and the organics washed with brine (2 x 25 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, methylene chloride to 80% ethyl acetate / methylene chloride) to provide (S)-tert-butyl 3-(4-(m-tolyloxy)piperidin-1-yl)pyrrolidine-1-carboxylate (0.04 g, 10%): ESI MS m / z 361 [C21H32N2O3+ H]+

[0802] Method D: Preparation of (5)-l-(Pyrrolidin-3-yl)-4-( / n-tolyloxy)piperidine.Attorney Docket No. 07039-2355WO1 / 2024-258

[0803]

[0804] To a solution of (S)-tert-butyl 3-(4-(m-tolyloxy)piperidin-1-yl)pyrrolidine-1-carboxylate (0.04 g, 0.10 mmol) in methylene chloride (3 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (0.12 mL, 1.5 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, 1 g of SCX-2 resin was added and stirred for 10 minutes. The resin was then filtered and washed with methanol (5 mL x 2). The product was eluted off the resin using 2 N ammonium hydroxide in methanol (2 x 5 mL) and the filtrate concentrated in vacuo to provide (S)-1-(pyrrolidin-3-yl)-4-(m-tolyloxy)piperidine (0.03 g, 115%): ESI MS m / z 260 [C16H24N2O + H]+

[0805] Method E: Preparation of (A)-4-((3-(4-( / M-Tolyloxy)piperidin-l-yl)py rrolidin- l-yl)methyl)pyridine»2HCl (C939-AQ-001).

[0806]

[0807] To a solution of (S)-l-(pyrrolidin-3-yl)-4-( / w-tolyloxy)piperidine (0.03 g, 0.11 mmol) in methylene chloride (10 mL) was added isonicotinaldehyde (0.01 g, 0.11 mmol) and magnesium sulfate (0.16 g, 1.2 mmol). The reaction was then stirred at room temperature overnight. In the morning, the reaction was filtered through diatomaceous earth and washed through with methylene chloride (x 3). The filtrate was concentrated in vacuo and redissolved in methanol (10 mL). Sodium borohydride (0.05 g, 1.36 mmol) was then added and the reaction stirred at room temperature for 3Attorney Docket No. 07039-2355WO1 / 2024-258

[0808] hours. The solvent was then reduced to about 2 mL in vacuo and 1: 1 saturated sodium

[0809] bicarbonate: brine added (10 mL) and the organics extracted with ethyl acetate (x 3).

[0810] The combined organics were dried over sodium sulfate, filtered and concentrated in

[0811] vacuo. Purification by column chromatography (12g RediSepRF Gold column,

[0812] methylene chloride to 10% methanol / methylene chloride) provided (< S -4-((3-(4-( / M-tolyloxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine which was diluted with

[0813] acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous

[0814] hydrochloric acid was added and the mixture lyophilized overnight to give (S)-4-((3-(4-( / w-tolyloxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine*2HCl (C939-AQ-001)

[0815] as a white solid (0.01 g, 13%); ESI MS m / z 352 [C22H29N3O + H]+

[0816]

[0817] Br To a solution of 3,5-dibromopyridine (4.00 g, 16.8 mmol) in

[0818] dimethylformamide (30 mL), under nitrogen atmosphere at 0 °C (ice / water bath), was

[0819] added sodium hydride (60% in mineral oil, 1.80 g, 44.9 mmol) and the reaction stirredAttorney Docket No. 07039-2355WO1 / 2024-258

[0820] at 0 °C for 3 hours. m-Cresol (4.71 g, 44.9 mmol) was then added and the reaction transferred to a pre-heated oil bath and stirred at 100 °C overnight. In the morning, the reaction was diluted with ethyl acetate (250 mL) and the organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (120g RediSepRF Gold column, hexanes to 30% methylene chloride / hexanes) to provide 3-bromo-5-(m-tolyloxy)pyridine (1.23 g, 28%): ESI MS m / z 264 [C12H10BrNO + H]+

[0821] Method R: Preparation of Diethyl 2-(5-(wt-Tolyloxy)pyridin-3-yl)malonate.

[0822]

[0823] To a solution of 3-bromo-5-(m-tolyloxy)pyridine (5.10 g, 19.3 mmol) in 1,4-dioxane (25 mL) was added diethyl malonate (5.89 mL, 38.6 mmol) and the reaction evacuated and purged with nitrogen three times. Sodium hydride (60% in mineral oil, 1.70 g, 42.4 mmol) was added and the reaction transferred to a pre-heated oil bath and stirred at 100 °C overnight. In the morning, the reaction was allowed to cool to room temperature, filtered through diatomaceous earth, and washed through with methylene chloride (3 x 20 mL). The filtrate was concentrated in vacuo and purified by column chromatography (120g RediSepRF Gold column, hexanes to 40% ethyl acetate / hexanes to provide diethyl 2-(5-( / w-tolyloxy)pyridin-3-yl)malonate (2.98 g, 45%): ESI MS m / z 344 [C20H19NO5+ H]+

[0824] Method S: Preparation of 2-(5-( / »-Tolyloxy)pyridin-3-yl)acetic Acid.

[0825]

[0826] Attorney Docket No. 07039-2355WO1 / 2024-258

[0827] To a solution of diethyl 2-(5-(m-toly loxy)pyridin-3-yl)malonate (2.97 g, 8.71 mmol) in tetrahydrofuran (30 mL) was added 2 N aqueous sodium hydroxide (30.5 mL, 61.0 mmol) and the reaction stirred at room temperature for 5 hours. After this time, the reaction was acidified to pH 4 with dropwise addition of concentrated hydrochloric acid and extracted with diethyl ether (2 x 20 mL). The aqueous layer was then adjusted with 1 N sodium hydroxide solution to pH 8 and the organics extracted with ethyl acetate (x 3) and methylene chloride (x 3). The combined ethyl acetate and methylene chloride layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide 2-(5-(m-tolyloxy)pyridin-3-yl)acetic acid (2.02 g, 96%)

[0828] Method T: Preparation of 7V-(Pyridin-4-ylmethyl)-2-(5-( / «-tolyl oxy)pyridin-3-yl)acetamide»2HCl (C042-AQ-001).

[0829]

[0830] To a solution of 2-(5-(m-tolyloxy)pyridin-3-yl)acetic acid (0.20 g, 0.82 mmol) in dimethylformamide (5 mL) was added pyridin-4-ylmethanamine (0.11 g, 0.98 mmol) and diisopropylethylamine (0.29 mL, 1.6 mmol). Propylphosph onic anhydride (50% in ethyl acetate, 0.78 mL, 1.2 mmol) was then added and the reaction stirred at room temperature overnight. In the morning, the reaction was quenched w ith saturated sodium bicarbonate solution (10 mL) and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, methylene chloride to 15% methanol / methylene chloride) to provide A-(pyridin-4-ylmethyl)-2-(5-( / w-tolyloxy)pyridin-3-yl)acetamide which was diluted with acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous hydrochloric acid was added and the mixture lyophilized overnight to give A-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)acetamide«2HCl (C042-AQ-001) as a white solid (0.16 g, 47%): ESI MS m / z 334 [C20H19NO5+ H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[0831]

[0832] Preparation of 3-Bromo-5-(wi-tolyloxy)pyridine.

[0833]

[0834] 3-Bromo-5-(m-tolyloxy)pyridine was prepared via Method Q.

[0835] Method U: Preparation of Ze / t-Butyl 2-(5-(»i-Tolyloxy)pyridin-3-yl)acetate.

[0836]

[0837] To a solution of 3-bromo-5-(m-tolyloxy)pyridine (1.00 g, 3.78 mmol) in

[0838] tetrahydrofuran (12 mL). under nitrogen atmosphere, was added

[0839] tris(dibenzylideneacetone) dipalladium(O) (0.17 g, 0.19 mmol) and

[0840] dicyclohexyl[2',4',6'-tris(propan-2-yl)[l, T-biphenyl]-2-yl]phosphane (0.09 g, 0.19

[0841] mmol), followed by (2-(te / 7-butoxy)-2-oxoethyl)zinc(II ) chloride (0.5 M in diethyl

[0842] ether. 15.1 mL. 7.57 mmol) and the reaction placed in a pre-heated oil bath and stirredAttorney Docket No. 07039-2355WO1 / 2024-258

[0843] at 70 °C for 3 hours. After this time, the reaction mixture was allowed to cool and concentrated in vacuo. The residue was treated with saturated ammonium chloride solution (20 mL) and the organics extracted with ethyl acetate (x3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, hexanes to 50% ethyl acetate / hexanes) to provide / ert-butyl 2-(5-( / w-tolyloxy)pyridin-3-yl)acetate (0.76 g, 67%): ESI MS m / z 300 [C18H21NO3+ H]+

[0844] Method V: Preparation of 2-(5-( / H-Tolyloxy)pyridin-3-yl)acetic Acid’TFA.

[0845]

[0846] To a solution of tert-butyl 2-(5-(m-tolyloxy)pyridin-3-yl)acetate (0.75 g, 2.5 mmol) in methylene chloride (6 mL) was added trifluoroacetic acid (2.75 mL, 75.2 mmol) and the reaction stirred at room temperature for 3 days. After this time, the reaction mixture was concentrated in vacuo and placed on a high vacuum line overnight to provide 2-(5-(m-tolyloxy)pyridin-3-yl)acetic acid»TFA (0.88 g, 98%): ESI MS m / z 244 [C14H13NO3 + H]+

[0847] Method W: Preparation of Methyl 2-(5-(zw-Tolyloxy)pyridin-3-yl)acetate.

[0848]

[0849] To a solution of 2-(5-(m-tolyloxy)pyridin-3-yl)acetic acid’TFA (0.87 g, 2.6 mmol) in methanol (12 mL), at 0 °C (ice / water bath) was added pyridine (0.61 mL, 7.6 mmol) followed by thionyl chloride (0.27 mL, 3.8 mmol). The ice / water bath was removed and the reaction stirred at room temperature for 18 hours. After this time, theAttorney Docket No. 07039-2355WO1 / 2024-258

[0850] reaction mixture was concentrated in vacuo and saturated sodium bicarbonate solution added (25 mL). The organics were extracted with ethyl acetate (x 3), dried over sodium sulfate, filtered and concentrated in vacuo to provide methyl 2-(5-(m-tolyloxy)pyridin-3-yl)acetate (0.59 g, 90%): ESI m / z 258 [C15H15NO3 + H]+

[0851] Method X: Preparation of Methyl 2-(5-( / n-Tolyloxy)pyridin-3-yl)propanoate).

[0852]

[0853] To a solution of methyl 2-(5-(m-tolyloxy)pyridin-3-yl)acetate (0.59 g, 2.3 mmol) in tetrahydrofuran (9 mL) at -78 °C (dry ice / acetone bath) was added sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 2.75 mL, 2.75 mmol) and the reaction stirred for 1 hour at -78 °C. After this time, iodomethane (0.17 mL, 2.8 mmol) was added, the dry ice / acetone bath removed, and the reaction stirred at room temperature overnight. In the morning, the reaction was quenched with water (15 mL) and brine (15 mL) and extracted with ethyl acetate (x 3), The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, hexanes to 30% ethyl acetate / hexanes) to provide methyl 2-(5-(m-tolyloxy)pyridin-3-yl)propanoate (0.19 g, 30 %): ESI MS m / z 271 [C16H17NO3 + H]+

[0854] Method Y: Preparation of 2-(5-( / n-Tolyloxy)pyridin-3-yl)propanoic Acid.

[0855]

[0856] O

[0857] To a solution of methyl 2-(5-( / w-tolyloxy)pyridin-3-yl)propanoate (0.14 g, 0.51 mmol) in methanol (3 mL) at 0 °C (ice / water bath) was added lithium hydroxideAttorney Docket No. 07039-2355WO1 / 2024-258

[0858] monohydrate (0.11 g, 2.6 mmol). The ice / water bath was removed and the reaction stirred at room temperature overnight. In the morning, the reaction mixture was concentrated in vacuo and water (5 mL) was added. 1 N Aqueous hydrogen chloride was then added slowly to pH~4 and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to provide 2-(5-( / n-tolyloxy)pyridin-3-yl)propanoic acid (0.14 g, quantitative): ESI MS m / z 258 [C15H15NO3+ H]+

[0859] Preparation of / V-(Pyridin-4-ylmethyl)-2-(5-( / n-tolyloxy)pyridin-3-yl)propanamide’HCl (C616-AQ-001).

[0860]

[0861] A-(Pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propanamide»HCl (C616-AQ-001) was prepared via Method T to give a white solid: ESI MS m / z 348 [C21H21N3O2 + H]+

[0862]

[0863]

[0864] Attorney Docket No. 07039-2355WO1 / 2024-258

[0865] Preparation of 4-( / n-Tolyloxy)piperidine.

[0866]

[0867] 4-( / 7?-Tolyloxy)piperidine was prepared via Method A and Method B using starting materials piperidin-4-ol and / w-cresol: ESI MS m / z 192 [C12H17NO + H]+

[0868] Method I: Preparation of (A)-t<? / - Butyl (l-Oxo-l-(4-( / w-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate.

[0869]

[0870] To a solution of 4-(m-tolyl oxy) piperidine (1.61 g, 8.42 mmol) in dimethylformamide (40 mL) was added GS')-2-(( / e / 7-butoxycarbonyl)amino)propanoic acid (1.91 g, 10.1 mmol) and diisopropylethylamine (2.94 mL, 16.8 mmol).

[0871] Propylphosphonic anhydride (50% in ethyl acetate, 8.06 mL, 12.6 mmol) was then added and the reaction stirred at room temperature overnight. In the morning, the reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (x 3). The combined organics were washed with water (10 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (80g RediSepRF Gold column, methylene chloride to 50% ethyl acetate / methylene chloride) to provide (S)-tert-butyl (1-oxo-l-(4-( / w-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate (2.75 g, 90%): ESI MS m / z 363 [C20H30N2O4 + H]+

[0872] Method D: Preparation of (5)-2-Amino-l-(4-(w / -tolyloxy)piperidin-l-yl)propan-l-one.Attorney Docket No. 07039-2355WO1 / 2024-258

[0873]

[0874] To a solution of (S)- / e / 7-butyl ( 1 -oxo- l-(4-( / n -tolyl oxy )piperidin-l-y l)propan-2-yl)carbamate (2.75 g, 7.59 mmol) in methylene chloride (23 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (8.71 mL, 113 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, the reaction mixture was concentrated in vacuo, taken up in methylene chloride and 25 g of SCX-2 resin was added and stirred for 10 minutes. The resin was then filtered and washed with methanol (25 mL x 3). The product was eluted off the resin using 2 N ammonium hydroxide in methanol (2 x 50 mL) and the filtrate concentrated in vacuo to provide (S)-2-amino-l-(4-(m-tolyloxy)piperidin-l-yl)propan-l-one (2.32 g, quantitative): ESI MS m / z 263 [C15H22N2O2 + H]+

[0875] Method Z: Preparation of (S)-1-(4-(m-Tolyloxy)piperidin-1-yl)propan-2-amine.

[0876] NH2

[0877]

[0878] To a solution of (S)-2-amino-l-(4-(»i -tolyl oxy )piperidin-l-yl)propan-l -one (2.32 g. 8.85 mmol) in tetrahydrofuran (70 mL) was added borane dimethylsulfide complex (4.42 mL, 44.2 mmol) under nitrogen atmosphere. The reaction was then placed in a pre-heated oil bath at 65 °C and stirred for 4 hours. The reaction was then cooled to 0 °C in an ice / water bath, methanol (10 mL) added and the reaction stirred at room temperature for 3 hours. 1 N hydrogen chloride in diethyl ether (10 mL) was added and the reaction re-heated to 65 °C for 1 hour. After this time, the reaction was allowed to cool and methanol (10 mL) added and the reaction concentrated in vacuo.Attorney Docket No. 07039-2355WO1 / 2024-258

[0879] Methanol (30 mL) was again added and the reaction mixture concentrated in vacuo and placed on a high-vac line overnight. In the morning, 1 N aqueous sodium hydroxide was added and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (80g RediSepRF Gold column, methylene chloride to 30% methanol / methylene chloride) to provide (< S)-1-(4-(m-tolyloxy)piperidin-l -yl)propan-2-amine (0.84 g, 38%): ESI MS m / z 249 [C15H24N2O + H]+

[0880] Method E: Preparation of (5')- / V-((2-Fhioropyridin-4-yl)methyl)-l-(4-( / M-tolyloxy)piperidin-l-yl)propan-2-amine»3HCl (C125-AQ-001)

[0881] ■3HCI

[0882]

[0883] To a solution of ( )-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine (0.05 g, 0.2 mmol) in methylene chloride (3 rnL) was added 2-fluoroisonicotinaldehyde (0.02 g, 0.2 mmol) and magnesium sulfate (0.24 g, 2.0 mmol). The reaction was then stirred at room temperature overnight. In the morning, the reaction mixture was filtered through diatomaceous earth and washed through with methylene chloride (x 3). The filtrate was concentrated in vacuo and redissolved in methanol (3 rnL). Sodium borohydride (0.02 g, 0.4 mmol) was then added and the reaction stirred at room temperature for 3 hours. The solvent w as then reduced to about 1 rnL in vacuo and 1:1 saturated sodium bicarbonate: brine added (10 mL) and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (12g RediSepRF Gold column, methylene chloride to 15% methanol / methylene chloride) provided (5)-A-((2-fluoropyridin-4-yl)methyl)- l-(4-(m -tolyloxy )piperidin-l-yl)propan-2-amine which was diluted with acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous hydrochloric acid was added and the mixture lyophilized overnight to give (, S)-A'-((2-l'luoropyridin-4-yl (methyl)- 1 -( 4-( / ?? -toly I oxy )pi per i di n- 1 -Attorney Docket No. 07039-2355WO1 / 2024-258

[0884] yl)propan-2-amine«3HCl (C125-AQ-001) as a white solid (0.08 g, 90%): ESI MS m / z

[0885] 358 [C21H28N3O + H]+

[0886] NH2

[0887]

[0888] (S)-1-(4-(m-Tolyloxy)piperidin-1-yl)propan-2-amine was prepared via

[0889] Scheme 10 using piperidin-4-ol and m-cresol: ESI MS m / z 249 [C15H24N2O + H]+

[0890] Preparation of (>')- / V-(l-(4-(Mi-Tolyloxy)pipcridin-l-yl)propan-2- yl)tetrahydro-2 / / -pyran-4-carboxamide.Attorney Docket No. 07039-2355WO1 / 2024-258

[0891] O

[0892]

[0893] (S)-l -(4-(m-Tolyloxy)piperidin-l -yl)propan-2-amine (0.07 g, 0.3 mmol) was reacted with tetrahydro-2H-pyran-4-carboxylic acid (0.05 g, 0.4 mmol) via Method H to provide (S)-N-(1-(4-(m-tolyloxy)piperidin-1-yl)propan-2-yl)tetrahydro-2H-pyran-4-carboxamide as a white solid (0.06 g, 55%): ESI MS m / z 361 [C21H32N2O3 + H]+

[0894] Preparation of (5)-7V-((Tetrahydro-2Z7-pyran-4-yl)methyI)-l-(4-( / «-tolyloxy)piperidin-l-yl)propan-2-amine«2HCl.

[0895]

[0896] (S)-N-(1-(4-(m-Tolyloxy)piperidin-1-yl)propan-2-yl)tetrahydro-2H-pyran-4-carboxamide (0.06 g, 0.2 mmol) was reacted via Method K to provide (S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-1-(4-(m-tolyloxy)piperidin-1-yl)propan-2-amine•2HCl (C234-AQ-001) as a white solid (0.04 g, 57%): ESI MS m / z 347

[0897]

[0898] [C21H34N2O2 + H]+

[0899] Scheme 12: Preparation of C438-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[0900]

[0901] O'

[0902]

[0903] (1R,3s,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (2.50 g, 11.0 mmol) and / w-cresol (1.15 g, 11.0 mmol) were reacted via Method A and Method B to provide (LR,3r,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane (1.45 g, quantitative): ESI MS m / z 218 [C14H19NO + H]+

[0904] Preparation of (5)-2-(U / -Pyrrolo[3,4-c]pyridin-2(3 / 7)-yl)propyl Methanesulfonate.

[0905]

[0906] (S)-2-(1H-Pyrrolo[3,4-c]pyridin-2(3H)-yl)propan-1-ol (0.06 g, 0.3 mmol) was reacted via Method O to provide (S)-2-(1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)propyl methanesulfonate (0.06 g, 78%). The crude residue was used in the next step without further purification.

[0907] Method AA: Preparation of 2-((S)-1-((1R,3S,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine•2HCl (C434-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[0908]

[0909] To a solution of (1R,3r,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane (0.05 g, 0.2 mmol) in acetonitrile (2 mL), at 0 °C in an ice / water bath, was added cesium carbonate (0.12 g, 0.34 mmol) followed by dropwise addition of (S)-2-(1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)propyl methanesulfonate (as a solution in 2 mL of acetonitrile) over 15 minutes. The reaction was then transferred to a pre-heated oil bath and stirred at 80 °C overnight. In the morning, the reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The organics were washed with water (x 2), dried over sodium sulfate, filtered and concentrated in vacuo.

[0910] Purification by column chromatography (12g RediSepRF Gold column, methylene chloride to 20% methanol / methylene chloride) provided 2-((S)-1-((1R,3S,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine which was diluted with acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous hydrochloric acid was added and the mixture lyophilized overnight to provide 2-((S)-1-((1R,3S,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine•2HCl (C438-AQ-001) as a white solid (0.04 g, 36%): ESI MS m / z 378

[0911]

[0912] [C24H31N3O + H]+

[0913] Scheme 13: Preparation of C480-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[0914]

[0915] Preparation of (A')-2-Amino-l-(4-( / ;-tolyloxy)piperidin-l-yl)propan-l-one.

[0916]

[0917] (S)-2-Amino-1-(4-(p-tolyloxy)piperidin-1-yl)propan-1-one was prepared via Scheme 3 using starting materials tert-butyl 4-hydroxypiperidine-l -carboxylate and p-cresol: ESI MS m / z 263 [C15H22N2O2 + H]+

[0918] Preparation of (S)-N-(1-Oxo-1-(4-(p-tolyloxy)piperidin-1-yl)propan-2-yl)tetrahydro-2H-pyran-4-carboxamide.

