Spleen Tyrosine Kinase Inhibitors

Abstract

The present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof, wherein R 4 is a 5-membered cycloalkene or a 5-membered heteroaryl, each of which may be fused to form a 5:6 or 5:5 aromatic or heteroaromatic bicycle; each R 4 The present invention relates to an optionally substituted compound of formula (I) or a pharma- ceutically acceptable salt or prodrug thereof. The present invention also relates to pharmaceutical compositions comprising the compounds, and to uses of the compounds, particularly in the treatment of diseases, disorders or conditions associated with spleen tyrosine kinase activity. TIFF2025511779000329.tif31170

Description

[Technical Field]

[0001] The present invention relates, inter alia, to compounds, pharmaceutical compositions of said compounds, and uses of said compounds, particularly for the inhibition of spleen tyrosine kinase. [Background technology]

[0002] Where a prior art publication is referred to herein, it will be expressly understood that this reference is not an admission that the publication forms part of the common general knowledge in the art in Australia or any other country.

[0003] Spleen tyrosine kinase (Syk) is a cytoplasmic non-receptor kinase that plays a central role in mediating inflammatory responses. Upon activation by its membrane-bound receptor, Syk phosphorylates numerous downstream targets primarily involved in the development and function of immune cells, including B cells, T cells, dendritic cells, natural killer (NK) cells, mast cells, basophils, macrophages, and microglia (Turner et al. 2000; Sedlik et al. 2003; Yi et al. 2014; Lee and Suk 2018).

[0004] Syk is known to be upregulated and plays an important role in neuroinflammatory diseases, autoimmune diseases, allergies, and B-cell malignancies. Syk has been implicated in glioblastoma (Moncayo et al., 2018), ovarian cancer (Yu et al., 2019), B-cell and T-cell lymphoma (Geahlen 2014), type I diabetes (Geahlen 2014), cutaneous and systemic lupus erythematosus (Braegelmann et al., 2016; Grammatikos et al., 2013; Wong et al., 2004), rheumatoid arthritis (Pine et al., 2007; Coffey et al., 2012; Wong et al., 2004), gout (Mocsai, Ruland, and Tybulewicz). 2010), multiple sclerosis (Wong et al., 2004), type I hypersensitivity reactions including allergic rhinitis, urticaria, asthma and anaphylactic asthma and allergic rhinitis (Wong et al., 2004), different liver diseases including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma (Kurniawan et al., 2020; Bukong et al., 2016;Qu et al., 2018), retinoblastoma (Zhang et al., 2012), peritoneal fibrosis (Liu et al., 2019), lipopolysaccharide / cigarette smoke-induced airway inflammation (Fan et al., 2019), head and neck cancer (Black et al., 2020), periodontal disease (Kittaka et al., 2020), Graves' disease, hantavirus pulmonary syndrome, rapidly progressive glomerulonephritis, macroglobulinemia, acquired epidermolysis bullosa, Wiskott-Aldrich syndrome, agammaglobulinemia, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu-Hakola disease) (Mocsai, Ruland, and Tybulewicz 2010), co-trimoxazole allergy, fasciitis, Mycobacterium abscessus infection, autoimmune hypersensitivity disorders, blood coagulation disorders, chromoblastomycosis, carbapenem allergy, Waldenstroem's macroglobulinemia (Munshi et al., 2020), thrombocytopenia (Bussel et al., 2018), Melnick-Needles syndrome, nail disorders, ear-palate-digital syndrome spectrum disorders, bone metabolic disorders (Shao et al., 2021), fungal infections / mycoses, chronic mucocutaneous candidiasis and dermatitis (Pavel et al., 2019), and thrombotic cardiovascular diseases (Andre et al., 2011).

[0005] Syk inhibitors are currently marketed (fostamatinib) or advanced to the clinic (entospletinib) for peripheral indications, including inflammatory diseases and oncology, providing strong evidence for their suitability as potential pharmaceuticals. Syk is highly conserved across species, and current clinical compounds show comparable in vitro activity against Syk orthologues from human, mouse, and rat (Lamb et al., 2016; Currie et al., 2014), confirming the conservation of Syk structure and its ability to be investigated across multiple species.

[0006] Commercially available and clinical Syk inhibitors (fostamatinib and entospletinib) support the safety profile of Syk inhibition. Fostamatinib has been extensively tested in long-term studies for several disease indications, with adverse events either mild or manageable with dose reduction, discontinuation, or secondary dosing (Bussel et al., 2018; Kang et al., 2019). Syk is expressed in most cell types, including neurons, astrocytes, and microglia (Hatterer et al., 2011; Xu et al., 2019; Lee and Suk 2018), but high levels of expression are primarily restricted to hematopoietic cells, including B cells, T cells, mast cells, macrophages, and neutrophils. Human safety data are supported in mice with an inducible knockout of Syk, which showed some reduced inflammatory responses but otherwise had no apparent effects on basic bodily functions (Wex et al., 2011).

[0007] Clinical trials using antibodies against Syk-related pathways are also being investigated, further supporting the safety and efficacy of direct Syk inhibitors. For example, TREM2, a receptor associated with an increased risk of Alzheimer's disease (AD), is also known to signal through Syk. Phase II trials using antibodies against TREM2 have been initiated. Phase I clinical trials are underway for antibodies against two receptors in the same inflammatory pathway as Syk (TREM2 and Siglec-3) (Alector, AL002 and AL003). The advantage of direct Syk inhibitors is that they target multiple pathways rather than just one or two receptors. Coupled with the positive clinical safety profiles of peripherally restricted Syk inhibitors established with commercially available drugs (fostamatinib) and clinical inhibitors such as entospletinib, direct Syk inhibition is highly desirable and may offer significant advantages over other untested preclinical drug targets. [Prior art documents] [Non-patent literature]

[0008] [Non-licensed document 1] Turner, Martin, Edina Schweighoffer, Francesco Colucci, James P Di Santo, and Victor L Tybulewicz. 2000. Immunology Today 21(3):148-54. https: / / doi.org / 10.1016 / S0167-5699(99)01574-1 [Non-licensed document 2] Sedlik, Christine, Daniel Orbach, Philippe Veron, Edina Schweighoffer, Francesco Colucci, Romina Gamberale, Andrea Ioan-Facsinayら2003. Journal of Immunology (Baltimore, Md.: 1950) 170(2):846-52. https: / / doi.org / 10.4049 / jimmunol.170.2.846 [Non-licensed document 3] Yi, Young-Su, Young-Jin Son, Chongsuk Ryou, Gi-Ho Sung, Jong-Hoon Kim, and Jae Youl Cho. 2014. Review Article. Mediators of Inflammation. June 18, 2014. https: / / doi.org / 10.1155 / 2014 / 270302

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[0009] In view of the above, the present invention relates in one aspect to small molecules that inhibit spleen tyrosine kinase (Syk).

[0010] In one aspect, the present invention relates, inter alia, to compounds or pharmaceutically acceptable salts or prodrugs thereof that are Syk inhibitors.

[0011] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: [ka] During the ceremony, Z is CR 1 or N, Y is CH or N; X is CR 2 or N, no more than one of X, Y, or Z is N; During the ceremony, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl, C 2~6 Fluoroalkynyl, C 3~6Cycloalkyl, halo, -OC 1~6 Alkyl, -OC 1~6 Fluoroalkyl, -OC 2~6 Alkenyl, -OC 2~6 Fluoroalkenyl, -OC 2~6 Alkynyl, -OC 2~6 selected from the group consisting of fluoroalkynyl and cyano; R 2 is hydrogen, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl, C 2~6 Fluoroalkynyl, halo, -OC 1~6 Alkyl, -OC 1~6 Fluoroalkyl, -OC 2~6 Alkenyl, -OC 2~6 Fluoroalkenyl, -OC 2~6 Alkynyl, -OC 2~6 selected from the group consisting of fluoroalkynyl and cyano; R 4 is a 5-membered cycloalkene or a 5-membered heteroaryl, each of which may be fused to form a 5:6 or 5:5 aromatic or heteroaromatic bicycle; 4 is optionally substituted, m is 0 or 1; R 6 is H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl; R 7 and R 7 ' are independently H, fluoro, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, or R 7 and R 7 ' together form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; R 8 and R 9 are independently H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, or R 8 and R 9 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; R 10 and R 11 are independently H, C 1~6 Alkyl, Fluoro, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, or R 10 and R 11 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; R 12 and R 13 are independently H, C 1~6 Alkyl, Fluoro, C 1~6Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, or R 12 and R 13 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; R 15 and R 16 are independently H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, or R 15 and R 16 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring, or ·R 7 or R 7 ' and R 8 or R 9 together form a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring; ·R 7 or R 7 ' and R 6 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; ·R 6 and R 8 or R 9together form a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring; ·R 6 and R 10 or R 11 taken together form a 4- to 6-membered heterocyclyl ring or a 4- to 6-membered fluoroheterocyclyl ring; ·R 8 or R 9 One of the following and R 12 or R 13 taken together form a 4- to 7-membered heterocyclyl ring or a 4- to 7-membered fluoroheterocyclyl ring; ·R 8 or R 9 One of the following and R 15 or R 16 taken together form a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring; ·R 10 or R 11 One of the following and R 12 or R 13 taken together form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring; ·R 10 or R 11 One of the following and R 15 or R 16 taken together form a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered fluorocycloalkyl ring; ·R 8 or R 9 One of the following and R 10 or R 11 taken together form a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring, and / or ·R 12 or R 13 One of the following and R 15 or R16 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring. Provided are compounds of formula (I) or pharmaceutically acceptable salts or prodrugs thereof:

[0012] In one embodiment of the first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: [ka] During the ceremony, Z is CR 1 or N, Y is CH or N; X is CR 2 or N, no more than one of X, Y or Z is N; During the ceremony, R 1 is hydrogen, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl, C 2~6 Fluoroalkynyl, C 3~6 Cycloalkyl, halo, -OC 1~6 Alkyl, -OC 1~6 Fluoroalkyl, -OC 2~6 Alkenyl, -OC 2~6 Fluoroalkenyl, -OC 2~6 Alkynyl, -OC 2~6 selected from the group consisting of fluoroalkynyl and cyano; R 2 is hydrogen, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl, C 2~6 Fluoroalkynyl, halo, -OC 1~6 Alkyl, -OC1~6 Fluoroalkyl, -OC 2~6 Alkenyl, -OC 2~6 Fluoroalkenyl, -OC 2~6 Alkynyl, -OC 2~6 selected from the group consisting of fluoroalkynyl and cyano; R 4 is a 5-membered cycloalkene or a 5-membered heteroaryl, each of which may be fused to form a 5:6 or 5:5 aromatic or heteroaromatic bicycle; 4 is one or more R 5 and each R 5 are independently, -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -cyclofluoroalkyl-R 19 , -R 14 -heterocyclyl-R 19 , -R 14 -fluoroheterocyclyl-R 19 , -R 14 -heteroaryl-R 19 , -R 14 -aryl-R 19 , -cycloalkyl-R 19 , -cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 , -fluoroheterocyclyl-R 19 , -heteroaryl-R 19 , -aryl-R 19 , -R 14 -OR 19 , Cl, F, cyano, -OR 19 , -SR 19 , -SOR 19 , -SO2R 19 , -N(R 19 )2, -N(R 19 )COR 19 , -CON(R 19 )2, -N(R 19 )CON(R 19 )2, -N(R 19 )COOR 19 , -OCON(R 19)2, -N(R 19 )SO2R 19 , -SO2N(R 19 )2, and ═O, and each R 14 are independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl, C 2~6 Fluoroalkynyl and C 3~6 cycloalkyl, and each R 19 are independently H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl, C 2~6 Fluoroalkynyl and C 3~6 cycloalkyl; m is 0 or 1; R 6 is H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl; R 7 and R 7 ' are independently H, fluoro, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, or R 7 and R 7' together form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; R 8 and R 9 are independently H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, or R 8 and R 9 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; R 10 and R 11 are independently H, C 1~6 Alkyl, Fluoro, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, or R 10 and R 11 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; R 12 and R 13 are independently H, C 1~6 Alkyl, Fluoro, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6fluoroalkynyl, or R 12 and R 13 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; R 15 and R 16 are independently H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, or R 15 and R 16 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring, or ·R 7 or R 7 ' and R 8 or R 9 together form a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring; ·R 7 or R 7 ' and R 6 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring; ·R 6 and R 8 or R 9 together form a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring; ·R 6 and R 10 or R 11taken together form a 4- to 6-membered heterocyclyl ring or a 4- to 6-membered fluoroheterocyclyl ring; ·R 8 or R 9 One of the following and R 12 or R 13 taken together form a 4- to 7-membered heterocyclyl ring or a 4- to 7-membered fluoroheterocyclyl ring; ·R 8 or R 9 One of the following and R 15 or R 16 taken together form a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring; ·R 10 or R 11 One of the following and R 12 or R 13 taken together form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring; ·R 10 or R 11 One of the following and R 15 or R 16 taken together form a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered fluorocycloalkyl ring; ·R 8 or R 9 One of the following and R 10 or R 11 taken together form a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring, and / or ·R 12 or R 13 One of the following and R 15 or R 16 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring. Provided are compounds of formula (I) or pharmaceutically acceptable salts or prodrugs thereof:

[0013] In one embodiment, the compound of formula (I) is a compound of formula (II). [ka]

[0014] In a further embodiment, the compound of formula (I) is a compound of formula (III). [ka]

[0015] Advantageously, the present inventors have found that compounds of formula (I) may provide potent inhibitors of Syk.

[0016] Syk is known to play multiple roles in Alzheimer's disease (AD) pathology, primarily in microglia, the brain's immune cells. Neuroinflammation is a key driver of AD pathology. Syk promotes neuroinflammation (Ye et al., 2020; Zeng et al., 2014) and acts as a proinflammatory signaling mediator for receptors such as TREM2, DAP12, Toll-like receptors (TLRs), and Fc receptors, all of which are correlated with or upregulated in AD brains (Fuller, Stavenhagen, and Teeling 2014; Nizami et al., 2019; Mielcarska et al., 2019; Guerreiro et al., 2013). Neuronal β-amyloid plaques and tau (tau) hyperphosphorylation are key hallmarks of AD, and both are affected by Syk regulation in vitro and in mouse models (Schweig et al., 2017; Paris et al., 2014; Schweig et al., 2019). Syk mediates the chronic pro-inflammatory microglial response to β-amyloid and can also increase β-amyloid production in neurons. Syk directly phosphorylates and colocalizes with tau in mouse neurons. Thus, in addition to its important role in neuroinflammation, Syk is involved in the generation and activation of β-amyloid and tau, which lead to prototypic AD pathology.

[0017] Syk has also been implicated in other neuroinflammatory-driven diseases, including other types of dementia, Parkinson's disease (PD), multiple sclerosis (MS), stroke (seizures), traumatic brain injury (TBI), and subarachnoid hemorrhage (SAH). In MS, Syk has dual effects, regulating both peripheral (T cells, B cells) and CNS (B cells, microglia, macrophages, T cells) immune responses, which are essential for MS pathology (Baecher-Allan, Kaskow, and Weiner 2018). Syk has been identified as a key mediator of neuroinflammation after stroke, and its inhibition has been shown to reduce inflammation after early reperfusion and improve post-infarction recovery (Ye et al., 2020). Syk inhibition has also been shown to improve neuronal function in a rat model of TBI (He et al., 2015). Syk has been implicated in both TBI (Morin, Front Aging Neurosci, 2018) and SAH (He, Stroke, 2015) in animal models.

[0018] Syk has been linked to other neuroinflammation-related diseases, such as AD, vascular dementia, and multiple sclerosis, through genome-wide association studies (Sierksma et al., 2020; Disanto et al., 2014; Kim, Kong, and Lee 2013; Ryu et al., 2014; International Multiple Sclerosis Genetics Consortium et al., 2011), highlighting its fundamental role in neuroinflammation. Further validating Syk as a target in AD, its expression and activation are increased in the brains of AD patients, particularly in degenerating neurites associated with β-amyloid plaques (Ghosh and Geahlen 2015; Schweig et al., 2017). Importantly, the upregulation of Syk expression and activation observed in the brains of human AD patients is mirrored in mouse models of the disease. Three mouse models of AD (one focused on tau pathology and two based on β-amyloid pathology) show an age-dependent increase in both the expression and activation of Syk in neurons, degenerating neurites, or microglia in the brain ( Schweig et al., 2017 ; Sierksma et al., 2020 ), which correlates with the human condition.

[0019] Syk kinase signaling has been found to regulate neuroinflammatory responses and immune activation in response to pathological protein aggregates found in PD and AD. Therefore, selective inhibition of the Syk kinase pathway could provide a multi-pronged approach to treating PD and AD, targeting the disease-modifying pathways of 1) tau phosphorylation, 2) amyloid-β production, and 3) neuroinflammation. The potential for inhibition of the Syk kinase pathway may be therapeutically beneficial for other neuroinflammatory diseases, such as stroke and multiple sclerosis.

[0020] PD and AD are extremely debilitating due to significant disability, functional impairment, and duration, and there is a significant unmet need for therapeutic agents that can modify disease progression. Current approved treatments for PD and AD provide only symptomatic benefit, and no disease-modifying drugs are available to patients. Failure rates from drugs that target only one pathway in AD, most notably β-amyloid-targeting antibodies and β-secretase (BACE) inhibitors, are high. Due to the heterogeneity of these diseases, mechanisms of action that address multiple pathogenic pathways in target populations have greater translational potential.

[0021] Therefore, Syk inhibitors that can penetrate the blood-brain barrier and have effects in the central nervous system could potentially be used to treat neurological disorders including AD, PD and MS.

[0022] However, to our knowledge, Syk has not been pursued for central nervous system (CNS) conditions, and based on their extensive benchmarking, current clinical compounds do not reach concentrations sufficient to inhibit Syk in the brain. Furthermore, to our knowledge, no small molecule Syk inhibitors that are sufficiently potent and brain-penetrant have been described in the literature.

[0023] To the best of our knowledge, few, if any, brain-penetrant small molecule Syk inhibitors for treating AD have been disclosed in the literature. Compared to other largely unsuccessful targets tested in AD, such as β-amyloid or tau-targeting biologics, Syk offers compelling advantages. Rather than targeting only one pathological process involved in AD, Syk is involved in multiple disease pathways. In addition to directly reducing neuroinflammation, Syk inhibition reduces β-amyloid production and tau hyperphosphorylation.

[0024] In one embodiment, the compounds of formula (I) may be capable of penetrating the blood-brain barrier. In one embodiment, the compounds of formula (I) may be capable of acting on the central nervous system in vivo.

[0025] Oral administration of small molecule Syk inhibitors capable of crossing the blood-brain barrier would have clear advantages in their direct mechanism of action against AD, PD, and MS pathologies, ease of use, patient compliance, and cost. However, due to the nature of this class of molecules that bind strongly to the active site of kinase enzymes, the design and synthesis of brain-penetrating kinase inhibitors has traditionally been very difficult to achieve. The class of molecules that have typically proven to be potent kinase inhibitors possesses high molecular weight, high polar surface area, and an excess of H-bond donors or acceptors. For a good CNS drug, low molecular weight (less than 500 daltons, preferably less than 450 daltons, most preferably less than 400 daltons), low polar surface area (less than 120 Å), and low surface area (less than 120 Å) are required. 2 (1.20nm 2 ), preferably less than 100 Å 2 (1.00nm 2 ), most preferably less than 80 Å 2 (0.80nm 2 ), a log P of 2-5 (most preferably 2-4), and 3 or fewer H-bond donors (preferably 2 or fewer, more preferably 1 or fewer H-bond donors) and 10 or fewer H-bond acceptors (preferably 8 or fewer, most preferably 6 or fewer H-bond acceptors) (Hitchcock et al., 2006). To the best of our knowledge, no Syk inhibitors have been described in the literature that meet the above criteria to achieve sufficient brain penetration of the free drug. In some embodiments of compounds of Formula (I), (II), or (III), we have surprisingly been able to achieve potent, brain-penetrating small molecule Syk inhibitors that have direct applicability for treating AD and many other neurological and peripheral conditions.

[0026] In one embodiment, the compounds of the present invention provide CNS-permeable selective antagonists suitable for oral administration, which may be used to treat neurological diseases or disorders such as AD, PD or MS.

[0027] By inhibiting Syk, the present invention may offer the advantage of simultaneously modulating multiple pathways in AD, with the primary goal of reducing neuroinflammation and additional effects on tau activation and β-amyloid formation. The proposed therapy is intended to reduce the likelihood of the condition progressing to a more advanced stage of the disease. Its differentiation over approved drugs that address only symptoms in AD, such as Aricept and Exelon, is its increased efficacy and disease-modifying potential. Its differentiation over β-amyloid and tau-targeting agents in clinical development is its increased efficacy by targeting multiple disease pathologies. Oral administration also offers advantages over biologics.

[0028] In some embodiments of the compound of Formula (I), Formula (II), or Formula (III),

[0029] One or more of the features of paragraphs

[0029] to

[0060] may be applied (the features of paragraphs

[0029] to

[0060] may be applied alone or in combination with the features of any other paragraphs

[0029] to

[0060] ). For the avoidance of doubt, Z, Y, X, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 7 ', R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 and R 16 Any of the definitions of Z, Y, X, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 7 ', R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 and R 16may be combined with any other definition of

[0029] In one embodiment, Z is CR 1 In another embodiment, Z is N.

[0030] In another embodiment, Y is CH. In a further embodiment, Y is N.

[0031] In one embodiment, X is CR 2 In another embodiment, X is N.

[0032] In one embodiment, R 1 is hydrogen, C 1~6 Alkyl, -OC 1~6 Alkyl and C 1~6 Fluoroalkyl, especially hydrogen, C 1~6 Alkyl and C 1~6 In one embodiment, R is selected from the group consisting of fluoroalkyl. 1 is H or C 1~6 alkyl, especially R 1 is H or CH3, more particularly R 1 is H.

[0033] In one embodiment, R 2 is hydrogen, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 2~6 Alkenyl and C 2~6 fluoroalkenyl, and in particular R 2 is H, C 1~6 Alkyl or C 2~6 alkenyl, more particularly R 2 is H, CH or -CH=CH, most especially R 2 is H.

[0034] In one embodiment, Z is N, Y is CH, and X is CR 2 and in particular Z is N, Y is CH, and X is CH, CC 1~6 Alkyl or CC 2~6Alkenyl, more particularly Z is N, Y is CH and X is CH.

[0035] In another embodiment, Y is N and Z is CR 1 and X is CR 2 and in particular Y is N and X is CH, CC 1~6 Alkyl or CC 2~6 alkenyl, Z is CH, CC 1~6 Fluoroalkyl, -COC 1~6 Alkyl or CC 1~6 alkyl, more particularly Y is N, X is CH, C-CH3 or C-CH=CH2, and Z is CH, C-CF3, C-CH3, C-CH2-CH3, or CO-CH3, most particularly Y is N, X is CH and Z is CH.

[0036] In a further embodiment, X is N, Y is CH, and Z is CR 1 and in particular X is N, Y is CH and Z is CH or CC 1~6 alkyl, more particularly X is N, Y is CH and Z is CH or C-CH3, most particularly X is N, Y is CH and Z is CH.

[0037] In another embodiment, X is CR 2 and Y is CH and Z is CR 1 In particular, X is CH, CC 1~6 Alkyl or CC 2~6 alkenyl, Y is CH, and Z is CH or CC 1~6 alkyl, more particularly X is CH, C-CH3 or C-CH=CH2, Y is CH and Z is CH or C-CH3, most particularly X is CH, Y is CH and Z is CH.

[0038] In one embodiment, R 4 is a 5-membered heteroaryl which may be fused to form a 5:6 or 5:5 aromatic bicyclic ring; R 4 is one or more R 5may be substituted by

[0039] In one embodiment, R 4 is a 5-membered cycloalkene or a 5-membered heteroaryl, each of which may be fused to form a 5:6 or 5:5 aromatic or heteroaromatic bicycle, and each R 4 is one or more R 5 may be substituted by

[0040] In a further embodiment, R 4 is selected from the group consisting of cyclopentenyl, pyrrolyl, 2,3-dihydro-pyrrolidinyl, pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiophenyl, 1,2-oxazolyl, 1,3-thiazolyl, and 1,2-thiazolyl, wherein R 4 The group is one or more R 5 In a further embodiment, R 4 is selected from the group consisting of pyrrolyl and pyrazolyl, 4 The group is one or more R 5 may be substituted by

[0041] In another embodiment, R 4 teeth, [ka] In a further embodiment, R 4 teeth, [ka] and in particular R 4 teeth, [ka] In the above embodiments, u is an integer from 0 to the maximum number of substitution positions on said group (especially 0, 1 or 2; more particularly 0 or 1).

[0042] In one embodiment, each R5 are independently, -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -cyclofluoroalkyl-R 19 , -R 14 -heterocyclyl-R 19 , -R 14 -fluoroheterocyclyl-R 19 , -R 14 -heteroaryl-R 19 , -R 14 -aryl-R 19 , -cycloalkyl-R 19 , -cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 , -fluoroheterocyclyl-R 19 , -heteroaryl-R 19 , -aryl-R 19 , -R 14 -OR 19 , Cl, F, cyano, -OR 19 , -SR 19 , -SOR 19 , -SO2R 19 , -N(R 19 )2, -N(R 19 )COR 19 , -CON(R 19 )2, -N(R 19 )CON(R 19 )2, -N(R 19 )COOR 19 , -OCON(R 19 )2, -N(R 19 )SO2R 19 , -SO2N(R 19 )2, and ═O, and each R 14 are independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl, C 2~6 Fluoroalkynyl and C 3~6 cycloalkyl, and each R 19 are independently H, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl, C 2~6 Fluoroalkynyl and C 3~6 In another embodiment, each R 5 are independently, -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -cyclofluoroalkyl-R 19 , -R 14 -heterocyclyl-R 19 , -R 14 -fluoroheterocyclyl-R 19 , -R 14 -heteroaryl-R 19 , -R 14 -aryl-R 19 , -cycloalkyl-R 19 , -cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 , -fluoroheterocyclyl-R 19 , -heteroaryl-R 19 , -aryl-R 19 , -R 14 -OR 19 , Cl, F, cyano, -OR 19 , -SR 19 and ═O, and each R 14 are independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl and C 2~6 fluoroalkynyl, and each R 19 are independently H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl and C 2~6fluoroalkynyl.