[0919]

[0920] (5)-2-Amino-l-(4-ty>-tolyloxy)piperidin-l-yl)propan-l-one (0.10 g, 0.38 mmol) was reacted with tetrahydro-2H-pyran-4-carboxylic acid (0.06 g, 0.4 mmol) via Method H to provide (S)-7V-(l-oxo-l-(4-( -tolyloxy)piperidin-l-yl)propan-2-Attorney Docket No. 07039-2355WO1 / 2024-258

[0921] yl)tetrahydro-2 / / -pyran-4-carboxamide (0.12 g, 84%): ESI MS m / z 375 [C21H30N2O4 + H]+

[0922] Method AB: Preparation of GS’)- / V-((Tetrahydro-27 / -pyran-4-yl)methyl)-1-(4-( / i-tolyloxy)piperidin-l-yl)propan-2-amine,2HCl (C448-AQ-001).

[0923] -2HCI

[0924]

[0925] To a solution of (S)-N-(1-oxo-1-(4-(p-tolyloxy)piperidin-1-yl)propan-2-yl)tetrahydro-2H-pyran-4-carboxamide (0.12 g, 0.32 mmol) in tetrahydrofuran (4 mL) was added borane dimethylsulfide complex (0.23 mL. 2.2 mmol) and the reaction placed in a pre-heated oil bath at 65 °C for 4 hours. The reaction was then cooled to 0 °C in an ice / water bath, methanol (2 mL) added and the reaction stirred at room temperature for 1 hour. 1 N hydrogen chloride in diethyl ether (1 mL) was added and the reaction stirred at room temperature overnight. In the morning, methanol (10 mL) was added and the reaction mixture concentrated in vacuo. 1 N Aqueous sodium hydroxide (10 mL) was added and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, methylene chloride to 20% methanol / methylene chloride) to provide (S)-N-((tetrahydro-27f-pyran-4-yl)methyl)-l-(4-( / 7-tolyloxy)piperidin-l-yl)propan-2-amine which was diluted with acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous hydrochloric acid was added and the mixture lyophilized overnight to provide (S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-1-(4-(p-tolyloxy)piperidin-1-yl)propan-2-amine•2HCl (C480-AQ-001) as a white solid (0.04 g, 33%): ESI MS m / z 347 [C21H34N2O2 + H]+

[0926] Scheme 14: Preparation of C558-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[0927]

[0928]

[0929] 4-Phenoxypiperidine was prepared via Method A and Method B using starting materials tert-butyl 4-hydroxypiperidine-1-carboxylate and phenol: ESI MS m / z 178 [C11H15NO + H]+

[0930] Method AC: Preparation of (5)-2-Morpholino-l-(4-phenoxypiperidin-l-yl)propan- 1-one.

[0931]

[0932] To a solution of 4-phenoxypiperidine (0.05 g, 0.3 mmol) in methylene chloride (2 mL) was added (5)-2-morpholinopropanoic acid»HCl (0.07 g, 0.3 mmol) and diisopropylethylamine (0.10 mL, 0.56 mmol). Propylphosphonic anhydride (50% in ethyl acetate, 0.27 mL, 0.42 mmol) was then added and the reaction stirred overnight at room temperature. In the morning, saturated sodium bicarbonate was added and the organics extracted with methylene chloride (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, methylene chloride to 20% methanol / methylene chloride) to provide (S)-2-Attorney Docket No. 07039-2355WO1 / 2024-258

[0933] morpholino-l-(4-phenoxypiperidin-l-yl)propan-l-one (0.06 g, 62%); ESI MS m / z 319 [C18H26FN2O3 + H]+

[0934] Preparation of (A)-4-(l-(4-Phenoxypiperidin-l-yl)propan-2-yl)morpholine*2HCl (C558-AQ-001).

[0935]

[0936] (S)-2 -Morpholino- 1 -(4-phenoxypiperi din- l-yl)propan-l -one (0.06 g, 0.2 mmol) was reacted via Method K to provide (< S)-4-(l-(4-phenoxypiperidin-l-yl)propan-2-yl)morpholine»2HCl (C558-AQ-001) as a white solid (0.04 g, 66%): ESI MS m / z 305 [C18H28N2O2 + H]+

[0937] Scheme 15: Preparation of C903-AQ-001.

[0938]

[0939] Preparation of (17?,5A)-3-( / M-Tolyloxy)-8-azabicyclo[3.2.1]octane.

[0940]

[0941] (1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octane (0.68 g, 71%) was prepared via Method A and Method B using starting materials (1R,5S)-tert-butyl 3-hydroxy-8-Attorney Docket No. 07039-2355WO1 / 2024-258

[0942] azabicyclo[3.2.1]octane-8-carboxylate and m-cresol: ESI MS m / z 218 [C14H19NO + H]

[0943] Preparation of 3-(Pyridin-4-yl)-l-((17?,5N)-3-(» / -tolyloxy)-8-azabicyclo [3.2.1] octan-8-yl)propan- l-one«HCl.

[0944]

[0945] (1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octane (0.12 g, 0.57 mmol) and 3-(pyridin-4-yl)propanoic acid (0.10 g, 0.69 mmol) were reacted via Method H to provide 3-(pyridin-4-yl)-l-((17?,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-l-one»HCl (C903-AQ-001, 0.04 g, 41%) as a white solid: ESI MS m / z 351 [C22H26N2O2 + H]+

[0946]

[0947]

[0948]

[0949] Attorney Docket No. 07039-2355WO1 / 2024-258

[0950]

[0951] NH2

[0952] (S)-1-(4-(m-Tolyloxy)piperidin-1-yl)propan-2-amine was synthesized via Scheme 10 using starting materials te / -butyl 4-hydroxypiperidine-l-carboxylate and m-cresol: ESI MS m / z 249 [C15H24N2O + H]+

[0953] Method AD: Preparation of (S)-N,N-Dimethyl-1-(4-(m-tolyloxy)piperidin-1-yl)propan-2-amine•2HCl (C663-AQ-001).

[0954]

[0955] To a solution of (5)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine (0.02 g, 0.1 mmol) in isopropyl alcohol (1 mL) was added formaldehyde (33% in water, 0.05 mL, 0.5 mmol) and formic acid (0.02 mL, 0.4 mmol). The reaction was then placed in a pre-heated oil bath at 100 °C and stirred overnight. In the morning, the reaction mixture was concentrated in vacuo and purified by column chromatography (4g RediSepRF Gold column, methylene chloride to 40% CMA (80%CHCh,18%MeOH,2%NH4OH) / methylene chloride to provide (S)-N,N-dimethyl-1-(4-(m-tolyloxy)piperidin-1-yl)propan-2-amine, which was diluted with acetonitrile and concentrated twice, then diluted again w ith acetonitrile. 1 N Aqueous hydrochloric acid was added and the mixture lyophilized overnight to give (S)-N,N-dimethyl-1-(4-(m-tolyloxy)piperidin-1-yl)propan-2-amine•2HCl (C663-AQ-001, 0.01 g, 80%) as a white solid: ESI MS m / z 277 [C17H28N2O + H]+

[0956] Scheme 17: Preparation of C664-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[0957]

[0958] Method AE: Preparation of rt-Butyl 8- Hydroxy-3, 4-dihydroisoquinoline-2(177)-carboxylate.

[0959] HO

[0960]

[0961] To a solution of 1,2,3,4-tetrahydroisoquinolin-8-ol (0.97 g, 6.5 mmol) in methylene chloride (80 mL) at 0 °C (ice / water bath) was added di- / m-butyl dicarbonate (1.57 g, 7.19 mmol) and the reaction stirred for 10 minutes. Triethylamine (2.40 mL, 16.3 mmol) was then added, the ice / water bath removed and the reaction stirred at room temperature overnight. In the morning, the reaction was diluted with saturated sodium bicarbonate solution and the organics were then extracted with methylene chloride (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (40g RediSepRF Gold column, 5-30% ethyl acetate / hexanes) to provide tert-butyl 8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.25 g, 74%): ESI MS m / z 250 [C14H19NO3 + H]+

[0962] Method AF: te / Y- Butyl 8-(m-tolyloxy)-3,4-dihydroisoquinoline- 2(177)-carboxylate.

[0963]

[0964] Attorney Docket No. 07039-2355WO1 / 2024-258

[0965] To a solution of tert-butyl 8-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.30 g, 1.2 mmol) in anhydrous dimethylsulfoxide (8 mL). degassing under argon, was added l-iodo-3-methylbenzene (0.39 g, 1.8 mmol), copper (I) iodide (0.02 g, 0.1 mmol), potassium phosphate (0.36 g, 2.4 mmol) and picolinic acid (0.02 g, 0.2 mmol). The reaction was then placed in a pre-heated oil bath at 90 °C and stirred overnight. In the morning, the reaction mixture was allowed to cool to room temperature and diluted with water (10 mL). The organics were then extracted with ethyl acetate (x 3), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (12g RediSepRF Gold column, 0.5-8% ethyl acetate / hexanes) to provide tert-butyl 8-(m-tolyloxy)-3,4-dihydroisoquinoline-2(177)-carboxylate (0.17 g, 59%): ESI MS m / z 340 [C21H25NO3 + H]

[0966] Preparation of 8-(» / -Tolyloxy)-l,2,3,4-tetrahydroisoquinoline.

[0967] O

[0968]

[0969] tert- Butyl 8-( / w-tolyloxy)-3,4-dihydroisoquinoline-2(177)-carboxylate (0.20 g, 0.64 mmol) was reacted via Method B to provide 8-(m-tolyloxy)-1,2,3,4-tetrahydroisoquinoline (0.12 g, 78%): ESI MS m / z 240 [C16H17NO + H]+

[0970] Method AG: Preparation of 2-(Pyridin-4-ylmethyl)-8-(m-tolyloxy)-1,2,3,4-tetrahydroisoquinoline•2HCl (C664-AQ-001)

[0971]

[0972] To a solution of 8-(m-tolyloxy)-1,2,3,4-tetrahydroisoquinoline (0.12 g, 0.51 mmol) in acetonitrile (5 mL) was added isonicotinaldehyde (0.05 g, 0.6 mmol) and sodium triacetoxyborohydride (0.12 g. 0.77 mmol) and the reaction stirred at room temperature overnight. In the morning, the reaction was quenched with saturatedAttorney Docket No. 07039-2355WO1 / 2024-258

[0973] sodium bicarbonate solution and the organics extracted with ethyl acetate (x 3). The

[0974] combined organics were washed with brine, dried over sodium sulfate, filtered and

[0975] concentrated in vacuo. The crude residue was purified by column chromatography (4g

[0976] RediSepRF Gold column, 5% to 80% ethyl acetate / hexanes) to provide 2-(pyridin-4-ylmethyl)-8-(m-tolyloxy)- 1.2.3.4-tetrahydroisoquinoline which was diluted with

[0977] acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous

[0978] hydrochloric acid was added and the mixture lyophilized overnight to give 2-(pyridin-4-ylmethyl)-8-( / w-tolyloxy)-l,2,3,4-tetrahydroisoquinoline»2HCl (C664-AQ-001) as a

[0979] white solid (0.13 g, 61%): ESI MS m / z 331 [C22H22N2O + H]+

[0980]

[0981] To a solution of tert-butyl pip erazine-1 -carboxylate (0.58 g, 3.1 mmol) in

[0982] methylene chloride (30 mL) was added benzyl bromide (0.30 mL, 2.5 mmol) and

[0983] potassium carbonate (1.30 g, 9.38 mmol). The reaction was then placed in a preheated oil bath at 45 °C and stirred overnight. In the morning, the reaction mixture

[0984] was allowed to cool, diluted with brine and the organics were extracted with

[0985] methylene chloride (x 3). The combined organics were dried over sodium sulfate,

[0986] filtered and concentrated in vacuo. The crude residue was purified by column

[0987] chromatography (12g RediSepRF Gold column, 2-16% ethyl acetate / hexanes) to

[0988] provide Zert-butyl 4-benzylpiperazine-l-carboxylate (0.65 g, 75%) as a clear oil: ESI

[0989] MS m / z 277 [C16H24N2O2 + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[0990] Preparation of 1-Benzylpiperazine.

[0991]

[0992] te / 7-Butyl 4-benzylpiperazine-l-carboxylate (0.63 g. 2.3 mmol) was reacted via Method B to provide 1 -benzylpiperazine (0.25 g, 62%) as a white solid: ESI MS m / z 177 [C11H16N2 + H]+

[0993] Preparation of (A)- 7t- Butyl (l-(4-Benzylpiperazin-l-yl)-l-oxopropan-2-yl)carbamate.

[0994] O / — \

[0995] y— N N

[0996]

[0997] 1 -Benzylpiperazine (0.24 g, 1.4 mmol) was reacted via Method I to provide (S)-tert-butyl (l-(4-benzylpiperazin-l-yl)-l-oxopropan-2-yl)carbamate (0.26 g. 55%) as a clear gum: ESI MS m / z 348 [C19H29N3O3 + H]+

[0998] Preparation of (5')- ’ / 7‘- Butyl (l-(4-Benzylpiperazin-l-yl)propan-2-yl)carbamate.

[0999] BocHN

[1000]

[1001] (S)-te / 7-Butyl (1 -(4-benzylpiperazin-l -yl)-l -oxopropan-2-yl)carbamate (0.25 g. 0.72 mmol) was reacted via Method Z to provide (S)-ter / -butyl (l-(4-benzylpiperazin-l-yl)propan-2-yl)carbamate (0.15 g, 64%): ESI MS m / z 334 [C19H31N3O2 + H]+

[1002] Preparation of (5)-l-(4-Benzylpiperazin-l-yl)propan-2-amine.

[1003]

[1004] Attorney Docket No. 07039-2355WO1 / 2024-258

[1005] (< S)-te / 7-Butyl (l-(4-benzylpiperazin-l-yl)propan-2-yl)carbamate (0.15 g, 0.45

[1006] mmol) was reacted via Method B to provide (< S)-l-(4-benzylpiperazin-l-yl)propan-2-amine (0.10 g, 93%) as a clear oil: ESI MS m / z 234 [C14H23N3 + H]+

[1007] Preparation of (A)-l-(4-Benzylpiperazin-l-yl)- / V-(pyridin-4-ylmethyl)propan-2-amine*4HCl (C065-AQ-001).

[1008]

[1009] GS')-l-(4-benzylpiperazin-l-yl)propan-2-amine (0.04 g, 0.18 mmol) was

[1010] reacted via Method E to provide (S)-l-(4-benzylpiperazin-l-yl)-JV-(pyridin-4-ylmethyl)propan-2-amine»4HCl (C065-AQ-001) as a white solid (0.05 g, 57%): ESI

[1011] MS m / z 325 [C20H28N4 + H]+

[1012]

[1013] Method AG: Preparation of (5)- / ert-Butyl (l-(4-Benzylpiperidin-l-yl)-l-oxopropan-2-yl)carbamate.

[1014]

[1015] To a solution of 4-benzylpiperidine (1.00 g, 5.70 mmol) in methylene chloride

[1016] (50 mL) was added (S)-2-((terf-butoxycarbonyl)amino)propanoic acid (1.30 g, 6.84

[1017] mmol) and diisopropylethylamine (2.00 mL, 17.1 mmol). Propylphosphonic

[1018] anhydride (50% in ethyl acetate, 5.10 mL, 8.55 mmol) was then added and theAttorney Docket No. 07039-2355WO1 / 2024-258

[1019] reaction stirred at room temperature overnight. In the morning, the reaction was diluted with saturated sodium bicarbonate solution and extracted with methylene chloride (x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue w as purified by column chromatography (24g RediSepRF Gold column, 5% to 50% ethyl acetate / hexanes) to provide (S)-tert-butyl (1-(4-benzylpiperidin-1-yl)-1-oxopropan-2-yl)carbamate (1.60 g, 81%): ESI MS m / z 347 [C19H29N2O3 + H]+

[1020] Method Z: Preparation of (S)-tert- Butyl (l-(4-Benzylpiperidin-l-yl)propan-2-yl)carbamate.

[1021]

[1022] BocHN

[1023] To a solution of (S)-tert-butyl (1-(4-benzylpiperidin-1-yl)-1-oxopropan-2-yl)carbamate (1.53 g, 4.42 mmol) in tetrahydrofuran (50 mL) was added borane dimethylsulfide complex (2.10 mL, 22.1 mmol) under nitrogen atmosphere. The reaction was then placed in a pre-heated oil bath at 65 °C and stirred for 4 hours. The reaction was then cooled to 0 °C in an ice / water bath, methanol (5 mL) added and the reaction stirred at room temperature for 3 hours. 1 N hydrogen chloride in diethyl ether (3 mL) was added and the reaction re-heated to 65 °C for 1 hour. After this time, the reaction was allowed to cool and methanol (10 mL) added and the reaction concentrated in vacuo. Methanol (30 mL) was again added and the reaction concentrated in vacuo and placed on a high-vac line overnight. In the morning, 1 N aqueous sodium hydroxide was added and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (40g RediSepRF Gold column, methylene chloride to 30% methanol / methylene chloride) to provide (S)-tert-butyl (1-(4-benzylpiperidin-1-yl)propan-2-yl)carbamate (1.03 g, 70%): ESI MS m / z 333 [C20H32N2O2 + H]+

[1024] Method B: Preparation of (5')-l-(4-Benzylpiperidin-l-yl)propan-2-amine.Attorney Docket No. 07039-2355WO1 / 2024-258

[1025]

[1026] To a solution of (S)-tert-butyl (1-(4-benzylpiperidin-1-yl)propan-2-yl)carbamate (1.03 g, 3.10 mmol) in methylene chloride (20 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (2.40 mL, 31.0 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, saturated sodium bicarbonate was added (75 mL) slowly to pH~10 and the organics extracted with methylene chloride (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (24g RediSepRF Gold column, 5% to 50% CMA (80% chloroform, 18% methanol, 2% ammonium hydroxide):methylene chloride) to provide (S)-l-(4-benzylpiperidin-l-yl)propan-2-amine (0.82 g, 80%): ESI MS m / z 233 [C15H24N2 + H]+

[1027] Method E: Preparation of (S)-1-(4-Benzylpiperidin-1-yl)-N-(pyridin-4-ylmethyl)propan-2-amine•3HCl (C477-AQ-001).

[1028]

[1029] To a solution of (S)-1-(4-benzylpiperidin-1-yl)propan-2-amine (0.05 g, 0.2 mmol) in methylene chloride (5 mL) was added isonicotinaldehyde (0.03 g, 0.2 mmol) and magnesium sulfate (0.26 g, 2.2 mmol). The reaction was then stirred at room temperature overnight. In the morning, the reaction mixture was filtered through diatomaceous earth and washed through with methylene chloride (x 3). The filtrate was concentrated in vacuo and redissolved in methanol (5 mL). Sodium borohydride (0.02 g, 0.43 mmol) was then added and the reaction stirred at room temperature for 3 hours. The solvent was then reduced to about 1 mL in vacuo and 1: 1 saturated sodium bicarbonate: brine added (10 mL) and the organics extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (4g RediSepRF Gold column, 5% to 30% CMA (80% chloroform, 18% methanol, 2% ammonium hydroxide):methyleneAttorney Docket No. 07039-2355WO1 / 2024-258

[1030] chloride) provided (S)-1-(4-Benzylpiperidin-1-yl)-N-(pyridin-4-ylmethyl)propan-2-amine which was diluted with acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous hydrochloric acid was added and the mixture lyophilized overnight to give (S)-1-(4-benzylpiperidin-1-yl)-N-(pyridin-4-ylmethyl)propan-2-amine•3HCl (C477-AQ-001) as a white solid (0.04 g, 48%): ESI MS m / z 324 [C21H29N3 + H]+

[1031] Scheme 20: Preparation of C598-AQ-001.

[1032]

[1033] Method AC: Preparation of l-(4-(3-Methylbenzyl)piperidin-l-yl)-3-(tetrahydro-2 / / -pyran-4-yl)propan- 1-one.

[1034] O

[1035]

[1036] To a solution of 4-(3-methylbenzyl)piperidine (0.07 g. 0.4 mmol) in methylene chloride (10 mL) was added 3-(tetrahydro-2H-pyran-4-yl)propanoic acid (0.09 g, 0.6 mmol) and diisopropylethylamine (0.14 mL, 1.2 mmol).

[1037] Propylphosphonic anhydride (50% in ethyl acetate, 0.35 mL, 0.59 mmol) was then added and the reaction stirred overnight at room temperature. In the morning, saturated sodium bicarbonate was added and the organics extracted with methylene chloride (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (4g RediSepRF Gold column, 20% to 70% ethyl acetate / hexanes) to provide l-(4-(3-methylbenzyl)piperidin-l-yl)-3-(tetrahydro-27f-pyran-4-yl)propan-l-one (0.10 g. 77%): ESI MS m / z 330 [C21H31NO2 + H]+

[1038] Preparation of 4-(3-Methylbenzyl)-l-(3-(tetrahydro-2 / / -pyran-4-yl)propyl)piperidine»HCl (C598-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[1039]

[1040] 1 -(4-(3-Methylbenzyl)piperidin-l -yl)-3-(tetrahydro-2 / / -pyran-4-yl)propan-l -one (0.10 g, 0.30 mmol) was reacted via Method K to provide 4-(3-methylbenzyl)-1-(3-(tetrahydro-277-pyran-4-yl)propyl)piperidine«HCl (C598-AQ-001) as a white solid

[1041] (0.05 g, 53%): ESI MS m / z 316 [C21H33NO + H]+

[1042]

[1043] Method AF: Preparation of { R,5S)-tert- Butyl 3-(3-Methylbenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[1044]

[1045] To a solution of (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.88 g, 4.2 mmol) in methylene chloride (30 mL) was added 1-(bromomethyl)-3-methylbenzene (0.61 g, 3.3 mmol) and potassium carbonate (1.72 g,

[1046] 12.4 mmol). The reaction was then placed in a pre-heated oil bath at 45 °C and stirred

[1047] overnight. In the morning, the reaction mixture was allowed to cool, diluted with

[1048] brine and the organics were extracted with methylene chloride (x 3). The combined

[1049] organics were dried over sodium sulfate, filtered and concentrated in vacuo. The

[1050] crude residue was purified by column chromatography (12g RediSepRF Gold column,

[1051] hexanes to 6% ethyl acetate / hexanes) to provide (1R,5S)-tert-butyl 3-(3-methylbenzyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 76%) as a clear

[1052] oil: ESI MS m / z 317 [C19H28N2O2 + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[1053] Prep ar ation of ( 1 / ?,5A)-3-(3- Meth ylb enzyl)-3,8-d iazabicyclo [3.2.1 ] octane.