[0043] In another embodiment, each R 5 are independently, -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -cyclofluoroalkyl-R 19 , -R 14 -heterocyclyl-R 19 , -R 14 -fluoroheterocyclyl-R 19 , -cycloalkyl-R 19 , -cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 , -fluoroheterocyclyl-R 19 , -R 14 -OR 19 , Cl, F, cyano, -OR 19 , -SR 19 and ═O, and each R 14 are independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl and C 2~6 fluoroalkynyl, and each R 19 are independently H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl and C 2~6 In a further embodiment, each R is selected from the group consisting of fluoroalkynyl. 5 are independently, -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -cyclofluoroalkyl-R 19 , -R 14 -heterocyclyl-R 19 , -cycloalkyl-R 19, -cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 , -R 14 -OR 19 , Cl, and ═O, and each R 14 are independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl and C 2~6 fluoroalkynyl, and each R 19 are independently H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Fluoroalkyl, C 2~6 Fluoroalkenyl and C 2~6 In yet another embodiment, each R is selected from the group consisting of fluoroalkynyl. 5 are independently, -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -cyclofluoroalkyl-R 19 , -R 14 -heterocyclyl-R 19 , -cycloalkyl-R 19 , -cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 , -R 14 -OR 19 , Cl, and ═O, and each R 14 are independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Fluoroalkyl and C 2~6 fluoroalkenyl, and each R 19 are independently H, C 1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Fluoroalkyl and C 2~6 fluoroalkenyl.

[0044] In one embodiment, each R 5 are independently -C 1~6 Alkyl, -C 1~6 Fluoroalkyl, -C 2~6 Fluoroalkenyl, -C 1~6 Alkyl-cycloalkyl, -C 1~6 Alkyl-cyclofluoroalkyl, -C 1~6 Alkyl-heterocyclyl, -cycloalkyl, -cyclofluoroalkyl, -cycloalkyl-C 1~6 Alkyl, -C 1~6 Alkyl-OC 1~6 Alkyl, -heterocyclyl, -heterocyclyl-C 1~6 In a further embodiment, each R 5 are independently -C 1~6 It is selected from the group consisting of alkyl and -heterocyclyl.

[0045] In one embodiment, R 4 teeth, [ka] is selected from the group consisting of:

[0046] In another embodiment, R 4 teeth, [ka] is selected from the group consisting of:

[0047] In one embodiment, R 6 is H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, in particular H, C 1~6 Alkyl and C 1~6 fluoroalkyl, most especially H and C 1~6In one embodiment, R 6 is selected from the group consisting of H, CH3, and CH2-CH3. In another embodiment, R 6 is H.

[0048] In one embodiment, R 7 and R 7 ' is independently H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 In another embodiment, R is selected from the group consisting of fluoroalkynyl. 7 and R 7 ' are independently H, fluoro, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 Fluoroalkynyl, especially H, C 1~6 Alkyl and C 1~6 Fluoroalkyl, more particularly H and C 1~6 In a further embodiment, R 7 and R 7 ' is independently selected from the group consisting of H, CH3 and CF3, more particularly H and CH3, most particularly H. In one embodiment, R 7 and R 7 At least one of the ' is H.

[0049] In one embodiment, R 8 and R 9 are independently H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 Fluoroalkynyl, especially H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 In a further embodiment, R is selected from the group consisting of fluoroalkynyl. 8 and R 9 are independently H, C 1~6 Alkyl and C 1~6 Fluoroalkyl, especially H and C 1~6 In one embodiment, R 8 and R 9 are independently selected from the group consisting of H, CH3 and CF3, more particularly H and CH3, most particularly H. In one embodiment, R 8 and R 9 At least one of is H.

[0050] In one embodiment, R 10 and R 11 are independently H, C 1~6 Alkyl, Fluoro, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, and C 3~6 fluorocycloalkyl, or R 10 and R 11 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring (such as oxetane, tetrahydrofuran, or pyran). 10 and R 11 are independently H, C 1~6 Alkyl, fluoro and C 1~6 fluoroalkyl, or R 10 and R 11are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring. 10 and R 11 are independently H, C 1~6 selected from the group consisting of alkyl and fluoro, or R 10 and R 11 are taken together to form a 3- to 6-membered cycloalkyl ring, or an oxetane ring, a tetrahydrofuran ring, or a pyran ring. 10 and R 11 are independently selected from the group consisting of H, CH, -CH-CH, F, CHF, CHF, and CF, or R 10 and R 11 are taken together to form a cyclopropyl, cyclobutyl, or oxetanyl ring. In another embodiment, R 10 and R 11 are independently selected from the group consisting of H, CH, -CH-CH, -CH-(CH), -C-(CH), F, cyclopropyl, CHF, and CF, or R 10 and R 11 are taken together to form a cyclopropyl, cyclobutyl, or oxetanyl ring. 10 and R 11 are independently H, CH 3、 -CH2-CH3 and CHF2, or R 10 and R 11 taken together form a cyclopropyl or cyclobutyl ring. In one embodiment, R 10 and R 11 and are both CH3. In another embodiment, R 10 and R 11 are both H.

[0051] In one embodiment, R 12 and R 13 are independently H, C 1~6 Alkyl, Fluoro, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, and in particular independently selected from the group consisting of H, C 1~6 Alkyl, Fluoro, C 1~6 Fluoroalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, and more particularly independently selected from the group consisting of H, C 1~6 Alkyl, fluoro and C 1~6 fluoroalkyl, most especially independently selected from the group consisting of H, C 1~6 In one embodiment, R is selected from the group consisting of alkyl and fluoro. 12 and R 13 is independently selected from the group consisting of H, CH3, and F. In another embodiment, R 12 and R 13 are both H.

[0052] In one embodiment, m is 0. In another embodiment, m is 1.

[0053] In one embodiment, R 15 and R 16 are independently H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~6 Fluorocycloalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6 fluoroalkynyl, and in particular independently selected from the group consisting of H, C 1~6 Alkyl, C 1~6 Fluoroalkyl, C 2~6 Alkenyl, C 2~6 Fluoroalkenyl, C 2~6 Alkynyl and C 2~6fluoroalkynyl, and more particularly independently selected from the group consisting of H, C 1~6 Alkyl and C 1~6 fluoroalkyl, most especially independently selected from the group consisting of H and C 1~6 In one embodiment, R 15 and R 16 is independently selected from the group consisting of H and CH. In another embodiment, R 15 and R 16 are both H.

[0054] In one embodiment, R 10 or R 11 One of the following and R 12 or R 13 may be taken together to form a 3- to 6-membered cycloalkyl or fluorocycloalkyl ring. 10 or R 11 One of the following and R 12 or R 13 may be taken together to form a cyclopropyl, cyclobutyl or cyclopentyl ring, especially a cyclopropyl or cyclopentyl ring.

[0055] In one embodiment, R 8 or R 9 One of the following and R 10 or R 11 may be taken together to form a 5- to 7-membered heterocyclyl or fluoroheterocyclyl ring. 8 or R 9 One of the following and R 10 or R 11 may be taken together to be -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-.

[0056] In one embodiment, R 8 or R 9 One of the following and R 12 or R 13may be taken together to form a 4- to 7-membered heterocyclyl or fluoroheterocyclyl ring. 8 or R 9 One of the following and R 12 or R 13 and one of R taken together may be -CH-, -CH-CH-, or -CH-CH-CH-, especially -CH-. In one embodiment, when m is 1, R 8 or R 9 One of the following and R 12 or R 13 may be taken together as a bond (thus forming a four-membered ring).

[0057] In one embodiment, R 7 or R 7 ' and R 8 or R 9 may be taken together to form a 5- or 6-membered cycloalkyl or fluorocycloalkyl ring. 7 or R 7 ' and R 8 or R 9 may be taken together to form a cyclopentyl or cyclohexyl ring, especially a cyclopentyl ring.

[0058] In one embodiment, ·R 7 or R 7 ' and R 8 or R 9 together form a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring, or ·R 7 or R 7 ' and R 6 are taken together to form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring, ·R 6and R 8 or R 9 together form a 5- or 6-membered cycloalkyl ring, a 5- or 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring, or ·R 6 and R 10 or R 11 taken together form a 4- to 6-membered heterocyclyl ring or a 4- to 6-membered fluoroheterocyclyl ring; or ·R 8 or R 9 One of the following and R 12 or R 13 taken together form a 4- to 7-membered heterocyclyl ring or a 4- to 7-membered fluoroheterocyclyl ring; or ·R 8 or R 9 One of the following and R 15 or R 16 taken together form a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring; or ·R 10 or R 11 One of the following and R 12 or R 13 together form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring, or ·R 10 or R 11 One of the following and R 15 or R 16 taken together form a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered fluorocycloalkyl ring, or ·R 8 or R 9 One of the following and R 10 or R 11 taken together form a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring; or ·R 12 or R13 One of the following and R 15 or R 16 taken together form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring.

[0059] In one embodiment of the compounds of formula (I), [ka] teeth, [ka] and in particular selected from the group consisting of [ka] is selected from the group consisting of:

[0060] In one embodiment of the compounds of formula (I), [ka] teeth, [ka] [ka] and in particular selected from the group consisting of [ka] is selected from the group consisting of:

[0061] In one embodiment, the compound of formula (I) is selected from the group consisting of the compounds in one of Tables 2-4, 6-8, and 10-15.

[0062] In another embodiment, the compound of formula (I) is selected from the group consisting of one of the following compounds, or a pharmaceutically acceptable salt thereof: [Table 1(1)] [Table 1(2)] [Table 1(3)]

[0063] In another embodiment, the compound of formula (I) is one of the following compounds: 7-(1-methyl-1H-pyrrol-3-yl)-5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]-1,6-naphthyridine 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-(1-methyl-1H-pyrrol-3-yl)-1,6-naphthyridine 7-(1-methyl-1H-pyrrol-3-yl)-5-{[(2S)-morpholin-2-yl]methoxy}-1,6-naphthyridine 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-(1-methyl-1H-pyrrol-3-yl)quinoline 5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]-7-[1-(propan-2-yl)-1H-pyrrol-3-yl]-1,6-naphthyridine 7-(1-ethyl-1H-pyrrol-3-yl)-5-{[(2S)-1,4-oxazepan-2-yl]methoxy}-1,6-naphthyridine 7-(1-methyl-1H-pyrrol-3-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-1,6-naphthyridine 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-[1-(propan-2-yl)-1H-pyrrol-3-yl]-1,6-naphthyridine 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-(1-ethyl-1H-pyrrol-3-yl)-1,6-naphthyridine 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]-1,6-naphthyridine 5-{[(2S)-morpholin-2-yl]methoxy}-7-[1-(propan-2-yl)-1H-pyrrol-3-yl]-1,6-naphthyridine 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-[(6,6-dimethylmorpholin-2-yl)methoxy]-4-methyl-1,6-naphthyridine 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-[1-(propan-2-yl)-1H-pyrazol-4-yl]quinoline 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-[1-(oxetan-3-yl)-1H-pyrrol-3-yl]quinoline 7-(1-methyl-1H-pyrazol-4-yl)-5-{[(6S)-5-oxa-8-azaspiro[3.5]nonan-6-yl]methoxy}-1,6-naphthyridine 5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]-7-[1-(propan-2-yl)-1H-pyrazol-4-yl]-1,6-naphthyridine 7-(1-tert-butyl-1H-pyrrol-3-yl)-5-{[(2S,6R)-6-methylmorpholin-2-yl]methoxy}quinoxaline 7-(2,3-Dihydro-1H-pyrrolizin-6-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]quinoline 7-(-tert-butyl-1H-pyrazol-4-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline 5-{[(5S)-4-oxa-7-azaspiro[2.5]octan-5-yl]methoxy}-7-[1-(propan-2-yl)-1H-pyrrol-3-yl]-1,6-naphthyridine 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-{[(2S,6S)-6-(difluoromethyl)morpholin-2-yl]methoxy}-1,6-naphthyridine or a pharmaceutically acceptable salt thereof.

[0064] The compound names in the previous paragraph were derived using ChemAxon Instant JChem 19.8.0.

[0065] In one embodiment, the compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, is an inhibitor of spleen tyrosine kinase (Syk).

[0066] The compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, has an EC50 activity against Syk of less than 500 nM, particularly less than 250 nM, more particularly less than 100 nM, and most particularly less than 50 nM. 50 may have

[0067] In one embodiment, the compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, is -6 cm / s, especially 15 × 10 -6 cm / s, most notably 20×10 -6 P over cm / s app In another embodiment, the compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, may have an efflux ratio of less than 2.0, particularly less than 1.5, and most particularly less than 1.0.

[0068] The compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, has a K of greater than 0.05, particularly greater than 0.1, more particularly greater than 0.2, and most particularly greater than 0.3. pu,uThe compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, following an oral dose of 10 mg / kg may have free brain levels of greater than 10 nM, in particular greater than 25 nM, or greater than 50 nM.

[0069] As used herein, [ka] Terms such as uR 5 Substituents may be attached to the ring system at any position, including on the nitrogen atom (such as the N of pyrrole) where appropriate, or on either ring (e.g., in 2,3-dihydropyrrolidine, R 5 may be attached to the pyrrole moiety or to the pyrrolidine moiety). For example, [ka] So, N of pyrrole is R 5 When not substituted by, N of pyrrole is NH.

[0070] 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 to which this invention belongs.

[0071] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more combinations.

[0072] The term "alkyl" refers to a straight-chain or branched alkyl substituent containing, for example, 1 to about 12 carbon atoms, preferably 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms, and even more preferably 1 to about 4 carbon atoms. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, 2-methylbutyl, 3-methylbutyl, hexyl, heptyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like. The carbon numbers referred to refer to the carbon backbone and carbon branches, but do not include carbon atoms belonging to any substituents, such as carbon atoms of alkoxy substituents branching from the main carbon chain.

[0073] The terms "fluoroalkyl," "cyclofluoroalkyl," "fluoroalkenyl," "fluoroalkynyl," "fluoroheterocyclyl," and the like refer to an alkyl, cycloalkyl, alkenyl, alkynyl, or heterocyclyl group in which one or more hydrogen atoms have been replaced with fluorine. In one embodiment, less than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the hydrogen atoms in the relevant group are replaced with fluorine. In another embodiment, more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the hydrogen atoms in the relevant group are replaced with fluorine. The fluoroalkyl group may, for example, contain only one fluorine atom or may be a perfluoroalkyl group. For example, the cyclofluoroalkyl group may be a 3- to 8-membered cyclofluoroalkyl ring, particularly a 3- to 7-membered cyclofluoroalkyl ring.

[0074] The term "alkenyl" refers to a straight-chain or branched alkenyl substituent containing, for example, 2 to about 12 carbon atoms, preferably 2 to about 8 carbon atoms, and more preferably 2 to about 6 carbon atoms. Examples of suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, and the like. Branched alkenyl groups may be branched at any suitable position, and exemplary branched alkenyl groups may include, for example, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 2-methyl-2-pentenyl, 2-methyl-3-pentenyl, 2-methyl-4-pentenyl, and the like. The carbon numbers referred to relate to the carbon backbone and carbon branches, but do not include carbon atoms belonging to any substituents, for example, carbon atoms of alkoxy substituents branching off from the main carbon chain.

[0075] The term "alkynyl" refers to a straight-chain or branched alkynyl substituent containing, for example, 2 to about 12 carbon atoms, preferably 2 to about 8 carbon atoms, and more preferably 2 to about 6 carbon atoms. Examples of suitable alkynyl groups include, but are not limited to, ethynyl, propynyl (prop-2-ynyl or prop-1-ynyl), butynyl, butadiynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, and the like. Branched alkynyl groups may be branched at any suitable position, and exemplary branched alkynyl groups may include, for example, 3-methyl-1-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, and the like. The carbon numbers referred to refer to the carbon backbone and carbon branches, but do not include carbon atoms belonging to any substituents, such as carbon atoms of alkoxy substituents branching from the main carbon chain.

[0076] The term "cycloalkyl" refers to a saturated non-aromatic cyclic hydrocarbon. The cycloalkyl ring may contain a specified number of carbon atoms. For example, a 3- to 8-membered cycloalkyl group contains 3, 4, 5, 6, 7, or 8 carbon atoms. The cycloalkyl group may be monocyclic, bicyclic, or tricyclic. When multiple rings are present, the rings may be fused together (e.g., bicyclic rings are fused when two atoms are common to both rings) or joined by a common atom (e.g., a spiro compound). Non-limiting examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group may be, for example, a 3- to 8-membered cycloalkyl ring, especially a 3- to 7-membered cycloalkyl ring.

[0077] The term "cycloalkenyl" or "cycloalkene" refers to a cyclic hydrocarbon having at least one double bond that is not aromatic. A cycloalkenyl ring may contain a specific number of carbon atoms. For example, a 5-membered cycloalkenyl group contains 5 carbon atoms. A cycloalkenyl group may be monocyclic, bicyclic, or tricyclic. When multiple rings are present, the rings may be fused together (e.g., bicyclic rings are fused when two atoms are common to both rings) or linked by a common atom (e.g., a spiro compound). Non-limiting examples may include cyclopentenyl and cyclopenta-1,3-dienyl.

[0078] The term "aryl" or "aromatic" refers to an aromatic carbocyclic substituent as commonly understood in the art. It is understood that the term aryl applies to cyclic substituents in which at least one ring is planar and contains 4n+2 pi-electrons according to Hückel's rule. Aryl groups may be monocyclic, bicyclic, or tricyclic. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Aryl groups do not encompass cycloalkyl groups; aryl groups have ring systems (e.g., monocyclic, bicyclic, or tricyclic rings) in which at least one ring is aromatic. For example, naphthyl and 1,2,3,4-tetrahydronaphthyl groups would both be aryl or aromatic groups. When multiple rings are present, the rings may be fused together (e.g., bicyclic rings are fused when two atoms are common to both rings) or linked by a common atom (e.g., spiro compounds, which may be present in a non-aromatic ring).

[0079] As used herein, the term "heterocyclic" or "heterocyclyl" refers to a cycloalkyl or cycloalkenyl group in which one or more carbon atoms are replaced by a heteroatom independently selected from N, S, and O. For example, 1 to 4 carbon atoms in each ring may be replaced by a heteroatom independently selected from N, S, and O. A heterocyclyl group may be monocyclic, bicyclic, or tricyclic, with at least one ring containing a heteroatom. When multiple rings are present, the rings may be fused together (e.g., bicyclic rings are fused when two atoms are common to both rings) or linked by a common atom (e.g., a spiro compound). Each of the rings of a heterocyclyl group may contain, for example, 5 to 7 atoms. Examples of heterocyclyl groups include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, dithiolyl, 1,3-dioxanyl, dioxinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, 1,4-dithianyl, and decahydroisoquinolyl. In bicyclic or tricyclic heterocyclyl groups, neither ring is aromatic. In one embodiment, the heterocyclyl is optionally substituted with =0.

[0080] The term "heteroaryl" or "heteroaromatic," as used herein, refers to a monocyclic, bicyclic, or tricyclic ring of up to seven atoms in each ring, wherein at least one ring is aromatic and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N, and S. When multiple rings are present, the rings are fused together (e.g., bicyclic rings are fused when two atoms are common to both rings) or linked by a common atom (e.g., spiro compounds, which may be present in non-aromatic rings). When determining whether a ring is a heterocyclyl or heteroaryl ring, tautomers of heteroatom-containing ring systems, for example, containing carbonyl groups, must be considered. Heteroaryls include, but are not limited to, 5-membered heteroaryls having one heteroatom (e.g., thiophene, pyrrole, furan); 5-membered heteroaryls having two heteroatoms at the 1,2 or 1,3 positions (e.g., oxazole, pyrazole, imidazole, thiazole); 5-membered heteroaryls having three heteroatoms (e.g., triazole, thiadiazole, oxadiazole, furazan); 5-membered heteroaryls having four heteroatoms (e.g., tetrazole); 6-membered heteroaryls having one heteroatom (e.g., pyridine); 6-membered heteroaryls having two heteroatoms (e.g., pyridazine, cinnoline, phthalazine, pyrazine, pyrimidine, quinazoline, quinoxaline); 6-membered heteroaryls having three heteroatoms (e.g., 1,3,5-triazine); and 6-membered heteroaryls having four heteroatoms.Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, furan, pyrrole, imidazole, pyrazole, triazole, triazine, thiadiazole, oxadiazole, tetrazole, furazan, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazan, and phenoxazine. Further exemplary heteroaryl groups may include, for example, indoline or 2,3-dihydrobenzofuran. In one embodiment, heteroaryl may be optionally substituted with =0.

[0081] When a range of the number of atoms in a structure is given (e.g., C 1~12 , C 1~6 It is specifically contemplated that whenever a group (e.g., alkyl, etc.) of 1 to 12 carbon atoms (e.g., C) is used in connection with any chemical group (e.g., alkyl, etc.) referenced herein, any subrange or individual number of carbon atoms falling within the indicated range can also be used. Thus, for example, the ranges of 1 to 12 carbon atoms (e.g., C 1~12 ), 1 to 6 carbon atoms (e.g., C 1~6) ranges may be expressed as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and / or 12 carbon atoms, as well as any subranges thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, as appropriate). atoms, 2 to 8 carbon atoms, 2 to 9 carbon atoms, 2 to 10 carbon atoms, 2 to 11 carbon atoms, 2 to 12 carbon atoms, 3 to 4 carbon atoms, 3 to 5 carbon atoms, 3 to 6 carbon atoms, 3 to 7 carbon atoms, 3 to 8 carbon atoms, 3 to 9 carbon atoms, 3 to 10 carbon atoms, 3 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 5 carbon atoms, 4 to 6 carbon atoms, 4 to 7 carbon atoms, 4 to 8 carbon atoms, 4 to 9 carbon atoms, 4 to 10 carbon atoms, 4 to 11 carbon atoms, and / or 4 to 12 carbon atoms, etc.

[0082] As used herein, "halo" refers to a halogen atom, especially F, Cl or Br, more especially F or Cl, most especially F.

[0083] As used herein, the terms "optionally substituted" and "optionally substituted" mean that any number of the hydrogen atoms on the optionally substituted group have been replaced with another moiety. Exemplary optional substituents are, for example, R 5 Discussed above in

[0084] The term "pharmaceutically acceptable salts," as used herein, refers to salts that are toxicologically safe for systemic or local administration, for example, salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids, especially salts prepared from pharmaceutically acceptable inorganic or organic acids.

[0085] The term "4-6 membered oxygen-containing heterocyclic ring" as used herein may include, for example, an oxetanyl ring system, a tetrahydrofuranyl ring system, or a pyranyl ring system. An oxetanyl ring system may be preferred.

[0086] Prodrug forms of the above compounds may include compounds of formula (I) derivatized at the nitrogen atom of the morpholine or homomorpholine group. Prodrug forms of the above compounds may include compounds of formula (I) derivatized at the nitrogen atom of the morpholine or homomorpholine group. 20 Ester or substituent R 4 The esters may also be considered to include esters containing, for example, a cycloalkyl or aryl moiety from an OH group in the aryl group. The aryl moiety may include a substituted phenyl or a fused bicyclic, tricyclic, or fused aromatic ring. Suitable prodrugs may include those defined in Simplacio, AL et al., 2008, Prodrugs for amines, Molecules, 13(3), pp. 519-547 or Safadi, M. et al., 1993, Phosphoryloxymethyl carbamates and carbonates - novel water-soluble prodrugs for amines and hindered alcohols, Pharmaceutical research 10(9), pp. 1350-1355, and may include N-alkyl, amide, carbamate, or carbonate (such as phosphoryloxymethyl carbamate and carbonate).

[0087] According to a second aspect of the present invention, there is provided a pharmaceutical composition comprising an effective amount of a compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, which composition may further comprise a pharmaceutically acceptable carrier, diluent and / or excipient.

[0088] While it is possible that the compounds of formula (I) (or pharmaceutical salts or prodrugs thereof) may be administered as the pure chemical, they may also be administered as part of a pharmaceutical composition comprising at least one carrier or excipient.

[0089] The type of pharmaceutical composition may depend on the absorption, distribution, metabolism, and excretion (ADME) profile of the compound of formula (I) (or a pharmaceutical salt or prodrug thereof). For example, it may be most suitable for the compound of formula (I) (or a pharmaceutical salt or prodrug thereof) to be administered parenterally, especially intravenously, and therefore the pharmaceutical composition may be formulated for parenteral or intravenous administration. However, and preferably, the pharmaceutical composition may include those suitable for oral or rectal administration, or administration by non-intravenous routes. Oral compositions for oral administration may be preferred.

[0090] Parenteral administration may include administration by one or more of the following routes: intravenous, intrathecal (intrathecal), intradermal, subcutaneous, intranasal, intramuscular, intraocular, transepithelial, vaginal, intraperitoneal, and topical. Topical administration includes buccal, sublingual, dermal, ocular, rectal, nasal, and administration by inhalation or aerosol means. For intravenous, cutaneous, or subcutaneous injection, or injection at the site where treatment is desired, the active agent may be in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity, and stability. Those skilled in the art will be able to prepare appropriate solutions.

[0091] The nature of the pharmaceutical composition and the carrier or excipient will depend on the route of administration and the nature of the condition and the patient to be treated. The selection of a particular carrier, excipient or delivery system, and administration route will be readily determined by one skilled in the art. In some situations, it may be necessary to protect the compound of formula (I) (or its pharmaceutical salt or prodrug) by means known in the art, for example, by microencapsulation. The administration route should also be selected so that the active agent reaches its site of action. The pharmaceutical composition may contain any suitable effective amount of the active agent corresponding to the intended dosage range used.