[1054]

[1055] ( I ’.5, S')- / c / ' / -But l 3-(3-methylbenzyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.94 g, 3.0 mmol) was reacted via Method B to provide (lA,5S)-3-(3- methylbenzyl)-3,8-diazabicyclo[3.2. l]octane (0.64 g, 98%) as a yellow oil: ESI MS m / z 217 [C14H20N2 + H]+

[1056] Preparation of (5)-l-((17?,55)-3-(3-Methylbenzyl)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2-morpholinopropan-1-one.

[1057] H

[1058]

[1059] ( IA’.5 )-3-(3-Methylbenzyl)-3.8-diazabicyclo|3.2.1 Iodane (0.06 g, 0.3 mmol) was reacted via Method AG to provide (1S’)-l-((17?,5S)-3-(3-methylbenzyl)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2-morpholinopropan-l-one (0.06 g, 60%) as a clear gum: ESI MS m / z 358 [C21H31N3O2 + H]+

[1060] Preparation of 4-((5)-l-((17f,55)-3-(3-Methylbenzyl)-3,8- diazabicyclo[3.2.1]octan-8-yl)propan-2-yl)morpholine»2HCl (C705-AQ-001).

[1061] H

[1062] ■2HCI

[1063]

[1064] (. S’)-l-((1?,51S)-3-(3-Methylbenzy'l)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2- morpholinopropan-l-one (0.05 g, 0.1 mmol) was reacted via Method Kto provide 4- ((S)-l-((lA,5S)-3-(3-methylbenzyl)-3,8-diazabicyclo[3.2. l]octan-8-yl)propan-2- yl)morpholine»2HCl (C705-AQ-001) as a white solid (0.02 g. 33%): ESI MS m / z 344 [C21H33N3O + H]+

[1065] Preparation of C390-AQ-002

[1066]

[1067] Attorney Docket No. 07039-2355WO1 / 2024-258

[1068]

[1069] N-( Pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propan amide (0.10 g, 0.28 mmol) was reacted via Method K to provide A-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propan-l-amine«2HCl (C390-AQ-002) (0.07 g, 65%): ESI MS m / z 334 [C21H23N3O + H]+

[1070] Preparation of C509-AQ-001.

[1071]

[1072] A-(Pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-l-amine»2HCl (C509-AQ-001) was prepared via Scheme 1 using (?)-tert-butyl 3-hydroxypyrrolidine-l-carboxylate (2.50 g, 13.3 mmol) and m-cresol (1.44 g, 13.3 mmol) as starting materials: ESI MS m / z 326 [C20H27N3O + H]+

[1073] Preparation of C510-AQ-001.

[1074]

[1075] A-(Pyridin-4-ylmethyl)-2-(4-(m-tolyloxy)piperidin-l-yl)propan-l-amine»2HCl (C510-AQ-001) was prepared via Scheme 1 using / -butyl 4-hydroxypiperidine-l-carboxylate (2.50 g, 12.4 mmol) and m-cresol (1.34 g, 12.4 mmol) as starting materials: ESI MS m / z 340 [C21H29N3O + H]+

[1076] IllAttorney Docket No. 07039-2355WO1 / 2024-258

[1077] Preparation of C698-AQ-001.

[1078]

[1079] A-Methyl-3-(pyridin-4-yl)-A-(3-(m-tolyloxy)phenyl)propanamide (C696-AQ-001, 0.07 g, 0.2 mmol) was reacted using Method K to provide A-methyl-jV-(3-(pyridin-4-yl)propyl)-3-( / ?7-tolyloxy)aniline,2HCl (C698-AQ-001, 0.03 g, 46%): ESI MS m / z 333 [C22H24N2O + H]+

[1080] Preparation of C699-AQ-001.

[1081] kO -2HCI

[1082] H

[1083]

[1084] N

[1085] A-(Pyridin-4-ylmethyl)-2-((7?)-3-(m-tolyloxy)piperidin-l-yl)propan-l-amine»2HCl (C699-AQ-001) was synthesized via Scheme 1, using (S)-ter / -butyl 3-hydroxypiperidine-1 -carboxylate and m-cresol as starting materials: ESI MS m / z 340 [C21H29N3O + H]+

[1086] Preparation of C700-AQ-001.

[1087] N

[1088]

[1089] A-Methyl-A-(2-(pyridin-4-yl)ethyl)-3-(m-tolyloxy)aniline,2HCl (C700-AQ- 001) was synthesized from C702-AQ-001 using Method K: ESI MS m / z 319 [C21H22N2O + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[1090]

[1091] 6-(m-Tolyloxy)-l,2,3,4-tetrahydroisoquinoline was synthesized using Method

[1092] F: ESI MS m / z 240 [C16H17NO + H]+

[1093] Preparation of 2-(Pyridin-4-ylmethyl)-6-(wi-tolyloxy)-l, 2,3,4-tetraliydroisoquinoline»HCl (C701-AQ-001).

[1094]

[1095] 2-(Pyridin-4-ylmethyl)-6-(m-tolyloxy)-l,2,3,4-tetrahydroisoquinoline,HCl

[1096] (C701-AQ-001) was synthesized using Method E: ESI MS m / z 331 [C22H22N2O +

[1097] H]+

[1098] Preparation of C702-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1099]

[1100] A-Methyl-2-(pyridin-4-yl)-A-(3-(m-tolyloxy)phenyl)acetamide»HCl (C702- AQ-001) was synthesized using Scheme 2: ESI MS m / z 333 [C21H20N2O2 + H]+

[1101] Preparation of C2703-AQ-001.

[1102]

[1103] 2V-(Pyri din-4-ylmethyl)-2-(GS')-3-(fl7-tolyloxy)piperi din-1 -yl)propan-1-amine•2HCl (C2703-AQ-001) was synthesized via Scheme 1 using starting materials ( )-te / 7-butyl 3-hydroxypiperidine-l -carboxylate and m-cresol: ESI MS m / z 340 [C21H29N3O + H]+

[1104] Preparation of C2704-AQ-001.

[1105]

[1106] A-(Pyridin-4-ylmethyl)-2-((17?,3r,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-amine•2HCl (C2704-AQ-001) was synthesized via Scheme 1 using starting materials ( l / .3.s.5 )-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and m-cresol: ESI MS m / z 366 [C23H31N3O + H]Attorney Docket No. 07039-2355WO1 / 2024-258

[1107] Preparation of C763-AQ-001.

[1108]

[1109] (5)-2-((Pyridin-4-ylmethyl)amino)-l-((5)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one»HCl (C762-AQ-001) was converted to CS')-A-(pyridm-4-ylmethyl)-l-((S)-3-( / w-tolyloxy)piperidin-l-yl)propan-2-amine,2HCl (C763-AQ-001) following

[1110] Method K: ESI MS m / z 340 [C21H29N3O + H]+

[1111]

[1112] ( -3-(«7-Tolyloxy)piperidine was prepared via Method A and Method B

[1113] using starting materials (J?)-piperidin-3-ol and m-cresol: ESI MS m'z 192 [C12H17NO

[1114] + H]+

[1115] Preparation of (A)-3-((Pyridin-4-ylmethyl)amino)-l-(3-( / M-tolyloxy)piperidin-l-yl)propan-l-one»HCl (C828-AQ-001)Attorney Docket No. 07039-2355WO1 / 2024-258

[1116]

[1117] 0S')-3-((Pyridin-4-ylmethyl)amino)-l-(3-( / «-tolyloxy)piperidin-l-yl)propan-l-one«HCI (C828-AQ-001) (0.17 g, 82%) was prepared via Scheme 6: ESI MS m / z 354 [C21H27N3O2 + H]+

[1118] Preparation of C829-AQ-001.

[1119]

[1120] (S)-3-((Pyridin-4-ylmethyl)amino)-l-(3-(m-tolyloxy)piperidin-l-yl)propan-l-one was converted to (S)-N-(pyridin-4-ylmethyl)-3-(3-(m-tolyloxy)piperidin-l -yl)propan-l-amine,2HCl (C829-AQ-001) following Method K: ESI MS m / z 340 [C21H29N3O + H]+

[1121] Preparation of C830-AQ-001.

[1122]

[1123] Preparation of (5)-3-(wz-Tolyloxy)piperidine.Attorney Docket No. 07039-2355WO1 / 2024-258

[1124]

[1125] (< S)-3-(m-Tolyloxy)piperidine was prepared via Method A and Method B using starting materials (A)-piperidin-3-ol and m-cresol: ESI MS m / z 192 [C12H17NO + H]+

[1126] Preparation of (A)-3-(Pyridin-4-yl)-l-(3-( / u-tolyloxy)piperidin-l-yl)propan-l-one»HCl (C830-AQ-001).

[1127]

[1128] (S)-3-(Pyridin-4-yl)-l-(3-(7M-tolyloxy)piperidin-l-yl)propan-l-one*HCl (C830-AQ-001) was prepared via Method H using (A)-3-(m-tolyloxy)piperidine and 3-(pyridin-4-yl)propanoic acid as starting materials: ESI MS m / z 325 [C20H24N2O2 + H]

[1129] Preparation of C831-AQ-001.

[1130] Cui, CS2CO3, 90JC

[1131] dimethylglycine*HCI

[1132] dioxane, 18 h

[1133]

[1134] Preparation of 7-(wz-Tolyloxy)-l -naphthonitrile.

[1135]

[1136] Attorney Docket No. 07039-2355WO1 / 2024-258

[1137] 7-Hydroxy-l -naphthonitrile and 1-i odo-3 -methylbenzene were reacted via Method F to provide 7-( / ??-tolyloxy)- 1 -naphthonitrile (0.10 g, 13%): ESI MS m / z 260 [C18H13NO + H]+

[1138] Preparation of (7-(»i-Tolyloxy)naphthalen-l-yl)methanamine.

[1139]

[1140] NH2

[1141] 7-(m-tolyloxy)-l -naphthonitrile was reacted via Method G to provide (7-(m- tolyloxy)naphthalen-l-yl)methanamine (0.07 g, 69%): ESI MS m / z 264 [C18H17NO + H]+

[1142] Preparation of l-(Pyridin-4-yl)- / V-((7-(m-tolyloxy)naphthalen-l- yl)methyl)methanamine»HCl (C831 - AQ-001).

[1143]

[1144] (7-(m-Tolyloxy)naphthalen-l-yl)methanamine (65 mg, 0.24) was reacted via Method E to provide l-(pvridin-4-yl)-A-((7-0w.-lolvloxy)naphthalen-l- yl)methyl)methanamine»HCl (C831-AQ-001) (0.09 g, 99%): ESI MS m / z 355 [C24H22N2O + H]+

[1145] Preparation of C832-AQ-001.

[1146]

[1147] Attorney Docket No. 07039-2355WO1 / 2024-258

[1148] (< S)-3-(Pyridin-4-yl)-l-(3-(m-tolyloxy)piperidin-l-yl)propan-l-one was reacted

[1149] via Method K to provide (S)-4-(3-(3-(m-tolyloxy)piperidin-1-yl)propyl)pyridine•HCl

[1150] (C832-AQ-001) (0.10 g, 84%): ESI MS m / z 340 [C21H29N3O + H]+

[1151]

[1152] CR)-3-(m-Tolyloxy)piperidine was prepared via Method A and Method B

[1153] using starting materials (?)-tert-butyl 3-hydroxypiperidine-l-carboxylate and m-cresol: ESI MS m / z 192 [C12H17NO + H]+

[1154] Preparation of ( / ?)-2-((Pyridin-4-ylmethyl)amino)-l-((A')-3-( / H-tolyloxy)piperidin-l-yl)propan-l-one»2HCl (C833-AQ-001).

[1155]

[1156] (7?)-2-((Pyridin-4-ylmethyl)amino)-l-(( )-3-(m-tolyloxy)piperidin-l-yl)propan-l-one»2HCl (C833-AQ-001) was prepared via Scheme 6 to give a white

[1157] solid (0.07 g, 63%): ESI MS m / z 354 [C21H27N3O2 + H]+

[1158] Preparation of C852-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1159]

[1160] (7?)-2-((Pyridin-4-ylmethyl)amino)-l-((< S)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one was reacted via Method Kto provide (7?)-JV-(Pyridin-4-ylmethyl)-l-((N)-3-(m-tolyloxy)piperidin-l-yl)propan-2-amine,2HCl (C852-AQ-001) (0.04 g.

[1161] 49%): ESI MS m / z 354 [C21H27N3O2 + H]+

[1162]

[1163] (7?)-3-(m-Tolyloxy)piperidine was prepared via Method A and Method B

[1164] using starting materials ( )-tert-butyl 3-hydroxypiperidine-l -carboxylate and m-cresol: ESI MS m / z 192 [C12H17NO + H]+

[1165] Preparation of (A)-2-((Pyridin-4-ylmethyl)amino)-l-(3-( / «-tolyloxy)piperidin-l-yl)ethanone»HCl (C853-AQ-001)

[1166]

[1167] Attorney Docket No. 07039-2355WO1 / 2024-258

[1168] (S)-2-((Pyridm-4-ylmethyl)amino)-l-(3-(m-tolyloxy)pipendin-l-yl)ethanone»HCl (C853-AQ-001) was synthesized via Scheme 6 using starting materials (7?)-tert-butyl 3-hydroxypiperidine-l-carboxylate and / w-cresol: ESI MS m / z 340 [C20H25N3O2+ H]+

[1169] Preparation of C854-AQ-001.

[1170]

[1171] (, S')-2-((Pyridm-4-ylmethyl)amino)-l -(3-(m-tolyloxy )piperi din-1 -yl)ethanone was reacted via Method Kto provide (S)-A-(Pyridin-4-ylmethyl)-2-(3-(m-tolyloxy)piperidin-l-yl)ethanamine,2HCl (C854-AQ-001) (0.05 g, 47%); ESI MS m / z 326 [C20H27N3O + H]

[1172] Preparation of C904-AQ-001.

[1173] 4

[1174] "■0. HCI

[1175]

[1176] \=N

[1177] 3-(Pyridin-4-yl)-l -((17?,5iS)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-l-one (0.07 g, 0.20) was reacted via Method Kto provide (17?,5S)-8-(3-(pyridin-4-yl)propyl)-3-( / M-tolyloxy)-8-azabicyclo[3.2. l]octane«HCl (C904-AQ-001, 0.05 g, 72%): ESI MS m / z 337 [C22H28N2O + H]+

[1178] Preparation of C2938-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1179]

[1180] 2-((Pyndin-4-ylmethyl)amino)-l-((l / .5, S')-3-( / M-tolylo\y)-8-azabicyclo[3.2.1]octan-8-yl)ethanone*2HCl (C2938-AQ-001, 0.03 g, 23%) was synthesized via Scheme 6: ESI MS m / z 366 [C22H27N3O2 + H]+

[1181] Preparation of C940-AQ-001.

[1182]

[1183] (3.3'S)-r-(Pyridin-4-ylmethyl)-3-(m-tolyloxy)-l,3'-bipyrrolidine»2HCl (C940-AQ-001, 0.02 g, 23%) was prepared via Scheme 7: ESI MS m / z 338 [C21H27N3O + H]+

[1184] Preparation of C969-AQ-001.

[1185] •2HCI

[1186]

[1187] Attorney Docket No. 07039-2355WO1 / 2024-258

[1188] 3-((Pyndm-4-ylmethyl)amino)-l-((lA,5d)-3-( / w-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-l-one*2HCl (C969-AQ-001, 0.01 g, 26%) was synthesized via Scheme 6: ESI MS m / z 380 [C23H29N3O2 + H]+

[1189] Preparation of C970-AQ-001.

[1190] Preparation of 2-((17?,55)-3-( / n-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)ethanamine.

[1191]

[1192] H2N

[1193] 2-((17?,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1 ]octan-8-yl)ethanamine was prepared via Scheme 11 using starting materials (17?,5 )-ferf-butj’l 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and / n-cresol: ESI MS m / z 261 [C16H24N2O + H]+

[1194] Preparation of A-(Pyridin-4-ylmethyI)-2-((17?, SV)-3-(» / -tolyloxy)-8-azabicyclo [3.2.1] octan-8-yl)ethanamine*2HCl (C970- AQ-001).

[1195]

[1196] 2-((17?,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)ethanamine (0.02 g, 0.07 mmol) was reacted via Method E to provide 7V-(Pyridin-4-ylmethyl)-2-(( IR, 5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1 ]octan-8-yl)ethanamine,2HCl (C970. 0.02 g. 65%) as a white solid: ESI MS m / z 352 [C22H29N3O + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[1197] Preparation of C971-AQ-001.

[1198] Preparation of (2 / ?)-2- Amino-1 -((! / ?, 5A')-3-( / n-toly loxy)-8-azabicyclo [3.2.1] octan-8-yl)propan- 1-one.

[1199] O=C —

[1200] (R)^—

[1201]

[1202] H2N

[1203] (2?)-2-Amino-l-((17?,51S)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-l-one was prepared via Scheme 6 using starting materials \R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and m-cresol: ESI MS m / z 289 [C17H24N2O2 + H]++

[1204] Preparation of (27?)-2-((Pyridin-4-ylmethyl)amino)-l-((17?,55)-3-( / n-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-l-one»2HCl (C971-AQ-001).

[1205]

[1206] (2A)-2-Amino-l-((lA,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-l-one (0.08 g, 0.3 mmol) was reacted via Method E to provide (2R)-2-((pyridin-4-ylmethyl)amino)-l-((1?,51S)-3-( / n-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-l-one*2HCl (C971-AQ-001, 0.10 g, 75%) as a white solid: ESI MS m / z 380 [C23H29N3O2 + H]+

[1207] Preparation of C987-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1208]

[1209] , A-(Pyridm-4-ylmethyl)-3-(( l / .5, S')-3-(m-tolylo\y)-8-azabicyclo|3.2. 1 |octan-8-yl)propan-l-amine*3HCl (C987-AQ-001, 0.01 g, 24%) was prepared via Scheme 10:

[1210] ESI MS m / z 366 [C23H31N3O + H]+

[1211] Preparation of C988-AQ-001.

[1212]

[1213] (25)-2-((Pyridin-4-ylmethyl)amino)-l-((17?,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-l-one*2HCl (C988-AQ-001, 0.02 g, 50%) was prepared via Scheme 6 to give a white solid: ESI MS m / z 380 [C23H29N3O2 + H]++

[1214] Preparation of C989-AQ-001.

[1215] Preparation of (AHc / Z- Butyl 3-((methylsulfonyl)oxy)pyrrolidine-l-carboxylate.

[1216] pMs

[1217]

[1218] BocAttorney Docket No. 07039-2355WO1 / 2024-258

[1219] (< S)-to7-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-l -carboxylate was prepared via Method O and used crude in the next step.

[1220] Preparation of ( / ?)-4-((3-(4-( / »-Tolyloxy)piperidin-l-yl)pyrrolidin-l- yl)methyl)py ridine*2H Cl (C989-AQ-001)

[1221] (7?)-4-((3-(4-(m-Tolyloxy)piperidin-l -yl)pyrrolidin-l - yl)methyl)pyridine«2HCl (C989-AQ-001, 0.02 g, 28%) was prepared via Scheme 7:

[1222] ESI MS m / z 352 [C22H29N3O + H]+

[1223] Preparation of C990-AQ-001.

[1224]

[1225] (S)-4-((3-(m-Tolyloxy)pyrrolidin-l-yl)methyl)pyridine»HCl (C990-AQ-001) was prepared via Scheme 7 to give a white solid: ESI MS m / z 269 [C17H20N2O + H]+

[1226] Preparation of C991-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1227]

[1228] 4-((GS')-3-(GS')-3- m-Toly loxy )pi peridi n- 1 -yl)py rrolidin- 1 -yl)methyl)pyndine*2HCl (C991-AQ-001) was prepared via Scheme 7 to give a white solid: ESI MS m / z 352 [C22H29N3O + H]++

[1229] Preparation of C992-AQ-001.

[1230]

[1231] 4-(((\S')-3-( t / )-3-( / n-Tolyloxy)pipen din-1 -yl)pyrrolidin-l -yl)methyl)pyridine*2HCl (C992-AQ-001) was prepared via Scheme 7 to give a white solid: ESI MS m / z 352 [C22H29N3O + H]+

[1232] Preparation of C040-AQ-001.

[1233]

[1234] Attorney Docket No. 07039-2355WO1 / 2024-258

[1235] ((2i?)-JV-(Pyridin-4-ylmethyl)-l-((lT?,5S)-3-(7?7-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine»3HCl (C040-AQ-001, 0.04 g, 36%) was

[1236] prepared via Scheme 3 to give a white solid: ESI MS m / z 366 [C23H31N3O + H]++

[1237] Preparation of C041-AQ-001.

[1238]

[1239] (2S)-A-(Pyridin-4-ylmethyl)-l-((17?,5< S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine»2HCl (C041-AQ-001, 0.02 g, 42%) was

[1240] prepared via Scheme 10 to give a white solid: ESI MS m / z 366 [C23H31N3O + H]+

[1241]

[1242] Attorney Docket No. 07039-2355WO1 / 2024-258

[1243] Preparation of (A)-4-((3-(3-(nt-Tolyloxy)pyrrolidin-l-yl)azetidin-l-yl)methyl)pyridine»2HCl (C043-AQ-001)

[1244]

[1245] (S)-4-((3-(3-( / w-Tolyloxy)pyrroli din-1 -yl)azeti din-1 -yl)methyl)pyridine«2HCl (C043-AQ-001) was prepared via Scheme 1 to give a white solid (123 mg, 41%); ESI MS m / z 338 [C21H27N3O + H]+

[1246] Preparation of C044-AQ-001.

[1247]

[1248] A-(Pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)acetamide was reacted via Method K to provide jV-(pyridin-4-ylmethyl)-2-(5-( / w-tolyloxy)pyridin-3-yl)ethanamine»2HCl (C044-AQ-001, 0.02 g, 34%) as a white solid: ESI MS m / z 320 [C20H21N3O + H]++

[1249] Preparation of C045-AQ-001.

[1250]

[1251] Attorney Docket No. 07039-2355WO1 / 2024-258

[1252] (< S)-4-((3-(3-( / M-Tolyloxy)pyrroli din-1 -yl)azeti din-1 -yl)methyl)pyridine«2HCl (C045-AQ-001, 0.19 g, 57%) was synthesized via Scheme 1 to give a white solid: ESI MS m / z 324 [C20H25N3O + H]+

[1253] Preparation of C617-AQ-001.

[1254]

[1255] 2-Methyl-A-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propanamide»HCl (C617-AQ-001, 0.03 g, 12%) was synthesized via Scheme 9 to give a white solid: ESI MS m / z 362 [C22H23N3O2 + H]+

[1256] Preparation of C618-AQ-001.

[1257]

[1258] (S)-2-((Pyridin-4-ylmethyl)amino)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-l-one»2HCl (C618-AQ-001, 0.03 g, 71%) was prepared via Scheme 6 to give awhite solid: ESI MS m / z 354 [C21H27N3O2 + H]+

[1259] Preparation of C619-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1260]

[1261] 2-Methyl-jV-(pyridin-4-ylmethyl)-2-(5-( / n-tolyloxy)pyridin-3-yl)propanamide was reacted via Method Kto provide 2-methyl-Ar-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propan-l-amine«2HCl (C619-AQ-001, 0.10 g, 70%) as a white solid: ESI MS m / z 348 [C22H25N3O + H]+

[1262] Preparation of C660-AQ-001.

[1263]

[1264] (7?)-2-((Pyridin-4-ylmethyl)amino)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-l-one»2HCl (C660-AQ-001, 0.03 g, 76%) was prepared via Scheme 6 to give a white solid: ESI MS m / z 354 [C21H27N3O2+ H]+

[1265] Preparation of C661-AQ-001.

[1266]

[1267] Attorney Docket No. 07039-2355WO1 / 2024-258

[1268] GS')-A-(Pyridin-4-ylmethyl)-l -(4-(m-tolyloxy )piperi din-1 -yl)propan-2-amine»2HCl (C661-AQ-001. 0.02 g. 96%) was prepared via Scheme 10 to give a white solid: ESI MS m / z 340 [C21H29N3O + H]+

[1269] Preparation of C662-AQ-001.

[1270] •3HCI

[1271]

[1272] CR)-A-(Pyridin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine»3HCl (C662-AQ-001, 0.02 g, 83%) was prepared via Scheme 10 to give a white solid: ESI MS m / z 340 [C21H29N3O + H]+

[1273]

[1274]

[1275] Preparation of ( / ?)-A'-(Pyridin-4-ylmethyl)-l-(4-( / n-tolyloxy)piperidin-l-yl)propan-2- amine.Attorney Docket No. 07039-2355WO1 / 2024-258

[1276]

[1277] (7?)-A-(Pyridin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine was synthesized via Scheme 10 using rert-butyl 4-hydroxypiperidine-l -carboxylate and m-cresol as starting materials: ESI MS m / z 340 [C21H29N3O + H]+

[1278] Method AE: Preparation of ( / ?)- / V-Methyl- / V-(pyridin-4-ylmethyl)- l-(4- ( / n-tolyloxy )piperidin- l-yl)propan-2-amine»3HCl (C665-AQ-001).

[1279]

[1280] To a solution of ( )-A-(pyridin-4-ylmethyl)-l-(4-( / w-tolyloxy)piperidin-l-yl)propan-2-amine (0.03 g, 0.08 mmol) in 1,2-di chloroethane (5 rnL) was added paraformaldehyde (0.01 g, 0.4 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol) and the reaction left to stir at room temperature overnight. In the morning, sodium triacetoxy borohydride (0.12 g, 0.57 mmol) and sodium cyanoborohydride (0.03 g, 0.57 mmol) were added and the reaction stirred over the weekend at room temperature. After this time, the reaction was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (4g RediSepRF Gold column, methylene chloride to 30%

[1281] CMA(80%chloroform,l 8%Methanol,2%ammonium hydroxide) / methylene chloride to provide (A)-A-methyl-A-(pyridin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine which was diluted with acetonitrile and concentrated twice, then diluted again wi th acetonitrile. 1 N Aqueous hydrochloric acid was added and theAttorney Docket No. 07039-2355WO1 / 2024-258

[1282] mixture lyophilized overnight to give (A)-A-methyl- V-(pyridin-4-ylmethyl)- l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine*3HCl (C665-AQ-001) as a white solid (0.10 g, 24%): ESI MS m / z 354 [C22H31N3O + H]+

[1283] Preparation of C3703-AQ-001.

[1284] Preparation of 2-((5)-3-( / / / -Tolyloxy)pyrrolidin-l-yl)propan-l-aniine.

[1285]

[1286] 2-((S)-3-( / w-Tolyloxy)pyrrolidin-l-yl)propan-l-amine was synthesized via Scheme 1 using (A)-to7-butyl 3-hydroxypyrrolidine-l-carboxylate and m-cresol as starting materials: ESI MS m / z 235 [C14H22N2O + H]+

[1287] Preparation of / V-(2-((5')-3-( / n-Tolyloxy)pyrrolidin-l-yl)propyl)isonicotinamide»HCl (C3703-AQ-001).

[1288]

[1289] 2-((S)-3-(m-Tolyloxy)pyrrolidin-l-yl)propan-l-amine (0.03 g. 0.14 mmol) was reacted via Method H to provide A-(2-((5)-3-(m-tolyloxy)pyrrolidin-l-yl)propyl)isonicotinamide»HCl (C3703-AQ-001) as a white solid (0.03 g, 54%): ESI MS m / z 340 [C20H25N3O2+ H]+

[1290] Preparation of C3704-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1291]

[1292] (l / )- / V-(Pyridin-4-ylmethyl)-2-(( )-3-( / w-tolyloxy)pyrrolidin-l-yl)cyclopentanamine«2HCl (C3704-AQ-001) was synthesized via Scheme 1 to provide a white solid (0.03 g, 68%): ESI MS m / z 352 [C22H29N3O + H]+

[1293] Preparation of C847-AQ-001.

[1294]

[1295] (1 )-jV-(Pyridin-4-ylmethyl)-2-((S)-3-(»7-tolyloxy)pyrrolidin-l-yl)cyclopentanamine«2HCl (C847-AQ-001) was synthesized via Scheme 1 to provide a white solid (0.02 g, 41%): ESI MS m / z 352 [C22H29N3O + H]+

[1296] Preparation of C848-AQ-001.

[1297]

[1298] V-Methyl-A-(pyridin-4-ylmethyl)-2-((< S)-3-(w-tolyloxy)pyrroli din-1-yl)propan-l-amine«3HCl (C848-AQ-001) was synthesized via Scheme 17 to give a white solid (0.04 g, 54%); ESI MS m / z 340 [C21H29N3O + H]+

[1299] Preparation of C877-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1300]

[1301] 4-(((7?)-2-(((< S’)-3-(m-Tolyloxy)pyrrolidin-l-yl)methyl)pyrrolidin-l-yl)methyl)pyridine«3HCl (C877-AQ-001) was synthesized via Scheme 10 to give a white solid (0.09 g, 71%); ESI MS m / z 352 [C22H29N3O + H]+

[1302] Preparation of C878-AQ-001.

[1303] Preparation of A-(Pyridin-4-ylmethyl)-2-((5)-3-( / M-tolyloxy)pyrrolidin-l-yl)propan-l-amine.

[1304] O

[1305]

[1306] A-(Pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-l -amine was synthesized via Scheme 1 using

[1307]

[1308] 3-hydroxypyrrolidine-l-carboxylate and m-cresol as starting materials: ESI MS m / z 326 [C20H27N3O + H]+

[1309] Method AF: Preparation of A-Isopropyl-A / -(pyridin-4-ylmethyl)-2-((5)-3-(zM-tolyloxy)pyrrolidin- l-yl)propan- l-amine*3HCl (C878-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[1310]

[1311] To a solution of JV-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-l -amine (0.06 g. 0.2 mmol) in acetonitrile (4 mL) was added acetone (0.08 mL, 1 mmol) and sodium triacetoxyborohydride (0.08 g, 1 mmol) and the reaction left to stir at room temperature overnight. In the morning, acetone (0.08 mL, 1 mmol) and sodium triacetoxy borohydride (0.08 g, 1 mmol) were added and the reaction stirred another night at room temperature. This sequence was repeated for 3 more days. After this time, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (4g RediSepRF Gold column, methylene chloride to 40% CMA(80%chloroform,18%Methanol,2%ammonium hydroxide) / methylene chloride to provide A-isopropyl-A-(pyridin-4-yhnethyl)-2-((A)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-l-amine which was diluted with acetonitrile and concentrated twice, then diluted again with acetonitrile. 1 N Aqueous hydrochloric acid was added and the mixture lyophilized overnight to give jV-isopropyl-A-(pyridin-4-ylmethyl)-2-((<S)-3-(m-tolyloxy)pyrrolidin-l -yl)propan-I -amine»3HCl (C878-AQ-001) as a white solid (0.02 g, 22%): ESI MS m / z 368 [C23H33N3O + H]+

[1312] Preparation of C879-AQ-001.

[1313]

[1314] Attorney Docket No. 07039-2355WO1 / 2024-258

[1315] 4-(((< S)-2-(((S)-3-(w-Tolyloxy)pyrrolidin-l-yl)methyl)pyrrolidin-l-yl)methyl)pyridine*3HCl (C879-AQ-001) was synthesized via Scheme 10 to give a white solid (0.11 g, 79%): ESI MS m / z 352 [C22H29N3O + H]+

[1316] Preparation of C890-AQ-001.

[1317]

[1318] (2S)-Ar-(Furan-3-ylmethyl)-l-((17?,5< S’)-3-(m-tolyloxy)-8-azabicyclo[3.2. I]octan-8-yl)propan-2-amine*2HCl (C890-AQ-001) was synthesized via Scheme 10 to give a white solid (0.03 g, 42%): ESI MS m / z 355 [C22H30N2O2+ H]+

[1319] Preparation of C891-AQ-001.

[1320] HN

[1321]

[1322] (2A)-N-(4-Fluorobenzyl)-l-((17?,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine«2HCl (C891-AQ-001) was synthesized via Scheme 10 to give a white solid (0.03 g, 38%): ESI MS m / z 383 [C24H31FN2O + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[1323] Preparation of C892-AQ-001.

[1324]

[1325] (2S^-A-((2-Fluoropyridin-4-yl)methyl)-l-((1?,5S)-3-( / w-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine»2HCl (C892-AQ-001) was synthesized via Scheme 10 to give a white solid (0.02 g. 30%): ESI MS m / z 384 [C23H30FN3O + H]+

[1326] Preparation of C893-AQ-001.

[1327]

[1328] Preparation of (l / ?,3 / ?)-IMethyl 3-( / n-tolyloxy)cyclohexanecarboxylate.

[1329]

[1330] CO2CH3

[1331] (1,37?)-Methyl 3-(m-tolyloxy)cyclohexanecarboxylate was prepared via Method A: ESI MS m / z 249 [C15H20O3+ H]+

[1332] Preparation of (l / ?,3 / ?)-3-( / n-Tolyloxy)cyclohexanecarboxylic acid.Attorney Docket No. 07039-2355WO1 / 2024-258

[1333]

[1334] CO2H

[1335] ( l / .3 / )-Methyl 3-( / n-tolyloxy)cyclohexanecarboxylate (0.54 g, 2.2 mmol) was converted to (17?,3 )-3-(m-tolyloxy)cyclohexanecarboxylic acid (0.37 g. 73%) via Method Y: ESI MS m / z 235 [C14H18O3+ H]+

[1336] Preparation of A-(Pyridin-4-ylmethyl)-2-(5-(zM-tolyloxy)pyridin-3-yl)propanamide hydrochloride»HCl (C893-AQ-001).

[1337]

[1338] V-(Pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propan amide hydrochloride»HCl (C893-AQ-001) was prepared via Method T to give a white solid (0.09 g, 85%): ESI MS m / z 339 [C21H26N2O2+ H]+

[1339] Preparation of C894-AQ-001.

[1340]

[1341] ( 17?,3S)-jV-(Pyridin-4-ylmethyl)-3-(»i-tolyloxy)cyclohexanecarboxamide (0.09 g, 0.3 mmol) was reacted via Method K to provide 1 -(pyridin-4-yl)- V-((( 17?,3< S)-3-(m-tolyloxy)cyclohexyl)methyl)methanamine«2HCl (C894-AQ-001) as a white solid (0.06 g. 56%): ESI MS m / z 311 [C20H26N2O + H]+

[1342] Preparation of C895-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1343]

[1344] (17?,3S)-JV-(2-(Pyridin-4-yl)ethyl)-3-(m-tolyloxy)cyclohexanecarboxamide (0.09 g, 0.3 mmol) was reacted via Method K to provide 2-(pyridin-4-yl)- / V- (((1R,3S)-3-(m-tolyloxy)cyclohexyl)methyl)ethanamine•2HCl (C895-AQ-001) as a white solid (0.03 g, 26%): ESI MS m / z 325 [C21H28N2O + H]+

[1345] Preparation of C896-AQ-001.

[1346]

[1347] (3-(Pyridin-4-yl)pyrrolidin-l-yl)((17?,35)-3-(m-tolyloxy )cyclohexyl)methanone (0.09 g, 0.4 mmol) was reacted via Method K to provide 4-(1-(((1R,3S)-3-(m-tolyloxy)cyclohexyl)methyl)pyrrolidin-3-yl)pyridine•2HCl (C896-AQ-001) as a white solid (0.04 g, 33%): ESI MS m / z 351 [C23H30N2O + H]+

[1348] Preparation of C897-AQ-001.

[1349]

[1350] Attorney Docket No. 07039-2355WO1 / 2024-258

[1351] 4-((3-(4-(3-(Trifluoromethyl)phenoxy)piperidin-l -yl)pyrroli din-1 -yl)methyl)pyridine*2HCl (C897-AQ-001) was synthesized via Scheme 1 to give a white solid (0.04 g, 20%): ESI MS m / z 406 [C22H26F3N3O + H]+

[1352] Preparation of C898-AQ-001.

[1353]

[1354] 4-((3-(4-Phenoxypiperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine*2HCl (C898-AQ-001) was synthesized via Scheme 1 to give a white solid (0.04 g. 20%): ESI MS m / z 338 [C21H27N3O + H]+

[1355] Preparation of C934-AQ-001.

[1356]

[1357] ( 17?,3r,5S)-8-( l-Benzyl-lH-pyrrol-3-yl)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octane»HCl (C934-AQ-001) was synthesized via Scheme 1 to give a white solid (0.02 g, 12%): ESI MS m / z 373 [C25H28N2O + H]+

[1358] Preparation of C935-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1359]

[1360] 4-((3 -(4-(3 -(Trifluoromethy l)phenoxy)piperidin- 1 -yl)- 1 H-py rrol- 1 -yl)methyl)pyridine«2HCl (C935-AQ-001) was synthesized via Scheme 1 to give a white solid (0.02 g, 8%): ESI MS m / z 402 [C22H22F3N3O + H]+

[1361] Preparation of C936-AQ-001.

[1362]

[1363] 4-((3-(4-Phenoxypiperidin-l-yl)-lH-pyrrol-l-yl)methyl)pyridine*2HCl (C936- AQ-001) was synthesized via Scheme 1 to give a white solid (0.02 g, 10%); ESI MS m / z 334 [C21H23N3O + H]

[1364] Preparation of C937-AQ-001.

[1365]

[1366] Attorney Docket No. 07039-2355WO1 / 2024-258

[1367] (< S)-4-((4-(3-( / M-Tolyloxy)pyrrolidin-l-yl)piperidin-l-yl)methyl)pyridine*2HCl (C937-AQ-001) was synthesized via Scheme 1 to give a white solid (0.05 g, 45%): ESI MS m / z 352 [C22H29N3O + H]+

[1368] Preparation of C3938-AQ-001.

[1369]

[1370] (1R,3r,5S)-8-(1-(Pyridin-4-ylmethyl)piperidin-4-yl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane•2HCl (C3938-AQ-001) was synthesized via Scheme 1 to give a white solid (0.01 g, 12%): ESI MS m / z 392 [C25H33N3O + H]+

[1371] Preparation of C976-AQ-001.

[1372]

[1373] (2S)-N-((2-Methoxypyridin-4-yl)methyl)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine•2HCl (C976-AQ-001) was synthesized via Scheme 10 to give a white solid (0.04 g. 38%): ESI MS m / z 396 [C24H33N3O2 + H]+

[1374] Preparation of C977-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1375]

[1376] (35)- 1 '-Benzyl-3-(m-tolyloxy)-l,3'-bipyrrolidine*2HCl (C977-AQ-001) was synthesized via Scheme 1 to give a white solid (0.05 g, 21%): ESI MS m / z 337 [C22H28N2O + H]+

[1377] Preparation of C978-AQ-001.

[1378]

[1379] 4-(( 3 -(4-( 3 -(T rifluoromethoxy )phenoxy)piperidin- 1 -yl)pyrrolidin- 1 -yl)methyl)pyridine*2HCl (C978-AQ-001) was synthesized via Scheme 1 to give a white solid (0.05 g, 71%): ESI MS m / z 422 [C22H26F3N3O2 + H]+

[1380] Preparation of C979-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1381]

[1382] 4-((3-(4-(3,5-Difluorophenoxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine*2HCl (C979-AQ-001) was synthesized via Scheme 1 to give a white solid (0.05 g, 66%): ESI MS m / z 374 [C21H25F2N3O + H]+

[1383] Preparation of C980-AQ-001.

[1384] Preparation of (25)-l-((17?,55)-3-( / M-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2- amine.

[1385]

[1386] (2S)-l-((17?,5, S)-3-(m-Tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-2-amine was synthesized via Scheme 10 using starting materials ( l / .55')- / e / 7-butyl 3-hydroxy-8-azabicyclo[3.2. l]octane-8-carboxylate and m-cresol: ESI MS m,'z 275 [C17H26N2O + H]++

[1387] Preparation of (25)-AyV-Dimethyl-!-((! / ?, 55)-3-(wi- tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine»2HCl (C980-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[1388]

[1389] (2S)-1-((1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine (0.06 g, 0.2 mmol) was reacted via Method AD to provide (2< S)-A, A-dimethyl-l-(( 17?,55)-3-(m-tolyloxy)-8-azabicyclo[3.2.1 ]octan-8-yl)propan-2-amine*2HCl (C980-AQ-001) (0.06 g. 70%) as a white solid: ESI MS m / z 303 [C17H30N2O + H]+

[1390] Preparation of C008-AQ-001.

[1391] Preparation of (2S)-1-((1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine.

[1392]

[1393] (2< S)-l-((17?,5S)-3-(ffi-Tolyloxy)-8-azabicy7clo[3.2.1]octan-8-yl)propan-2-amine was prepared via Scheme 10 using ( l / .5, S')- / e / 7-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and m-cresol: ESI MS m / z' 275 [C17H26N2O + H]+

[1394] Preparation of N-((2A)-l-((l / ?,55’)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)tetrahydro-2E / -pyran-4-carboxamide.Attorney Docket No. 07039-2355WO1 / 2024-258

[1395]

[1396] o

[1397] (2S)-l-((17?,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-2-amine (0.06 g, 0.2 mmol) was reacted with tetrahydro-27 / -pyran-4-carboxylic acid (0.03 g, 0.2 mmol) via Method H to provide jV-((2S)-l-((17?,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)tetrahydro-2E7-pyran-4-carboxamide (0.03 g, 45%); ESI MS m / z 387 [C23H34N2O3 + H]+

[1398] Preparation of (2A)-A-((Tetrahydro-2 / / -pyran-4-yl)methyl)-l-((17?,5A)-3-(zw-tolyloxy)-S- azabicyclo [3.2. l]octan-8-yl)propan-2-amine»2HCl (C008-AQ-001)

[1399]

[1400] A-((2iS)-l-((17?,5<. S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)tetrahydro-2E7-pyran-4-carboxamide (0.03 g, 0.07 mmol) was reacted via Method K to provide (2<S)-JV-((tetrahydro-277-pyran-4-yl)methyl)-l-((17?,5S)-3-( / w-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine»2HCl (C008-AQ-001) as a white solid (0.03 g, 78%): ESI MS m / z 373 [C23H36N2O2 + H]+

[1401] Preparation of C009-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1402]

[1403] 4-((3-(4-Methoxypiperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine»2HCl (C009- AQ-001) was synthesized via Scheme 1 to give a white solid (0.15 g, 41%): ESI MS m / z 276 [C16H25N3O + H]+

[1404] Preparation of C038-AQ-001.

[1405]

[1406] (25)-jV-(4-Methoxybenzyl)-l-((17?,5A)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine»2HCl (C038-AQ-001) was synthesized via Scheme 10 to give a white solid (0.03 g, 35%): ESI MS m / z 395 [C25H34N2O2 + H]+

[1407] Preparation of C066-AQ-001.

[1408]

[1409] (S)-1-(4-Benzylpiperazin-1-yl)-N-((2-methylpyridin-4-yl)methyl)propan-2-amine•4HCl (C066-AQ-001) was prepared via Scheme 18 to give a white solid (0.04 mg, 52%): ESI MS m / z 339 [C21H30N4 + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[1410] Preparation of C067-AQ-001.

[1411]

[1412] 3-((l-(l-(Pyridin-4-ylmethyl)pyrrolidin-3-yl)piperidin-4-yl)oxy)-5- (trifluoromethyl)pyridine*3HCl (C067-AQ-001) was synthesized via Scheme 1 to give a white solid (0.17 g, 95%): ESI MS m / z 407 [C21H25F3N4O + H]+

[1413] Preparation of C068-AQ-001.

[1414]

[1415] (2S)-N-(Pyridin-3-ylmethyl)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine•3HCl (C068-AQ-001) was synthesized via Scheme 10 to give a white solid (0.02 g, 40%): ESI MS m / z 366 [C23H31N3O + H]

[1416] Preparation of C117-AQ-001.

[1417]

[1418] Attorney Docket No. 07039-2355WO1 / 2024-258

[1419] (2< S)-JV-((2-Methylpyridin-4-yl)methyl)-l-((1?,5S)-3-( / M-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine»2HCl (C117-AQ-001) was synthesized via Scheme 10 to give a white solid (0.03 g, 45%): ESI MS m / z 380 [C24H33N3O + H]+

[1420] Preparation of C118-AQ-001.

[1421]

[1422] (< S)-l-(4-(3-Methylbenzyl)piperazin-l-yl)-jV-(pyridin-4-ylmethyl)propan-2-amine»4HCl (Cl 18-AQ-001) was prepared via Scheme 18 to give a white solid (0.06 g, 63%): ESI MS m / z 339 [C21H30N4 + H]’

[1423] Preparation of C119-AQ-001.

[1424]

[1425] (S)-l-(4-(3-Methylbenzyl)piperazin-l-yl)-jV-((2-methylpyri din-4-yl)methyl)propan-2-amine«4HCl (Cl 19-AQ-001) was prepared via Scheme 18 to give a white solid (0.06 g, 62%): ESI MS m / z 353 [C22H32N4 + H]+

[1426] Preparation of C120-AQ-001.