[0092] The pharmaceutical compositions may be in solid (including tablets, filled capsules, powders, cachets, capsules, troches, suppositories, wafers, dispersible granules, and pessaries) or liquid (including solutions, suspensions, syrups, emulsions, colloids, elixirs, creams, gels, and foams) form. In one embodiment, the pharmaceutical compositions may be in the form of a sterile injectable solution for parenteral use.

[0093] A pharmaceutically acceptable carrier or excipient must be acceptable in the sense of being compatible with other ingredients in the composition and not harmful to the patient. Pharmaceutically acceptable carriers or excipients may be solid or liquid. Carriers or excipients may act as diluents, buffers, stabilizers, isotonicity agents, flavoring agents, antioxidants, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Suitable carriers and excipients will be known to those skilled in the art. Regarding buffers, aqueous compositions may contain buffers to maintain the composition at a pH close to physiological pH or at least within the range of about pH 6.0 to 9.0.

[0094] When the pharmaceutical composition is a powder, both the active agent (a compound of formula (I) or a pharmaceutically acceptable salt thereof) and the carrier or excipient may be finely divided powders that are mixed using processes known in the art, such as dry blending or wet granulation.

[0095] When the pharmaceutical composition is a tablet, the active agent may be mixed with a suitable amount of a carrier or excipient having the necessary binding capacity before being compressed into tablets of the desired shape and size.

[0096] The powders or tablets may contain any suitable amount of active agent, with exemplary amounts of active agent in a powder or tablet ranging from about 5 or 10 percent to about 70 percent. Exemplary carriers or excipients for powders and tablets may include, for example, magnesium carbonate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, a low melting point wax, cocoa butter, and the like.

[0097] Liquid form preparations may contain, for example, water, saline, water-dextrose, water-propylene glycol, petroleum, or oil solutions (including animal, vegetable, mineral, or synthetic oils). For example, parenteral injection liquid preparations may be formulated as solutions in aqueous polyethylene glycol solution. Such liquid form preparations may contain at least 0.1% by weight of the active compound.

[0098] Liquid pharmaceutical compositions may be formulated in unit dose form. For example, the compositions may be provided in ampoules, prefilled syringes, small volume injections, or multi-dose containers. Such compositions may contain preservatives. The compositions may also contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. The compositions may also be in powder form for constitution with a suitable vehicle (such as sterile water) before use. Liquid carriers and excipients may include colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, suspending agents, etc.

[0099] Aqueous solutions for oral use may be prepared by dissolving the active agent in water and adding colorants, thickeners, flavorings, and stabilizers as desired. Aqueous suspensions for oral use may be prepared by dispersing the active agent in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, or other suspending agents.

[0100] For topical administration to the epidermis, the compounds may be formulated as ointments, creams or lotions, or as a transdermal patch.

[0101] The compositions may also be administered by inhalation in the form of an aerosol spray from a pressurized dispenser or container which contains a propellant such as carbon dioxide gas, hydrofluoroalkane, nitrogen, propane, or other suitable gas or combination of gases. The pharmaceutical composition may be in a form suitable for administration by inhalation or insufflation.

[0102] The pharmaceutical composition may be adapted to provide sustained release of the active agent.

[0103] Pharmaceutical compositions may be in the form of unit dosage forms.In such forms, pharmaceutical compositions may be prepared as a unit dose containing an appropriate amount of active agent.The unit dosage form may be a packaged preparation, the package containing individual amounts of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of capsules, tablets, cachets, or lozenges in packaged form.

[0104] According to a third aspect of the present invention, there is provided a method for treating or preventing a disease, disorder, or condition associated with spleen tyrosine kinase activity in a subject, the method comprising administering to the subject an effective amount of a compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of the second aspect. The disease, disorder, or condition associated with spleen tyrosine kinase activity may affect or be located in the central nervous system. In another embodiment, the disease, disorder, or condition associated with spleen tyrosine kinase activity may affect or be located in the peripheral nervous system. The disease, disorder, or condition associated with spleen tyrosine kinase activity may be associated with the brain of the subject. The disease, disorder, or condition associated with spleen tyrosine kinase activity may be associated with a region of the subject outside the brain.

[0105] According to a fourth aspect of the present invention, the present invention is directed to a method for treating glioblastoma, cancer (particularly ovarian cancer, head and neck cancer, eye cancer (retinoblastoma), leukemia (particularly B-cell and T-cell lymphoma), lymphoma (including Waldenström's macroglobulinemia), bone cancer, liver cancer, lung cancer (particularly small cell lung cancer), blood cancer (including macroglobulinemia), osteoporosis, rheumatoid arthritis, liver disease (including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma), fibrosis (particularly peritoneal fibrosis), periodontal disease (e.g. diseases associated with alveolar bone resorption), diabetes (particularly type 1 diabetes), inflammation (particularly dermatitis, fasciitis or pulmonary inflammation), Graves' disease, lung diseases or disorders (including hantavirus pulmonary syndrome), kidney diseases (including glomerulonephritis), epidermolysis bullosa acquisita, Wiskott-Aldrich syndrome, agammaglobulinemia, Nasu-Hakola disease, allergies, and subarachnoid hemorrhage, the method comprising administering to a subject an effective amount of a compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of the second aspect.

[0106] According to a fifth aspect of the present invention, there is provided use of a compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for treating or preventing a disease, disorder, or condition associated with spleen tyrosine kinase activity in a subject. The disease, disorder, or condition associated with spleen tyrosine kinase activity may affect or be located in the central nervous system. In another embodiment, the disease, disorder, or condition associated with spleen tyrosine kinase activity may affect or be located in the peripheral nervous system. The disease, disorder, or condition associated with spleen tyrosine kinase activity may be associated with the brain of the subject. The disease, disorder, or condition associated with spleen tyrosine kinase activity may be associated with a region of the subject outside the brain.

[0107] According to a sixth aspect of the present invention, there is provided a method for treating glioblastoma, cancer (particularly ovarian cancer, head and neck cancer, eye cancer (retinoblastoma), leukemia (particularly B-cell and T-cell lymphoma), lymphoma (including Waldenstrom's macroglobulinemia), bone cancer, liver cancer, lung cancer (particularly small cell lung cancer), blood cancer (including macroglobulinemia), osteoporosis, rheumatoid arthritis, liver disease (including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma), fibrosis (particularly peritoneal fibrosis), periodontal disease (e.g. diseases associated with alveolar bone resorption), diabetes (particularly type 1 diabetes), inflammation (particularly dermatitis, fasciitis or pulmonary inflammation), Graves' disease, lung disease or disorder (including hantavirus pulmonary syndrome), kidney disease (including glomerulonephritis), epidermolysis bullosa acquisita, Wiskott-Aldrich syndrome, non-cancer There is provided use of a compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of one or more of maglobulinemia, Nasu-Hakola disease, allergies (including drug allergies, especially co-trimoxazole allergies and carbapenem allergies), microbial infections (especially bacterial infections, more especially Mycobacterium abscessus), fungal infections (including chromoblastomycosis and mycoses), autoimmune hypersensitivity diseases, blood clotting disorders, thrombocytopenia, bone or skeletal disorders (including Melnick-Needles syndrome and Oto-Palato-Digital syndrome spectrum disorders), nail diseases, chronic mucocutaneous candidiasis, neurological diseases or disorders (including Alzheimer's disease, dementia and Parkinson's disease), neuroinflammatory diseases, stroke, traumatic brain injury, and subarachnoid hemorrhage.

[0108] According to a seventh aspect of the present invention, there is provided a compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of the second aspect, for use in the treatment or prevention of a disease, disorder, or condition associated with spleen tyrosine kinase activity. The disease, disorder, or condition associated with spleen tyrosine kinase activity may affect or be located in the central nervous system. In another embodiment, the disease, disorder, or condition associated with spleen tyrosine kinase activity may affect or be located in the peripheral nervous system. The disease, disorder, or condition associated with spleen tyrosine kinase activity may be associated with the brain of a subject. The disease, disorder, or condition associated with spleen tyrosine kinase activity may be associated with a region of the subject outside the brain.

[0109] According to an eighth aspect of the present invention, the present invention is directed to a cancer (particularly ovarian cancer, head and neck cancer, eye cancer (retinoblastoma), leukemia (particularly B-cell and T-cell lymphoma), lymphoma (including Waldenström's macroglobulinemia), bone cancer, liver cancer, lung cancer (particularly small cell lung cancer), blood cancer (including macroglobulinemia)), osteoporosis, rheumatoid arthritis, liver disease (including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma), fibrosis (particularly peritoneal fibrosis), periodontal disease (e.g. diseases associated with alveolar bone resorption), diabetes (particularly type 1 diabetes), inflammation (particularly dermatitis, fasciitis or pulmonary inflammation), Graves' disease, lung diseases or disorders (including hantavirus pulmonary syndrome), kidney diseases (including glomerulonephritis), epidermolysis bullosa acquisita, Wiskott-Aldrich syndrome, agammaglobulinemia, provided is a compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of the second aspect, for use in the treatment or prevention of one or more of: hemoglobinemia, Nasu-Hakola disease, allergies (including pharmaceutical allergies, particularly co-trimoxazole allergies and carbapenem allergies), microbial infections (particularly bacterial infections, more particularly Mycobacterium abscessus), fungal infections (including chromoblastomycosis and mycoses), autoimmune hypersensitivity diseases, blood clotting disorders, thrombocytopenia, bone or skeletal disorders (including Melnick-Needles syndrome and Oto-Palato-Digital syndrome spectrum disorders), nail diseases, chronic mucocutaneous candidiasis, neurological diseases or disorders (including Alzheimer's disease, dementia and Parkinson's disease), neuroinflammatory diseases, stroke, traumatic brain injury, and subarachnoid hemorrhage.

[0110] Diseases, disorders or conditions associated with spleen tyrosine kinase activity include glioblastoma, cancer (especially ovarian cancer, head and neck cancer, eye cancer (retinoblastoma), leukemia (especially B-cell and T-cell lymphoma), lymphoma (including Waldenstrom's macroglobulinemia), bone cancer, liver cancer, lung cancer (especially small cell lung cancer), blood cancer (including macroglobulinemia), osteoporosis, rheumatoid arthritis, liver disease (including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma), fibrosis (especially peritoneal fibrosis), periodontal disease (e.g., diseases associated with alveolar bone resorption), diabetes (especially type 1 diabetes), inflammation (especially dermatitis, fasciitis or pulmonary inflammation), Graves' disease, lung diseases or disorders (including hantavirus pulmonary syndrome), kidney disease (including glomerulonephritis). The disease, disorder, or condition associated with spleen tyrosine kinase activity may be selected from one or more of the following: epidermolysis bullosa acquisita, Wiskott-Aldrich syndrome, agammaglobulinemia, Nasu-Hakola disease, allergies (including medication allergies, particularly co-trimoxazole allergies and carbapenem allergies), microbial infections (particularly bacterial infections, more particularly Mycobacterium abscessus), fungal infections (including chromoblastomycosis and mycoses), autoimmune hypersensitivity disorders, blood clotting disorders, thrombocytopenia, bone or skeletal disorders (including Melnick-Needles syndrome and ear-palate-digital syndrome spectrum disorders), nail disorders, chronic mucocutaneous candidiasis, neurological diseases or disorders (including Alzheimer's disease, dementia, and Parkinson's disease), neuroinflammatory diseases, stroke, traumatic brain injury, and subarachnoid hemorrhage. The disease, disorder, or condition associated with spleen tyrosine kinase activity may affect or be in the central nervous system.

[0111] In this specification and claims, the terms "comprising" and derivatives thereof, including "comprises" and "comprise," include each of the listed elements but do not exclude the inclusion of one or more additional elements.

[0112] As used herein, the terms "treatment" (or "treating") and "prevention" (or "preventing") should be considered in their broadest context. For example, the term "treatment" does not necessarily mean that a patient is treated until total recovery. The term "treatment" includes amelioration of symptoms of a disease, disorder, or condition, or reducing the severity of a disease, disorder, or condition. Similarly, "prevention" does not necessarily mean that a subject will never contract a disease, disorder, or condition. "Prevention" may also be considered as reducing the likelihood of the onset of a disease, disorder, or condition, or averting or otherwise reducing the risk of developing a disease, disorder, or condition.

[0113] As used herein, the terms "subject" or "individual" or "patient" may refer to any subject for whom treatment is desired, particularly a vertebrate subject, and even more particularly a mammalian subject. Suitable vertebrates include, but are not limited to, primates, birds, livestock animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory test animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs), and captive wild animals (e.g., foxes, deer, dingoes). A preferred subject is a human.

[0114] As used herein, an "effective amount" refers to the administration of an amount of the relevant active agent sufficient to at least partially achieve a desired response, or to prevent the onset of symptoms of the disease, disorder, or condition being treated, or to halt the worsening of symptoms, or to treat, alleviate, or at least reduce the severity of the symptoms. This amount may vary depending on factors such as the health and physical condition of the individual to whom the compound is administered, the taxonomic group of the individual to whom the compound is administered, the degree of treatment / prevention desired, the formulation of the composition, and an evaluation of the medical condition. It is expected that the "effective amount" will fall within a broad range that can be determined through routine testing. An effective amount for a human patient may be, for example, in the range of about 0.1 ng / kg to 1 g / kg of body weight per dose, or about 100 ng to 100 mg / kg of body weight per dose. Dosage regimens may be adjusted to provide the optimal therapeutic response. For example, several doses may be administered daily, biweekly, or weekly, or at other appropriate time intervals, or the dose may be proportionally reduced if circumstances indicate. Determination of dosage etc. will be within the skill of the physician or veterinarian in charge of the patient's care.

[0115] The compounds of formula (I) (or pharmaceutically acceptable salts or prodrugs thereof) may be administered with additional active agents. For example, when the disease, disorder, or condition being treated or prevented is cancer, the compounds of formula (I) may be administered with other anti-cancer agents (docetaxel, 5-fluorouracil, etc.).

[0116] In a ninth aspect, the present invention provides a method of synthesizing a compound of formula (I) of the first aspect, comprising: (a) [ka] and [ka] Coupling with [ka] providing (b) [ka] and R 23 -R 4 and coupling in the presence of a catalyst, [ka] providing (c) [ka] removing PG from the compound of formula (I); Including, X, Y, Z, R 4 , R 6 , R 7 , R 7 ', R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 and R 16 is as defined in the first aspect, R 20 and R 22 one of which is OH and the other is a leaving group, PG is a protecting group, ·R 21 is a leaving group and R 23 is R 4 R in 23 is a group that provides activated carbon to the carbon to which it is attached, or ·R 23 is a leaving group and R 21 is R 21 is a group that provides activated carbon to the carbon to which it is attached. Regarding the method.

[0117] As used herein, the term "leaving group" may refer to, for example, a halo (such as F, Cl, Br, or I) or an activated oxygen group (such as a sulfonyloxy group, including a toluenesulfonyloxy group, a trifluoromethylsulfonyloxy group, or a methylsulfonyloxy group).

[0118] As used herein, the term "protecting group" with respect to PG above refers to a group of atoms that masks, reduces, or prevents the reactivity of the nitrogen atom to which PG is attached. Examples of protecting groups may be found in "Greene's Protective Groups in Organic Synthesis" (Wiley, 4th Edition, 2007). In one embodiment, PG may be a Boc group or a Cbz group.

[0119] In one embodiment, R 20 and R 22 One of the groups is OH and the other is Cl, Br, I or an activated oxygen group (such as a sulfonyloxy group, including a toluenesulfonyloxy group, a trifluoromethylsulfonyloxy group or a methylsulfonyloxy group).

[0120] In one embodiment of step (b), the catalyst is a palladium catalyst. Exemplary palladium catalysts may include palladium catalysts having phosphine ligands. Exemplary catalysts may include tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II), or (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0121] In one embodiment, step (b) provides a Suzuki coupling, a Negishi coupling, a Kumada coupling, a Stille coupling, a Heck coupling, or a variant thereof, in particular a Suzuki coupling or a Heck coupling. Step (b) may provide an sp2-sp2 coupling reaction.

[0122] In one embodiment, R 23 is R 4 In one embodiment, R is a metal or metalloid bonded to a carbon atom in the aryl group. The metal or metalloid may be selected from a boron group, a zinc group, or a tin group, or a Grignard reagent, especially a boron group (e.g., a boronic acid or ester). In one embodiment, R 21 is a metal or metalloid bonded to a carbon atom. This metal or metalloid may be selected from a boron group, a zinc group or a tin group or a Grignard reagent, especially a boron group (e.g., a boronic acid or ester).

[0123] In step (c), a person skilled in the art would be able to identify appropriate conditions for removing the protecting group. For example, when PG is Boc, step (c) may involve treatment with trifluoroacetic acid. When PG is Cbz, step (c) may involve treatment with hydrobromic acid.

[0124] In one embodiment, step (b) comprises R 24 -R 5 and [ka] and R 24 is a leaving group (e.g., halo (including fluoro, chloro, bromo, or iodo) or an activated oxygen group (e.g., sulfonyloxy groups, including toluenesulfonyloxy, trifluoromethylsulfonyloxy, or methylsulfonyloxy groups)), and R 5 is R 4 through the nitrogen atom in R 4 In this embodiment, R in step (c) 4 is R 5 R is replaced by 4 is.

[0125] The features of the second to ninth aspects of the present invention may be as described for the first aspect of the present invention. The pharmaceutical of the fifth and sixth aspects of the present invention may be the pharmaceutical composition described above.

[0126] Any of the features described herein may be combined with any one or more of the other features described herein, in any combination, within the scope of the present invention.

[0127] Preferred features, embodiments and variations of the present invention may be discerned from the following examples, which provide sufficient information for those skilled in the art to practice the invention, and should not be construed as limiting the scope of the above-described Summary of the Invention in any way. [Example]

[0128] compound synthesis Abbreviation Various abbreviations are used throughout the Examples section, and although most will be understood by those skilled in the art, an explanation of some of the abbreviations follows: Bn: Benzyl Boc: t-butyloxycarbonyl Cbz: Carboxybenzyl DMSO: Dimethyl sulfoxide HPLC: High-Performance Liquid Chromatography H2O: Water Hz: Hertz LCMS: Liquid Chromatography Mass Spectrometry MeCN: Acetonitrile ·PG: Protecting group ·Prep: preparative separation Rac: Racemic Rel: Relative UPLC: Ultra-high performance liquid chromatography

[0129] General method: Purification method: Method 1: Silica gel chromatography techniques include either automated techniques or manual chromatography on pre-packed cartridges, manually packed flash columns or ionic solid phase extraction cartridges.

[0130] Method 2: Prep-HPLC was performed using the following conditions: Shimadzu UFLC XR. Column: Xterra Prep MS C18 OBD, 19 x 150 mm, 10 microns (10 μm). Column temperature: ambient temperature. Mobile phase A: H2O + 0.05% formic acid. Mobile phase B: MeCN. Flow rate: 15 mL / min. Mobile phase gradient and run time varied depending on the compound.

[0131] Method 3: Prep-HPLC was performed using the following conditions: Shimadzu UFLC XR. Column: Xterra Prep MS C18 OBD, 19 x 150 mm, 10 microns (10 μm). Column temperature: ambient temperature. Mobile phase A: H2O + 10 mM ammonium bicarbonate. Mobile phase B: MeCN. Flow rate: 15 mL / min. Mobile phase gradient and run time varied depending on the compound.

[0132] 1 H NMR method: H NMR spectra were recorded on a Bruker AVANCE III HD 600 MHz or Varian 400 MHz spectrometer at 298 K in the indicated deuterated solvents and referenced to residual solvent signals (H: δ 7.26 for chloroform-d; H: δ 2.50 for DMSO-d; H: δ 3.31 for methanol-d; H: δ 4.79 for deuterium oxide). Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, hept = septet, m = multiplet, app = apparent, br = broad.

[0133] LC-MS method: Method 1: Shimadzu LCMS-2020 Nexera UHPLC, Column: Xterra MS-C18, 2.1 x 50 mm, 2.5 microns (2.5 μm). Column temperature: 40 °C. Mobile phase A: HO + 0.05% formic acid, Mobile phase B: MeCN. Mobile phase gradient details: T = 0 min (95% A, 5% B); T = 0.3 min (95% A, 5% B); Gradient to T = 3 min (5% A, 95% B); End of run at T = 4 min (5% A, 95% B). Flow rate: 0.5 mL / min, Analysis time: 5.5 min. Detection method was UV at 254 nm and positive / negative mode electrospray ionization on the Shimadzu LCMS-2020.

[0134] Method 2: Shimadzu LCMS-2020 Nexera UHPLC, Column: Xterra MS-C18, 2.1 x 50 mm, 3.5 microns (3.5 μm). Column temperature: 40 °C. Mobile phase A: HO + 0.05% formic acid. Mobile phase B: MeCN. Mobile phase gradient details: T = 0 min (95% A, 5% B); T = 0.3 min (95% A, 5% B); gradient to T = 3 min (5% A, 95% B); end of run at T = 4 min (5% A, 95% B). Flow rate: 0.5 mL / min, analysis time: 5.5 min. Detection method was UV at 254 nm and positive / negative mode electrospray ionization on the Shimadzu LCMS-2020.

[0135] Method 3: Shimadzu LCMS-2020 Nexera UHPLC. Column: X-Bridge BEH C18, 2.1 x 50 mm, 2.5 microns (2.5 μm). Column temperature: 40 °C. Mobile phase A: 10 mM ammonium bicarbonate. Mobile phase B: MeCN. Mobile phase gradient details: T = 0 min (95% A, 5% B); T = 0.3 min (95% A, 5% B); gradient to T = 3 min (5% A, 95% B); end of run at T = 4 min (5% A, 95% B). Flow rate: 0.5 mL / min, analysis time 5.5 min. Detection method was UV at 254 nm and positive / negative mode electrospray ionization on the Shimadzu LCMS-2020.

[0136] Method 4: Water Acquity UPLC equipped with a binary solvent manager, PDA detector, and Acquity QDA performance mass detector. Column temperature: 35°C, autosampler temperature: 5°C. Mobile phase A: 0.1% formic acid in Milli Q water (pH = 2.70), mobile phase B: 0.1% formic acid in water:MeCN (10:90). Mobile phase gradient details: T = 0 min (97% A, 3% B) flow rate: 0.8 mL / min; T = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min; gradient to T = 2.7 min (2% A, 98% B), flow rate: 0.8 mL / min; gradient to T = 3 min (0% A, 100% B), flow rate: 1 mL / min; T = 3.5 min (0% A, 100% B) flow rate: 1 mL / min; gradient to T = 3.51 min (97% A, 3% B), flow rate: 0.8 mL / min; end of run at T = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Column 1: X-Bridge C18 50 x 2.1 mm, 2.5 microns (2.5 μm); Column 2: YMC tri-art C18 50 x 2.0 mm, 1.9 microns (1.9 μm); Column 3: X-Bridge C18 50 x 4.6 mm, 3.5 microns (3.5 μm); Column 4: Sunfire C18 150 x 4.6 mm, 3.5 microns (3.5 μm); Column 5: YMC C18 50 x 2.0 mm, 1.9 microns (1.9 μm); Column 6: X-Bridge C18 250 x 4.6 mm, 5.0 microns (5.0 μm); Column 7: X-Bridge BEH C18 50 x 2.1 mm, 2.5 microns (2.5 μm); Column 8: X-Bridge C18 50 x 2.5 mm, 2.5 microns (2.5 μm); Column 9: Xtimate C18 50 x 2.1, 1.8 microns (1.8 μm).

[0137] Method 5: Agilent 1200 LCMS 6130, Column: Atlantis dC18, 4.6 x 50 mm, 5 micron (5 μm). Column temperature: 25 °C. Mobile phase A: H2O + 0.1% formic acid, Mobile phase B: MeCN. Mobile phase gradient details: T = 0 min (95% A, 5% B); T = 2.5 min (5% A, 95% B); Gradient to T = 4 min (5% A, 95% B); End of run at T = 4.5 min (95% A, 5% B). Flow rate: 1.5 mL / min, run time 6.0 min. UV detection: Maximum absorbance.

[0138] Method 6: Agilent 1290 Infinity II LCMS 6130, Column: X-Bridge C8, 4.6 x 50 mm, 3.5 micron (3.5 μm). Column temperature: 25 °C. Mobile phase A: 10 mM ammonium bicarbonate in water, Mobile phase B: MeCN. Mobile phase gradient details: T = 0 min (95% A, 5% B); T = 8.0 min (0% A, 100% B); gradient to T = 8.1 min (0% A, 100% B); end of run at T = 8.5 min (95% A, 5% B). Flow rate: 1.0 mL / min, run time 10.0 min. UV detection: absorbance maximum.

[0139] Method 7: Agilent 1200 Series. Column: X-Bridge C18 50 x 4.6 mm, 3.5 micron (3.5 μm). Column temperature: 25°C. Mobile phase A: 0.1% formic acid in water, Mobile phase B: MeCN. Mobile phase gradient details: T = 0 min (95% A, 5% B); T = 8.0 min (0% A, 100% B); gradient to T = 8.1 min (0% A, 100% B); end of run at T = 8.5 min (95% A, 5% B). Flow rate: 1.0 mL / min, run time 10 min. UV detection: absorbance maximum.

[0140] Method 8: Waters Alliance 2690 and 996 PDA detectors and Micromass ZQ. Column temperature: 25°C. Mobile phase A: 5 mM ammonium acetate + 0.1% formic acid in water (pH = 3.5). Mobile phase B: methanol. Gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9 min (0% A, 100% B); gradient to T = 14 min (0% A, 100% B); gradient to T = 14.1 min (90% A, 10% B); T = 17.0 min (90% A, 10% B). Flow rate: 1 mL / min, run time 17 min. Column 1: Welch C18 4.6 x 150 mm, 5 microns (5 μm); Column 2: Sunfire C18, 150 x 4.6 mm, 3.5 microns (3.5 μm); Column 3: X-Bridge C18, 250 x 4.6 mm, 5 microns (5 μm).