[1427]

[1428] Attorney Docket No. 07039-2355WO1 / 2024-258

[1429] (S)-l-(4-(3-Methylbenzyl)piperazin-l-yl)-jV-(pyridin-3-ylmethyl)propan-2-amine»4HCl (C120-AQ-001) was prepared via Scheme 18 to give a white solid (0.06 g, 66%): ESI MS m / z 339 [C21H30N4 + H]’

[1430] Preparation of C121-AQ-001.

[1431] F

[1432] ■3HCI

[1433]

[1434] (5)-2-((Pyridin-4-ylmethyl)amino)-l-(4-(3- (trifluoromethyl)phenoxy)piperidin-l-yl)propan-l-one (0.13 g, 0.32 mmol) was reacted via Method K to provide (S)-A-(pyridin-4-ylmethyl)-l-(4-(3- (trifluoromethyl)phenoxy)piperidin-l-yl)propan-2-amine’3HCl (C121-AQ-001) to give a white solid (0.15 g, 90%): ESI MS m / z 394 [C21H26F3N3O + H]+

[1435] Preparation of C122-AQ-001.

[1436] ■3HCI

[1437]

[1438] (S)-l-(4-(3,5-Difluorophenoxy)piperidin-l-yl)-2-((pyridin-4-ylmethyl)amino)propan-l-one (0.24 g, 0.64 mmol) was reacted via Method Kto provide (S)-l-(4-(3,5-difluorophenoxy)piperidin-l-yl)-JV-(pyridin-4-ylmethyl)propan-2-amine»3HCl (C122-AQ-001) as a white solid (0.13 g. 30%): ESI MS m / z 362 [C20H25F2N3O + H]+

[1439] Preparation of C123-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1440]

[1441] (< S')-2-((Pyridin-4-ylmethyl)amino)-l-(4-(3-(trifluoromethoxy)phenoxy)piperidin-l-yl)propan-l-one (0.14 g, 0.33 mmol) was reacted via Method K to provide (S)-N-(pyridin-4-ylmethyl)-1-(4-(3-(trifluoromethoxy)phenoxy)piperidin-1-yl)propan-2-amine•3HCl (C123-AQ-001) as a white solid (0.11 g, 66%): ESI MS m / z 410 [C21H26F3N3O2 + H]+

[1442] Preparation of C124-AQ-001.

[1443]

[1444] (S)-l-(4-Phenoxypiperidin-l-yl)-2-((pyridin-4-ylmethyl)amino)propan-l-one (0.24 g. 0.70 mmol) was reacted via Method Kto provide (5)-l-(4-phenoxypiperidin-l-yl)-A-(pyridin-4-ylmethyl)propan-2-amine»3HCl (C124-AQ-001) as a white solid (0.13 g, 44%): ESI MS m / z 326 [C20H27N3O + H]+

[1445] Preparation of C126-AQ-001.

[1446]

[1447] Attorney Docket No. 07039-2355WO1 / 2024-258

[1448] (S)-A-(Quinolin-4-ylmethyl)-l-(4-( / n -tolyl oxy )piperidin-l-yl)propan-2-amine»3HCl (C126-AQ-001) was prepared via Scheme 10 to give a white solid (0.06 g, 58%): ESI MS m / z 390 [C25H31N3O + H]+

[1449] Preparation of C229-AQ-001.

[1450] Preparation of (5)-l-(4-(3-Methylbenzyl)piperazin-l-yl)propan-2-amine.

[1451]

[1452] H2N

[1453] (< S)-l-(4-(3-Methylbenzyl)piperazin-l-yl)propan-2-amine was prepared via Scheme 18 to give a clear oil (0.22 g, 69%): ESI MS m / z 248 [C15H25N3 + H]+

[1454] Preparation of (A)-A-(l-(4-(3-Methylbenzyl)piperazin-l-yl)propan-2-yl)tetrahydro-2 / / -pyran-4-carboxamide.

[1455] N N

[1456] H

[1457]

[1458] (5)-l-(4-(3-Methylbenzyl)piperazin-l-yl)propan-2-amine (0.05 g, 0.2 mmol)) was reacted with tetrahydro-277-pyran-4-carboxylic acid (0.03 g, 0.2 mmol) via Method I to provide (S)-2V-(l-(4-(3-methylbenzyl)piperazin-l-yl)propan-2-yl)tetrahydro-2E7-pyran-4-carboxamide (0.04 g, 59%) as a clear oil: ESI MS m / z 360 [C21H33N3O2 + H]+

[1459] Preparation of (A)-l-(4-(3-Methylbenzyl)piperazin-l-yl)-A'-((tetrahydro-2 / / -pyran-4-yl)methyl)propan-2-amine*3HCl (C229-AQ-001).

[1460] HN " ■3HCI

[1461]

[1462] Attorney Docket No. 07039-2355WO1 / 2024-258

[1463] (S)-N-(1-(4-(3-Methylbenzyl)piperazin-1-yl)propan-2-yl)tetrahydro-2H-pyran-4-carboxamide (0.04 g, 0.1 mmol)) was reacted via Method K to provide (S)-l-(4-(3-methylbenzyl)piperazin-l-yl)-A-((tetrahydro-2E7-pyran-4-yl)methyl)propan-2-amine»3HCl (C229-AQ-001) as a white solid (0.04 g, 82%): ESI MS m / z 346 [C21H35N3O + H]+

[1464] Preparation of C230-AQ-001.

[1465]

[1466] (5')-N-(Pyridin-4-ylmethyl)-l -(4-(3-(trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine«4HCl (C230-AQ-001) was prepared via Scheme 18 to give a white solid (0.05 g, 62%): ESI MS m / z 393 [C21H27F3N4 + H]+

[1467] Preparation of C231-AQ-001).

[1468]

[1469] (<S’)-A-((2-Methylpyridin-4-yl)methyl)-l-(4-(3- (trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine«4HCl (C231-AQ-001) was prepared via Scheme 18 to give a white solid (0.05 g, 56%): ESI MS m / z 407 [C22H29F3N4 + H]+

[1470] Preparation of C232-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[1471]

[1472] (5)-A-(Pyridin-3-ylmethyl)-l-(4-(3-(trifluoromethyl)benzy’l)piperazin-l-yl)propan-2-amine*4HCl (C232-AQ-001) was prepared via Scheme 18 to give a white solid (0.05 g, 62%): ESI MS m / z 393 [C21H27F3N4+ H]+

[1473] Preparation of C233-AQ-001.

[1474] •2HCI

[1475]

[1476] GS')-6-(((l-(4-(fli-Tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyrimidine-2,4( 1 H.3H)-dione*2HCI (C233-AQ-001) was prepared via Scheme 10 to give a white solid (0.02 g, 18%):

[1477]

[1478] ESI MS m / z 373 [C20H28N4O3 + H]+

[1479] Preparation of C271-AQ-001.

[1480]

[1481] (S)-4-(((l-(4-(m-Tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridin- 2(l / 7)-one*2HCl (C271-AQ-001) was prepared via Scheme 10 to give a white solid (0.03 g, 40%): ESI MS m / z 356 [C21H29N3O2 + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[1482] Preparation of C272-AQ-001.

[1483] •2HCI

[1484] (5)-5-((( l-(4-(m-Tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridin- 2(l / 7)-one»2HCl (C272-AQ-001) was prepared via Scheme 10 to give a white solid (0.05 g, 54%): ESI MS m / z 356 [C21H29N3O2 + H]+

[1485] Preparation of C273-AQ-001.

[1486] (5)-4-(((l-(4-(m-Tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridine l-oxide»3HCl (C273-AQ-001) was prepared via Scheme 10 to give a white solid (0.02 g, 22%): ESI MS m / z 356 [C21H29N3O2 + H]+

[1487] Alternatively, C273 was prepared as follows:

[1488] Preparation of C273-AQ-001.

[1489] Step 1: Preparation of 4-( / n-Tolyloxy (piperidine.

[1490]

[1491] Attorney Docket No. 07039-2355WO1 / 2024-258

[1492]

[1493] 4-(m-Tolyloxy)piperidine was prepared via Method A and Method B using starting materials piperidin-4-ol instead of (S)-tert-\>vAy\ 3-hydroxypyrrolidine-l-carboxylate and m-cresol: ESI MS m / z 192 [C12H17NO + H]+. 4-(m-Tolyloxy)piperidine could also be purchased.

[1494] Method A: Preparation of ( / ?)- / <?r / -Butyl 3-(wz-Tolyloxy)pyrrolidine-l-carboxylate.

[1495] N

[1496]

[1497] 1

[1498] Boc

[1499] To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2.50 g, 13.4 mmol) in tetrahydrofuran (60 mL) was added triphenylphosphine (4.20 g, 16.0 mmol) and the reaction cooled to 0°C in an ice / water bath. / n-Cresol (1.44 g, 13.4 mmol) was then added followed by dropwise addition of diisopropylazodicarboxylate (2.62 mL, 13.4 mmol). The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, the reaction was diluted with ethyl acetate and the organics were washed with 1 N aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (120g RediSepRF Gold column, 0-25% ethyl acetate / heptanes) to provide (R)-tert-butyl 3-(m-tolyloxy)pyrrolidine-1-carboxylate (2.95 g, 80%) as a white solid: ESI MS m / z 222 [M-t-Bu+H]+, [C12H15NO3+ H]+

[1500] Method B: Preparation of (7?)-3-(wt-Tolyloxy)pyrrolidine.Attorney Docket No. 07039-2355WO1 / 2024-258

[1501]

[1502] To a solution of (R)-tert-butyl 3-(m-tolyloxy)pyrrolidine-1-carboxylate (2.95 g, 10.6 mmol) in methylene chloride (25 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (8.14 mL, 106 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, saturated sodium bicarbonate was added (75 mL) slowly to pH~10 and the organics extracted with methylene chloride (x 3). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (80g RediSepRF Gold column, 100% methylene chloride to 60% CMA (80% chloroform, 18% methanol, 2% ammonium hydroxide):methylene chloride to provide (7?)-3-(m-tolyloxy)pyrrolidine (1.91 g. quantitative): ESI MS m / z 178 [C11H15NO + H]+

[1503] Step 2: Preparation of (. S')- / e / 7-Butyl ( l-Oxo-l-(4-( / w-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate.

[1504]

[1505] To a solution of 4-( / w-tolyloxy)piperidine (10 g, 52.3 mmol) in dimethylformamide (50 mL) was added (5)-2-((ter?-butoxycarbonyl)amino)propanoic acid (11.9 g, 62.7 mmol) and diisopropylethylamine (18.6 mL, 104.6 mmol).

[1506] Propylphosphonic anhydride (50% in ethyl acetate, 47.2 mL, 78.4 mmol) was then added and the reaction stirred at room temperature overnight. In the morning, the reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate (200 mL x 3). The combined organics were washed with water (100Attorney Docket No. 07039-2355WO1 / 2024-258

[1507] mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (80g RediSepRF Gold column, heptane to 50% ethyl acetate / heptane) to provide (S)- / er / -butyl ( 1-oxo-l -(4-(m-tolyloxy)piperidin-l-yl)propan-2-yl)carbamate (7.9 g, 42%): ESI MS m / z 363 [C20H30N2O4 + H]+

[1508] Step 3: Preparation of (5)-2- Amino- l-(4-( / n-tolyloxy)piperidin-l-yl)propan- 1-one.

[1509]

[1510] To a solution of (S)- / er / -butyl ( 1 -oxo- l-(4-(7n -tolyl oxy )piperidin-l-y l)propan-2-yl)carbamate (7.9 g, 21.8 mmol) in methylene chloride (50 mL), at 0 °C in an ice / water bath, was added trifluoroacetic acid (16.7 mL, 218 mmol) dropwise over 15 minutes. The reaction was then left to stir overnight (do not remove ice / water bath, let it melt). In the morning, the reaction mixture was concentrated in vacuo, taken up in methylene chloride and extracted with saturated sodium bicarbonate solution. The combined organics were washed with water (100 mL), brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide (S)-2-amino-1-(4-(m-tolyloxy)piperidin-1-yl)propan-1-one (5.5 g, quantitative): ESI MS m / z 263 [C15H22N2O2 + H]+

[1511] Step 4: Preparation of (A)-l-(4-( / n-Tolyloxy)piperidin-l-yl)propan-2-amine.

[1512]

[1513] Attorney Docket No. 07039-2355WO1 / 2024-258

[1514] To a solution of (5)-2-amino-l-(4-( / n -tolyl oxy )piperidin-l-yl)propan-l -one (5.5 g, 21 mmol) in tetrahydrofuran (100 mL) was added borane dimethylsulfide complex (21 mL, 42 mmol) under nitrogen atmosphere. The reaction was then placed in a pre-heated oil bath at 65 °C and stirred for 4 hours. The reaction was then cooled to 0 °C in an ice / water bath, methanol (20 mL) added and the reaction stirred at room temperature for 3 hours. Methanol (30 mL) was again added and the reaction mixture concentrated in vacuo and placed on a high-vac line overnight to provide (> S’)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine (4.5 g, crude): ESI MS m / z 249 [C15H24N2O + H]+

[1515] Step 5: Preparation of (X)-4-(((l-(4-( / n-Tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridine l-oxide»3HCl (C273-AQ-001)

[1516]

[1517] To a solution of (5)-l-(4-(m-tolyloxy)piperidin-l -yl)propan-2-amine (4.5 g, 18.1 mmol) and 4-formylpyridine 1 -oxide (2.2 g, 18.1 mmol) in methanol (45 mL) and acetic acid (cat). The reaction was then stirred at room temperature overnight. After 12h, STAB (9.6 g, 45.2 mmol) was then added and the reaction stirred at room temperature for 4 hours. The solvent was removed in vacuo. Purification by column chromatography (24g RediS epRF Gold column, methylene chloride to 10% methanol / methylene chloride) provided (5)-4-(((l-(4-(m-Tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridine 1 -oxide (3.75 g), which was purified by reverse phase column chromatography (column X Bridge C8 (19*250) 5p, 0.1% Ammonium hydroxide in water B: 100%ACN ) to provide (< S -4-(((l-(4-(m-Tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridine 1 -oxide (500 mg, 7% over two step). (< S)-4-(((l-(4-(m-Tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridine 1-oxide (20 mg) was diluted with acetonitrile and then 1 N Aqueous hydrochloric acid was added and the mixture lyophilized overnight to give (< S’)-4-(((l-(4-(m-Tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridine 1-Attorney Docket No. 07039-2355WO1 / 2024-258

[1518] oxide. HCl (C273-AQ-001) as a white sticky solid (22 mg ): ESI MS m / z 356 [C21H29N3O2 + H]

[1519] Preparation of C274-AQ-001.

[1520] Preparation of (S)-1-(4-(3-(Trifluoromethyl)benzyl)piperazin-1-yl)propan-2-amine.

[1521]

[1522] (S)-1-(4-(3-(Trifluoromethyl)benzyl)piperazin-1-yl)propan-2-amine was prepared via Scheme 18 to give a clear oil (0.27 g, 56%); ESI MS m / z 302 [C15H22F3N3 + H]+

[1523] Preparation of (S)-N-(1-(4-(3-(Trifluoromethyl)benzyl)piperazin-1-yl)propan-2-yl)tetrahydro-2H-pyran-4-carboxamide.

[1524] 1F

[1525] N

[1526]

[1527] (S)-1-(4-(3-(Trifluoromethyl)benzyl)piperazin-1-yl)propan-2-amine (0.05 g, 0.2 mmol) was reacted with tetrahydro-2H-pyran-4-carboxylic acid (0.03 g, 0.20 mmol) via Method I to provide (S)-A-(l-(4-(3-(trifluoromethyl)benzyl)piperazin-l-yl)propan-2-yl)tetrahydro-27 / -pyran-4-carboxamide (0.05 g, 75%) as a clear oil: ESI MS m / z 414 [C21H30F3N3O2 + H]+

[1528] Preparation of (S)-N-((Tetrahydro-2H-pyran-4-yl)methyl)-1-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)propan-2-amine•3HCl (C274-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[1529]

[1530] (5)-A-(l-(4-(3-(Trifluoromethyl)benzyl)piperazin-l-yl)propan-2-yl)tetrahydro-2 / / -pyran-4-carboxamide (0.05 g, 0.1 mmol)) was reacted via Method K to provide (S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-1-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)propan-2-amine•3HCl (C274-AQ-001) as a white solid (0.04 g, 72%): ESI MS m / z 400 [C21H32F3N3O + H]+

[1531] Preparation of C275-AQ-001.

[1532] Preparation of (S)-1-(4-(3-(Trifluoromethyl)benzyl)piperazin-1-yl)propan-2-amine.

[1533]

[1534] (S)-l -(4-(3-(Trifluoromethyl)benzyl)piperazin-l -yl)propan-2-amine was prepared via Scheme 18 to give a clear oil (0.27 g, 56%); ESI MS m / z 302 [C15H22F3N3 + H]+

[1535] Preparation of N-((S)-1-(4-(3-(Trifluoromethyl)benzyl)piperazin-1-yl)propan-2-yl)tetrahydrofuran-3-carboxamide.

[1536]

[1537] (S)-l-(4-(3-(Trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine (0.04 g, 0.1 mmol) was reacted with tetrahydrofuran-3-carboxylic acid (0.02 mg, 0.15 mmol)Attorney Docket No. 07039-2355WO1 / 2024-258

[1538] via Method I to provide N-((S)- 1 -(4-(3-(trifluoromethyl)benzyl)piperazin- 1 -yl)propan-2-yl)tetrahydrofuran-3-carboxamide (0.04 g, 78%) as a clear oil: ESI MS m / z 399 [C20H28F3N3O2 + H]+

[1539] Preparation of (2S)-N-((Tetrahydrofuran-3-yl)methyl)-1-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)propan-2-amine•3HCl (C275-AQ-001).

[1540]

[1541] N-((S)-1-(4-(3-(Trifluoromethyl)benzyl)piperazin-1-yl)propan-2-yl)tetrahydrofuran-3-carboxamide (0.04 g, 0.1 mmol)) was reacted via Method Kto provide (2S)-N-((tetrahydrofuran-3-yl)methyl)-1-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)propan-2-amine•3HCl (C275-AQ-001) as a white solid (0.03 g, 55%): ESI MS m / z 386 [C20H30F3N3O + H]+

[1542] Preparation of C298-AQ-001.

[1543] O

[1544]

[1545] 4-((((2S)-1-((1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)amino)methyl)pyridin-2(1H)-one•2HCl (C298-AQ-001) was synthesized via Scheme 10 to give a white solid (0.04 g, 49%): ESI MS m / z 382 [C23H31N3O2 + H]+

[1546] Preparation of C299-AQ-001.

[1547] Preparation of (25)- 1-((1J?, 55)-3-(wt-Tolyloxy)-8-azabicyclo [3.2.1] octan-8-yl)propan-2- amine.Attorney Docket No. 07039-2355WO1 / 2024-258

[1548]

[1549] NH2

[1550] (2S)-1-((1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine was synthesized via Scheme 10 to give a clear oil (0.40 g, 37%): ESI MS m / z 274 [C17H26N2O + H]++

[1551] Preparation of / V-((25’)-l-(( l / ?,55)-3-( / ;z-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)tetrahydrofuran-3-carboxamide.

[1552] HN

[1553]

[1554] O

[1555] (2S)-1-((1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine (0.06 g, 0.2 mmol) was reacted with tetrahydrofuran-3-carboxylic acid (0.04 g, 0.3 mmol) via Method 1 to provide N-((2S)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)tetrahydrofuran-3-carboxamide (0.06 g, 72%) as a clear oil: ESI MS m / z 373 [C22H32N2O3 + H]+

[1556] Preparation of (2S)-N-((Tetrahydrofuran-3-yl)methyl)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine•2HCl (C299-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[1557]

[1558] N-((2S)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)tetrahydrofuran-3-carboxamide (0.06 g, 0.2 mmol)) was reacted via Method Kto provide (2S)-N-((tetrahydrofuran-3-yl)methyl)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine•2HCl (C299-AQ-001) as a white solid (0.02 g, 30%): ESI MS m / z 359 [C22H34N2O2 + H]+

[1559] Preparation of C300-AQ-001.

[1560]

[1561] 5-((((2. S’)-l-((17?,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1 ]octan-8-yl)propan-2-yl)amino)methyl)pyridin-2(lE / )-one«2HCl (C300-AQ-001) was synthesized via Scheme 10 to give a white solid (0.03 g. 39%): ESI MS m / z 382 [C23H31N3O2 + H]+

[1562] Preparation of C301-AA-001.

[1563] O

[1564]

[1565] (S)-1-(4-(tert-Butoxy)piperidin-1-yl)-N-(pyridin-4-ylmethyl)propan-2-amine (C301-AA-001) was prepared via Scheme 10 to give a white solid (0.03 g, 17%): ESI MS m / z 306 [C18H31N3O + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[1566] Preparation of C439-AQ-001.

[1567] Preparation of (1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octane.

[1568]

[1569] (1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octane was prepared via Method A and Method B using starting materials ( 17?,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and m-cresol: ESI MS m / z 218 [C14H19NO + H]+

[1570] Preparation of (2S)-2-Morpholino-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one.

[1571]

[1572] (1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octane (0.11 g, 0.52 mmol) was reacted with (S)-2-morpholinopropanoic acid’HCI (0.12 g, 0.63 mmol) via Method AC to provide (2S)-2-morpholino-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-1-one (0.09 g. 51%): ESI MS m / z 359 [C21H30N2O3 + H]+

[1573] Preparation of 4-((2S)-1-((1R,5S)-3-(m-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)morpholine (C439-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[1574] •2HCI

[1575]

[1576] (2S)-2-Morpholino-l-((17?.5< S’)-3-(m-tolyloxy)-8-azabicyclo[3.2. l]octan-8-yl)propan-l-one (0.08 g, 0.2 mmol) was reacted via Method K to provide 4-((2S)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)morpholine (C439-AQ-001) as a white solid (

[1577]

[1578] 0.06 g, 62%): ESI MS m / z 345 [C21H32N2O2 + H]+

[1579] Preparation of C440-AQ-001.

[1580]

[1581] (2S)-N-(Quinolin-4-ylmethyl)-1-((1R,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine•2HCl (C440-AQ-001) was synthesized via Scheme 10 to give a white solid (0.03 g, 41%): ESI MS m / z 416 [C27H33N3O + H]

[1582] Preparation of C476-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1583]

[1584] A-((2S)-l-((17?,5S)-3-( / n-Tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)tetrahydro-227-pyran-4-amine’2HCl (C476-AQ-001) was synthesized via Scheme 10 to give a white solid (0.01 g, 19%): ESI MS m / z 359 [C22H34N2O2 + H]+

[1585] Preparation of C478-AQ-001.