[0141] Method 9: Aquity equipped with PDA and SQ detectors. Column: X-Bridge C18, 50 x 2.1 mm, 2.5 microns (2.5 μm). Column temperature: 35°C, autosampler temperature: 25°C. Mobile phase A: 5 mM ammonium bicarbonate in water (pH = 7.35). Mobile phase B: acetonitrile. Mobile phase gradient details: T = 0 min (97% A, 3% B); T = 0.20 min (97% A, 3% B); gradient to T = 2.7 min (2% A, 98% B); gradient to T = 3 min (0% A, 100% B); T = 3.5 min (0% A, 100% B); gradient to T = 3.51 min (97% A, 3% B); end of run at T = 4 min (97% A, 3% B). Flow rate: 0.5 mL / min, run time 4 min.

[0142] HPLC method: Waters HPLC-e2695 equipped with a Waters 2998-PDA detector. Column: X-Bridge C18, 150 x 4.6 mm, 3.5 microns (3.5 μm). Column temperature: room temperature; autosampler temperature: 15°C. Mobile phase A: 0.1% ammonia solution (25%) in Milli-Q water (pH ∼9); Mobile phase B: 100% acetonitrile. Mobile phase gradient details: T = 0 min (90% A, 10% B); gradient to T = 7 min (10% A, 90% B); gradient to T = 9 min (0% A, 100% B); T = 14 min (0% A, 100% B); gradient to T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B); flow rate: 1 mL / min; run time: 17 min.

[0143] General Scheme General Scheme Overview Compounds of formula (I) may be prepared by the general process described below. The preparation method may involve substitution or alkylation of a bicyclic compound to provide an intermediate, which is then coupled in an sp2-sp2 coupling reaction to form R 4 The R group is introduced. 4 The group may be added prior to removing the protecting group (PG) on the nitrogen (e.g., R 5 may be modified to provide a group. [ka]

[0144] A variety of compounds of formula (I) may be prepared using the synthetic schemes described below, employing readily available starting materials and employing techniques available in the art. The methods described may be readily adapted to provide other compounds falling within the scope of formula (I).

[0145] The following examples are intended to illustrate embodiments and should not be construed as limiting in any way. Additional compounds may be prepared using similar reaction schemes and methods.

[0146] General Scheme 1 - Naphthyridines [ka] In the above scheme, for example, the step marked "A" is General Procedure A below. Similarly, the step marked "B" is General Procedure B below, and so on. The substituents are as defined above. PG is a protecting group.

[0147] General Scheme 2 - Quinoxalines and Quinolines [ka]

[0148] In the above scheme, for example, the step marked "E" is General Procedure E below. Similarly, the step marked "F" is General Procedure F below, and so on. The substituents are as defined above. PG is a protecting group.

[0149] General Scheme 3 - Quinazolines [ka] In the above scheme, for example, the step marked "J" is the following general procedure J. The substituents are as defined above. PG is a protecting group.

[0150] General Procedure A [ka]

[0151] To a solution (0.05-0.1 M) of the alcohol (1.2 equiv) in acetonitrile cooled to 0°C, sodium hydride 57-63% oil dispersion (2.0 equiv) was added portionwise and the reaction was stirred for 5 min. After this, the appropriate heteroaryl chloride (1.0 equiv) was added and the reaction was stirred at room temperature for 1-5 h.

[0152] The reaction mixture was quenched by slow addition of water, and the product was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated. The crude material was purified using Purification Method 1.

[0153] [Table 2(1)] [Table 2(2)] [Table 2(3)] [Table 2(4)] [Table 2(5)] [Table 2(6)] [Table 2(7)] [Table 2(8)] [Table 2(9)] [Table 2 (10)] [Table 2(11)]

[0154] General Procedure B [ka]

[0155] To a microwave vial was added tetrakis(triphenylphosphine)palladium (0.1 equiv.), sodium carbonate (3.0 equiv.), the appropriate boronic acid / ester (1.2–1.5 equiv.), and an appropriately substituted heteroaryl halide (1.0 equiv.). The vial was evacuated and backfilled with nitrogen. This was repeated two more times, followed by the addition of a degassed solution of 1,4-dioxane / water (0.1–0.4 M in a 10:1 ratio). The reaction was heated at 135°C under microwave irradiation for 30 min–1 h. The cooled reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organics were washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated. The residue was either purified by standard purification methods 1, 2, or 3, or carried on crude to the next step, where the protecting groups were removed using one of the following conditions:

[0156] Boc deprotection Condition 1: To a solution (0.05-0.2 M) of the protected intermediate (1.0 equiv.) in dichloromethane was added trifluoroacetic acid (6-60 equiv.). The reaction mixture was stirred at room temperature for 1-24 hours. Once the starting material was consumed, the reaction mixture was purified using one of the standard purification methods described above.

[0157] Condition 2: A solution of the intermediate (1.0 equiv.) in 1,4-dioxane / water (1:3 ratio, 0.05-0.2 M) was heated by microwave irradiation at 140-170 °C for 1-2 h. The solvent was removed under reduced pressure, and the reaction mixture was purified using one of the standard purification methods described above.

[0158] Cbz deprotection To the protected intermediate (1.0 equiv.) was added hydrobromic acid solution (30 wt.% in acetic acid, 25-50 equiv.), and the resulting solution was stirred at room temperature for 10 minutes. After this time, the reaction mixture was treated with hydrochloric acid (1 M aqueous solution), and the resulting mixture was extracted with dichloromethane. The aqueous phase was neutralized with sodium hydroxide, and the product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated to give the deprotected product.

[0159]

Table 3(1)

Table 3(2)

Table 3(3)

Table 3(4)

Table 3(5)

Table 3(6)

Table 3(7)

Table 3(8)

Table 3(9)

Table 3(10)

Table 3(11)

Table 3(12)

Table 3(13)

Table 3(14)

Table 3(15)

Table 3(16)

Table 3(17)

Table 3(18)

Table 3(19)

Table 3(20)

Table 3(21)

Table 3(22)

Table 3(23)

Table 3(24)

Table 3(25)

Table 3(26)

Table 3(27)

[0160] General hand order C

change

[0161] [Table 4(1)] [Table 4(2)] [Table 4(3)] [Table 4(4)]

[0162] General Procedure D [ka]

[0163] If an alkyl halide starting material is used: To a solution (0.05–0.3 M) of the heterocyclic starting material (1.0 equiv.) and the appropriate alkyl halide (5.0–10.0 equiv.) in N,N-dimethylformamide was added sodium hydride (57–63% oil dispersion) (1.0–3.0 equiv.), and the reaction mixture was stirred at room temperature for 1–24 h. Water was added, and the product was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated. The residue was either purified by standard purification methods 1, 2, or 3, or subjected crude to the deprotection step.

[0164] If using an alkyl tosylate or alkyl mesylate starting material: To a solution (0.05–0.3 M) of the heterocyclic starting material (1.0 equiv.) and the appropriate alkyl tosylate or alkyl mesylate (1.0–10.0 equiv.) in dimethyl sulfoxide was added cesium carbonate (1.0–3.0 equiv.). The reaction was heated to 110°C for 1–24 h. Water was added and the product was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated. The residue was either purified by standard purification methods 1, 2, or 3 or taken crude for protection group removal using one of the following conditions:

[0165] Boc deprotection condition 1: To a solution (0.05-0.2 M) of the protected intermediate (1.0 equiv.) in dichloromethane was added trifluoroacetic acid (6-60 equiv.). The reaction mixture was stirred at room temperature for 1-24 hours. Once the starting material was consumed, the reaction mixture was purified using one of the standard purification methods described above.

[0166] Boc deprotection conditions: A solution of the intermediate (1.0 equiv.) in 2:1,4-dioxane:water (1:3 ratio, 0.05-0.2 M) was heated at 140-170 °C for 1-2 h by microwave irradiation. The solvent was removed under reduced pressure, and the reaction mixture was purified using one of the standard purification methods described above.

[0167] [Table 5(1)] [Table 5(2)] [Table 5(3)] [Table 5(4)] [Table 5(5)]

Table 5(6)

Table 5(7)

Table 5(8)

Table 5(9)

Table 5(10)

Table 5(11)

Table 5(12)

Table 5(13)

Table 5(14)

Table 5(15)

Table 5(16)

Table 5(17)

Table 5(18)

Table 5(19)

Table 5(20)

[0168] Generally smooth E

change

[0169] General Procedure F [ka] To a solution (0.1–0.4 M) of heteroaryl bromide (7-bromoquinoxalin-5-ol or 7-bromoquinolin-5-ol) (1.0 equiv.) and mesylated alcohol (1.1 equiv.) in an appropriate solvent (dimethyl sulfoxide or N,N-dimethylformamide) was added cesium carbonate (3.0 equiv.). The reaction mixture was heated at 100°C for 4–16 h. The cooled reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organics were washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated in vacuo. The residue was purified using purification method 1.

[0170] [Table 6(1)] [Table 6(2)] [Table 6(3)]

[0171] General Procedure G: [ka] To a degassed solution of the appropriate heteroaryl halide (1 equiv.) and arylboronic acid / ester (1.1–1.25 equiv.) in 1,4-dioxane / water (0.5 M in a 0.1–4:1 ratio), tripotassium phosphate (3.0 equiv.) was added, followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex in dichloromethane (Pd(dppf)Cl2·CHCl2) (5–10 mol%). The reaction mixture was sealed and heated to 90–120 °C for 30 min–4 h. The cooled reaction mixture was diluted with 2 M aqueous sodium hydroxide or saturated brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate / magnesium sulfate and concentrated. The residue was either purified by standard purification methods 1, 2, or 3, or used crude for protection group removal using one of the following conditions:

[0172] To a solution (0.05-0.2 M) of the protected intermediate (1.0 equiv.) in dichloromethane was added trifluoroacetic acid (6.0-60 equiv.). The reaction mixture was stirred at room temperature for 1-24 hours. Once the starting material was consumed, the reaction mixture was purified using one of the standard purification methods described above.

[0173] [Table 7(1)] [Table 7(2)] [Table 7(3)] [Table 7(4)] [Table 7(5)] [Table 7(6)] [Table 7(7)] [Table 7(8)]

[0174] General Procedure H: [ka] To a degassed solution of heteroaryl halide (1.0 equiv.) and arylboronic acid / ester (1.1–1.25 equiv.) in tetrahydrofuran / 2M aqueous sodium carbonate (0.5 M in a 0.1–10:1 ratio) was added (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3) (2–10 mol%). The reaction mixture was sealed and heated to 135 °C for 1 h. The cooled reaction mixture was diluted with 2M aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated. The residue was either purified by standard purification methods 1, 2, or 3, or used crude for deprotection using one of the following conditions:

[0175] Condition 1: To a solution (0.05-0.2 M) of the protected intermediate (1.0 equiv.) in dichloromethane was added trifluoroacetic acid (6.0-60 equiv.). The reaction mixture was stirred at room temperature for 1-24 hours. Once the starting material was consumed, the reaction mixture was purified using one of the standard purification methods described above.

[0176] Condition 2: A solution of the intermediate (1.0 equiv.) in 1,4-dioxane / water (1:3 ratio, 0.05-0.2 M) was heated by microwave irradiation at 140-170 °C for 1-2 h. The solvent was removed under reduced pressure, and the reaction mixture was purified using one of the standard purification methods described above.

[0177] [Table 8(1)] [Table 8(2)] [Table 8(3)] [Table 8(4)] [Table 8(5)]

[0178] General Procedure I: [ka]

[0179] Boc deprotection Condition 1: To a solution (0.05-0.2 M) of the protected intermediate (1.0 equiv.) in dichloromethane was added trifluoroacetic acid (6.0-60 equiv.). The reaction mixture was stirred at room temperature for 1-24 hours. Once the starting material was consumed, the reaction mixture was purified using one of the standard purification methods described above.

[0180] Condition 2: A solution of the intermediate (1.0 equiv.) in 1,4-dioxane / water (1:3 ratio, 0.05-0.2 M) was heated by microwave irradiation at 140-170 °C for 1-2 h. The solvent was removed under reduced pressure, and the reaction mixture was purified using one of the standard purification methods described above.

[0181] Cbz deprotection To the protected intermediate (1.0 equiv.) was added hydrobromic acid solution (30 wt. %, 25-50 equiv.), and the resulting solution was stirred at 20 °C for 10 min. After this time, the reaction mixture was treated with hydrochloric acid (1 M aqueous solution), and the resulting mixture was extracted with dichloromethane. The aqueous phase was neutralized with aqueous sodium hydroxide, and the product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated to give the deprotected product.

[0182] [Table 9(1)] [Table 9(2)] [Table 9(3)]

[0183] General procedure J [ka] To a solution (0.05-0.1 M) of the alcohol (1.2 equiv) in acetonitrile cooled to 0°C, sodium hydride (57-63% oil dispersion, 2.0 equiv) was added portionwise, and the reaction was stirred for 5 minutes. After this time, the appropriate heteroaryl chloride (1.0 equiv) was added, and the reaction was stirred at room temperature for 1-5 hours. The reaction mixture was quenched by the slow addition of water, and the product was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated. The crude material was purified using Purification Method 1.

[0184] [Table 10]

[0185] Synthesis of key building blocks Synthesis of 1-[(dibenzylamino)methyl]cyclopropan-1-ol [ka] To a suspension of ethyl 2-(dibenzylamino)acetate (19.0 g, 67.1 mmol) in tetrahydrofuran (60 mL) cooled to 0 °C under nitrogen, tetraisopropyl titanate (4.0 mL, 13.4 mmol) and bromo(ethyl)magnesium (2 M in tetrahydrofuran, 100 mL, 201.2 mmol) were added dropwise. The reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, and the product was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 10–15% ethyl acetate in petroleum ether to give 1-[(dibenzylamino)methyl]cyclopropan-1-ol (14.0 g, 52.4 mmol, 78% yield) as a colorless solid. LCMS (Method 5): Retention time = 1.44 min, [MH]+ = 268.

[0186] Synthesis of 1-[(benzylamino)methyl]cyclopropan-1-ol [ka] To a cooled suspension of 1-[(dibenzylamino)methyl]cyclopropan-1-ol (6.4 g, 23.9 mmol) in methanol (30 mL) and hydrochloric acid (6 N aqueous solution, 6.0 mL, 36.0 mmol) under nitrogen, palladium(II) hydroxide (20% supported wet support, 640 mg, 0.46 mmol) was added. A hydrogen bag was attached and the reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite® with methanol, and the filtrate was concentrated. The reaction was repeated on the same scale, filtered, and combined with the first reaction. The crude reaction mixture was made basic with 28% aqueous ammonia, and the product was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 1-[(benzylamino)methyl]cyclopropan-1-ol (8.0 g, 45.1 mmol, 94% yield) as a pale yellow liquid. No purification was performed; the product was used crude in the next step. LCMS (Method 5): Retention time = 0.92 min, [MH]+=178.

[0187] Synthesis of [(5S)-7-benzyl-4-oxa-7-azaspiro[2.5]octan-5-yl]methanol [ka] To a suspension of 1-[(benzylamino)methyl]cyclopropan-1-ol (8.0 g, 45.1 mmol) in toluene (30 mL) was added (R)-(-)-epichlorohydrin (5.4 mL, 69.2 mmol) and lithium perchlorate (4.8 g, 45.1 mmol). The reaction was stirred at room temperature for 72 hours. Sodium methoxide (6.1 g, 112.8 mmol) was then added, and the reaction was stirred at room temperature for an additional 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 40–50% ethyl acetate in petroleum ether to give [(5S)-7-benzyl-4-oxa-7-azaspiro[2.5]octan-5-yl]methanol (4.2 g, 18.0 mmol, 40% yield) as a light brown gum. 1H NMR(400MHz,DMSO-d6) δ 7.41-7.18(m,5H),4.60(t,1H),3.63-3.53(m,1H),3.47(s,2H),3.38-3.34(m,1H),3.30-3.21(m,1H),2.82(dt,1 H),2.12(dd,1H),1.92-1.79(m,1H),0.76-0.64(m,1H),0.64-0.53(m,1H),0.53-0.44(m,1H),0.44-0.35(m,1H). LCMS (Method 5): Retention time = 1.18 min, [MH]+=234.

[0188] Synthesis of [(5S)-4-oxa-7-azaspiro[2.5]octan-5-yl]methanol [ka] To a suspension of [(5S)-7-benzyl-4-oxa-7-azaspiro[2.5]octan-5-yl]methanol (4.2 g, 18.0 mmol) in methanol (30 mL) under nitrogen, palladium(II) hydroxide (20% supported wet, 400 mg, 0.29 mmol) was added, a hydrogen bag was attached, and the reaction was stirred at room temperature for 2 h. The reaction mixture was filtered through Celite®, washed with methanol, and the filtrate was concentrated to give [(5S)-4-oxa-7-azaspiro[2.5]octan-5-yl]methanol (2.3 g, 16.1 mmol, 89% yield). 1H NMR (400MHz, methanol-d4) δ 3.69-3.61(m,1H),3.45(dd,2H),3.19(dd,1H),2.91(ddd,1H),2.57(dd,1 H),2.24(dd,1H),0.85-0.78(m,1H),0.73-0.66(m,1H),0.59-0.50(m,2H). LCMS (Method 5): Retention time = 0.52 min, [MH]+=144.

[0189] Synthesis of tert-butyl (5S)-5-(hydroxymethyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylate [ka] To a solution of [(5S)-4-oxa-7-azaspiro[2.5]octan-5-yl]methanol (1.4 g, 9.8 mmol) in dichloromethane (10 mL) and water (20 mL) was added sodium hydroxide (390 mg, 9.8 mmol). A solution of di-tert-butyl dicarbonate (2.1 g, 9.8 mmol) in dichloromethane (10 mL) was added dropwise, and the reaction was stirred at room temperature for 2-3 hours. The reaction mixture was poured into ice-cold water, and the product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 10–15% ethyl acetate in petroleum ether to give tert-butyl (5S)-5-(hydroxymethyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylate (1.1 g, 4.5 mmol, 46% yield) as a syrupy liquid. 1H NMR (400 MHz, DMSO-d6) δ 4.72 (t, 1H), 3.93 (br s, 1H), 3.55–3.42 (m, 1H), 3.42–3.17 (m, 4H), 2.67 (br s, 1H), 1.40 (s, 9H), 0.81–0.73 (m, 1H), 0.72–0.61 (m, 1H), 0.61–0.51 (m, 1H), 0.49–0.39 (m, 1H). LCMS (Method 5): Retention time = 2.40 min, [(M-100)H]+=144.

[0190] Synthesis of tert-butyl (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylate [ka] To a solution of (S)-N-Boc-2-hydroxymethylmorpholine (3.4 g, 15.7 mmol) in dichloromethane (30 mL) cooled to 0 °C, Dess-Martin periodinane (8.0 g, 18.8 mmol) was added, and the reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with dichloromethane. The resulting precipitate was removed by filtration. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 5 to 80% tert-butyl methyl ether in heptane to give tert-butyl (2S)-2-formylmorpholine-4-carboxylate (2.2 g, 7.5 mmol, 48% yield) as a colorless residue.

[0191] To a solution of tert-butyl (2S)-2-formylmorpholine-4-carboxylate (2.1 g, 9.8 mmol) in tetrahydrofuran (30 mL) cooled to 0 °C, methylmagnesium chloride (3 M in tetrahydrofuran, 3.9 mL, 11.7 mmol) was added, and the reaction was stirred at room temperature for 16 h. The crude reaction mixture was quenched with saturated aqueous ammonium chloride, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 5 to 60% tert-butyl methyl ether in heptane to afford tert-butyl (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylate (999 mg, 4.1 mmol, 42% yield) as a mixture of diastereoisomers in a 3:2 ratio. 1H NMR (400 MHz, chloroform-d) δ 4.04-3.77 (m, 3H), 3.71-3.61 (m, 0.5H), 3.59-3.47 (m, 1.5H), 3.34-3.24 (m, 0.5H), 3.17 (ddd, 0.5H), 3.00-2.87 (m, 1.5H), 2.82 (dd, 0.5H), 2.77-2.57 (m, 0.5H), 2.52-2.33 (m, 0.5H), 1.47 (s, 9H), 1.20 (d, 1.5H), 1.18 (d, 1.5H). Although it is a mixture of diastereoisomers in a 3:2 ratio, the signals were assigned as a 1:1 ratio.

[0192] Synthesis of 1-(benzylamino)-2-methylpropan-2-ol [ka] A suspension of benzaldehyde (10.0 g, 94.2 mmol) and 1-amino-2-methylpropan-2-ol (8.4 g, 94.2 mmol) in ethanol (40 mL) was stirred at room temperature for 3 hours. The reaction was cooled to 0° C., and sodium borohydride (3.9 g, 103.7 mmol) was added portionwise. The reaction was stirred at room temperature overnight. The reaction mixture was quenched with ice-cold water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 1-(benzylamino)-2-methylpropan-2-ol (14.6 g, 81.4 mmol, 86% yield) as a colorless solid. 1H NMR (400MHz, DMSO-d6) δ 7.36-7.27(m,4H),7.26-7.17(m,1H),4.20(brs,1H),3.72(s,2H),2.36(s,2H),1.09(s,6H). LCMS (Method 5): Retention time = 1.46 min, [MH]+=180.

[0193] Synthesis of [(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]methanol [ka] To a solution of 1-(benzylamino)-2-methylpropan-2-ol (12.0 g, 66.9 mmol) in toluene (200 mL) was added ((R)-(-)-epichlorohydrin (9.3 mg, 100.4 mmol), followed by the slow addition of lithium perchlorate (7.1 g, 66.9 mmol). The reaction was stirred at room temperature for 72 hours. Sodium methoxide (25% w / w in methanol, 14.2 mL, 66.9 mmol) was added, and the reaction was stirred at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 30-50% ethyl acetate in petroleum ether to give [(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]methanol (8.0 g, 34.0 mmol, 51% yield) as a syrupy liquid. 1H NMR(400MHz,DMSO-d6): δ 7.33-7.25(m,5H),4.58-4.55(m,1H),3.70-3.68(m,1H),3.45-3.33(m,3H),3.20-3.18(m,1H),2.8 1-2.79(m,1H),2.51-2.47(m,1H),1.75-1.72(m,1H),1.65-1.59(m,1H),1.27(s,3H),1.05(s,3H). LCMS (Method 5): Retention time = 0.99 min, [MH]+=236.

[0194] Synthesis of [(2S)-6,6-dimethylmorpholin-2-yl]methanol [ka] To a solution of [(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]methanol (13.5 g, 57.4 mmol) in methanol (200 mL) under nitrogen, palladium(II) hydroxide (20% supported wet, 1.4 g, 1.0 mmol) was added, a hydrogen bag was attached, and the reaction was stirred at room temperature for 2-3 h. The reaction mixture was filtered through Celite®, eluting with methanol, and the filtrate was concentrated to give [(2S)-6,6-dimethylmorpholin-2-yl]methanol (8.3 g, 57.2 mmol, 100% yield). No purification was performed; the product was used crude in the next step. 1H NMR(400MHz,DMSO-d6): δ 4.49(br s 1H),3.55-3.52(m,1H),3.29-3.14(m,2H),2.83-2.80(m,1H),2.51-2.50(m,1H),2.35-2.17(m,1H),1.20(s,3H),1.00(s,3H). LCMS (Method 5): Retention time = 1.28 min, [MH]+=146.

[0195] Synthesis of tert-butyl (6S)-6-(hydroxymethyl)-2,2-dimethylmorpholine-4-carboxylate [ka] To a solution of [(2S)-6,6-dimethylmorpholin-2-yl]methanol (8.3 g, 57.2 mmol) in a mixture of dichloromethane (100 mL) and water (50 mL) was added di-tert-butyl dicarbonate (12.5 g, 57.2 mmol) and aqueous sodium hydroxide (2N, 28.6 mL, 57.2 mmol). The reaction was stirred at room temperature for 4–5 h. The reaction mixture was quenched with ice-cold water, and the product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 10–20% ethyl acetate in petroleum ether to give tert-butyl (6S)-6-(hydroxymethyl)-2,2-dimethylmorpholine-4-carboxylate (11.2 g, 45.7 mmol, 80% yield) as a syrupy liquid. 1H NMR(400MHz,DMSO-d6) δ 4.68(t,1H),4.04-3.80(m,1H),3.73-3.52(m,2H),3.37(ddd,1H),3.29-3. 20 (m, 1H), 2.75-2.56 (m, 1H), 2.48-2.35 (m, 1H), 1.40 (s, 9H), 1.11 (s, 6H). LCMS (Method 5): Retention time = 1.80 min, [(M-56)H]+=190.

[0196] Synthesis of (2S)-1-amino-3-(benzyloxy)propan-2-ol [ka] A solution of (2S)-2-[(benzyloxy)methyl]oxirane (10.0 g, 60.9 mmol) in ammonium hydroxide (25-30% in water, 100 mL) was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure, and the resulting mixture was azeotroped with toluene to give (2S)-1-amino-3-(benzyloxy)propan-2-ol (11.1 g, 61.2 mmol, 100% yield). H NMR (400 MHz, deuterium oxide) δ 7.47-7.30 (m, 5H), 4.62-4.51 (m, 2H), 3.83-3.73 (m, 1H), 3.56 (dd, 1H), 3.52-3.42 (m, 1H), 2.74-2.65 (m, 1H), 2.64-2.54 (m, 1H). LCMS (Method 4 - Column 7): Retention time = 1.14 min, [MH]+ = 182.

[0197] Synthesis of (2R)-N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide [ka] To a solution of (2S)-1-amino-3-phenylmethoxypropan-2-ol (11.0 g, 60.7 mmol) in ethanol (90 mL) was added methyl (2R)-2-chloropropanoate (8.2 g, 66.8 mmol) dropwise. The reaction was stirred at 80° C. for 28 hours. The solvent was removed under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution and brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give (2R)-N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide (6.2 g, 22.8 mmol, 38% yield) as a pale yellow oil. 1H NMR(400MHz,DMSO-d6) δ 8.26-8.12(m,1H),7.44-7.19(m,5H),5.04(d,1H),4.60-4.50(m,1H),4.48(s,2H),3. 75-3.63(m,1H),3.44-3.36(m,1H),3.31-3.20(m,1H),3.09-2.93(m,1H),1.49(d,3H). LCMS (Method 8 - Column 2): Retention time = 7.83 min, [MH]+ = 272.