[1586]

[1587] (S)-1-(4-Benzylpiperidin-1-yl)-N-((2-methylpyridin-4-yl)methyl)propan-2-amine•3HCl (C478-AQ-001) was synthesized via Scheme 19 to give a white solid (0.04 g, 43%): ESI MS m / z 338 [C22H31N3 + H]’

[1588] Preparation of C479-AQ-001.

[1589]

[1590] (5)-l-(4-Benzylpiperidin-l-yl)-7V-(pyridin-3-ylmethyl)propan-2-amine»3HCl (C479-AQ-001) was synthesized via Scheme 19 to give a white solid (0.06 g, 46%): ESI MS m / z 324 [C21H29N3 + H]+

[1591] Preparation of C481-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1592] Cl

[1593]

[1594] (S)-1-(4-(3-Chlorophenoxy)piperidin-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine•2HCl (C481-AQ-001) was prepared via Scheme 13 to give a white solid (0.11 g, 69%); ESI MS m / z 367 [C20H31N2O2 + H]+

[1595] Preparation of C482-AQ-001.

[1596]

[1597] (S)-1-(4-(4-Chlorophenoxy)piperidin-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine•2HCl (C482-AQ-001) was prepared via Scheme 13 to give a white solid (0.10 g, 62%): ESI MS m / z 367 [C20H31N2O2 + H]+

[1598] Preparation of C483-AQ-001.

[1599] Cl

[1600]

[1601] (S)-1-(4-(3-Chlorophenoxy)piperidin-1-yl)-N-(pyridin-4-ylmethyl)propan-2-amine•2HCl (C483-AQ-001) was prepared via Scheme 3 to give a white solid (0.04 g, 32%): ESI MS m / z 360 [C20H26N3O + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[1602] Preparation of C489-AQ-001.

[1603] Preparation of (A)-l-(4-Benzylpiperidin-l-yl)propan-2-amine.

[1604]

[1605] (S)-l-(4-Benzylpiperidin-l-yl)propan-2-amine was synthesized via Scheme 19 to give a clear oil (0.82 g, 80%); ESI MS m / z 233 [C15H24N2 + H]+

[1606] Preparation of (A)-A-(l-(4-Benzylpiperidin-l-yl)propan-2-yl)tetrahydro- 2H-pyran-4-carboxamide.

[1607]

[1608] (< S)-l-(4-Benzylpiperidin-l-yl)propan-2-amine (0.06 g, 0.2 mmol) was reacted with tetrahydro-2 / / -pyran-4-carboxylic acid (0.04 g. 0.3 mmol) via Method AG to give (S)-A-(I -(4-benzylpiperidin-l -yl)propan-2-yl)tetrahydro-2 / 7-pyran-4-carboxamide as a clear oil (0.06 g, 67%): ESI MS m z 345 [C21H32N2O2 + H]+

[1609] Preparation of (5)-l-(4-Benzylpiperidin-l-yl)-A-((tetrahydro-2Ef-pyran-4-yl)methyl)propan-2-amine»2HCl (C489-AQ-001).

[1610]

[1611] (, S')-N-( I -(4-Benz lpiperi din-1 -yl)propan-2-yl)t etrahydro-27f-pyran-4-carboxamide (0.06 g, 0.2 mmol) was reacted via Method K to give (S)-l-(4-benzylpiperidin-l-yl)-A-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine’2HCl (C489-AQ-001) as a white solid (0.03 g. 54%): ESI MS m / z 331 [C21H34N2O + H]+

[1612] Preparation of C490-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1613]

[1614] (< S)-l-(4-Benzylpiperidin-l-yl)-A-(quinolin-4-ylmethyl)propan-2-amine’3HCl (C490-AQ-001) was synthesized via Scheme 19 to give a white solid (0.04 g, 31%): ESI MS m / z 374 [C25H31N3 + H]+

[1615] Preparation of C529-AQ-001.

[1616]

[1617] GS')-l-(4-(3-Isopropylphenoxy)piperidin-l-yl)-A-((tetrahydro-2 / / -pyran-4-yl)methyl)propan-2-amine*2HCl (C529-AQ-001) was prepared via Scheme 13 (0.04 g, 38%) to give a white solid: ESI MS m / z 375 [C23H38N2O2 + H]+

[1618] Preparation of C530-AQ-001.

[1619]

[1620] (S)-l-(4-(3-Isopropylphenoxy)piperidin-l-yl)-jV-(pyridin-4-ylmethyl)propan-2-amine»2HCl (C530-AQ-001) was prepared via Scheme 3 to give a white solid (0.01 g, 9%): ESI MS m / z 368 [C23H33N3O + H]+

[1621] Preparation of C531-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1622]

[1623] (< S)-A-(Pyridazin-4-ylmethyl)-l-(4-(ffl-tolyloxy)piperidin-l-yl)propan-2-amine* 2HC1 (C53 l-AQ-001) was prepared via Scheme 3 to give a white solid (0.05 g, 57%): ESI MS m / z 341 [C20H28N4O + H]+

[1624] Preparation of C532-AQ-001.

[1625]

[1626] GS')-I -(4-Phenylpiperi din-1 -yl)-A-(pyridin-4-ylmethyl)propan-2-amine*3HCl (C532-AQ-001) was synthesized via Scheme 19 to give a white solid (0.05 g, 41%): ESI MS m / z 310 [C20H27N3 + H]+

[1627] Preparation of C533-AQ-001.

[1628]

[1629] (< S)-A-((2-Methylpyridin-4-yl)methyl)-l -(4-phenylpiperi din-1 -yl)propan-2-amine*3HCl (C533-AQ-001) was synthesized via Scheme 19 to give a white solid (0.03 g, 29%): ESI MS m / z 324 [C21H29N3 + H]’

[1630] Preparation of C534-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1631]

[1632] (5)-l-(4-Phenylpiperi din-1 -yl)-A-(pyridin-3-ylmethyl)propan-2-amine»3HCl (C534-AQ-001) was synthesized via Scheme 19 to give a white solid (0.05 g, 39%):

[1633] ESI MS m / z 310 [C20H27N3 + H]+

[1634] Preparation of C557-AQ-001.

[1635]

[1636] (< S)-l-(4-((5-Fluoropyridin-3-yl)oxy)piperidin-l-yl)-Ar-((tetrahydro-27 / -pyran- 4-yl)methyl)propan-2-amine*2HCl (C557-AQ-001) was prepared via Scheme 13 to give a white solid (0.04 g, 33%): ESI MS m 352 LC19H30FN3O2 + H]+

[1637] Preparation of C559-AQ-001.

[1638]

[1639] 4-Phenoxy-1-(3-(tetrahydro-2H-pyran-4-yl)propyl)piperidine•2HCl (C559-AQ-001) was prepared via Scheme 14 to give a white solid (0.01 g, 24%): ESI MS m / z 304 [C19H29NO2 + H]+

[1640] Preparation of C560- AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1641]

[1642] (5)-l-(4-Phenylpiperi din-1 -yl)-A-(quinolin-4-ylmethyl)propan-2-amine,3HCl (C560-AQ-001) was synthesized via Scheme 19 to give a white solid (0.05 g, 29%): ESI MS m / z 360 [C24H29N3 + H]+

[1643] Preparation of C561-AQ-001.

[1644] Preparation of (A)-l-(4-Phenylpiperidin-l-yl)propan-2-amine.

[1645]

[1646] (5)-l-(4-Phenylpiperidin-l-yl)propan-2-amine was synthesized via Scheme 19 to give a clear oil (0.84 g, 74%): ESI MS m / z 219 [C14H22N2 + H]+

[1647] Preparation of (5')-A'-(l-(4-Phenylpiperidin-l-yl)propan-2-yl)tetrahydro- 2H- pyran-4-carb oxamide.

[1648]

[1649] (S)-l -(4-Phenylpiperidin-l -yl)propan-2-amine (84 mg, 0.38 mmol) was reacted with tetrahydro-2 / / -pyran-4-carboxylic acid (0.06 g, 0.5 mmol) via Method AG to give (S)-N-( l-(4-phenylpiperidin-l -yl)propan-2-yl)tetrahydro-27 / -pyran-4-carboxamide as a white solid (0.04 g, 31%): ESI MS m / z 331 [C20H30N2O2 + H]+

[1650] Preparation of (A)-l-(4-Phenylpiperidin-l-yl)- / V-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine*2HCl (C561-AQ-001).Attorney Docket No. 07039-2355WO1 / 2024-258

[1651]

[1652] (S)-N-( 1 -(4-Phenylpiperi din-1 -yl)propan-2-y l)tetrahydro-2H-pyran-4-carboxamide (0.04 g, 0.1 mmol) was reacted via Method K to give (S)-l-(4-phenylpiperidin-l-yl)-jV-((tetrahydro-2E7-pyran-4-yl)methyl)propan-2-amine’2HCl (C561-AQ-001) as a white solid (0.04 g:83%): ESI MS m / z 317 [C20H32N2O + H]+

[1653] Preparation of C562-AQ-001.

[1654] Preparation of (5)-l-(4-Phenylpiperidin-l-yl)propan-2-amine.

[1655]

[1656] GS')- 1 -(4-Phenylpiperidin-l -yl)propan-2-amine was synthesized via Scheme 19 to give a clear oil (0.84 g, 74%): ESI MS m / z 219 [C14H22N2 + H]+

[1657] Preparation of Ar-((5)-l-(4-Phenylpiperidin-l-yl)propan-2-yl)tetrahydrofuran-3-carboxamide.

[1658]

[1659] GS')-l-(4-Phenylpipendin-l-yl)propan-2-amine (0.08 g, 0.4 mmol) was reacted with tetrahydrofuran-3-carboxylic acid (0.05 g, 0.4 mmol) via Method AG to giveA-((5)-l-(4-phenylpiperidin-l-yl)propan-2-yl)tetrahydrofuran-3-carboxamide as a clear oil (0.03 g, 25%): ESI MS m z 317 [C19H28N2O2 + H]+Attorney Docket No. 07039-2355WO1 / 2024-258

[1660] Preparation of (25)-l-(4-Phenylpiperidin-l-yl)-7V-((tetrahydrofuran-3-yl)niethyl)propan-2-amine»2HCl (C562-AQ-001.

[1661]

[1662] A-((5)-l-(4-Phenylpiperidin-l-yl)propan-2-yl)tetrahydrofuran-3-carboxamide (0.03 g. 0.08 mmol) was reacted via Method K to give (2S)-l-(4-phenylpiperidin-l-yl)-A-((tetrahydrofuran-3-yl)methyl)propan-2-amine»2HCl (C562-AQ-001) as a white solid (0.02 g, 79%): ESI MS m / z 303 [C19H30N2O + H]+

[1663] Preparation of C563-AQ-001.

[1664]

[1665] (l,5S)-8-(2-(Tetrahydro-2 / / -pyran-4-yl)ethyl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane»HCl (C563-AQ-001) was synthesized via Scheme 14 to give a white solid (0.02 g, 55%): ESI MS m / z 330 [C21H31NO2 + H]+

[1666] Preparation of C564-AQ-001.

[1667]

[1668] 4-(3-(( l / .5, S')-3-(m-Tolyloxy)-8-azabicyclo|3.2.1 ]octan-8-yl)propyl)morpholine*2HCl (C564-AQ-001) was synthesized via Scheme 14 to give a white solid (0.08 g, 85%); ESI MS m / z 345 [C21H32N2O2 + H]+

[1669] Preparation of C597-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1670]

[1671] (17?,5S)-8-(3-(Tetrahydro-277-pyran-4-yl)propyl)-3-( / w-tolyloxy)-8-azabicyclo[3.2.1]octane»HCl (C597-AQ-001) was synthesized via Scheme 14 to give a white solid (0.08 g, 65%): ESI MS m / z 344 [C22H33NO2 + H]+

[1672] Preparation of C599-AQ-001.

[1673]

[1674] (S)-4-(l-(4-(3-Methylbenzyl)piperidin-l-yl)propan-2-yl)morpholine»2HCl (C599-AQ-001) was synthesized via Scheme 20 to give a white solid (0.07 g, 55%): ESI MS m / z 317 [C20H32N2O + H]+

[1675] Preparation of C600-AQ-001.

[1676]

[1677] l-(2-(Tetrahydro-2 / 7-pyran-4-yl)ethyl)-4-(3-(trifluoromethyl)phenoxy)piperidine»2HCl (C600-AQ-001) was prepared via Scheme 14 to give a white solid (0.11 g, 57%); ESI MS m / z 358 [C19H26F3NO2 + H]+

[1678] Preparation of C601-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1679]

[1680] (S)-V-(Py rimidin-4-ylmethyl)- 1 -(4-(m-tolyloxy )piperi din-1 -y l)propan-2-amine»2HCl (C601-AQ-001) was prepared via Scheme 10 to give a white solid (0.10 g, 95%): ESI MS m / z 341 [C20H28N4O + H]+

[1681] Preparation of C602-AQ-001.

[1682]

[1683] GS')-N-((Tetrahydro-2 / / -pyran-4-yl)methyl)-l-((5')-3-(fl7-tolylo\\)pyrrolidin-l-yl)propan-2-amine*2HCl (C602-AQ-001) was prepared via Scheme 13 to give a white solid (0.07 g, 55%): ESI MS m / z 333 [C20H32N2O2 + H]+

[1684] Preparation of C603-AQ-001.

[1685]

[1686] Attorney Docket No. 07039-2355WO1 / 2024-258

[1687] (< S)-A-(Pyridin-4-ylmethyl)-l -((< S)-3-(w-toly loxy)pyrroli din-1 -yl)propan-2-amine»2HCl (C603-AQ-001) was prepared via Scheme 3 to give a white solid (0.08 g, 60%): ESI MS m / z 326 [C20H27N3O + H]+

[1688] Preparation of C628-AQ-001.

[1689]

[1690] 4-(3-Methylbenzyl)-l-(2-(tetrahydro-277-pyran-4-yl)ethyl)piperidine»HCl (C628-AQ-001) was synthesized via Scheme 20 to give a white solid (0.05 g, 46%): ESI MS m / z 302 [C20H31NO + H]+

[1691] Preparation of C629-AQ-001.

[1692] •2HCI

[1693]

[1694] 4-(3-(4-(3-Methylbenzyl)piperidin-l-yl)propyl)morpholine’2HCl (C629-AQ-001) was synthesized via Scheme 20 to give a white solid (0.08 g, 61%): ESI MS m / z 317 [C20H32N2O + H]+

[1695] Preparation of C644-AQ-001.

[1696] •HCI

[1697]

[1698] l-(3-(Tetrahydro-2 / / -pyran-4-yl)propyl)-4-(m-tolyl)piperidine*2HCl (C644- AQ-001) was synthesized via Scheme 20 to give a white solid (0.08 g, 55%); ESI MS m / z 302 [C20H30NO + H]+

[1699] Preparation of C645-AQ-001.

[1700]

[1701] Attorney Docket No. 07039-2355WO1 / 2024-258

[1702] (S)-4-( l-(4-(m-Tolyl)piperidin-l -yl)propan-2-yl)morpholine*2I IC1 (C645-AQ-001) was synthesized via Scheme 20 to give a white solid (0.12 g, 64%): ESI MS m / z 303 [C19H30N2O + H]+

[1703] Preparation of C646-AQ-001.

[1704] •2HCI

[1705]

[1706] 4-(3-(4-(m-Tolyl)piperidin-l-yl)propyl)morpholine»2HCl (C646-AQ-001) was synthesized via Scheme 20 to give a white solid (0.09 g, 68%): ESI MS m / z 303 [C19H30N2O + H]+

[1707] Preparation of C672-AQ-001.

[1708]

[1709] l-(2-(Tctrahydro-2H-pyran-4-yl)cthyl)-4-(m-tolyl)pipcndine*HCI (C672-AQ-001) was synthesized via Scheme 20 to give a white solid (0.05 g, 47%); ESI MS m / z 288 [C19H29NO + H]+

[1710] Preparation of C673-AQ-001.

[1711] •2HCI

[1712]

[1713] 4-(3-(4-(3-(Trifluoromethyl)phenoxy)piperidin-l-yl)propyl)morpholine*2HCl (C673-AQ-001) was synthesized via Scheme 14 to give a white solid (0.04 g, 61%); ESI MS m / z 373 [C19H27F3N2O2+ H]+

[1714] Preparation of C4703-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1715]

[1716] (S)-N-(Quinolin-4-ylmethyl)-1-(4-(m-tolyl)piperidin-1-yl)propan-2-amine•2HCl (C4703-AQ-001) was synthesized via Scheme 19 to give a white solid (0.05 g, 48%): ESI MS m / z 374 [C25H31N3 + H]’

[1717] Preparation of C4704-AQ-001.

[1718]

[1719] (S)-N-(Pyridin-4-ylmethyl)-1-(4-(m-tolyl)piperidin-1-yl)propan-2-amine•3HCl (C4704-AQ-001) was synthesized via Scheme 19 to give a white solid (0.04 g, 38%): ESI MS m / z 324 [C21H29N3 + H]+

[1720] Preparation of C733-AQ-001.

[1721]

[1722] (S)-N-((2-Methylpyridin-4-yl)methyl)-1-(4-(m-tolyl)piperidin-1-yl)propan-2-amine•3HCl (C733-AQ-001) was synthesized via Scheme 19 to give a white solid (0.04 g, 42%): ESI MS m / z 338 [C22H31N3 + H]’

[1723] Preparation of C734-AQ-001.Attorney Docket No. 07039-2355WO1 / 2024-258

[1724]

[1725] (S)-N-(Pyridin-3-ylmethyl)-1-(4-(m-tolyl)piperidin-1-yl)propan-2-amine•3HCl (C734-AQ-001) was synthesized via Scheme 19 to give a white solid (0.04 g, 42%): ESI MS m / z 324 [C21H29N3 + H]+

[1726] Preparation of C735-AQ-001.

[1727]

[1728] (S)-N-((Tetrahydro-2H-pyran-4-yl)methyl)-1-(4-(m-tolyl)piperidin-1-yl)propan-2-amine•2HCl (C735-AQ-001) was synthesized via Scheme 11 to give a white solid (0.02 g, 70%): ESI MS m / z 331 [C21H34N2O + H]+

[1729] Preparation of C736-AQ-001.

[1730]

[1731] (2S)-N-((Tetrahydrofuran-3-yl)methyl)-1-(4-(m-tolyl)piperidin-1-yl)propan-2-amine•2HCl (C736-AQ-001) was synthesized via Scheme 11 to give a white solid (0.01 g. 30%): ESI MS m / z 317 [C20H32N2O + H]+

[1732] Preparation of C771-AQ-001.

[1733]

[1734] Attorney Docket No. 07039-2355WO1 / 2024-258

[1735] (S)-1-((1R,5S)-3-(3-Methylbenzyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(quinolin-4-ylmethyl)propan-2-amine•3HCl (C771-AQ-001) was synthesized via Scheme 18 to give a white solid (0.01 g, 8%): ESI MS m / z 415 [C27H34N4 + H]+

[1736] Example 2 - Assays:

[1737] While the compounds herein can be used to treat neurodegenerative disorders, the improvement of mitochondrial function and cellular energetics together with enhanced protection against oxidative stress induced by these compounds are indicative of high relevance of such compounds to treating multiple human diseases or conditions. An example of such treatments is in vitro fertilization (IVF). It is well known that early embryonic development is characterized by rapid cell division and gene activation, making the embryo extremely sensitive to environmental influences, including generation of reactive oxygen species (ROS) by culture media utilized during the IVF. ROS have detrimental effects on early embryos, accounting for alterations in the segregation of chromosomes during meiosis, impaired fertilization, the blockade of embryos in the 2-cell stage, and low pregnancy rates.

[1738] Figures 1 and 2 show that the addition of representative compound C273 to the culture media enhances mouse early embryonic development and specifically protects against oxidative stress, one of the greatest risk factors involved in early embryo maturation in IVF. Treatment with C273 shortens time of embryonic cell division (Fig. 1), most likely due to a reduced oxidative DNA damage (Fig. 2) that requires less time for repair, enhancing the progression of embryonic development.

[1739] Figures 3-4 show the ability of representative compound C273 to protect MC65 neuroblastoma cells against Aβ toxicity (Fig. 3) and increase levels of NADPH and Glutathione in MC65 cells (Fig. 4), which show that C273 can be useful in treating neurodegenerative diseases such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and other neurodegenerative diseases disclosed herein.

[1740] The table below shows the results of two assays for a tested compound: a) a potency assay against amyloid beta toxicity in MC65 cells (columns 2-5); and b) cytotoxicity in MC65 cells Tet-On. The data were generated according to the following protocols:

[1741] Assay 1 (Cytotoxicity) and Assay 2 (Efficacy against Aβ) SOP

[1742]

[1743] Attorney Docket No. 07039-2355WO1 / 2024-258

[1744] 1. Cell Plating (0 hrs)

[1745] After cells are trypsinized and subsequentially quenched with DMEM media, cells are counted using Orflo Moxi Flow (cat # MX001). DMEM medium may be added to reach desired cell count of 500,000 cells / mL. To avoid clumping, cells are strained through a 40 mm Cell strainer (Falcon, cat#352340). After 1 µg / mL of Tetracycline is added (prepare fresh and use within 24 hours), cells are ready for plating. Cells are plated using Integra Assist plus robotic device (cat # 4505). Cells are mixed 3 times using a pipette, then 25 mL of the cell solution is put in a 25 mL reservoir. The cell solution is mixed again by the Assist plus, and 100 pL of the cell solution is dispensed into each well of a 96 well plate (Greiner cat # 655083). 2 plates can be dispensed at one time, and the cell solution is mixed by the Assist plus in between each plate. The plates are then left at room temperature out of the hood for ~ 20 minutes before being placed in the tissue culture incubator (37°C, 5% CO2). The number of plates seeded depends on the number of cells available for plating.

[1746] 2. Cell Treatment / Washing (24 hrs)

[1747] 1. Add DMSO (Sigma- Aldrich Cat# D2660) to a 10 mL boat and place in the automatic pipetor (Integra Assist Plus). Next, place 384-well polypropylene plates (Thermo Fisher Cat# 269390 in automatic pipetor.

[1748] 2. Run 384 FILL+SERIAL DILUTION program using 300 µL pipette. This will dispense 30 µL of DMSO into all wells in columns 2-12 on 384 well plate, except for column 3, which will dispense 54 µL of DMSO (Figure 10). The program will then pause and wait for the operator to add 6.0 µL of compound from 10 mM stock in DMSO into column 3 (yielding a 10-fold dilution to 1 mM). The operator will add 1 compound per row on the serial dilution plate.

[1749] 3. Place the 384-well plate back on the automatic pipetor and continue the program. The robot will mix wells in column 3, then take 30 pL and do a 2-fold serial dilution to column 12, mixing after each dilution. The mixing volume is 40 pL. NOTE: all mixes are done 6 times with 5 seconds pause in between

[1750] 4. Fill 25 rnL boat with sterile OPTI-MEM media and place in the automatic pipetor. Next, put the 384-well plate in the automatic pipetor.

[1751] 5. Run 384 WATER FILL program using 300 pL pipete. This will add 76 pL of OPTI-MEM in columns 14-24 (Figure 10)Attorney Docket No. 07039-2355WO1 / 2024-258

[1752] 6. Run 384 SD TRANSFER program using 12.5 µL pipette. This will transfer 4 µL from columns 2-12 and add them to columns 14-24 (for an overall 20-fold dilution = 4 / (4+76) @ 5% DMSO). It will also rearrange the serial dilution so that the lowest concentration is on the left and the highest concentration is on the right (Figure 10).

[1753] 7. Run 384 DILUTION MIX program using 300 pL pipette. This will mix the water / DMSO mixture using the same protocol as what was used during the serial dilution. The mixing volume is 50 pL.

[1754] 8. Run 384 transfer AB on 12 channel 12.5 µL pipette. This will transfer 5 µL / well from row A, columns 14-24 to rows A-D on the white 96 well plate for assays 1 and 2 (Evergreen Cat# 333-8091-W1L) or clear 96 well plate for assay 3 (Falcon Cat# 353072) in 245 µL OPTI-MEM media (for an overall 50-fold dilution (5 / (5+245) @ 0.1% DMSO final concentration). Then, it will use new tips to transfer 5 µL / well from row B, columns 14-24 to rows E-H on the same white 96 well plate. Compounds 1 and 2 will be transferred to the same plate using 384 transfer AB (Figure 11) and compounds 3 and 4 will be transferred to a different plate using 384 transfer CD (Figure 11).

[1755] Washing SOP

[1756] 1. Dump old media.

[1757] 2. Add 200 pL / well phenol red free OPTI-MEM media with 1250 pL automatic pipette (dispense speed 3)

[1758] 3. Wait at least 30 minutes.

[1759] 4. Dump media

[1760] 5. Add 245 pL / well phenol red free OPTI-MEM media with 1250 pL automatic pipette (dispense speed 3). For TET-ON MC65 cells, add tetracycline to a final concentration of 1 pg / mL.

[1761] 3. ATP Luminescence Assay Reading (48 hrs) 1. Using the Integra Assist Plus 300 pL pipette run the MT ASPIRATION program to aspirate the excess volume where 40 uL of OPTI-MEM is left inside well.Attorney Docket No. 07039-2355WO1 / 2024-258

[1762] 2. Add 25 mL of the ATP Cell Titer Gio assay reagent to a 25 mL boat for the Integra Assist Plus robot and using the 300 pL automatic pipette run the Cell titer 40 uL program to add 40 uL of the ATP reagent to each well of the plate.

[1763] 3. Incubate the plates with the cell-titer gio added in well for 15 minutes before 5 reading luminescence in the microplate reader.

[1764] Compound ID EC50 run 1 EC50 run 2 average EC 50 EC50 ranking: Cytotoxicity (nM) (nM) (nM)

[1765] EC50: Cytotoxic at 1 pM: + 1000 - EC50: No cy to toxicity at 1 pM: - 250-999 +

[1766] EC50: 100-249

[1767] ++ EC50: 50-99

[1768] +++ EC50: 2-49

[1769] ++++ EC50: <2

[1770] +++++

[1771] C771 8.86 8.86 ++++ - C736 1000 1000 - - C735 1000 1000 1000 - + C734 16.7 16.7 ++++ - C733 1.32 2.09 1.705 +++++ - C705 1000 1000 - + C4704 2.54 2.86 2.7 ++++ + C4703 9.18 7.08 8.13 ++++ - C673 4.06 6.5 5.28 ++++ - C672 1000 1000 - + C646 1000 1000 - + C645 1000 1000 1000 - + C644 1000 1000 - - C629 1000 1000 - + C628 1000 1000 1000 - - C603 15.3 15.3 ++++ + C602 0.74 1.46 1.1 +++++ - C601 4.13 4.13 ++++ -

[1772]

[1773] Attorney Docket No. 07039-2355WO1 / 2024-258

[1774] C600 1000 1000 - - C599 1000 1000 - + C598 1000 1000 1000 - - C597 1000 1000 1000 - - C564 1000 1000 - - C563 1000 1000 - - C562 14.8 21.4 18.1 ++++ - C561 2.03 2.8 2.415 ++++ + C560 251 251 + - C559 9.98 9.98 ++++ - C558 1000 1000 - - C557 2.2 3.38 2.79 ++++ - C534 2 2 ++++ - C533 2 12.8 7.4 ++++ - C532 3.41 3.41 ++++ - C531 4.99 4.99 ++++ - C530 4.47 9.93 7.2 ++++ - C529 2 2 ++++ - C490 9.86 9.86 ++++ - C489 2 2 ++++ - C483 2 2 ++++ - C482 0.062 0.125 0.0935 +++++ - C481 0.062 0.062 0.062 +++++ - C480 2 2 ++++ + C479 16.2 6.33 11.265 ++++ - C478 4.38 4.38 ++++ - C477 11.7 11.7 ++++ - C476 0.18 0.234 0.207 +++++ + C440 3.33 11.4 7.365 ++++ - C439 2 2 ++++ - C438 0.293 0.139 0.216 +++++ - C301 55.3 55.3 +++ - C300 2 2 ++++ - C299 3.02 1.33 2.175 ++++ + C298 5.7 5.7 ++++ -

[1775]

[1776] Attorney Docket No. 07039-2355WO1 / 2024-258

[1777] C275 22.9 22.9 ++++ - C274 5.2 5.2 ++++ - C273 35.7 35.7 ++++ - C272 2 2 ++++ - C271 12.8 12.8 ++++ - C234 2 0.125 1.0625 +++++ - C233 440 440 + - C232 16.3 9.89 13.095 ++++ - C231 20.5 20.5 ++++ - C230 8.83 8.19 8.51 ++++ - C229 69.3 20.1 44.7 ++++ - C126 11.2 11.9 11.55 ++++ - C125 7.45 3.99 5.72 ++++ - C124 2 0.545 1.2725 +++++ - C123 3.72 3.72 ++++ - C122 2 0.125 1.0625 +++++ + C121 2 0.125 1.0625 +++++ - C120 9.62 18.3 13.96 ++++ - C119 42.9 42.9 ++++ - C118 34.1 34.1 ++++ - C117 2 2.23 2.115 ++++ - C068 7.88 10.7 9.29 ++++ - C067 1.23 1.4 1.315 +++++ - C066 2 2 ++++ - C065 16.2 11.8 14 ++++ - C038 1.74 0.82 1.28 +++++ - C009 1000 1000 - - C008 2 0.528 1.264 +++++ - C980 2.5 5.38 3.94 ++++ - C979 1000 1000 - + C978 1000 1000 - + C977 3.73 8.428 6.079 ++++ - C976 0.676 1.53 1.103 +++++ - C3938

[1778] C937 1000 1000 - -

[1779]

[1780] Attorney Docket No. 07039-2355WO1 / 2024-258

[1781] C936 1000 1000 1000 - - C935 253 483 368 + - C934 1000 1000 - - C898 1000 1000 - - C897 0.877 2.02 1.4485 +++++ - C896 1000 1000 - + C895 1000 1000 - + C894 1000 1000 - + C893 1000 1000 - + C892 1000 1000 - - C891 1000 1000 - + C890 3.68 2.64 3.16 ++++ - C879 1000 1000 - - C878 1000 1000 - - C877 1000 1000 - - C848 1000 1000 - - C847 1000 1000 - - C3704 1000 1000 - - C3703 1000 1000 - - C665 0.696 1.41 1.053 +++++ - C664 1000 1000 - - C663 5.18 30.2 17.69 ++++ - C662 3.9 3.76 3.83 ++++ - C661 0.125 0.176 0.1505 +++++ - C660 219.7 219.7 ++ - C619 1000 1000 - - C618 1000 1000 - + C617 1000 1000 - - C616 1000 1000 - - C064 1000 1000 - - C045 42.4 94.8 68.6 +++ - C044 1000 1000 - - C043 1000 1000 - - C042 1000 1000 - - C041 3.05 6.21 4.63 ++++ +

[1782]

[1783] Attorney Docket No. 07039-2355WO1 / 2024-258

[1784] C040 1000 1000 1000 - + C992 1000 1000 - - C991 1000 1000 - - C990 1000 1000 - - C989 8.36 6.81 7.585 ++++ - C988 1000 1000 1000 - + C987 2 2 ++++ - C971 1000 1000 1000 - - C970 5.99 8.24 7.115 ++++ - C969 1000 1000 - - C940 5.99 8.24 7.115 ++++ - C939 1000 1000 1000 - - C2938 1000 1000 1000 - - C904 68.3 35.3 51.8 +++ - C903 1000 1000 1000 - - C854 1000 1000 - - C853 1000 1000 - - C852 1000 1000 - - C833 1000 1000 - - C832 1000 1000 - - C831 1000 1000 - - C830 1000 1000 - - C829 1000 1000 - - C828 1000 1000 - - C764 185.6 179.5 182.55 ++ - C763 1000 1000 - - C762 1000 1000 - + C761 100 100 ++ - C2704 4.73 6.74 5.735 ++++ - C2703 1000 1000 1000 - - C702 1000 1000 - - C701 1000 1000 - - C700 1000 1000 - - C699 1000 1000 - - C698 1000 1000 1000 - +

[1785]

[1786] Attorney Docket No. 07039-2355WO1 / 2024-258

[1787] C697 1000 1000 1000 - - C696 1000 1000 1000 - - C510 4.32 3.14 3.73 ++++ - C509 10.7 8.19 9.445 ++++ - C508 6.8 7.13 6.965 ++++ -

[1788]

[1789] Assay 3 - Effect of compound C273 on AMPKa and mitochondrial biogenesis

[1790] Figure 12 shows that compound C273 activates AMPKa and mitochondrial biogenesis in human PBMCs. Treatment of human Peripheral Blood Mononuclear Cells (PBMCs) with C273 resulted in the activation of mechanisms of action associated with the efficacy of small molecule mitochondrial complex I inhibitors.

[1791] These mechanisms include the activation of AMP-activated protein kinase (AMPK) and mitochondrial biogenesis, resulting in increased expression of the OXPHOS complexes I-V. For comparison, the data include treatment with vehicle (Veh), CP2 and its individual diastereoisomers (DI and D2), and metformin (MF). Note that metformin, a non-specific complex I inhibitor, induced similar mechanisms at significantly higher concentrations compared to CP2, DI, D2 and C273. This suggests that the activation of the mechanism of action associated with the efficacy of C273 and other complex I inhibitors could be observed in human blood cells.

[1792] Assay 4 - Binding to mitochondrial complex I is required for the therapeutic efficacy of small-molecule complex I inhibitors.

[1793] Figure 13 demonstrates that C273, like other small molecules C458 and CP2 used for C273 rational design, binds to the Q site of complex I. Since rotenone also binds irreversibly to the same pocket with higher affinity, rotenone was used at concentrations that do not cause cellular toxicity for the competitive binding experiment. The efficacy of C273 was assessed in MC65 Tet OFF cells both with and without rotenone pretreatment (Figure 13). The data indicate that the efficacy of C273 against Ap toxicity in MC65 Tet OFF cells (Figure 13, blue line) was lost after pretreatment with rotenone (Figure 13, red line). These data suggest that rotenone binding to the Q site of complex I blocks C273 efficacy, confirming that binding toAttorney Docket No. 07039-2355WO1 / 2024-258

[1794] the Q site is essential for C273-dependent activation of neuroprotective mechanisms. These data indicate the specificity and selectivity of complex I as a target of C273.

[1795] Assay 5 - C273 reduces inflammation by decreasing NF-KB activation induced by IL-ip and TNFa in HEK293 cells.

[1796] As shown in Figure 14, treatment with IL-1 or TNFa induces NF-KB activation and inflammation. Treatment with small molecule complex I inhibitors CP2 and C273 reduces NF-kB -dep endent inflammation. AICAR was used as a positive control for AMPK activation. Complex I inhibitor metformin shows similar protection at a significantly higher concentration.

[1797] Assay 6 - Preliminary toxicology study on wild-type female mice administered C273.

[1798] Wild-type female mice were treated with C273 for 30 days viaa<7 libitum drinking water. Four groups (n = 5 mice per group) were treated with vehicle, 20 mg / kg / day, 50 mg / kg / day, and 80 mg / kg / day of C273. Weight was measured weekly. After 4 weeks, mice were evaluated for locomotor activity. Afterward, the mice were sacrificed, and their tissues were sent for histopathological evaluation to the CRO. As shown in Figure 15, analyses suggest that C273 did not elicit any toxicity and did not affect weight gain or locomotor activity at any C273 concentration tested.

[1799] Assay 7 - C273 has a good safety margin regarding hERG inhibition.

[1800] As shown in Figure 16, no hERG inhibition was detected at concentrations up to 1 pM, and incomplete inhibition of -80% at much higher concentrations (30 pM) with IC50= 6.31 μM for C273. This IC50 exceeds the efficacious EC50 established in the MC65 Tet OFF assay (protection against Ab toxicity) by 500-fold, indicating a good safety profile.

[1801] Assay 8 - Effect of treatment with C458 on the levels of Ap and p-Tau T181Attorney Docket No. 07039-2355WO1 / 2024-258

[1802] Figure 17 shows the effect of treatment with C458 on the levels of Ap and p-Tau T181 in iPSC-derived organoids from patients with sporadic AD. a-c The levels of Aβ40, Aβ42, and Aβ42 / Aβ40 in RIPA fractions from human iPSC-derived organoids treated with vehicle or C458 w^ere measured by ELISA, d-f The levels of p-Tau T181. total tau. and pTau / Tau in RIPA fractions from human iPSC-derived organoids treated with vehicle or C458 were measured by ELISA. The data were normalised to the total protein concentration of each sample (n = 3

[1803] organoids per treatment, measured in duplicate). The data are expressed as the means ± SDs. Statistical analysis was performed via Student's t tests or one-way ANOVA. *P < 0.05, ** < 0.01. *** < 0.001.

[1804] OTHER EMBODIMENTS

[1805] It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Attorney Docket No. 07039-2355WO1 / 2024-258Claims:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:Ais Ci-Ce alkyl orAr is phenyl or 6-membered heteroaryl having one or two ring heteroatoms atoms each independently selected from O, S andN;n = 0-5:each R1is independently selected from CN, NO2, C(O)ORal, ORal, NRclRdl, Cy1, Ci-6 alkyl, and Ci-6 haloalkyl, wherein said Ci-6 alkyl is optionally substituted with CN, C(O)ORal, ORal. NRclRdl, or Cy2;X1is absent, O. NR2or CR3R4;X2is N or CR3;m = 0 or 1;R2, R3, R4, R5, R6and R7are each independently selected from H, Cy3, C(=O)Cy3, Ci-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2.6alkynyl, C(O)Rbl, C(O)NRclRdl, C(O)ORal, S(O)2Rbl, and S(O)2NRclRdl, wherein said C1-6 alkyl is optionally substituted with Cy4, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, or NRclRdl;or R5and R6taken together with atoms connecting them form a 4. 5, 6, 7- or 8- carbocyclic or heterocyclic ringor 2 R7taken together with the atoms connecting them form a 5, 6, or 7-cycloaliphatic or heterocycloaliphatic ring;or 2 R7bonded to the same carbon atom form C=O;X3=N or CR3;L = Co-C6alkylene optionally substituted with 1-6 R7;Attorney Docket No. 07039-2355WO1 / 2024-258R10is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl or NR8R9;R8and R9are each independently selected from H, Cy5, C(=O)Cy5, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rbl, C(O)NRclRdl, C(O)ORal, S(O)2Rbl, S(O)2NRclRdl,wherein said C1-6 alkyl is optionally substituted with Cy6, CN. NO2, ORal, C(O)Rbl. C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0. orNRclRdlwherein said R105-10-membered carbocyclyl OR 5- 10-membered heterocyclyl is optionally substituted with Cy7-Ci-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl;each Rblis independently selected from C1-3 alkyl, C1-3 haloalkyl, Cy8, Cy8-Ci-3 alkylene, NRc2Rd2-Ci-3 alkylene, C(O)ORa2-Ci-3 alkylene, and ORa2-Ci-3 alkylene;each Ral, Rcland Rdlis independently selected from H, C1-3 alkyl, C1-3 haloalkyl, Cy9, Cy9-Ci-3 alkylene, NRc2Rd2-Ci-3 alkylene, C(O)ORa2-Ci-3 alkylene, and ORa2-Ci-3 alkylene;Cy1, Cy2, Cy3. Cy4, Cy5, Cy6, Cy7’ Cy8and Cy9are each independently selected from Ce-io aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl such as 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy; each RCyis independently selected from halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, S(O)2Rb2, and S(O)2NRc2Rd2; wherein said C1-6 alkyl is optionally substituted with CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, S(O)2Rb2, or S(O)2NRc2Rd2;each Ra2, Rc2, and Rd2is independently selected from H, C1-6 alkyl, and C1-4 haloalkyl; andeach Rb2is independently selected from C1-6 alkyl and C 1-4 haloalkyl.

2. The compound of claim 1, wherein A is3. The compound of claim 2, wherein Ar is phenyl.

4. The compound of any one of the preceding claims, wherein X1is O.

5. The compound of any one of claims 1-3, wherein X1is CH2.Attorney Docket No. 07039-2355WO1 / 2024-2586. The compound of any one of claims 1-3, wherein X1is absent.

7. The compound of any one of the preceding claims, wherein R1is CH3.

8. The compound of any one of claims 1-6, wherein R1is CF3.

9. The compound of any one of the preceding claims, whereinR®X2'N,510. The compound of any one of claims 1 -8, w herein,611. The compound of any one of the preceding claims, wherein R10is NR8R9and R9is H and R8is Ci-6 alkyl optionally substituted with Cy^.

12. The compound of claim 11, wherein Cy6is 5-14 membered heteroaryl such as 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected from RCy.

13. The compound of claim 11, wherein Cy6is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from RCy.

14. The compound of claim 11, wherein Cy6is pyridinyl optionally substituted with RCy.

15. The compound of claim 11, wherein Cy6is 4-pyridinyl optionally substituted with RCy.

16. The compound of claim 11, wherein Cy6is quinolinyl optionally substituted with RCy.

17. The compound of claim 11, wherein Cy6is 3-pyridinyl optionally substituted with RCy.

18. The compound of claim 11, wherein Cy6is pyrimidinyl optionally substituted with RCy.Attorney Docket No. 07039-2355WO1 / 2024-25819. The compound of claim 11, wherein Cy6is tetrahydropyranyl (THP) optionally substituted with RCy.

20. The compound of claim 11, wherein Cy6is tetrahydrofuranyl (THF)optionally substituted with RCy.

21. The compound of claim 11, wherein Cy6is morpholino optionally substituted with RCy.

22. The compound of any one of claims 1-10, wherein R10is a 5-6-membered heterocyclyl wherein an N atom is connected to L.

23. The compound of any one of claims 1-10, wherein R10is a 5-10-membered heterocyclyl, optionally substituted with Cy7-Ci-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl.

24. The compound of any one of claims 1-10, wherein R10is a 5-10-membered heterocycloalkyl, optionally substituted with Cy7-Ci-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl.

25. The compound of any one of claims 1-10, wherein R10is a 5-10-membered heteroaryl, optionally substituted with Cy7-Ci-2 alkyl, CN, NO2. ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl.

26. The compound of any one of claims 1-10, wherein R10is l,3-dihydro-2H- pyrrolo[3,4-c]pyridine, optionally substituted withCy7-Ci-2 alky l, CN, NO2, ORal. C(O)Rbl. C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0. orNRclRdl.

27. The compound of any one of claims 1-10, wherein R10is pyridinyl, optionally substituted with Cy7-Ci-2alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl.

28. The compound of any one of claims 1-10, wherein R10is 4-pyridinyl, optionally substituted with Cy7-Ci-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl.

29. The compound of any one of claims 1-10, wherein R10is 3-pyridinyl, optionally substituted with Cy7-Ci-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0. orNRclRdl.

30. The compound of any one of claims 1-10, wherein R10is pyrimidinyl, optionally substituted with Cy7-Ci-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl.

31. The compound of any one of claims 1-10, wherein R10is tetrahydropyranylAttorney Docket No. 07039-2355WO1 / 2024-258(THP), optionally substituted with Cy7-Ci-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl.

32. The compound of any one of claims 1-10, wherein R10is tetrahydrofuranyl (THF), optionally substituted with Cy7-Ci-2 alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl.

33. The compound of any one of claims 1-10, wherein R10is morpholino, optionally substituted with Cy7-Ci-2 alkyl. CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, orNRclRdl.

34. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (IA):whereinX1is O, CH2, or absent;m is 0 or 1;R3and R6are each H; or R3and R6taken together with atoms connecting them form a 4, 5, 6, 7- or 8- carbocyclic or heterocyclic ring;L = is C2-C3alkylene optionally substituted with methyl;andR10is a 5-10-membered heterocyclyl orNHR9,wherein the 5-10-membered heterocyclyl is optionally substituted with Cy7- C1-2 alkyl, CN. NO2, OR11. C(O)Rbl. C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2, =0, or NRclRdl>; andandR1and R9are defined as in claim 1.

35. The compound of claim 34, wherein X1is O.

36. The compound of claim 34 or 35, wherein m is 0.

37. The compound of claim 34 or 35, wherein m is 1.

38. The compound of any one of claims 34-37, wherein R10is a 5-10-membered heterocycloalkyl, optionally substituted as defined in claim 34.Attorney Docket No. 07039-2355WO1 / 2024-25839. The compound of any one of claims 34-37, wherein R10is a 5-10-membered heteroaryl, optionally substituted as defined in claim 34.

40. The compound of any one of claims 34-37, wherein R10is NHCI-6 alkyl substituted with heterocycloalkyl optionally substituted with RCy.