[0198] Synthesis of (2S,6S)-6-[(benzyloxy)methyl]-2-methylmorpholin-3-one [ka] To a solution of (2R)-2-chloro-N-[(2S)-2-hydroxy-3-phenylmethoxypropyl]propanamide (6.2 g, 22.8 mmol) in tetrahydrofuran (310 mL) cooled to 0°C was added sodium hydride (57-63% w / w oil dispersion, 3.7 g, 91.3 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was quenched with isopropyl alcohol (14 mL) and diluted with Dowex® 50H. +The mixture was acidified by adding resin (1.5 g) and filtered. The filtrate was washed with water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 2% methanol in dichloromethane to give (2S,6S)-6-[(benzyloxy)methyl]-2-methylmorpholin-3-one (3.9 g, 16.6 mmol, 73% yield) as a pale yellow oil. 1H NMR(400MHz,DMSO-d6) δ 7.85(d,1H),7.40-7.24(m,5H),4.55-4.48(m,2H),4.09(q,1H),3.98-3.86(m,1H),3.55-3.43(m,2H),3.21-3.06(m,2H),1.25(d,3H). LCMS (Method 8 - Column 2): Retention time = 7.75 min, [MH]+ = 236.

[0199] Synthesis of (2S,6S)-2-[(benzyloxy)methyl]-6-methylmorpholine [ka] To a solution of (2S,6S)-2-methyl-6-(phenylmethoxymethyl)morpholin-3-one (3.8 g, 16.1 mmol) in tetrahydrofuran (30 mL) cooled to 0° C. under nitrogen was added lithium aluminum hydride (1 M solution in tetrahydrofuran, 48.5 mL, 48.5 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 8% methanol in dichloromethane to give (2S,6S)-2-[(benzyloxy)methyl]-6-methylmorpholine (2.8 g, 12.7 mmol, 78% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6) δ 7.40-7.23(m,5H),4.48(s,2H),3.84-3.75(m,1H),3.74-3.63(m,1H),3.45(dd,1H) ),3.40(dd,1H),3.05-2.94(m,2H),2.64-2.52(m,1H),2.42(dd,1H),1.07(d,3H). LCMS (Method 8 - Column 2): Retention time = 10.50 min, [MH]+=222.

[0200] Synthesis of tert-butyl (2S,6S)-2-[(benzyloxy)methyl]-6-methylmorpholine-4-carboxylate [ka] To a solution of (2S,6S)-2-methyl-6-(phenylmethoxymethyl)morpholine (2.8 g, 12.7 mmol) in dichloromethane (50 mL) was added di-tert-butyl dicarbonate (6.8 g, 31.6 mmol), 4-(dimethylamino)pyridine (0.1 g, 0.82 mmol), and triethylamine (4.2 mL, 31.6 mmol). The reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 8% ethyl acetate in hexane to afford tert-butyl (2S,6S)-2-[(benzyloxy)methyl]-6-methylmorpholine-4-carboxylate (3.2 g, 9.6 mmol, 76% yield) as a pale yellow oil. 1H NMR (400MHz, DMSO-d6) δ 7.42-7.24(m,5H),4.49(s,2H),3.94-3.67(m,2H),3.62-3.51(m,1H),3.51-3.38(m,3H),1.40(s,9H),1.07(d,3H). LCMS (Method 8 - Column 2): Retention time = 9.94 min, [MH]+ = 266.

[0201] Synthesis of tert-butyl (2S,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate [ka] To a solution of (tert-butyl (2S,6S)-2-[(benzyloxy)methyl]-6-methylmorpholine-4-carboxylate (2.8 g, 8.7 mmol) in methanol (30 mL) was added palladium(II) hydroxide (20% supported wet, 1.0 g, 0.71 mmol) and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 15-25% ethyl acetate in hexane to give tert-butyl (2S,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (1.4 g, 6.1 mmol, 70% yield) as a yellow liquid. 1H NMR (400 MHz, chloroform-d) δ 4.03-3.75(m,2H),3.73-3.64(m,1H),3.62-3.50(m,3H),2.80-2.39(m,2H),1.46(s,9H),1.19(d,3H). LCMS (Method 4 - Column 1): Retention time = 1.33 min, [(M-56)H]+ = 177.

[0202] Synthesis of (2S)-N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide [ka] To a solution of (2S)-1-amino-3-phenylmethoxypropan-2-ol (10.5 g, 57.9 mmol) in ethanol (34 mL) was added methyl (2S)-2-chloropropanoate (7.8 g, 63.7 mmol) dropwise over 15 minutes. The reaction was heated to 75 °C for 16 hours. The solvent was removed under reduced pressure, and the resulting residue was diluted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid solution and brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 2 to 5% methanol in dichloromethane to give (2S)-N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide (8.0 g, 25.9 mmol, 45% yield) as a yellow liquid. 1H NMR(400MHz,DMSO-d6) δ 8.27-8.14(m,1H),7.40-7.24(m,5H),5.03(d,1H),4.53(q,1H),4.50-4.45( m,2H),3.77-3.63(m,1H),3.29-3.18(m,1H),3.10-2.97(m,1H),1.49(d,3H). LCMS (Method 4 - Column 1): Retention time = 1.38 min, [MH]+ = 272.

[0203] Synthesis of (2R,6S)-6-[(benzyloxy)methyl]-2-methylmorpholin-3-one [ka] To a solution of (2S)-2-chloro-N-[(2S)-2-hydroxy-3-phenylmethoxypropyl]propanamide (8.0 g, 29.4 mmol) in tetrahydrofuran (200 mL) cooled to 0°C, sodium hydride (57-63% w / w oil dispersion, 4.7 g, 117.8 mmol) was added portionwise. The reaction was stirred at 0°C for 5 minutes and then at room temperature for 6 hours. The reaction mixture was quenched with isopropyl alcohol (30 mL) and diluted with Dowex® 50H. +The mixture was acidified by the portionwise addition of resin (50 g). The reaction was filtered, and the resin was washed thoroughly with ethyl acetate. The filtrate was then concentrated, and the crude material was purified by silica gel column chromatography eluting with 2–5% methanol in dichloromethane to give (2R,6S)-6-[(benzyloxy)methyl]-2-methylmorpholin-3-one (5.5 g, 23.4 mmol, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.42–7.21 (m, 5H), 4.51 (s, 2H), 4.19 (q, 1H), 4.03 (dq, 1H), 3.58–3.44 (m, 2H), 3.25–3.03 (m, 2H), 1.29 (d, 3H). LCMS (Method 4 - Column 1): Retention time = no UV signal, [M−H]+ = 236.

[0204] Synthesis of (2S,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine [ka] To a solution of (2R,6S)-2-methyl-6-(phenylmethoxymethyl)morpholin-3-one (5.5 g, 23.4 mmol) in tetrahydrofuran (30 mL) cooled to 0° C. under nitrogen was added lithium aluminum hydride (1 M solution in tetrahydrofuran, 25.7 mL, 25.7 mmol). The reaction was stirred at room temperature for 2.5 hours. The reaction was cooled to 0° C. and quenched with water followed by sodium hydroxide solution (1 N aqueous solution, 1 mL). The reaction was then filtered through Celite®, washing well with dichloromethane. The combined organics were washed with water, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 2–5% methanol in dichloromethane to give (2S,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine (3.6 g, 16.3 mmol, 70% yield) as a yellow liquid. H NMR (400 MHz, DMSO-d) δ 7.41–7.23 (m, 5H), 4.58–4.41 (m, 2H), 3.91–3.73 (m, 2H), 3.65–3.53 (m, 2H), 2.87–2.78 (m, 2H), 2.67 (dd, 1H), 2.44 (dd, 1H), 1.09 (d, 3H). LCMS (Method 4 - Column 7): Retention time = 0.95 min, [MH]+ = 222.

[0205] Synthesis of tert-butyl (2S,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine-4-carboxylate [ka] To a solution of (2S,6R)-2-methyl-6-(phenylmethoxymethyl)morpholine (3.6 g, 16.3 mmol) in dichloromethane (25 mL) was added di-tert-butyl dicarbonate (9.2 g, 42.3 mmol), 4-(dimethylamino)pyridine (120 mg, 0.98 mmol), and triethylamine (4.3 mL, 42.3 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was poured into water, and the product was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 6–8% ethyl acetate in hexane to afford tert-butyl (2S,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine-4-carboxylate (4.0 g, 12.1 mmol, 74% yield) as a pale yellow oil. 1H NMR (400MHz, DMSO-d6) δ 7.42-7.24(m,5H),4.50(s,2H),3.95-3.71(m,2H),3.61-3.18(m,5H),3.12-2.74(m,1H),1.39(s,9H),1.07(d,3H). LCMS (Method 4 - Column 2): Retention time = 2.20 min, [(M-56)H]+=266.

[0206] Synthesis of tert-butyl (2S,6R)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate [ka] To a solution of (tert-butyl (2S,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine-4-carboxylate (5.0 g, 15.6 mmol) in methanol (32 mL) was added palladium(II) hydroxide (20% supported wet, 1.0 g, 0.71 mmol) and the reaction was stirred at room temperature for 1.5 hours. The reaction was filtered through Celite® and the filtrate was concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 15-25% ethyl acetate in hexane to afford tert-butyl (2S,6R)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (3.3 g, 14.0 mmol, 92% yield) as a yellow oil. H NMR (400 MHz, DMSO-d) δ 4.68(dd,1H),3.90-3.76(m,1H),3.70-3.57(m,1H),3.50-3.34(m,3H),3.30-2.87(m,2H),1.40(s,9H),1.07(d,3H). LCMS (Method 4 - Column 2): Retention time = 1.26 min, [(M-100)H]+=132.

[0207] Synthesis of 3-(benzylamino)-2,2-dimethylpropan-1-ol [ka] A solution of 3-amino-2,2-dimethylpropan-1-ol (10.0 g, 96.9 mmol) and benzaldehyde (10.8 g, 101.7 mmol) in benzene (170 mL) was refluxed for 4 hours using a Dean-Stark apparatus to remove water. The reaction was evaporated to give an oily intermediate. To a solution of this imine intermediate in methanol (150 mL) cooled to 0°C, sodium borohydride (5.5 g, 145.1 mmol) was added in three portions. The reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched with sodium hydroxide solution (6N aqueous solution, 25 mL), and the solvent was evaporated. Water was added to the residue, and the product was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on neutral alumina eluting with a gradient of 15-20% ethyl acetate in hexane to give 3-(benzylamino)-2,2-dimethylpropan-1-ol (17.0 g, 62.0 mmol, 91% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.45-7.23 (m, 5H), 3.79 (s, 2H), 3.51 (s, 2H), 2.66 (s, 2H), 0.95 (s, 6H). LCMS (Method 4 - Column 7): Retention time = 1.15 min, [MH]+ = 194.

[0208] Synthesis of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-2,2-dimethylpropan-1-ol [ka] To a solution of 3-(benzylamino)-2,2-dimethylpropan-1-ol (17.0 g, 87.9 mmol) in 2-propanol (200 mL) was added (2S)-2-[(benzyloxy)methyl]oxirane (15.8 g, 96.4 mmol), and the reaction was heated to 50° C. for 16 h. Volatiles were removed under reduced pressure, and the crude material was purified by silica gel column chromatography eluting with a gradient of 15 to 20% ethyl acetate in hexanes to give 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-2,2-dimethylpropan-1-ol (25.0 g, 69.4 mmol, 79% yield) as a viscous oil. 1H NMR (400MHz, chloroform-d) δ 7.46-7.20(m,10H),4.51(s,2H),4.06-3.96(m,1H),3.80(d,1H),3.58( d,1H),3.47-3.32(m,4H),2.71-2.45(m,4H),0.99(s,3H),0.90(s,3H). LCMS (Method 4 - Column 7): Retention time = 1.49 min, [MH]+ = 358.

[0209] Synthesis of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-2,2-dimethylpropyl methanesulfonate [ka] Note: The reaction was performed as 6 × 1 g parallel experiments. To a solution of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-2,2-dimethylpropan-1-ol (1.0 g, 2.8 mmol) in dichloromethane (6.7 mL) cooled to 0 °C, N,N-diisopropylamine (0.5 mL, 2.8 mmol) and methanesulfonyl chloride (217 μL, 2.8 mmol) were slowly added. The reaction was stirred at 0 °C for 45 min, then poured into saturated aqueous sodium bicarbonate, and the product was extracted with dichloromethane. The combined organic layers from six separate reactions were dried over anhydrous sodium sulfate and concentrated to give 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-2,2-dimethylpropyl methanesulfonate (7.5 g, 17.2 mmol, 102% yield) as a viscous oil. No purification was performed and this material was used crude in the next step. LCMS (Method 4 - Column 7): Retention time = 1.89 min, [MH]+ = 436.

[0210] Synthesis of (2S)-4-benzyl-2-[(benzyloxy)methyl]-6,6-dimethyl-1,4-oxazepane [ka] Note: The reaction was carried out as 7 × 1 g parallel experiments. To a solution of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-2,2-dimethylpropyl methanesulfonate (1.0 g, 2.3 mmol) in tetrahydrofuran (5 mL) cooled to 0 °C, sodium hydride (57–63% w / w oil dispersion, 129 mg, 3.2 mmol) was added portionwise. The reaction was stirred at room temperature for 16 h. The reaction mixture was poured into water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The combined crude material was purified by silica gel column chromatography eluting with 1% ethyl acetate in hexane to give (2S)-4-benzyl-2-[(benzyloxy)methyl]-6,6-dimethyl-1,4-oxazepane (0.9 g, 2.7 mmol, 17% yield) as a viscous oil. 1H NMR(400MHz,DMSO-d6) δ 7.48-7.07(m,10H),4.43-4.29(m,2H),3.73-3.47(m,3H),3.41-3.22( m,4H),2.84-2.70(m,1H),2.43-2.20(m,3H),0.80(s,3H),0.69(s,3H). LCMS (Method 9): Retention time = 3.18 min, [MH]+=340.

[0211] Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-6,6-dimethyl-1,4-oxazepane-4-carboxylate [ka] To a solution of (2S)-4-benzyl-2-[(benzyloxy)methyl]-6,6-dimethyl-1,4-oxazepane (1.5 g, 4.4 mmol) in ethanol (30 mL) was added di-tert-butyl dicarbonate (1.2 g, 5.3 mmol) and palladium on carbon (10% w / w, 2.0 g, 1.9 mmol). The reaction was stirred in a hydrogenation apparatus at 200 psi (approximately 1.38 MPa) for 24 hours. The reaction was filtered through Celite®, eluting with methanol, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give (tert-butyl (2S)-2-(hydroxymethyl)-6,6-dimethyl-1,4-oxazepane-4-carboxylate (1.0 g, 3.9 mmol, 87% yield) as a viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 4.79-4.60 (m, 1H), 3.78-3.36 (m, 4H), 3.31-2.96 (m, 4H), 1.39 (s, 9H), 0.97-0.63 (m, 6H). LCMS (Method 4 - Column 7): Retention time = 1.56 min, [(M-56)H]+ = 204.

[0212] Synthesis of 2-ethenyl-3-phenyloxirane [ka] The reaction was carried out in five parallel batches, which were combined during workup.

[0213] To a solution of benzaldehyde (960 μL, 9.4 mmol) in tert-butanol (7 mL) was added allyl bromide (2.4 mL, 28.3 mmol), potassium carbonate (6.5 g, 47.1 mmol), and tetrahydrothiophene (84 μL, 0.94 mmol). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the product was extracted with hexane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-ethenyl-3-phenyloxirane as a mixture of cis and trans isomers (6.0 g, 41.0 mmol, 87% yield) as a pale yellow liquid. The crude material was used in the next step without purification. 1H NMR (400 MHz, chloroform-d) (1:1 mixture of cis and trans isomers) δ 7.38-7.27 (m, 5H), 5.78-5.66 (m, 1H), 5.59-5.49 (m, 1H), 5.37-5.25 (m, 1H), 4.25 (d, 0.5H), 3.78 (d, 0.5H), 3.67 (dd, 0.5H), 3.37 (dd, 0.5H).

[0214] Synthesis of rel-(1R,2R)-2-aminocyclopentan-1-ol [ka] To a solution of 6-oxabicyclo[3.1.0]hexane (10.0 g, 118.9 mmol) in ethanol (33 mL) was added ammonium hydroxide (25-30% in water, 200 mL, 118.9 mmol). The reaction mixture was stirred at room temperature for 24 h. The volatiles were removed under reduced pressure to give rel-(1R,2R)-2-aminocyclopentan-1-ol (8.8 g, 73.9 mmol, 62% yield) as a pale yellow oil. No purification was performed; this material was used crude in the next step. 1H NMR (400MHz, DMSO-d6) δ 3.84-3.68(m,1H),3.05-2.83(m,1H),1.98-1.77(m,2H),1.71-1.55(m,2H),1.54-1.38(m,1H),1.32-1.17(m,1H). LCMS (Method 4 - Column 3): Retention time = 0.70 min, [MH]+=102.

[0215] Synthesis of N-[rel-(1R,2R)-2-hydroxycyclopentyl]acetamide [ka] To a solution of rel-(1R,2R)-2-aminocyclopentan-1-ol (5.3 g, 52.4 mmol) in tetrahydrofuran (100 mL) cooled to 0 °C, triethylamine (7.3 mL, 52.4 mmol) was added, followed by the dropwise addition of a solution of acetyl chloride (4.1 g, 52.4 mmol) in tetrahydrofuran (50 mL). The reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered and the volatiles removed under reduced pressure to afford N-[rel-(1R,2R)-2-hydroxycyclopentyl]acetamide (8.3 g, 48.7 mmol, 93% yield) as a pale yellow oil. No purification was performed; this material was used crude in the next step. 1H NMR (400 MHz, deuterium oxide) δ 4.01-3.90 (m, 1H), 3.90-3.79 (m, 1H), 2.07-1.94 (m, 1H), 1.91 (s, 3H), 1.88-1.79 (m, 1H), 1.74-1.59 (m, 2H), 1.59-1.45 (m, 1H), 1.45-1.31 (m, 1H). LCMS (Method 4 - Column 2): Retention time = 0.69 min, [MH]+ = 144.

[0216] Synthesis of rel-(3aS,6aR)-2-methyl-3aH,4H,5H,6H,6aH-cyclopenta[d][1,3]oxazole [ka] A solution of N-[rel-(1R,2R)-2-hydroxycyclopentyl]acetamide (11.3 g, 78.9 mmol) in chloroform (50 mL) was added dropwise to a flask containing thionyl chloride (23.5 mL, 323.6 mmol) under a nitrogen atmosphere, maintaining the temperature at −10°C to −5°C. The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give rel-(3aS,6aR)-2-methyl-3aH,4H,5H,6H,6aH-cyclopenta[d][1,3]oxazole (15.5 g, 123.8 mmol, 157% yield). This crude material was used in the next step. 1H NMR (400MHz, DMSO-d6) δ 5.66 (dd, 1H), 4.83-4.68 (m, 1H), 2.38 (s, 3H), 2.11-1.96 (m, 1H), 1.92-1.64 (m, 4H), 1.66-1.48 (m, 1H). MS:[MH]+=126.

[0217] Synthesis of rel-(1R,2S)-2-aminocyclopentan-1-ol hydrochloride [ka] A solution of rel-(3aS,6aR)-2-methyl-3aH,4H,5H,6H,6aH-cyclopenta[d][1,3]oxazole (15.0 g, 119.8 mmol) in 10% aqueous hydrochloric acid (10.0 mL, 119.8 mmol) was heated at 100 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was triturated with methanol to give rel-(1R,2S)-2-aminocyclopentan-1-ol hydrochloride (9.6 g, 69.5 mmol, 58% yield) as a pale yellow solid, which was used in the next step without further purification. 1H NMR (400 MHz, deuterium oxide) δ 4.27-4.16 (m, 1H), 3.48-3.41 (m, 1H), 2.11-1.97 (m, 1H), 1.97-1.84 (m, 1H), 1.84-1.72 (m, 1H), 1.75-1.47 (m, 3H). MS: [MH]+ = 101.

[0218] Synthesis of N-[rel-(1S,2R)-2-hydroxycyclopentyl]-4-methylbenzene-1-sulfonamide [ka] To a solution of rel-(1R,2S)-2-aminocyclopentan-1-ol hydrochloride (9.5 g, 69.0 mmol) in dichloromethane (15 mL) was added triethylamine (2.9 mL, 207.1 mmol), followed by p-toluenesulfonyl chloride (13.1 g, 69.0 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[rel-(1S,2R)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide (10.4 g, 39.1 mmol, 57% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6) δ 7.72(d,2H),7.36(d,2H),7.21(d,1H),4.62(d,1H),3.76-3.64(m,1H),3.20(ddd,1H),2.37(s,3H),1.68-1.49(m,2H),1.49-1.19(m,4H). LCMS (Method 4 - Column 2): Retention time = 1.91 min, [MH]+ = 256.

[0219] Synthesis of rel-(2R,4aS,7aR)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylethenyl]-octahydrocyclopenta[b][1,4]oxazine and rel-(2R,4aR,7aS)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylethenyl]-octahydrocyclopenta[b][1,4]oxazine [ka] To a degassed solution of 2-ethenyl-3-phenyloxirane (7.4 g, 50.9 mmol) and N-[rel-(1R,2S)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide (10.0 g, 39.2 mmol) in dichloromethane (30 mL), palladium-tetrakis(triphenylphosphine) (450 mg, 0.39 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Iron(III) chloride hexahydrate (1.1 g, 3.9 mmol) was added under an inert atmosphere, and the reaction mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 6% ethyl acetate in n-hexane to give a mixture of two diastereomeric products, which was triturated with a mixture of n-hexane and dichloromethane to give Isomer 1: rel-(2R,4aS,7aR)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylethenyl]-octahydrocyclopenta[b][1,4]oxazine (2.9 g, 6.4 mmol, 16% yield) as a yellow solid. The filtrate was concentrated under reduced pressure to give Isomer 2: (2S,4aR,7aS)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylethenyl]-octahydrocyclopenta[b][1,4]oxazine (6.2 g, 13.6 mmol, 35% yield) as a yellow oil.

[0220] Isomer 1: rel-(2R,4aS,7aR)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylethenyl]-octahydrocyclopenta[b][1,4]oxazine 1H NMR(400MHz,DMSO-d6) δ 7.71(d,2H),7.40(d,2H),7.37-7.31(m,4H),7.31-7.23(m,1H),6.61(dd,1H),6.36(dd,1H),4.54-4.45(m,1H),4. 17-4.10(m,1H),3.93-3.81(m,1H),3.44(dd,1H),3.22(dd,1H),2.38(s,3H),1.82-1.60(m,2H),1.58-1.36(m,4H). LCMS (Method 4 - Column 2): Retention time = 2.65 min, [MH]+ = 384.

[0221] Isomer 2: rel-(2R,4aR,7aS)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylethenyl]-octahydrocyclopenta[b][1,4]oxazine 1H NMR(400MHz,DMSO-d6) δ 7.73(d,2H),7.48-7.22(m,7H),6.65(d,1H),6.26(dd,1H),4.08-3.88(m,2H),3.88-3.74(m,1H), 3.59(dd,1H),2.70(dd,1H),2.40(s,3H),1.86-1.60(m,2H),1.63-1.44(m,2H),1.44-1.26(m,2H). LCMS (Method 4 - Column 2): Retention time = 2.73 min, [MH]+ = 384.

[0222] Synthesis of [rel-(2S,4aR,7aS)-4-(4-methylbenzenesulfonyl)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol [ka] To a solution of rel-(2R,4aR,7aS)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylethenyl]-octahydrocyclopenta[b][1,4]oxazine (5.5 g, 14.3 mmol) in water (10 mL) and acetone (80 mL), N-methylmorpholine N-oxide (3.4 g, 28.7 mmol) was added, followed by osmium tetroxide (109 mg, 0.43 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium thiosulfate (70 mL), and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 200 mg of the crude intermediate. The diol intermediate was redissolved in water (40 mL) and ethanol (50 mL), and sodium periodate (18.4 g, 86.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and the product was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting residue was dissolved in ethanol (50 mL), and sodium borohydride (2.2 g, 57.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure, and the residue was poured into water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting crude material was purified by silica gel column chromatography eluting with 25% ethyl acetate in n-hexane to give [rel-(2S,4aR,7aS)-4-(4-methylbenzenesulfonyl)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol (2.5 g, 7.7 mmol, 54% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6) δ 7.68(d,2H),7.42(d,2H),4.85-4.74(m,1H),3.98-3.83(m,1H),3.77-3.66(m,1H),3.54(dd,1H),3.44 -3.38(m,1H),3.32-3.23(m,2H),2.64-2.55(m,1H),2.40(s,3H),1.78-1.55(m,2H),1.53-1.25(m,4H). LCMS (Method 8 - Column 2): Retention time = 8.38 min, [MH]+ = 312.

[0223] Synthesis of [rel-(2R,4aS,7aR)-4-(4-methylbenzenesulfonyl)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol [ka] To a solution of rel-(2S,4aS,7aR)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylethenyl]-octahydrocyclopenta[b][1,4]oxazine (2.5 g, 6.5 mmol) in water (5 mL) and acetone (40 mL), N-methylmorpholine N-oxide (1.5 g, 13.0 mmol) was added, followed by osmium tetroxide (50 mg, 0.20 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium thiosulfate (70 mL), and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 200 mg of the crude intermediate. The diol intermediate was dissolved in water (20 mL) and ethanol (30 mL), and sodium periodate (8.3 g, 39.1 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and the product was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting residue was dissolved in ethanol (30 mL), and sodium borohydride (990 mg, 26.1 mmol) was added. The reaction was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure, and the crude residue was poured into water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 25% ethyl acetate in n-hexane to give [rel-(2R,4aS,7aR)-4-(4-methylbenzenesulfonyl)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol (1.6 g, 4.7 mmol, 73% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6) δ 7.67(d,2H),7.41(d,2H),4.73(dd,1H),3.98-3.93(m,1H),3.78-3.64(m,2H),3.58-3.46( m,2H),3.32-3.26(m,1H),3.04(dd,1H),2.40(s,3H),1.74-1.57(m,2H),1.52-1.34(m,4H). LCMS (Method 8 - Column 2): Retention time = 8.33 min, [MH]+ = 312.

[0224] Synthesis of [rel-(2S,4aR,7aS)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol [ka] To a solution of [rel-(2S,4aR,7aS)-4-(4-methylbenzenesulfonyl)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol (2.4 g, 7.7 mmol) in hydrobromic acid (30-33% in acetic acid, 84 mL) was added phenol (2.2 g, 23.1 mmol), and the reaction was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C, basified to pH = 8 by portionwise addition of solid sodium hydroxide, and concentrated. The product was extracted with a mixture of ethyl acetate and dichloromethane (1:1), followed by a mixture of methanol and dichloromethane (1:9). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude [rel-(2S,4aR,7aS)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol (1.3 g, 8.3 mmol, 107% yield) as a pale yellow oil. This crude material was used in the next step without further purification. MS: [MH]+ = 158.

[0225] Synthesis of [rel-(2S,4aS,7aR)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol [ka] To a solution of [rel-(2S,4aS,7aR)-4-(4-methylbenzenesulfonyl)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol (1.4 g, 4.5 mmol) in hydrobromic acid (30-33% in acetic acid, 50 mL) was added phenol (1.3 g, 13.5 mmol), and the reaction was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C, basified to pH = 8 by portionwise addition of solid sodium hydroxide, and concentrated under reduced pressure. The product was extracted with a mixture of ethyl acetate and dichloromethane (1:1), followed by a mixture of methanol and dichloromethane (1:9). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude [rel-(2S,4aS,7aR)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol (5.0 g, 31.8 mmol, 660% yield) as a yellow oil. This crude material was used in the next step without further purification. MS: [MH]+ = 158.

[0226] Synthesis of tert-butyl rel-(2S,4aR,7aS)-2-(hydroxymethyl)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate [ka] To a solution of [rel-(2S,4aR,7aS)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol (1.2 g, 7.6 mmol) in dichloromethane (50 mL) was added triethylamine (3.2 mL, 22.9 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol). After stirring the reaction mixture at room temperature for 5 minutes, di-tert-butyl dicarbonate anhydride (1.7 g, 7.6 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 4 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 20% ethyl acetate in n-hexane to give tert-butyl rel-(2S,4aR,7aS)-2-(hydroxymethyl)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate (90 mg, 0.35 mmol, 5% yield) as a pale yellow oil. 1H NMR (400 MHz, chloroform-d) δ 4.22-4.03 (m, 1H), 4.05-3.92 (m, 1H), 3.91-3.81 (m, 1H), 3.81-3.42 (m, 4H), 2.91-2.66 (m, 1H), 2.04-1.52 (m, 6H), 1.46 (s, 9H). LCMS (Method 4 - Column 2): Retention time = 1.82 min, [(M-100)H]+=158. HPLC: Retention time = 6.61 minutes.

[0227] Synthesis of tert-butyl rel-(2S,4aS,7aR)-2-(hydroxymethyl)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate [ka] To a solution of [rel-(2S,4aS,7aR)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol (0.8 g, 5.1 mmol) in dichloromethane (30 mL) were added triethylamine (2.1 mL, 15.3 mmol) and 4-dimethylaminopyridine (62 mg, 0.51 mmol). The reaction mixture was stirred at room temperature for 5 minutes. Di-tert-butyl dicarbonate anhydride (1.1 g, 5.1 mmol) was then added, and the reaction mixture was stirred at room temperature for an additional 4 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 20% ethyl acetate in n-hexane to give tert-butyl rel-(2S,4aS,7aR)-2-(hydroxymethyl)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate (570 mg, 2.1 mmol, 41% yield) as a pale yellow oil. 1H NMR (400 MHz, chloroform-d) δ 4.21-3.99 (m, 2H), 3.94-3.80 (m, 2H), 3.71-3.55 (m, 2H), 3.29 (d, J = 13.9 Hz, 1H), 1.99-1.75 (m, 5H), 1.67-1.54 (m, 2H), 1.46 (s, 9H). LCMS (Method 4 - Column 2): Retention time = 1.79 min, [(M-100)H]+=158. HPLC: Retention time = 6.40 minutes.

[0228] Synthesis of oxiran-2-ylmethoxy-tri(propan-2-yl)silane [ka] To a solution of oxiran-2-ylmethanol (20.0 g, 270.0 mmol) in N,N-dimethylformamide (150 mL) was added triisopropylsilyl chloride (58 mL, 270.0 mmol), triethylamine (45 mL, 323.8 mmol), and N,N-dimethylaminopyridine (1.7 g, 13.5 mmol), and the reaction was stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and diethyl ether. The product was extracted with diethyl ether, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 1% ethyl acetate in hexane to give oxiran-2-ylmethoxy-tri(propan-2-yl)silane (14.5 g, 62.9 mmol, 23% yield) as a colorless liquid. 1H NMR (400 MHz, chloroform-d) δ 3.92 (dd, 1H), 3.75 (dd, 1H), 3.12 (ddd, 1H), 2.78 (dd, 1H), 2.67 (dd, 1H), 1.15-0.99 (m, 21H).

[0229] Synthesis of benzyl(2,2-dimethoxyethyl)amine [ka] To a solution of 2,2-dimethoxyethanamine (15.0 g, 142.7 mmol) in methanol (150 mL) was added benzaldehyde (14.6 mL, 142.7 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0° C., sodium borohydride (8.1 g, 214.0 mmol) was added, and the reaction was stirred at room temperature for an additional 16 hours. 2 M aqueous hydrochloric acid was added to adjust the pH to 9. The volatiles were removed under reduced pressure, the reaction mixture was diluted with water, and the pH was readjusted to pH 9. The product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford benzyl(2,2-dimethoxyethyl)amine (27.0 g, 138.3 mmol, 97% yield) as a colorless liquid. This material was used crude in the next step. H NMR (400 MHz, chloroform-d) δ 7.35-7.29 (m, 4H), 7.27-7.22 (m, 1H), 4.49 (t, 1H), 3.80 (s, 2H), 3.36 (s, 6H), 2.75 (d, 2H). LCMS (Method 4 - Column 7): Retention time = 1.21 min, [MH]+ = 196.

[0230] Synthesis of 5-benzyl-3-methoxy-11-methyl-10,10-bis(propan-2-yl)-2,9-dioxa-5-aza-10-siladodecan-7-ol [ka] To a solution of oxiran-2-ylmethoxy-tri(propan-2-yl)silane (14.5 g, 62.9 mmol) in ethanol (150 mL) was added benzyl(2,2-dimethoxyethyl)amine (12.3 g, 62.9 mmol). The reaction was heated to 80° C. for 16 hours. The cooled reaction mixture was concentrated under reduced pressure to give 5-benzyl-3-methoxy-11-methyl-10,10-bis(propan-2-yl)-2,9-dioxa-5-aza-10-siladodecan-7-ol (26.0 g, 61.1 mmol, 97% yield) as a colorless liquid. This material was used crude in the next step. 1H NMR (400MHz, chloroform-d) δ 7.35-7.20(m,5H),4.36(t,1H),3.84-3.77(m,1H),3.76-3.67(m,3H),3.66-3.60(m,1H),3.56-3 .45(m,1H),3.30(s,3H),3.25(s,3H),2.80-2.68(m,2H),2.68-2.55(m,2H),1.12-0.99(m,21H). LCMS (Method 4 - Column 7): Retention time = 2.39 min, [MH]+ = 426.

[0231] Synthesis of 4-benzyl-2-methoxy-6-({[tris(propan-2-yl)silyl]oxy}methyl)morpholine [ka] A mixture of 5-benzyl-3-methoxy-11-methyl-10,10-bis(propan-2-yl)-2,9-dioxa-5-aza-10-siladodecan-7-ol (26.0 g, 61.1 mmol) and para-toluenesulfonic acid (4.2 g, 24.4 mmol) was heated to 115 °C for 16 h. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The organic layer was then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography eluting with 10% ethyl acetate in n-hexane to give 4-benzyl-2-methoxy-6-({[tris(propan-2-yl)silyl]oxy}methyl)morpholine (23.0 g, 58.4 mmol, 96% yield) as a 5:7 mixture of diastereoisomers as a pale yellow oil. H NMR (400 MHz, chloroform-d) (5:7 mixture of diastereoisomers but reported as 1:1) δ 7.35-7.27 (m, 5H), 4.50 (dd, 0.5H), 4.11-4.01 (m, 0.5H), 3.88-3.79 (m, 1H), 3.79-3.70 (m, 1H), 3.68-3.49 (m, 3H), 3.47 (s, 1.5H), 3.39 (s, 1.5H), 2.99-2.80 (m, 2H), 1.98-1.80 (m, 2H), 1.13-0.97 (m, 21H). LCMS (Method 4 - Column 7): Retention times = 2.39 and 2.68 min, [MH]+ = 394.

[0232] Synthesis of benzyl 2-({[tris(propan-2-yl)silyl]oxy}methyl)-3,4-dihydro-2H-oxazine-4-carboxylate [ka] To a solution of 4-benzyl-2-methoxy-6-({[tris(propan-2-yl)silyl]oxy}methyl)morpholine (10.0 g, 25.4 mmol) in dichloromethane (100 mL) was added benzyl chloroformate (5.8 mL, 40.6 mmol), and the reaction was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, the residue was dissolved in toluene (800 mL), and p-toluenesulfonic acid (1.7 g, 10.2 mmol) was added. The reaction mixture was heated to reflux in a Dean-Stark apparatus for 2 hours. The cooled reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution, and the product was extracted with diethyl ether. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give benzyl 2-methoxy-6-({[tris(propan-2-yl)silyl]oxy}methyl)morpholine-4-carboxylate (4.8 g, 11.8 mmol, 49% yield) as a pale yellow oil. 1H NMR (400MHz, chloroform-d) Mixture of rotamers δ 7.42-7.30(m,5H),6.31(d,0.5H),6.20(dd,0.5H),6.01(d,0.5H),5.90(d,0.5H),5.27-5.05(m,2H),4.21-4.09(m,0.5H),4.09 -4.01(m,0.5H),4.01-3.93(m,1H),3.93-3.83(m,1H),3.83-3.66(m,1H),3.43(dd,0.5H),3.31(dd,0.5H),1.10-1.00(m,21H). LCMS (Method 4 - Column 2): Retention time = 3.59 min, [MH]+ = 406.

[0233] Synthesis of benzyl 3-({[tris(propan-2-yl)silyl]oxy}methyl)-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate [ka] To a solution of benzyl 2-({[tris(propan-2-yl)silyl]oxy}methyl)-3,4-dihydro-2H-oxazine-4-carboxylate (4.8 g, 11.8 mmol) in benzene (60 mL) cooled to 0° C. was added diiodomethane (47.6 g, 177.5 mmol) and diethylzinc (1 M solution in hexanes) (177 mL, 177.5 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched by the addition of a saturated aqueous solution of sodium bicarbonate, and the product was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give benzyl 3-({[tris(propan-2-yl)silyl]oxy}methyl)-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (1.8 g, 4.3 mmol, 36% yield) as a colorless liquid. 1H NMR (400 MHz, chloroform-d) δ 7.49-7.28 (m, 5H), 5.27-5.11 (m, 2H), 3.98-3.50 (m, 5H), 2.98-2.75 (m, 2H), 1.42-1.15 (m, 2H), 1.12-0.96 (m, 18H), 0.94-0.78 (m, 3H). LCMS (Method 4 - Column 2): Retention time = 3.53 min, [MH]+ = 420.

[0234] Synthesis of benzyl 3-(hydroxymethyl)-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate [ka] To a solution of benzyl 3-({[tris(propan-2-yl)silyl]oxy}methyl)-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (2.8 g, 6.7 mmol) in tetrahydrofuran (140 mL) cooled to 0 °C, tetra-n-butylammonium fluoride (TBAF, 1 M solution in tetrahydrofuran, 6.8 mL, 23.4 mmol) was added dropwise. The reaction mixture was stirred for 3 hours, quenched by the addition of saturated aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 35% ethyl acetate in hexane to give benzyl 3-(hydroxymethyl)-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate (1.7 g, 6.5 mmol, 97% yield) as a colorless oil. 1H NMR (400MHz, chloroform-d) δ 7.44-7.30(m,5H),5.27-5.11(m,2H),3.79-3.73(m,1H),3.72-3.60(m,3H),2.97-2.76(m,2H),1.96-1.84(m,1H),0.88-0.80(m,2H). LCMS (Method 4 - Column 7): Retention time = 1.37 min, [MH]+ = 264.

[0235] Synthesis of rel-(2S,3R)-3-aminobutan-2-ol [ka] rel-(2R,3R)-2,3-Dimethyloxirane (2.2 g, 30.5 mmol) was dissolved in ammonium hydroxide (28% in water, 12 mL, 30.5 mmol), and the reaction mixture was stirred at room temperature for 72 h. The solvent was removed under reduced pressure to give crude rel-(2S,3R)-3-aminobutan-2-ol (2.0 g, 22.4 mmol, 74% yield) as a pale yellow oil, which was used in the next step without purification. 1H NMR (400 MHz, chloroform-d) δ 3.65 (qd, 1H), 2.92 (qd, 1H), 1.09 (d, 3H), 1.00 (d, 3H). LCMS (Method 9): Retention time = 0.32 min, [MH]+ = 90.

[0236] Synthesis of N-[rel-(2S,3R)-3-hydroxybutan-2-yl]-4-methylbenzene-1-sulfonamide [ka] To a solution of rel-(2S,3R)-3-aminobutan-2-ol (6.0 g, 67.3 mmol) in dichloromethane (100 mL) at 0 °C was added triethylamine (7.5 g, 74.0 mmol), followed 15 minutes later by p-toluenesulfonyl chloride (12.8 g, 67.3 mmol). The reaction mixture was then warmed to room temperature and stirring was continued for 48 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by column chromatography eluting with 15% ethyl acetate in hexane to give N-[rel-(2S,3R)-3-hydroxybutan-2-yl]-4-methylbenzene-1-sulfonamide (9.0 g, 37.0 mmol, 55% yield) as a colorless solid. 1H NMR (400MHz, chloroform-d) δ 7.77(d,2H),7.31(d,2H),4.84(d,1H),3.78(qd,1H),3.29(dqd,1H),2.43(s,3H),1.10(d,3H),0.95(d,3H). LCMS (Method 4 - Column 1): Retention time = 1.51 min, [MH]+ = 244.

[0237] Synthesis of rel-(2S,3R,6S)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylethenyl]morpholine and rel-(2S,3R,6R)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylethenyl]morpholine [ka] To a degassed solution of N-[rel-(2S,3R)-3-hydroxybutan-2-yl]-4-methylbenzene-1-sulfonamide (6.0 g, 24.7 mmol) and 2-ethenyl-3-phenyloxirane (4.7 g, 32.1 mmol) in dichloromethane (15 mL), tetrakis(triphenylphosphine)palladium (280 mg, 0.25 mmol) was added, and the reaction was stirred at room temperature for 16 hours. After this time, iron(III) chloride hexahydrate (670 mg, 2.5 mmol) was added, and the reaction was stirred for an additional 16 hours. The reaction mixture was poured into water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography eluting with 6-8% ethyl acetate in hexane to isolate both diastereoisomers.

[0238] Isomer 1: rel-(2S,3R,6S)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylethenyl]morpholine: Obtained as a yellow liquid (3.0 g, 8.1 mmol, 33% yield) 1H NMR (400MHz, chloroform-d) δ 7.70(d,2H),7.43-7.28(m,7H),6.66(d,1H),6.10(dd,1H),4.14(ddd,1H),3.91-3.83(m,1 H),3.84-3.76(m,1H),3.65(dd,1H),2.87(dd,1H),2.43(s,3H),1.13(d,3H),0.95(d,3H). LCMS (Method 4 - Column 1): Retention time = 2.51 min, [MH]+ = 372.

[0239] Isomer 2: rel-(2S,3R,6R)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylethenyl]morpholine: Obtained as a colorless solid (2.0 g, 5.4 mmol, 22% yield). 1H NMR (400MHz, chloroform-d) δ 7.70(d,2H),7.38-7.21(m,7H),6.62(dd,1H),6.27(dd,1H),4.53-4.43(m,1H),4.14-4.03( m,1H),3.90-3.78(m,1H),3.59(d,1H),3.39(dd,1H),2.41(s,3H),1.05(d,3H),1.02(d,3H). LCMS (Method 4 - Column 1): Retention time = 2.39 min, [MH]+ = 372.

[0240] Synthesis of rel-(2S,3R,6S)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylethenyl]morpholine [ka] To a solution of rel-(2S,3R,6S)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylethenyl]morpholine (3.0 g, 8.1 mmol) in acetone (55 mL) and water (7 mL), N-methylmorpholine N-oxide (1.9 g, 16.1 mmol) and osmium tetroxide (2.5 g, 0.24 mmol) were added, and the reaction was stirred at room temperature for 16 hours. The reaction was quenched by the addition of a saturated aqueous solution of sodium thiosulfate, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude diol intermediate was dissolved in water (27 mL) and ethanol (35 mL), and sodium periodate (10.4 g, 48.5 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and the product was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was dissolved in ethanol (50 mL) and sodium borohydride (1.2 g, 32.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure, and the crude material was poured into a saturated aqueous solution of ammonium chloride, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography eluting with 19% ethyl acetate in hexane to give [(rel-2R,5R,6S)-5,6-dimethyl-4-(4-methylbenzenesulfonyl)morpholin-2-yl]methanol (1.8 g, 6.0 mmol, 74%) as a yellow oil. 1H NMR(400MHz,DMSO-d6) δ 7.68(d,2H),7.42(d,2H),4.82-4.74(m,1H),3.81-3.69(m,1H),3.60-3.46(m,2H),3.44- 3.37(m,1H),3.32-3.26(m,2H),2.78-2.62(m,1H),2.40(s,3H),0.97(d,3H),0.81(d,3H). LCMS (Method 4 - Column 1): Retention time = 1.55 min, [MH]+ = 300.

[0241] Synthesis of rel-(2S,3R,6R)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylethenyl]morpholine [ka] To a solution of rel-(2S,3R,6R)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylethenyl]morpholine (2.0 g, 5.4 mmol) in acetone (35 mL) and water (4.5 mL), N-methylmorpholine N-oxide (1.3 g, 10.8 mmol) and osmium tetroxide (1.6 g, 0.16 mmol) were added, and the reaction was stirred at room temperature for 16 hours. The reaction was quenched by the addition of a saturated aqueous solution of sodium thiosulfate, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude diol intermediate was then dissolved in water (18 mL) and ethanol (23 mL), and sodium periodate (6.9 g, 32.3 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and the product was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was then dissolved in ethanol (32 mL), sodium borohydride (810 mg, 21.5 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure, the crude material was poured into a saturated aqueous solution of ammonium chloride, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography eluting with 21% ethyl acetate in hexane to afford [rel-(2S,5R,6S)-5,6-dimethyl-4-(4-methylbenzenesulfonyl)morpholin-2-yl]methanol (1.2 g, 4.0 mmol, 74% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6) δ 7.72-7.62(m,2H),7.46-7.36(m,2H),4.72-4.63(m,1H),3.81-3.70(m,1H),3.70-3.58(m,2 H),3.53-3.34(m,3H),3.15-3.02(m,1H),2.40(s,3H),0.94-0.89(m,3H),0.86-0.79(m,3H) LCMS (Method 4 - Column 1): Retention time = 1.51 min, [MH]+ = 300.

[0242] Synthesis of tert-butyl rel-(2S,3R,6R)-6-(hydroxymethyl)-2,3-dimethylmorpholine-4-carboxylate [ka] To a solution of [rel-(2R,5R,6S)-5,6-dimethyl-4-(4-methylbenzenesulfonyl)morpholin-2-yl]methanol (1.8 g, 6.0 mmol) in hydrobromic acid (30-33% solution in acetic acid, 40 mL, 6.0 mmol) was added (1.7 g, 18.0 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and the product was extracted with a 10% mixture of methanol in dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the intermediate [rel-(2R,5R,6S)-5,6-dimethylmorpholin-2-yl]methanol (870 mg, 6.0 mmol) as a yellow oil, which was not purified. MS: [MH]+ = 146.5

[0243] To a solution of the above crude intermediate in dichloromethane (40 mL) was added triethylamine (1.8 g, 18.0 mmol) and 4-(dimethylamino)pyridine (70 mg, 0.6 mmol). The reaction was cooled to 0 °C, and di-tert-butyl dicarbonate (1.3 g, 6.0 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography eluting with 12% diethyl ether in petroleum ether to afford tert-butyl rel-(2S,3R,6R)-6-(hydroxymethyl)-2,3-dimethylmorpholine-4-carboxylate (400 mg, 1.6 mmol, 27% yield) as a pale yellow oil. 1H NMR (400MHz, chloroform-d) δ 4.06-3.96(m,0.5H),3.88-3.80(m,0.5H),3.79-3.63(m,3H),3.63-3.48(m,2H),2.88 (dd,0.5H),2.76(dd,0.5H),1.52-1.39(m,9H),1.16-1.09(m,3H),1.09-1.03(m,3H). LCMS (Method 4 - Column 1): Retention time = 1.45 min, [MH]+ = 146. HPLC: Retention time = 5.99 minutes.

[0244] Synthesis of tert-butyl rel-(2S,3R,6S)-6-(hydroxymethyl)-2,3-dimethylmorpholine-4-carboxylate [ka] To a solution of [rel-(2S,5R,6S)-5,6-dimethyl-4-(4-methylbenzenesulfonyl)morpholin-2-yl]methanol (1.2 g, 4.0 mmol) in hydrobromic acid solution (30-33% in acetic acid, 30 mL, 4.0 mmol) was added phenol (1.1 g, 12.0 mmol). The reaction was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was poured into water, and the product was extracted with a mixture of methanol in dichloromethane (10%). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the intermediate [rel-(2R,5R,6S)-5,6-dimethylmorpholin-2-yl]methanol (580.0 mg, 4.0 mmol) as a yellow liquid. No purification was performed on this intermediate. MS: [MH]+ = 146.

[0245] To a solution of the above crude intermediate in dichloromethane (40 mL) was added triethylamine (1.2 g, 12.0 mmol) and 4-(dimethylamino)pyridine (50.0 mg, 0.40 mmol). The reaction mixture was cooled to 0 °C, and then di-tert-butyl dicarbonate (870 mg, 4.0 mmol) was added. After the addition, the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography eluting with 12% diethyl ether in petroleum ether to afford tert-butyl tert-butyl rel-(2S,3R,6S)-6-(hydroxymethyl)-2,3-dimethylmorpholine-4-carboxylate (160 mg, 0.65 mmol, 16% yield) as a pale yellow oil. 1H NMR (400MHz, chloroform-d) δ 4.02-3.83(m,4H),3.65(d,1H),3.60-3.52(m,1H),3.30(dd,1H),1.46(s,9H),1.15(d,3H),1.09(d,3H). LCMS (Method 4 - Column 1): Retention time = 1.43 min, [MH]+ = 146. HPLC: Retention time = 5.73 minutes.

[0246] Synthesis of ethyl 3-(benzylamino)-3-methylbutanoate [ka] A solution of ethyl 3-methylbut-2-enoate (25.0 g, 195.1 mmol) and benzylamine (20.9 g, 195.1 mmol) in ethanol (200 mL) was heated to 90 °C for 48 h. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give ethyl 3-(benzylamino)-3-methylbutanoate (12.0 g, 51.0 mmol, 26% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.43-7.28 (m, 4H), 7.25-7.20 (m, 1H), 4.14 (q, 2H), 3.73 (s, 2H), 2.53 (s, 2H), 1.30-1.20 (m, 9H). LCMS (Method 4 - Column 7): Retention time = 1.00 min, [MH]+ = 236.

[0247] Synthesis of 3-(benzylamino)-3-methylbutan-1-ol [ka] To a solution of ethyl 3-(benzylamino)-3-methylbutanoate (12.0 g, 51.0 mmol) in tetrahydrofuran (250 mL) cooled to 0° C. under a nitrogen atmosphere was added a solution of lithium aluminum hydride (2.5 M in tetrahydrofuran, 41 mL, 82.0 mmol) dropwise. The reaction mixture was slowly warmed to room temperature and stirring was continued for 2 hours. The reaction mixture was cooled to 0° C. and quenched by the addition of water. The mixture was filtered through Celite® and washed with ethyl acetate. The product was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 3-(benzylamino)-3-methylbutan-1-ol (9.5 g, 49.1 mmol, 96% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 7.40-7.21 (m, 5H), 3.90-3.84 (m, 2H), 3.76 (s, 2H), 1.69-1.63 (m, 2H), 1.26 (s, 6H). LCMS (Method 4 - Column 7): Retention time = 0.79 min, [MH]+ = 194.