41. The compound of any one of claims 34-37, wherein R10is NHCI-6 alkyl substituted with 5-10 heteroaryl optionally substituted with RCy.

42. The compound of any one of claims 34-37, wherein R10is NHCI-6 alkyl substituted with pyridinyl optionally substituted with RCy.

43. The compound of any one of claims 34-37, wherein R10is NHCI-6 alkyl substituted with pyridinyl N-oxide optionally substituted with RCy.

44. The compound of any one of claims 34-37, wherein R10is morpholino optionally substituted with RCy.

45. A compound of Formula (II)L.^R1°(II),or a pharmaceutically acceptable salt thereof, wherein:Ar is phenyl or 6-membered heteroaryl having one or tw o ring heteroatoms atoms each independently selected from O, S andN;n = 0-5;each R1is independently selected from CN, NO2, C(O)ORal, ORal, NRclRdl, Cy1, C1-6 alky l, and Ci-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with CN, C(O)ORal, ORal. NRclRdl. or Cy2;X1is absent, O, NR2or CR3R4;X2is N or CR3;m = 0 or 1;R2, R3, R4, and R7are each independently selected from H, Cy3, C(=O)Cy3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl. C2-6 alkynyl. C(O)Rbl. C(O)NRclRdl, C(O)ORal, S(O)2Rbl, and S(O)2NRclRdl, wherein said C1-6 alkyl is optionallyAttorney Docket No. 07039-2355WO1 / 2024-258substituted with Cy4, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NHC(=NH)NH2. orNRclRdl;or R5and R6taken together with atoms connecting them form a 4, 5, 6, 7- or 8- carbocyclic or heterocyclic ringor 2 R7taken together with the atoms connecting them form a 5, 6, or 7- cycloaliphatic or heterocycloaliphatic ring;or 2 R7bonded to the same carbon atom form C=O;X3=N or CR3;L = C(O), or C(R7)2;R10is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl or NR8R9;R8and R9are each independently selected from H, Cy5, C(=O)Cy5, C1-6 alkyl, C1-6 haloalkyl, C2.6alkenyl, C2.6alkynyl, C(O)Rbl, C(O)NRclRdl, C(O)ORal, S(O)2Rbl, S(O)2NRclRdl,wherein said C1-6 alkyl is optionally substituted with Cy6, CN. NO2. ORal, C(O)Rbl, C(O)NRelRdl, C(O)ORal, NHC(=NH)NH2, =0. or NRelRdlwherein said R105-10-membered carbocyclyl OR 5- 10-membered heterocyclyl is optionally substituted with Cy7-Ci-2alkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORa1, NHC(=NH)NH2, =0, orNRc,Rd1;each Rblis independently selected from C1-3 alkyl, C1-3 haloalkyl, Cy8, Cy8-Cu 3 alkylene, NRc2Rd2-Ci-3 alkylene, C(O)ORa2-Ci-3 alkylene, and ORa2-Ci-3 alkylene;each Ral, Rcland Rdlis independently selected from H, C1-3 alkyl, C1-3 haloalkyl, Cy9, Cy9-Ci-3 alkylene, NRc2Rd2-Ci-3 alkylene, C(O)ORa2-Ci-3 alkylene, and ORa2-Ci-3 alkylene;Cy1, Cy2, Cy3, Cy4, Cy5, Cy6, Cy7,Cy8and Cy9are each independently selected from Ce-io aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl such as 5-10 membered heteroaiyl, and 4-10 membered heterocycloal ky I. each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCy; each RCyis independently selected from halo, CN. NO2. C1-6 alkyl, C1-6 haloalkyl, C2.6alkenyl, C2.6alkynyl, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, S(O)2Rb2, and S(O)2NRc2Rd2; wherein said C1-6 alkyl is optionally substituted with CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2,Attorney Docket No. 07039-2355WO1 / 2024-258NRc2C(O)Rb2, NRC2C(O)OR“2, S(O)2Rb2, or S(O)2NRc2Rd2;each Ra2, Rc2. and Rd2is independently selected from H. Ci-6 alkyl, and C1-4 haloalkyl; andeach Rb2is independently selected from C1-6 alkyl and C 1-4 haloalkyl.

46. A compound selected from group consisting of the following compounds:2-((R)-3 -(m-toly loxy )py rrolidin- 1 -y l)propan- 1 -amine;N-methyl-3-(pyridin-4-yl)-N-(3-(m-tolyloxy)phenyl)propan amide;(S)-N-(pyridin-4-ylmethyl)-l-((R)-3-(m-tolyloxy)piperidin-l-yl)propan-2-amine;(R)-N 1 -methyl -N2-(py ridin-4-ylmethyl)-N 1 -(3 -(m-toly loxy )phenyl)propane-1,2-di amine;1-(pyridin-4-yl)-N-((4-(m-tolyloxy)quinolin-8-yl)methyl)methanamine; (S)-2-((pyridin-4-ylmethyl)amino)-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one;(S)-4-((3-(4-(m-tolyl oxy)piperi din-1 -yl)pyrroli din-1 -yl)methyl)pyri dine; N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyndin-3-yl)acetamide;N-(Pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propanamide;(S)-N-((2-fluoropyridin-4-yl)methyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;(S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;2-((S)-l-((lR,3S,5S)-3-(m-tolyloxy)-8-azabicyclo[3.

2. l]octan-8-yl)propan-2-yl)-2,3-dihydro-lH-pyrrolo[3,4-c]pyridine;(S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-(4-(p-tolyloxy)piperidin-l-y 1 )propan-2-amine;(S)-4-(l -(4-phenoxypiperidin-l -yl)propan-2-yl)morpholine;3-(pyridin-4-yl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-l-one;(S)-N, N-dimethyl-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;2-(pyridin-4-ylmethyl)-8-(m-tolyloxy)-l,2,3,4-tetrahydroisoquinoline;(S)-l-(4-benzylpiperazin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine»4HCl (S)-l-(4-Benzylpiperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine;4-(3-methylbenzyl)-1-(3-(tetrahydro-2H-pyran-4-yl)propyl)piperidine;Attorney Docket No. 07039-2355WO1 / 2024-2584-((S)-l-((lR,5S)-3-(3-methylbenzyl)-3,8-diazabicyclo[3.

2. l]octan-8-yl)propan-2-yl)morpholine;N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyndin-3-yl)propan-l -amine;N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-l -amine; N-(pyridin-4-ylmethyl)-2-(4-(m-tolyloxy)piperidin-l-yl)propan-l -amine; N-methyl-N-(3-(pyridin-4-yl)propyl)-3-(m-tolyloxy)aniline;N-(pyridin-4-ylmethyl)-2-((R)-3-(m-tolyloxy)piperidin-l-yl)propan-l -amine; N-methyl-N-(2-(pyridin-4-yl)ethyl)-3-(m-tolyloxy)aniline;2-(pyridin-4-ylmethyl)-6-(m-tolyloxy)-l,2,3,4-tetrahydroisoquinoline;N-methyl-2-(pyridin-4-yl)-N-(3-(m-tolyloxy)phenyl)acetamide;N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-l -amine; N-(pyridin-4-ylmethyl)-2-((lR,3r,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-l-amine;(S)-N-(pyridin-4-ylmethyl)-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-2-amine;(S)-3-((pyridin-4-ylmethyl)amino)-1-(3-(m-tolyloxy)piperidin-l-yl)propan-l-one;(S)-N-(pyridin-4-ylmethyl)-3-(3-(m-tolyloxy)piperidin-l-yl)propan-l -amine; (S)-3-(pyridin-4-yl)-l-(3-(m-tolyloxy)piperidin-l-yl)propan-l-one;1 -(pyridin-4-yl)-N-((7 -(m-tolyloxy )naphthalen- 1 -yl)methyl)methanamine; (S)-4-(3-(3-(m-tolyloxy)piperidin-l-yl)propyl)pyridine;(R)-2-((pyridin-4-ylmethyl)amino)-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-l-one;(R)-N-(pyridin-4-ylmethyl)-l-((S)-3-(m-tolyloxy)piperidin-l-yl)propan-2-amine;(S)-2-((pyridin-4-ylmethyl)amino)-l-(3-(m-tolyloxy)piperidin-l-yl)ethanone; (S)-N-(pyridin-4-ylmethyl)-2-(3-(m-tolyloxy)piperidin-l-yl)ethanamine; (lR,5S)-8-(3-(pyridin-4-yl)propyl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane; 2-((pyridin-4-ylmethyl)amino)-l-((lR.5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)ethanone;(3S,3'S)-r-(pyridin-4-ylmethyl)-3-(m-tolyloxy)-l,3'-bipyrrolidine;3-((pyridin-4-ylmethyl)amino)-1-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-l-one;Attorney Docket No. 07039-2355WO1 / 2024-258N-(pyridin-4-ylmethyl)-2-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)ethanamine;(2R)-2-((pyridin-4-ylmethyl)amino)-l-((lR,5S)-3-(m-tolyloxy)-8-azabi cy cl o [3.2.1 ] octan-8 -y l)propan- 1 -one;N-(pyridin-4-ylmethyl)-3-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan- 1 -amine;(2S)-2-((pyridin-4-ylmethyl)amino)-l-((lR,5S)-3-(m-tolyloxy)-8-azabi cy cl o [3.2.1 ] octan-8 -yl)propan- 1 -one;(R)-4-((3-(4-(m-tolyloxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine; (S)-4-((3-(m-tolyloxy)pyrrolidin-l-yl)methyl)pyridine;4-(((S)-3-((S)-3-(m-tolyloxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine; 4-(((S)-3-((R)-3-(m-tolyloxy)piperidin-l-yl)pyrrolidin-l-yl)rnethyl)pyridine; ((2R)-N-(pyridin-4-ylmethyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;(2S)-N-(py ridin-4-y Imethy 1)- 1 -(( 1 R, 5 S)-3 -(m-toly loxy )-8-azabicyclo|3.

2. l]octan-8-yl)propan-2-amine;(S)-4-((3-(3-(m-tolyloxy)pyrrolidin-l-yl)azeti din-1 -yl)methyl)pyri dine;N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)ethanamine;(S)-4-((3-(3-(m-tolyloxy)pyrrolidin-l-yl)azetidin-l-yl)methyl)pyridine;2-methyl-N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propanamide; (S)-2-((pyridin-4-ylmethyl)amino)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-l-one;2-methyl-N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propan-l-amine;(R)-2-((pyridin-4-ylmethyl)amino)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-l-one;(S)-N-(pyridin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine; (R)-N-(pyridin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine; (R)-N-methyl-N-(pyridin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;N-(2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propyl)isonicotinamide;(lR)-N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)cyclopentanamine;Attorney Docket No. 07039-2355WO1 / 2024-258(lS)-N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)cyclopentanamine;N-methyl-N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-y l)propan- 1 -amine;4-(((R)-2-(((S)-3-(m-tolyloxy)pyrrolidin-l-yl)methyl)pyrrolidin-l-yl)methyl)pyridine;N-isopropyl-N-(pyridin-4-ylmethyl)-2-((S)-3-(m-tolyloxy)pyrrolidin-l-y l)propan- 1 -amine;4-(((S)-2-(((S)-3-(m-tolyloxy)pyrrolidin-l-yl)methyl)pyrrolidin-l-yl)methyl)pyridine;(2S)-N-(furan-3-ylmethyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.

2. l]octan-8-yl)propan-2-amine;(2S)-N-(4-fluorobenzyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;(2S)-N-((2-fluoropyridin-4-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo|3.

2. l]octan-8-yl)propan-2-amine;N-(pyridin-4-ylmethyl)-2-(5-(m-tolyloxy)pyridin-3-yl)propanamide hydrochloride;1 -(pyridin-4-yl)-N-((( 1 R.3 S)-3-(m-tolyloxy)cyclohexyl)methyl)methanamine; 2-(pyridin-4-yl)-N-(((lR.3S)-3-(m-tolyloxy)cyclohexyl)methyl)ethanamine; 4-(l-(((lR,3S)-3-(m-tolyloxy)cyclohexyl)methyl)pyrrolidin-3-yl)pyridine; 4-((3 -(4-(3 -(trifluoromethy l)phenoxy)piperidin- 1 -y l)py rrolidin- 1 -yl)methyl)pyridine;4-((3-(4-phenoxypiperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine;(lR,3r,5S)-8-(l-benzyl-lH-pyrrol-3-yl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane;4-((3 -(4-(3 -(trifluoromethy l)phenoxy)piperi din- 1 -yl)- 1 H-pyrrol- 1 -yl)methyl)pyridine;4-((3-(4-phenoxypiperidin-l-yl)-lH-pyrrol-l-yl)methyl)pyridine;(S)-4-((4-(3-(m-tolyl oxy )pyrrolidin-l-yl)piperidin-l-yl)methyl)pyri dine; (lR,3r,5S)-8-(l-(pyridin-4-ylmethyl)piperidin-4-yl)-3-(m-tolyloxy)-8-azabicy clo [3.2.1 ] octane;Attorney Docket No. 07039-2355WO1 / 2024-258(2S)-N-((2-methoxypyridin-4-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;(3S)-r-benzyl-3-(m-tolyloxy)-l,3'-bipyrrolidine;4-((3-(4-(3-(trifluoromethoxy)phenoxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine;4-((3-(4-(3,5-difluorophenoxy)piperidin-l-yl)pyrrolidin-l-yl)methyl)pyridine; (2S)-N. N-dimethyl-l-((lR.5S)-3-(m-tolyloxy)-8-azabicyclo[3.

2. l]octan-8-y l)propan-2-amine;(2S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;4-((3-(4-methoxypiperi din-1 -yl)pyrrolidin-l-yl)methyl)pyridine;(2S)-N-(4-methoxybenzyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;(S)-l-(4-benzylpiperazin-l-yl)-N-((2-methylpyridin-4-yl)methyl)propan-2-amine»4HCl3-((l-(l-(pyridin-4-ylmethyl)pyrrolidin-3-yl)piperidin-4-yl)oxy)-5-(trifluoromethyl)pyridine;(2S)-N-(pyridin-3-ylmethyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;(2S)-N-((2-methylpyridin-4-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.

2. l]octan-8-yl)propan-2-amine;(S)-l-(4-(3-methylbenzyl)piperazin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine*4HCl(S)-l-(4-(3-methylbenzyl)piperazin-l-yl)-N-((2-methylpyridin-4-yl)methyl)propan-2-amine,4HCl(S)-l-(4-(3-methylbenzyl)piperazin-l-yl)-N-(pyridin-3-ylmethyl)propan-2-amine*4HCl(S)-N-(pyridin-4-ylmethyl)-l-(4-(3-(trifluoromethyl)phenoxy)piperidin-l-yl)propan-2-amine;(S)-l-(4-(3,5-difluorophenoxy)piperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine;(S)-N-(pyridin-4-ylmethyl)-l-(4-(3-(trifluoromethoxy)phenoxy)piperidin-l-yl)propan-2-amine;Attorney Docket No. 07039-2355WO1 / 2024-258(S)-l-(4-phenoxypiperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine; (S)-N-(quinolin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine; (S)-l-(4-(3-methylbenzyl)piperazin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;(S)-N-(pyridin-4-ylmethyl)-l-(4-(3-(trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine«4HCl(S)-N-((2-methylpyridin-4-yl)methyl)-l-(4-(3- (trifluoromethy l)benzyl)piperazin- 1 -yl)propan-2-amine*4HCl(S)-N-(pyridin-3-ylmethyl)-l-(4-(3-(tifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine«4HCl(S)-6-(((l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyrimidine-2,4(lH,3H)-dione;(S)-4-(((l-(4-(m-tolyloxy)piperi din-1 -yl)propan-2-yl)amino)methyl)pyridin-2(lH)-one;(S)-5-(((l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-yl)amino)methyl)pyridin- 2(lH)-one;(S)-4-(((l-(4-(m-tolyloxy)piperi din-1 -yl)propan-2-yl)amino)methyl)pyridine 1 -oxide;(S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-(4-(3- (trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine:(2S)-N-((tetrahydrofuran-3-yl)methyl)-l-(4-(3- (trifluoromethyl)benzyl)piperazin-l-yl)propan-2-amine;4-((((2S)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)amino)methyl)pyridin-2(lH)-one;(2S)-N-((tetrahydrofuran-3-yl)methyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;5-((((2S)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)amino)methyl)pyridin-2(lH)-one;(S)-l-(4-(tert-butoxy)piperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine 4-((2S)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)morpholine(2S)-N-(quinolin-4-ylmethyl)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propan-2-amine;Attorney Docket No. 07039-2355WO1 / 2024-258N-((2S)-l-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.

2. l]octan-8-yl)propan-2-yl)tetrahydro-2H-pyran-4-amine;(S)-l-(4-benzylpiperidin-l-yl)-N-((2-methylpyridin-4-yl)methyl)propan-2-amine;(S)-l-(4-benzylpiperidin-l-yl)-N-(pyridin-3-ylmethyl)propan-2-amine;(S)-l-(4-(3-chlorophenoxy)piperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;(S)-l-(4-(4-chlorophenoxy)piperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;(S)-l-(4-(3-chlorophenoxy)piperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine;(S)-l-(4-benzylpiperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;(S)-l-(4-benzylpiperidin-l-yl)-N-(quinolin-4-ylmethyl)propan-2-amine; (S)-l-(4-(3-isopropylphenoxy)piperidin-l-yl)-N-((tetahydro-2H-pyran-4-yl)methyl)propan-2-amine;(S)-l-(4-(3-isopropylphenoxy)piperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine;(S)-N-(pyridazin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;(S)-l-(4-phenylpiperidin-l-yl)-N-(pyridin-4-ylmethyl)propan-2-amine;(S)-N-((2-methylpyridin-4-yl)methyl)-l -(4-phenylpiperi din-1 -yl)propan-2-amine;(S)-l-(4-phenylpiperidin-l-yl)-N-(pyridin-3-ylmethyl)propan-2-amine;(S)-l-(4-((5-fluoropyridin-3-yl)oxy)piperidin-l-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine;4-phenoxy-l-(3-(tetrahydro-2H-pyran-4-yl)propyl)piperidine;(S)-l-(4-Phenylpiperidin-l-yl)-N-(quinolin-4-ylmethyl)propan-2-amine; (S)-l-(4-phenylpiperi din-1 -yl)-N-((tetrahy dro-2H-pyran-4-yl)methyl)propan-2-amine;(2S)-l-(4-phenylpiperidin-l-yl)-N-((tetrahydrofuran-3-yl)methyl)propan-2-amine;Attorney Docket No. 07039-2355WO1 / 2024-258(lR,5S)-8-(2-(tetahydro-2H-pyran-4-yl)ethyl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane;4-(3-((lR,5S)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octan-8-yl)propyl)morpholine;(lR,5S)-8-(3-(tetrahydro-2H-pyran-4-yl)propyl)-3-(m-tolyloxy)-8-azabicyclo[3.2.1]octane;(S)-4-(l-(4-(3-methylbenzyl)piperidin-l-yl)propan-2-yl)morpholine;l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-4-(3- (trifluoromethyl)phenoxy)piperidine;(S)-N-(pyrimidin-4-ylmethyl)-l-(4-(m-tolyloxy)piperidin-l-yl)propan-2-amine;(S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-((S)-3-(m-tolyloxy)pyrrolidin-l-y l)propan-2-amine;(S)-N-(pyridin-4-ylmethyl)-l-((S)-3-(m-tolyloxy)pyrrolidin-l-yl)propan-2-amine;4-(3-methylbenzyl)-l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperidine;4-(3-(4-(3-methylbenzyl)piperidin-l-yl)propyl)morpholine;l-(3-(tetrahydro-2H-pyran-4-yl)propyl)-4-(m-tolyl)piperidine;(S)-4-(l-(4-(m-tolyl)piperidin-l-yl)propan-2-yl)morpholine;4-(3 -(4-(m-toly 1) piperidin- 1 -yl)propy l)morpholine;l-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-4-(m-tolyl)piperidine;4-(3-(4-(3-(trifluoromethyl)phenoxy)piperidin-l-yl)propyl)morpholine;(S)-N-(quinolin-4-ylmethyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine; (S)-N-(pyridin-4-ylmethyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine; (S)-N-((2-methylpyridin-4-yl)methyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine;(S)-N-(pyridin-3-ylmethyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine; (S)-N-((tetrahydro-2H-pyran-4-yl)methyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine;(2S)-N-((tetrahydrofuran-3-yl)methyl)-l-(4-(m-tolyl)piperidin-l-yl)propan-2-amine;andAttorney Docket No. 07039-2355WO1 / 2024-258(S)-l-((lR,5S)-3-(3-methylbenzyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(quinolin-4-ylmethyl)propan-2-amine;or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

48. A method of improving mitochondrial biogenesis and mitochondria function, and increasing autophagy in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 -46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47.

49. A method of inhibiting mitochondrial complex I (MCI) in a subject in need thereof, comprising administering to the subj ect an effective amount of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47.

50. A method of treating neurodegenerative diseases such as Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Down Syndrome, Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Lewy' body dementia, Parkinson’s Disease, Restless Legs Syndrome, Niemann-Pick Disease, Epilepsy, Huntington's Disease, Multiple Sclerosis, Beta-propeller protein-associated neurodegeneration (BPAN); Chronic Traumatic Encephalopathy, Traumatic Brain Injury, Tumor, Stroke, Cockayne syndrome, Ataxia telangiectasia, diabetes, Mucopolysaccharidosis (MPS) ty pe III, Familial dysautonomia, and Niemann-Pick Type C: diseases related to aging; and mitochondrial diseases such as Disorders of pyruvate carboxylase and pyruvate dehydrogenase complex, Leigh syndrome, Barth syndrome, and Disorders of mitochondrial depletion, Mitochondrial fatty acid oxidation disorders, and Primary carnitine deficiency, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-46. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47.

51. A method of protecting against amyloid beta toxicity in a subject in need thereof, comprising administering to the subject an effective amount of aAttorney Docket No. 07039-2355WO1 / 2024-258compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47.

52. A method of improving glutathione and NADPH levels in a subject in need thereof, comprising administering to the subj ect an effective amount of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47.

53. A method of protecting against oxidative stress.in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmacal composition of claim 47.

54. A method of protecting an embryo from oxidative stress, such as oxidative stress associated with culturing early embryos in the lab, comprising treating an embry o culture medium with an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

55. A method of inhibiting mitochondrial complex I, comprising contacting a cell expressing MCI with an effective amount of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47.

56. A method of protecting against amyloid beta toxicity; comprising contacting a cell expressing amyloid beta with an effective amount of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47.

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