[0248] Synthesis of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-3-methylbutan-1-ol [ka] To a solution of 3-(benzylamino)-3-methylbutan-1-ol (9.5 g, 49.1 mmol) was added (2S)-2-(phenylmethoxymethyl)oxirane (9.7 g, 59.0 mmol) in 2-propanol (80 mL), and the reaction mixture was heated to 70° C. for 16 hours. After this time, the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography eluting with 2% methanol in dichloromethane to afford 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-3-methylbutan-1-ol (9.5 g, 26.6 mmol, 54% yield) as a yellow oil. 1H NMR (400MHz, chloroform-d) δ 7.39-7.18(m,10H),4.48-4.34(m,2H),4.06-3.90(m,2H),3.88-3.72(m,1H),3.61-3.47(m,1H),3.42(br s,1H),3.30-3.15(m,2H),2.90(dd,1H),2.60(d,1H),2.10-1.95(m,1H),1.61-1.51(m,1H),1.22(s,3H),1.16(s,3H). LCMS (Method 4 - Column 1): Retention time = 1.48 min, [MH]+ = 358.

[0249] Synthesis of (2S)-4-benzyl-2-[(benzyloxy)methyl]-5,5-dimethyl-1,4-oxazepane [ka] To a solution of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-3-methylbutan-1-ol (500 mg, 1.4 mmol) in dichloromethane (7 mL) cooled to 0 °C, diisopropylethylamine (0.25 mL, 1.4 mmol) and methanesulfonyl chloride (110 μL, 1.4 mmol) were added, and the reaction mixture was stirred at 0 °C for 15 minutes. After this time, the reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude mesylate intermediate as a red oil.

[0250] To a solution of the above mesylate intermediate in tetrahydrofuran (5 mL) cooled to 0 °C was added sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) in portions. The reaction mixture was warmed to room temperature and stirring was continued for 16 h. Upon completion, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The above two-step sequence was carried out 16 times in parallel. The crude residues were combined and purified by column chromatography on neutral alumina eluting with 1% ethyl acetate in hexane to give (2S)-4-benzyl-2-[(benzyloxy)methyl]-5,5-dimethyl-1,4-oxazepane (2.0 g, 5.9 mmol, 24% yield) as a yellow liquid. 1H NMR(400MHz,DMSO-d6) δ 7.42-7.34(m,2H),7.33-7.17(m,6H),7.04-6.96(m,2H),4.23-4.05(m,2H),3.87(d,1H),3.79(ddd,1H),3.71(ddd,1H),3. 45-3.35(m,1H),3.35-3.32(m,2H),3.23(dd,1H),3.00(dd,1H),2.69(dd,1H),1.85-1.70(m,2H),1.17(s,3H),1.06(s,3H). LCMS (Method 4 - Column 1): Retention time = 3.18 min, [MH]+ = 341.

[0251] Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-5,5-dimethyl-1,4-oxazepane-4-carboxylate [ka] To a solution of (2S)-4-benzyl-2-[(benzyloxy)methyl]-5,5-dimethyl-1,4-oxazepane in ethanol (10 mL) was added palladium on carbon (10% w / w, 2.0 g, 1.9 mmol) and di-tert-butyl dicarbonate (1.6 g, 7.6 mmol). The reaction mixture was placed in a hydrogenation apparatus and stirred under 200 psi (approximately 1.38 MPa) of hydrogen at room temperature for 96 hours. After this time, the reaction mixture was filtered through Celite®, washed with methanol, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give tert-butyl (2S)-2-(hydroxymethyl)-5,5-dimethyl-1,4-oxazepane-4-carboxylate (900 mg, 3.5 mmol, 59% yield) as a pale yellow liquid. 1H NMR(400MHz,DMSO-d6) δ 4.65(t,1H),3.92(d,1H),3.82(ddd,1H),3.60(dd,1H),3.44-3.37(m,1H),3.29-3.12(m ,2H),3.04(dd,1H),2.01(dd,1H),1.72(dd,1H),1.44(s,3H),1.39(s,9H),1.28(s,3H). LCMS (Method 4 - Column 1): Retention time = 1.73 min, [(M-100)H]+=160. HPLC: Retention time = 6.72 minutes.

[0252] Synthesis of ethyl 4-benzyl-2-methylmorpholine-2-carboxylate [ka] To a solution of ethyl 4-benzylmorpholine-2-carboxylate (4.8 g, 19.3 mmol) in tetrahydrofuran (50 mL) cooled to −78°C under nitrogen, lithium diisopropylamide (2.0 M solution in THF / heptane / ethylbenzene, 14.4 mL, 28.9 mmol) was added and allowed to react for 30 minutes. After this, iodomethane (1.2 mL, 19.3 mmol) was added. The reaction was stirred at −78°C for an additional hour and quenched by the addition of saturated aqueous ammonium chloride. The product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with 5–10% ethyl acetate in petroleum ether to give ethyl 4-benzyl-2-methylmorpholine-2-carboxylate (3.6 g, 13.7 mmol, 71% yield) as an oil. 1H NMR (400MHz, chloroform-d) δ 7.32-7.24(m,5H),4.23(qd,2H),4.03(td,1H),3.77(ddd,1H),3.55(d,1H),3.40(d,1H) ,3.23(dd,1H),2.66-2.57(m,1H),2.24(td,1H),1.98(d,1H),1.32(s,3H),1.27(t,3H). LCMS (Method 5): Retention time = 1.91 min, [MH]+=264.

[0253] Synthesis of [(2S)-4-benzyl-2-methylmorpholin-2-yl]methanol and [(2R)-4-benzyl-2-methylmorpholin-2-yl]methanol [ka] To a solution of ethyl 4-benzyl-2-methylmorpholine-2-carboxylate (3.6 g, 13.7 mmol) in ethanol (50 mL) cooled to 0 °C was added sodium borohydride (1.0 g, 27.3 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched by the addition of ice, and the product was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 20-50% ethyl acetate in petroleum ether to afford the title compound as a mixture of enantiomers. The enantiomers were separated by chiral supercritical fluid chromatography (LUX A1 (250 × 30 mm), 5 micron (5 μm) column; mobile phase: CO2:methanol (90:10)) to give Enantiomer 1: [(2S)-4-benzyl-2-methylmorpholin-2-yl]methanol (1.1 g, 4.7 mmol, 38% yield) and Enantiomer 2: [(2R)-4-benzyl-2-methylmorpholin-2-yl]methanol (1.0 g, 4.5 mmol, 36% yield). The absolute configuration was not assigned.

[0254] Enantiomer 1: [(2S)-4-benzyl-2-methylmorpholin-2-yl]methanol 1H NMR(400MHz,DMSO-d6) δ 7.36-7.28(m,4H),7.27-7.19(m,1H),4.58(t,1H),3.70-3.56(m,2H),3.46( d,1H),3.41-3.30(m,3H),2.42-2.32(m,1H),2.28-2.12(m,3H),1.15(s,3H). LCMS (Method 6): Retention time = 3.90 min, [MH]+=222. SFC: retention time = 3.76 minutes, 99%ee.

[0255] Enantiomer 2: [(2R)-4-benzyl-2-methylmorpholin-2-yl]methanol 1H NMR(400MHz,DMSO-d6) δ 7.42-7.07(m,5H),4.57(t,1H),3.70-3.55(m,2H),3.47(d,1H),3.39-3.27(m,3H),2.42-2.33(m,1H),2.28-2.10(m,3H),1.13(s,3H). LCMS (Method 6): Retention time = 2.22 min, [MH]+=222. SFC: retention time = 4.35 minutes, 99%ee.

[0256] Synthesis of [(2S)-2-methylmorpholin-2-yl]methanol [ka] To a solution of [(2S)-4-benzyl-2-methylmorpholin-2-yl]methanol (1.0 g, 4.5 mmol) in methanol (20 mL) was added palladium(II) hydroxide (20% supported wet, 317 mg, 0.22 mmol) under nitrogen. The reaction mixture was sealed, a hydrogen bag was attached, and stirring was continued for 6 h. After this time, the reaction mixture was filtered through a pad of Celite®, washed with methanol, and the filtrate was concentrated under reduced pressure. The resulting crude product [(2S)-2-methylmorpholin-2-yl]methanol (590 mg, 4.5 mmol, 100% yield) was carried on to the next step without purification. 1H NMR (400MHz, methanol-d4) δ 3.77-3.64(m,2H),3.54(d,1H),3.46(d,1H),2.84(d,1H),2.80-2.72(m,2H),2.62(d,1H),1.20(s,3H). LCMS (Method 5): Retention time = 0.52 min, [MH]+=132.

[0257] Synthesis of [(2R)-2-methylmorpholin-2-yl]methanol [ka] [(2R)-4-Benzyl-2-methylmorpholin-2-yl]methanol (1.0 g, 4.52 mmol) was debenzylated under the same conditions as for Isomer 1 to give [(2R)-2-methylmorpholin-2-yl]methanol (600 mg, 4.6 mmol, 101% yield). The crude material was carried to the next step without purification. 1H NMR (400 MHz, methanol-d4) δ 3.77-3.65 (m, 2H), 3.54 (d, 1H), 3.46 (d, 1H), 2.84 (d, 1H), 2.79-2.72 (m, 2H), 2.62 (d, 1H), 1.20 (s, 3H). LCMS (Method 5): Retention time = 0.71 min, [MH]+ = 132.

[0258] Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-2-methylmorpholine-4-carboxylate [ka] To a solution of [(2S)-2-methylmorpholin-2-yl]methanol (600 mg, 4.6 mmol) in dichloromethane (10 mL) and water (10 mL) was added a solution of sodium hydroxide (4 M, 183 mg, 4.6 mmol), followed by a solution of di-tert-butyl dicarbonate (1.0 g, 4.8 mmol) in dichloromethane (10 mL), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and dichloromethane, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of ethyl acetate in petroleum ether to afford (2S)-2-(hydroxymethyl)-2-methylmorpholine-4-carboxylate (400 mg, 1.7 mmol, 38% yield) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ 4.71(t,1H),3.63-3.50(m,2H),3.48-3.40(m,1H),3.31-3.22(m,3H),3.17-2.99(m,2H),1.40(s,9H),1.05(s,3H). LCMS (Method 5): Retention time = 2.23 min, [(M-100)H]+=132.

[0259] Synthesis of tert-butyl (2R)-2-(hydroxymethyl)-2-methylmorpholine-4-carboxylate [ka] [(2R)-2-Methylmorpholin-2-yl]methanol (600 mg, 4.6 mmol) was subjected to the same procedure as for [(2S)-2-methylmorpholin-2-yl]methanol (isomer 1) to give tert-butyl (2R)-2-(hydroxymethyl)-2-methylmorpholine-4-carboxylate (400 mg, 1.7 mmol, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ 4.72 (t, 1H), 3.64-3.50 (m, 2H), 3.49-3.38 (m, 1H), 3.31-3.22 (m, 3H), 3.19-2.98 (m, 2H), 1.40 (s, 9H), 1.05 (s, 3H). LCMS (Method 5): Retention time = 2.23 min, [(M-100)H]+=132.

[0260] Synthesis of 1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethan-1-one [ka] To a solution of (1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethane-1,2-diol (40.0 g, 152.5 mmol) in dichloromethane (200 mL) warmed to 30° C., 10% aqueous sodium bicarbonate (20 mL) was added, followed by the portionwise addition of sodium metaperiodate (48.9 g, 228.8 mmol). The reaction mixture was stirred at 30° C. for 2 hours. After this time, the reaction mixture was cooled to room temperature, and anhydrous magnesium sulfate was added and stirred for 10 minutes. The reaction mixture was filtered, and the solvent was removed under reduced pressure to give (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (31.8 g, 244.4 mmol, 160.2% yield). This material was carried on to the next step without purification.

[0261] To a solution of crude (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (31.8 g, 244.4 mmol) in tetrahydrofuran (100 mL) cooled to −78° C., methylmagnesium bromide (3 M in diethyl ether, 122 mL, 244.3 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for an additional 30 minutes, then warmed to room temperature and stirring continued for 2 hours. The reaction mixture was cooled to 0° C. and quenched by the dropwise addition of saturated aqueous ammonium chloride solution, and the product was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and distilled to give 1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethan-1-ol (28.3 g, 193.6 mmol, 79% yield, recovered at 30° C. and 150 mbar). This material was taken to the next step without purification.

[0262] To a solution of dimethyl sulfoxide (71 mL, 997.0 mmol) in dichloromethane (250 mL) cooled to -78°C, oxalyl chloride (34 mL, 396.9 mmol), (1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (28.3 g, 193.6 mmol), and triethylamine (283 mL, 2.0 mol) were added sequentially, and the reaction mixture was warmed to -20°C. The mixture was stirred at this temperature for 1 hour. After this time, the reaction mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and distilled at 25 °C and 150 mbar to give 1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethan-1-one (36.6 g, 253.9 mmol, 131% yield). This material was carried on to the next step without purification. 1H NMR (400 MHz, chloroform-d) δ 4.40 (dd, 1H), 4.19 (dd, 1H), 3.99 (dd, 1H), 2.25 (s, 3H), 1.48 (s, 3H), 1.39 (s, 3H).

[0263] Synthesis of benzyl[(rel-1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]amine [ka] To a solution of (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (36.6 g, 253.9 mmol) and benzylamine (32.6 g, 304.6 mmol) in 1,2-dichloroethane (200 mL) was added acetic acid (1.4 mL, 25.4 mmol), and the reaction mixture was cooled to 0 °C. Sodium triacetoxyborohydride (80.7 g, 380.8 mmol) was added portionwise, and the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution, and the product was extracted with dichloromethane. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with 30% ethyl acetate in petroleum ether to give benzyl[rel-(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]amine (14.6 g, 62.0 mmol, 24% yield) as a pale yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.35-7.29 (m, 4H), 7.27-7.21 (m, 1H), 4.08-3.96 (m, 2H), 3.94-3.85 (m, 2H), 3.75 (d, 1H), 2.89-2.78 (m, 1H), 1.41 (d, 3H), 1.35 (d, 3H), 1.10 (d, 3H). LCMS (Method 7): Retention time = 3.00 min, [MH]+=236.

[0264] Synthesis of rel-(2S,3R)-3-(benzylamino)butane-1,2-diol [ka] To a solution of benzyl[rel-(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]amine (14.6 g, 62 mmol) in acetone (20 mL) was added p-toluenesulfonic acid monohydrate (23.6 g, 124.1 mmol) and water (40 mL), and the reaction mixture was heated to 80° C. for 3 h. The cooled reaction mixture was neutralized with 10% aqueous sodium hydroxide, and the product was extracted with dichloromethane. The combined organic layers were concentrated under reduced pressure to give rel-(2S,3R)-3-(benzylamino)butane-1,2-diol (10.5 g, 53.6 mmol, 86% yield). This material was carried on to the next step without purification. 1H NMR(300MHz,DMSO-d6) δ 7.40-7.26(m,4H),7.26-7.16(m,1H),4.64(br s,1H),4.46(d,1H),3.77(d,1H),3.66(d,1H),3.53-3.41(m,1H),3.41-3.26(m,2H),2.70-2.54(m,1H),1.99-1.68(m,1H),0.97(d,3H). LCMS (Method 6): Retention time = 2.69 min, [MH]+=196.

[0265] Synthesis of rel-(2S,3R)-3-(benzylamino)-1-[(tert-butyldimethylsilyl)oxy]butan-2-ol [ka] To a solution of rel-(2S,3R)-3-(benzylamino)butane-1,2-diol (10.4 g, 53.3 mmol) in dichloromethane (50 mL) cooled to 0 °C, 1H-imidazole (10.9 g, 159.8 mmol) and tert-butyldimethylchlorosilane (8.0 g, 53.3 mmol) were added. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with 4% methanol in dichloromethane to give rel-(2S,3R)-3-(benzylamino)-1-[(tert-butyldimethylsilyl)oxy]butan-2-ol (12.8 g, 41.4 mmol, 78% yield) as a colorless oil. 1H NMR(300MHz,DMSO-d6) δ 7.43-6.98(m,5H),4.47(br s,1H),3.75(d,1H),3.67(d,1H),3.33(s,1H),2.78-2.58(m,1H),1.85(br s,1H),0.94(d,3H),0.82(s,9H),0.01(s,6H). LCMS (Method 5): Retention time = 2.32 min, [MH]+=310.

[0266] Synthesis of N-benzyl-N-[rel-(2R,3S)-4-[(tert-butyldimethylsilyl)oxy]-3-hydroxybutan-2-yl]-2-chloroacetamide [ka] To a solution of rel-(2S,3R)-3-(benzylamino)-1-[(tert-butyldimethylsilyl)oxy]butan-2-ol (12.8 g, 41.4 mmol) and triethylamine (8.4 g, 82.7 mmol) in dichloromethane (50 mL) cooled to 0 °C, chloroacetyl chloride (5.6 g, 49.6 mmol) was added dropwise, and the reaction was stirred at this temperature for 30 minutes and then at room temperature for 16 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with 9% ethyl acetate in petroleum ether to give N-benzyl-N-[rel-(2S,3S)-4-[(tert-butyldimethylsilyl)oxy]-3-hydroxybutan-2-yl]-2-chloroacetamide (11.6 g, 30.1 mmol, 73% yield) as a colorless oil. 1H NMR (400MHz, DMSO-d6) (2:1 mixture of rotamers) δ 7.51-7.09(m,5H),5.05(d,0.6H),4.87(d,0.3H),4.78-4.57(m,2H),4.45-4.30(m,1H),4.27-3.95(m,1H),3.82- 3.72(m,0.3H),3.70-3.59(m,0.6H),3.51-3.37(m,2H),1.10(d,2H),1.04(d,1H),0.87(s,9H),0.07-0.03(m,6H). LCMS (Method 5): Retention time = 3.55 min, [MH]+=386.

[0267] Synthesis of rel-(5S,6S)-4-benzyl-6-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylmorpholin-3-one [ka] To a solution of N-benzyl-N-[rel-(2S,3S)-4-[(tert-butyldimethylsilyl)oxy]-3-hydroxybutan-2-yl]-2-chloroacetamide (11.6 g, 30.1 mmol) in tert-butanol (100 mL) was added potassium tert-butoxide (3.5 g, 31.6 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and the product was extracted with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated. The crude residue was purified by silica gel column chromatography eluting with 5% ethyl acetate in petroleum ether to give rel-(5S,6S)-4-benzyl-6-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylmorpholin-3-one (8.5 g, 24.3 mmol, 81% yield) as a pale yellow oil. 1H NMR (400MHz, chloroform-d) δ 7.36-7.21(m,5H),5.39(d,1H),4.33(dd,1H),4.26(d,1H),3.91(d,1H),3.75-3.63(m, 2H),3.45(dd,1H),3.35(qd,1H),1.17(d,3H),0.78(s,9H),0.00(s,3H),-0.03(s,3H). LCMS (Method 5): Retention time = 3.66 min, [MH]+=350.

[0268] Synthesis of rel-(2S,3S)-4-benzyl-2-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methylmorpholine [ka] To a solution of rel-(5S,6S)-4-benzyl-6-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylmorpholin-3-one (8.5 g, 24.3 mmol) in tetrahydrofuran (30 mL) cooled to 0° C. was added borane dimethyl sulfide (4.6 mL, 48.6 mmol) dropwise. After stirring at 0° C. for 30 minutes, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was cooled to 0° C. and methanol (50 ml) was added dropwise, then heated to reflux for 30 minutes. Upon completion, the reaction mixture was cooled to room temperature and concentrated. The crude residue was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to give rel-(2S,3S)-4-benzyl-2-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methylmorpholine (7.5 g, 22.4 mmol, 92% yield) as a colorless oil. 1H NMR (400MHz, chloroform-d) δ 7.38-7.33(m,2H),7.33-7.27(m,2H),7.26-7.20(m,1H),3.83-3.72(m,2H),3.70-3.50(m,4H), 3.44(dd,1H),2.92(qd,1H),2.65(td,1H),2.29(dd,1H),0.93(d,3H),0.85(s,9H),0.05(s,6H). LCMS (Method 5): Retention time = 2.44 min, [MH]+=336.

[0269] Synthesis of [(2S,3S)-4-benzyl-3-methylmorpholin-2-yl]methanol and [(2R,3S)-4-benzyl-3-methylmorpholin-2-yl]methanol [ka] To a solution of rel-(2S,3S)-4-benzyl-2-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methylmorpholine (7.4 g, 22.1 mmol) in tetrahydrofuran (75 mL) cooled to 0° C. was added a solution of tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 33 mL, 33.1 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 27% ethyl acetate in petroleum ether to give the desired product as a racemic mixture (4.3 g) as a red oil. The enantiomers were separated by chiral supercritical fluid chromatography (LUX A1 (250 × 30 mm) 5 micron (5 μm) column; mobile phase: CO2:0.5% isopropylamine in isopropyl alcohol (60:40)) to give [(2R,3R)-4-benzyl-3-methylmorpholin-2-yl]methanol (420 mg, 1.9 mmol, 9% yield) and [(2S,3S)-4-benzyl-3-methylmorpholin-2-yl]methanol (2.8 g, 12.7 mmol, 57% yield) as red oils.

[0270] Isomer 1: 1H NMR (400MHz, chloroform-d) δ 7.36-7.29(m,4H),7.27-7.22(m,1H),3.91(dt,1H),3.78(dt,1H),3.75-3.62(m, 3H), 3.57-3.47 (m, 2H), 2.83 (qd, 1H), 2.68 (ddd, 1H), 2.32 (dt, 1H), 0.98 (d, 3H). LCMS (Method 6): Retention time = 2.59 min, [MH]+ = 222.

[0271] Isomer 2: 1H NMR (400MHz, chloroform-d) δ 7.37-7.28(m,4H),7.27-7.20(m,1H),3.91(dt,1H),3.77(dt,1H),3.74-3.64(m, 3H), 3.56-3.44 (m, 2H), 2.83 (qd, 1H), 2.68 (ddd, 1H), 2.32 (dt, 1H), 0.98 (d, 3H). LCMS (Method 6): Retention time = 2.59 min, [MH]+ = 222.

[0272] Synthesis of [(2S,3S)-3-methylmorpholin-2-yl]methanol [ka] To a degassed solution of [(2S,3S)-4-benzyl-3-methylmorpholin-2-yl]methanol (2.7 g, 12.2 mmol) in methanol (60 mL) was added palladium(II) hydroxide (20% supported wet, 550 mg, 0.39 mmol), and the reaction was stirred at room temperature for 16 h. After this time, the reaction mixture was filtered through Celite®, washed with methanol, and the filtrate was concentrated to give [(2S,3S)-3-methylmorpholin-2-yl]methanol (1.5 g, 11.4 mmol, 94% yield) as a colorless oil. 1H NMR(300MHz,DMSO-d6) δ 4.56(br s,1H),3.68-3.65(m,1H),3.49-3.48(m,1H),3.47-3.37(m,2H),3.25-3.17(m,2H),2.87-2.83(m,2H),0.97(d,3H). LCMS (Method 6): Retention time = 0.94 min, [MH]+=132.

[0273] Synthesis of tert-butyl (2S,3S)-2-(hydroxymethyl)-3-methylmorpholine-4-carboxylate [ka] To a solution of [(2S,3S)-3-methylmorpholin-2-yl]methanol (1.3 g, 9.9 mmol) in dichloromethane (60 mL) was added triethylamine (1.4 g, 13.6 mmol), followed by di-tert-butyl dicarbonate (2.2 g, 10.1 mmol), and the reaction was stirred at room temperature for 3 hours. After this time, the reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with 23% ethyl acetate in petroleum ether to afford tert-butyl (2S,3S)-2-(hydroxymethyl)-3-methylmorpholine-4-carboxylate (1.9 g, 8.2 mmol, 83% yield) as a colorless oil. 1H NMR(300MHz,DMSO-d6) δ 4.75(br s,1H),4.03-3.94(m,1H),3.83-3.76(m,1H),3.58-3.52(m,1H),3.41-3.34( m,3H),3.28-3.19(m,1H),3.03-2.92(m,1H),1.40(s,9H),0.99-0.97(m,3H). LCMS (Method 6): Retention time = 1.45 min, [(M-100)H]+=132.

[0274] Synthesis of 3-bromo-1-tert-butyl-1H-pyrrole [ka] To a solution of 1-tert-butyl-1H-pyrrole (2.0 g, 16.2 mmol) in tetrahydrofuran (30 mL) cooled to −78° C. was added N-bromosuccinimide (2.3 g, 13.0 mmol). After 2 h, the reaction mixture was treated with water (100 mL), and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 2% ethyl acetate in n-hexane to give 3-bromo-1-tert-butyl-1H-pyrrole (2.1 g, 10.4 mmol, 64% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ 6.80 (dd, 1H), 6.73 (app t, 1H), 6.14 (dd, 1H), 1.50 (s, 9H). LCMS (Method 4 - Column 5): Retention time = 2.47 min, [MH]+ = 202 / 204.

[0275] Synthesis of 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole [ka] To a solution of 3-bromo-1-tert-butylpyrrole (2.0 g, 9.9 mmol) in toluene (3 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 11.9 mmol), bis(acetonitrile)dichloropalladium(II) (77 mg, 0.03 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (365 mg, 0.09 mmol), and triethylamine (3.5 mL, 24.7 mmol). The reaction mixture was heated to 80°C for 6 hours. The reaction mixture was partitioned between water and ethyl acetate, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 2% ethyl acetate in n-hexane to give 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (0.9 g, 3.6 mmol, 37% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (s, 1H), 7.01-6.86 (m, 1H), 6.19 (app t, 1H), 1.46 (s, 9H), 1.22 (s, 12H). LCMS (Method 4 - Column 2): Retention time = 2.43 min, [MH]+ = 250.

[0276] Synthesis of 3-[2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propanenitrile [ka] To a solution of 3-(1H-pyrrol-1-yl)propanenitrile (5.0 g, 41.6 mmol) in dichloromethane (100 mL) cooled to 0 °C, trichloroacetyl chloride (5.7 mL, 49.9 mmol) was added, and the reaction was stirred for 2 h. The reaction mixture was treated with a mixture of ice and water, and the product was extracted with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 10–20% ethyl acetate in petroleum ether to give 3-[2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propanenitrile (4.3 g, 16.2 mmol, 39% yield) as a colorless solid. 1H NMR (400 MHz, chloroform-d) δ 7.65-7.63 (m, 1H), 7.20-7.18 (m, 1H), 6.37-6.35 (m, 1H), 4.60 (t, 2H), 2.94 (t, 2H).

[0277] Synthesis of 3-[4-bromo-2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propanenitrile [ka] To a solution of 3-[2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propanenitrile (5.0 g, 18.8 mmol) in dichloromethane (500 mL) cooled to −20° C., N-bromosuccinimide (3.4 g, 18.8 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. A mixture of ice and water was added, and the product was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 10–20% ethyl acetate in petroleum ether to give 3-[4-bromo-2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propanenitrile (4.6 g, 13.4 mmol, 71% yield) as a colorless solid. 1H NMR (400MHz, DMSO-d6): δ 7.79 (s, 1H), 7.52 (s, 1H), 4.59 (t, 2H), 3.04 (t, 2H).

[0278] Synthesis of methyl 4-bromo-1-(2-cyanoethyl)-1H-pyrrole-2-carboxylate [ka] To a solution of 3-[4-bromo-2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propanenitrile (5.2 g, 15.1 mmol) in methanol (100 mL) was added potassium carbonate (4.2 g, 15.1 mmol), and the reaction was stirred at room temperature for 2 hours. A mixture of ice and water was added, and the product was extracted with ethyl acetate. The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 5 to 15% ethyl acetate in petroleum ether to give methyl 4-bromo-1-(2-cyanoethyl)-1H-pyrrole-2-carboxylate (3.6 g, 14.0 mmol, 93% yield) as a colorless solid. 1H NMR (400MHz, DMSO-d6): δ 7.44 (s, 1H), 6.94 (s, 1H), 4.54 (t, 2H), 3.76 (s, 3H), 3.02 (t, 2H).

[0279] Synthesis of methyl 4-bromo-1-(3-methoxy-3-oxopropyl)-1H-pyrrole-2-carboxylate [ka] A solution of methyl 4-bromo-1-(2-cyanoethyl)-1H-pyrrole-2-carboxylate (3.5 g, 13.6 mmol) in a 1:5 mixture of sulfuric acid (15 mL, 13.6 mmol) and methanol (75 mL) was heated to 80 °C for 5 h in a sealed vessel. A mixture of ice and water was added, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 5 to 10% ethyl acetate in petroleum ether to give methyl 4-bromo-1-(3-methoxy-3-oxopropyl)-1H-pyrrole-2-carboxylate (2.3 g, 7.9 mmol, 58% yield) as a liquid. 1H NMR (400MHz, DMSO-d6): δ 7.33 (s, 1H), 6.88 (s, 1H), 4.50 (t, 2H), 3.75 (s, 3H), 3.59 (s, 3H), 2.80 (t, 2H).

[0280] Synthesis of 4-bromo-1-(2-carboxyethyl)-1H-pyrrole-2-carboxylic acid [ka] To a solution of methyl 4-bromo-1-(3-methoxy-3-oxopropyl)-1H-pyrrole-2-carboxylate (4.6 g, 15.9 mmol) in tetrahydrofuran (100 mL) cooled to 0 °C was added a solution of lithium hydroxide (950 mg, 39.6 mmol) in water (50 mL). The reaction was stirred at room temperature for 4 hours. The reaction mixture was acidified to pH = 3 by dropwise addition of concentrated hydrochloric acid. The product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 4-bromo-1-(2-carboxyethyl)-1H-pyrrole-2-carboxylic acid (2.9 g, 11.1 mmol, 70% yield) as a colorless solid. This intermediate was used in the next step without purification. 1H NMR (400MHz, DMSO-d6): δ 12.49(bs,2H),7.25(s,1H),6.82(s,1H),4.45(t,2H),2.70(t,2H). LCMS (Method 5): Retention time = 1.95 min, [M-2H]-=260.

[0281] Synthesis of 6-bromo-2,3-dihydro-1H-pyrrolidin-1-one [ka] To a solution of 4-bromo-1-(2-carboxyethyl)-1H-pyrrole-2-carboxylic acid (0.7 g, 2.7 mmol) in acetic anhydride (20 mL) was added sodium acetate (154 mg, 1.9 mmol), and the reaction mixture was heated to 100 °C for 15 h. The cooled reaction mixture was cooled, treated with ice-cold water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica eluting with a gradient of 20 to 40% ethyl acetate in petroleum ether to give 6-bromo-2,3-dihydro-1H-pyrrolidin-1-one (290 mg, 1.5 mmol, 63% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6): δ 7.51 (s, 1H), 6.75 (s, 1H), 4.31 (t, 2H), 2.97 (t, 2H). LCMS (Method 5): Retention time = 1.87 min, [MH]+=201.

[0282] Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolidin-1-one [ka] To a degassed solution of 6-bromo-2,3-dihydropyrrolidin-1-one (600 mg, 3.0 mmol) in N,N-dimethylformamide (10 mL) was added potassium acetate (736 mg, 7.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (244 mg, 0.3 mmol), and bis(pinacolato)diboron (1.1 g, 4.5 mmol). The microwave vial was sealed, evacuated under vacuum, and backfilled with nitrogen gas twice more, and the reaction mixture was heated to 100 °C under microwave irradiation for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 30-50% ethyl acetate in petroleum ether to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolidin-1-one (145 mg, 0.6 mmol, 19%) as a solid. 1H NMR (400 MHz, CDCl3): δ 7.40 (s, 1H), 7.05 (s, 1H), 4.32 (t, 2H), 3.13 (t, 2H), 1.34 (s, 12H). LCMS (Method 5): Retention time = 2.22 min, [MH]+ = 248.

[0283] Synthesis of benzyl N-(but-3-en-1-yl)carbamate [ka] To a solution of but-3-en-1-amine hydrochloride (10 g, 93.0 mmol) in dichloromethane (1 L) cooled to 0 °C was added sodium carbonate (4 M aqueous solution, 90 mL, 360.0 mmol). The reaction was stirred at 0 °C for 15 minutes, after which benzyl chloroformate (15.9 g, 93.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. After this time, the reaction mixture was poured into water, the layers were separated, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 20 to 30% ethyl acetate in n-hexane to afford benzyl N-(but-3-en-1-yl)carbamate (6.0 g, 29.2 mmol, 31% yield) as a yellow oil. 1H NMR (400MHz, chloroform-d) δ 7.45-7.29(m,5H),5.83-5.65(m,1H),5.20-4.96(m,4H),4.78(s,1H),3.35-3.17(m,2H),2.37-2.17(m,2H). LCMS (Method 4 - Column 1): Retention time = 1.94 min, [MH]+ = 206.

[0284] Synthesis of benzyl (1R,5S,7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate (isomer 1) and benzyl (1S,5R,7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate (isomer 2) [ka] To a solution of benzyl N-(but-3-en-1-yl)carbamate (3.0 g, 14.6 mmol) and 2,3-isopropylidene-(R)-glyceraldehyde (2.3 g, 17.5 mmol) in acetonitrile (250 mL) was added p-toluenesulfonic acid monohydrate (3.9 g, 20.5 mmol). The reaction was stirred at room temperature for 16 hours. After this time, additional 2,3-isopropylidene-(R)-glyceraldehyde (2.3 g, 17.5 mmol) and p-toluenesulfonic acid monohydrate (3.9 g, 20.5 mmol) were added. After an additional 16 h, the volatiles were removed under reduced pressure, and the crude material was purified by preparative HPLC eluting with isopropanol and heptane to afford Isomer 1: benzyl (1R,5S,7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate (280 mg, 1.0 mmol, 7% yield) and Isomer 2: benzyl (1S,5R,7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate (560 mg, 2.0 mmol, 14% yield) as clear oils. Relative stereochemistry was arbitrarily assigned.

[0285] Isomer 1: (Benzyl (1R,5S,7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate) 1H NMR (400MHz, chloroform-d) δ 7.43-7.29(m,5H),5.13(s,2H),4.76-4.52(m,2H),4.16(dd,1H),4.10-3.90(m,1H),3.69 -3.53(m,1H),3.53-3.42(m,1H),3.39-3.22(m,1H),2.08-1.85(m,1H),1.84-1.66(m,3H). LCMS (Method 4 - Column 1): Retention time = 1.41 min, [MH]+ = 278.

[0286] Isomer 2: Benzyl (1S,5R,7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylate 1H NMR (400MHz, chloroform-d) δ 7.40-7.30(m,5H),5.18(s,2H),4.69(br s,1H),4.59-4.46(m,1H),4.00(ddd,1H),3.71(dd,1H),3.50-3.34(m,2H),2.17-2.00(m,1H),1.92-1.68(m,3H). LCMS (Method 4 - Column 1): Retention time = 1.40 min, [MH]+ = 278.

[0287] Synthesis of 1-[(benzylamino)methyl]cyclobutan-1-ol [ka] To a solution of benzaldehyde (4.5 g, 42.4 mmol) in ethanol (150 mL) was added 1-(aminomethyl)cyclobutanol (4.3 g, 42.4 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was cooled to 0° C., and sodium borohydride (1.8 g, 46.6 mmol) was added portionwise. The reaction mixture was allowed to warm to room temperature, and stirring was continued for 16 hours. The reaction mixture was quenched by the addition of ice water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 1-[(benzylamino)methyl]cyclobutan-1-ol (5.2 g, 27.2 mmol, 64% yield) as a colorless solid. This intermediate was used in the next step without further purification. 1H NMR(300MHz,DMSO-d6) δ 7.42-7.02(m,5H),4.89(s,1H),3.74(s,2H),2.54-2.51(m,1H),2.04-1.71(m,4H),1.71-1.49(m,1H),1.49-1.26(m,1H). LCMS (Method 5): Retention time = 1.59 min, [MH+] = 192.

[0288] Synthesis of [(6S)-8-benzyl-5-oxa-8-azaspiro[3.5]nonan-6-yl]methanol [ka] To a solution of 1-[(benzylamino)methyl]cyclobutan-1-ol (9.5 g, 49.7 mmol) in toluene (200 mL) was added (R)-(-)-epichlorohydrin (6.9 g, 74.5 mmol) and lithium perchlorate (5.3 g, 49.7 mmol), and the reaction mixture was stirred at room temperature for 3 days. Sodium methoxide (25% w / w solution in methanol, 16 mL, 74.5 mmol) was added, and the reaction was stirred at room temperature for an additional day. The reaction mixture was quenched by the addition of ice-cold water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 20-60% ethyl acetate in petroleum ether to give [(6S)-8-benzyl-5-oxa-8-azaspiro[3.5]nonan-6-yl]methanol (10.0 g, 40.4 mmol, 81% yield) as an oil. LCMS (Method 5): Retention time = 1.64 min, [MH]+ = 248.

[0289] Synthesis of [(6S)-5-oxa-8-azaspiro[3.5]nonan-6-yl]methanol [ka] To a solution of [(6S)-8-benzyl-5-oxa-8-azaspiro[3.5]nonan-6-yl]methanol (10.0 g, 40.4 mmol) in methanol (200 mL) under nitrogen, palladium hydroxide on carbon (20% supported wet, 2.0 g, 1.4 mmol) was added. The reaction flask was evacuated and refilled with hydrogen gas. After 6 h, the reaction mixture was filtered through Celite® and washed with additional methanol. The combined filtrate was concentrated under reduced pressure to give [(6S)-5-oxa-8-azaspiro[3.5]nonan-6-yl]methanol (5.6 g, 35.6 mmol, 88% yield) as a yellow oil. This intermediate was used in the next step without purification. LCMS (Method 5): Retention time = 0.80 min, [MH]+ = 158.

[0290] Synthesis of tert-butyl (6S)-6-(hydroxymethyl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate [ka] To a solution of [(6S)-5-oxa-8-azaspiro[3.5]nonan-6-yl]methanol (5.6 g, 35.6 mmol) in dichloromethane (100 mL) and water (50 mL), sodium hydroxide solution (2 M aqueous solution, 18 mL, 36.0 mmol) and di-tert-butyl carbonate (7.8 g, 35.6 mmol) were added, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was partitioned between water and dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 10 to 20% ethyl acetate in n-heptane to give tert-butyl (6S)-6-(hydroxymethyl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (4.5 g, 17.5 mmol, 49% yield) as an oil. 1H NMR(400MHz,DMSO-d6) δ 4.73(t,1H),4.04-3.72(m,2H),3.46-3.36(m,1H),3.35-3.21(m,2H),2.01-1.70(m,5H),1.67-1.49(m,1H),1.41(s,9H). LCMS (Method 5): Retention time = 2.01 min, [(M-100)H]+=158.

[0291] Synthesis of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol [ka] To a solution of 3-(benzylamino)propan-1-ol (20.0 g, 121.0 mmol) in 2-propanol (200 mL) was added (2S)-2-(phenylmethoxymethyl)oxirane (21.8 g, 132.8 mmol). The reaction was stirred at 40° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and co-distilled with toluene (500 mL). The crude material was purified by column chromatography on neutral alumina eluting with 1% methanol in dichloromethane to give 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol (31.0 g, 94.1 mmol, 78% yield) as a gummy liquid. 1H NMR (400MHz, chloroform-d) δ 7.45-7.17(m,10H),4.53(s,2H),4.06-3.95(m,1H),3.81-3.67(m,3H),3.56(d,1H),3.48( dd,1H),3.41(dd,1H),2.78(ddd,1H),2.72-2.59(m,2H),2.53(dd,1H),1.87-1.64(m,2H). LCMS (Method 4 - Column 2): Retention time = 1.34 min, [MH]+ = 330.

[0292] Synthesis of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate [ka] To a solution of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol (30.0 g, 91.1 mmol) in dichloromethane (300 mL) cooled to −6° C., N,N-diisopropylethylamine (16.0 mL, 91.1 mmol) was added, followed 5 minutes later by the addition of methanesulfonyl chloride (7.1 mL, 91.1 mmol). The reaction mixture was stirred at −6° C. for an additional 30 minutes. The reaction mixture was poured onto ice and then diluted with saturated aqueous sodium bicarbonate, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate (37.0 g, 90.8 mmol, 100% yield) as a gummy liquid. 1H NMR (400MHz, chloroform-d) δ 7.41-7.23(m,10H),4.56(s,2H),4.29-4.20(m,2H),3.98-3.87(m,1H),3.76(d,1H),3.58-3. 39(m,3H),3.14(s,1H),2.93(s,3H),2.77-2.65(m,1H),2.64-2.51(m,3H),1.97-1.84(m,2H). LCMS (Method 4 - Column 7): Retention time = 1.46 min, [MH]+ = 408.

[0293] Synthesis of (2S)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane [ka] To a suspension of sodium hydride (57-63% w / w oil dispersion, 3.1 g, 127.1 mmol) in tetrahydrofuran (400 mL) cooled to 0 °C was added a solution of 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate (37.0 g, 90.8 mmol) in tetrahydrofuran (100 mL). The reaction was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C and quenched by the addition of saturated aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give (2S)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane (12.3 g, 39.5 mmol, 43% yield). H NMR (400 MHz, DMSO-d) δ 7.54-6.92 (m, 10H), 4.49-4.24 (m, 2H), 3.86-3.64 (m, 3H), 3.61 (s, 2H), 3.42-3.35 (m, 1H), 3.31-3.15 (m, 1H), 2.84 (d, 1H), 2.79-2.64 (m, 1H), 2.47-2.41 (m, 1H), 2.35 (dd, 1H), 1.92-1.76 (m, 1H), 1.76-1.60 (m, 1H). LCMS: retention time = 7.26 min, [M−H]+ = 312. Samples were analyzed using the following method: Waters Alliance 2690 and 996 PDA detectors with Micromass ZQ LCMS. Column: Sunfire C18, 150 x 4.6 mm, 3.5 micron (3.5 μm). Column temperature: 35°C. Mobile phase A: 5 mM ammonium acetate with 0.1% formic acid in Milli-Q water. Mobile phase B: Methanol. Mobile phase gradient details: T = 0 min (90% A, 10% B); gradient to T = 7 min (40% A, 60% B); gradient to T = 9 min (0% A, 100% B); T = 14 min (0% A, 100% B); gradient to T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B). Flow rate: 1 mL / min, run time 17 min.

[0294] Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate [ka] To a solution of (2S)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane (11.3 g, 36.3 mmol) in ethanol (120 mL) was added di-tert-butyl dicarbonate (10.0 mL, 43.5 mmol) and palladium on carbon (10% w / w, 17.0 g, 16.0 mmol). The reaction mixture was placed under a hydrogen atmosphere and stirred at room temperature for 16 hours. The reaction mixture was filtered through a Celite® bed and washed with ethanol (500 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 2% methanol in dichloromethane to give tert-butyl (2S)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (6.7 g, 29.0 mmol, 80% yield) as a gummy liquid. 1H NMR(400MHz,DMSO-d6) δ 4.78-4.64(m,1H),4.01-3.86(m,1H),3.78-3.62(m,1H),3.62-3.46(m,1 H),3.46-3.16(m,4H),3.07-2.86(m,1H),1.84-1.64(m,2H),1.39(s,9H). LCMS (Method 4 - Column 9): Retention time = 1.48 min, [(M-100)H]+=132. HPLC: Retention time = 5.21 minutes.

[0295] Synthesis of 3-{benzyl[(2R)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol [ka] To a solution of 3-(benzylamino)propan-1-ol (10.0 g, 60.5 mmol) in 2-propanol (100 mL) was added (2R)-2-(phenylmethoxymethyl)oxirane (9.9 g, 60.5 mmol). The reaction mixture was stirred at 40° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography on neutral alumina to give 3-{benzyl[(2R)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol (16.0 g, 48.6 mmol, 80% yield) as a colorless liquid. 1H NMR (400MHz, chloroform-d) δ 7.45-7.23(m,10H),4.53(s,2H),4.06-3.92(m,1H),3.81-3.67(m,3H),3.57(d,1H),3.48( dd,1H),3.41(dd,1H),2.78(ddd,1H),2.72-2.58(m,2H),2.54(dd,1H),1.87-1.64(m,2H). LCMS (Method 4 - Column 5): Retention time = 1.36 min, [MH]+ = 330.

[0296] Synthesis of 3-{benzyl[(2R)-3-(benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate [ka] To a solution of 3-{benzyl[(2R)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol (16.0 g, 48.6 mmol) in dichloromethane (150 mL) cooled to −6° C., N,N-diisopropylethylamine (6.8 mL, 48.6 mmol) was added, followed 5 minutes later by the addition of methanesulfonyl chloride (3.8 mL, 48.6 mmol). The reaction was stirred at −6° C. for an additional 30 minutes. The reaction mixture was poured onto ice and then diluted with saturated aqueous sodium bicarbonate. The product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 3-{benzyl[(2R)-3-(benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate (17.0 g, 25.4 mmol, 52% yield) as a colorless liquid. 1H NMR (400MHz, chloroform-d) δ 7.41-7.26(m,10H),4.55(s,2H),4.27-4.20(m,2H),3.99-3.88(m,1H),3.80(d,1H),3. 64-3.40(m,3H),2.93(s,3H),2.80-2.66(m,1H),2.69-2.54(m,3H),2.01-1.87(m,2H). LCMS (Method 4 - Column 7): Retention time = 1.46 min, [MH]+ = 408.

[0297] Synthesis of (2R)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane [ka] To a solution of 3-{benzyl[(2R)-3-(benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate (17.5 g, 42.9 mmol) in tetrahydrofuran (200 mL) cooled to 0 °C, sodium hydride (2.4 g, 60.1 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by reverse-phase column chromatography eluting with a gradient of 50–75% acetonitrile in water. The isolated material was further purified by silica gel column chromatography eluting with a gradient of 10–40% ethyl acetate in hexane to give (2R)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane (3.1 g, 9.4 mmol, 22% yield) as a colorless liquid. 1H NMR(400MHz,DMSO-d6) δ 7.40-7.17(m,10H),4.47-4.27(m,2H),3.82-3.71(m,2H),3.71-3.63(m,1H),3.61(s,2H),3.40-3.35(m,1H),3.2 4(dd,1H),2.85(d,1H),2.79-2.66(m,1H),2.49-2.44(m,1H),2.36(dd,1H),1.89-1.75(m,1H),1.78-1.64(m,1H). LCMS (Method 8 - Column 2): Retention time = 7.23 min, [MH]+ = 312.

[0298] Synthesis of tert-butyl (2R)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate [ka] To a solution of (2R)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxazepane (2.8 g, 9.0 mmol) in ethanol (30 mL) was added di-tert-butyl dicarbonate (2.4 g, 10.8 mmol) and palladium on carbon (10% w / w, 2.8 g, 2.6 mmol). The reaction mixture was stirred under 200 psi (approximately 1.38 MPa) of hydrogen at room temperature for 14 hours. The reaction mixture was filtered through Celite® and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 2 to 4% methanol in dichloromethane to give tert-butyl (2R)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (0.97 g, 3.9 mmol, 44% yield) as a colorless liquid. 1H NMR(400MHz,DMSO-d6) δ 4.83-4.60(m,1H),4.02-3.86(m,1H),3.70(ddd,1H),3.58-3.17(m,4H),2.97(ddd,1H),1.84-1.61(m,2H),1.39(s,9H). LCMS (Method 4 - Column 9): Retention time = 1.48 min, [MNa]+=254. HPLC: Retention time = 5.18 minutes.

[0299] Synthesis of tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate [ka] To a solution of (S)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (60.0 g, 259.5 mmol) in dichloromethane (1.0 L), N,N-diisopropylethylamine (110 mL, 648.6 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (197.2 g, 518.9 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, and then N,O-dimethylhydroxylamine hydrochloride (38.0 g, 389.2 mmol) was added in portions, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate (165.0 g, 246.6 mmol, 95% yield) as a pale yellow oil. No purification was performed and the material was used crude in the next step. LCMS (Method 4 - Column 7): Retention time = 1.56 min, [MNa]+ = 297.

[0300] Synthesis of tert-butyl (2S)-2-acetylmorpholine-4-carboxylate [ka] To a solution of tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate (165.0 g, 601.5 mmol) in tetrahydrofuran (800 mL) cooled to 0 °C under a nitrogen atmosphere, methylmagnesium bromide (3 M in diethyl ether, 275 mL, 825.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and quenched by the addition of saturated aqueous ammonium chloride solution. The product was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 20% ethyl acetate in n-hexane to give tert-butyl (2S)-2-acetylmorpholine-4-carboxylate (50.0 g, 218.1 mmol, 36% yield) as a pale yellow oil. 1H NMR (400MHz, chloroform-d) δ 4.23-4.05(m,1H),3.97(ddd,1H),3.86(d,2H),3.56(td,1H),3.05-2.88(m,1H),2.88-2.65(m,1H),2.23(s,3H),1.46(s,9H). LCMS (Method 4 - Column 2): Retention time = 2.21 min, [MH]+ = 230.

[0301] Synthesis of tert-butyl (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylate [ka] To a solution of tert-butyl (2S)-2-acetylmorpholine-4-carboxylate (52.5 g, 229.0 mmol) in methanol (500 mL) cooled to 0 °C, sodium borohydride (13.1 g, 343.5 mmol) was added portionwise. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the volatiles were removed under reduced pressure. The product was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylate as a 1:1 mixture of diastereoisomers (51.0 g, 220.5 mmol, 96% yield) as a pale yellow oil. This material was used crude in the next step without purification. Isomer 1 LCMS (Method 8 - Column 3): Retention time = 10.72 min, [MH]+ = 232. Isomer 2 LCMS (Method 8 - Column 3): Retention time = 11.41 min, [MH]+ = 232.

[0302] Synthesis of tert-butyl (2S)-2-[(1S)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate and tert-butyl (2S)-2-[(1R)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate [ka] To a solution of tert-butyl (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylate (51.0 g, 220.5 mmol) in dichloromethane (800 mL) was added (2R)-2-methoxy-2-phenylacetic acid (40.3 g, 242.6 mmol) and N,N'-dimethylaminopyridine (6.7 g, 55.1 mmol). The reaction mixture was cooled to 0 °C, and N,N'-dicyclohexylcarbodiimide (54.5 g, 264.6 mmol) was added portionwise. The reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered to remove the N,N'-dicyclohexylurea by-product, and the filtrate was poured into water. The product was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 8 to 20% ethyl acetate in n-hexane to give isomer 1: tert-butyl (2S)-2-[(1R)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate (16.0 g, 42.2 mmol, 19% yield) and isomer 2: tert-butyl (2S)-2-[(1S)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate (10.3 g, 27.1 mmol, 12% yield).

[0303] Isomer 1: tert-butyl (2S)-2-[(1R)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate 1H NMR(400MHz,DMSO-d6) δ 7.40-7.32(m,5H),4.91(s,1H),4.88-4.73(m,1H),4.29(t,1H),3.87- 3.58(m,3H),3.33(s,3H),3.29-3.23(m,3H),1.38(s,9H),1.17(d,3H). LCMS (Method 4 - Column 2): Retention time = 2.88 min, [MH]+ = 380.

[0304] Isomer 2: tert-butyl (2S)-2-[(1S)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate 1H NMR(400MHz,DMSO-d6) δ 7.42-7.28(m,5H),5.00-4.91(m,1H),4.90(s,1H),3.81(d,1H),3.76-3.54(m,2H), 3.34-3.20(m,5H),2.94-2.73(m,1H),2.73-2.55(m,1H),1.39(s,9H),1.02(d,3H). LCMS (Method 4 - Column 2): Retention time = 2.92 min, [MH]+ = 380.

[0305] Synthesis of tert-butyl (2S)-2-[(1S)-1-hydroxyethyl]morpholine-4-carboxylate [ka] To a solution of tert-butyl (2S)-2-[(1S)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate (9.2 g, 24.3 mmol) in methanol (100 mL) was added potassium carbonate (5.0 g, 36.4 mmol). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure, the reaction was poured into water, and the pH of the solution was adjusted to pH = 7 using 1 N aqueous hydrochloric acid. The product was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting crude material was purified by silica gel column chromatography eluting with 36% methyl tert-butyl ether in n-heptane to afford tert-butyl (2S)-2-[(1S)-1-hydroxyethyl]morpholine-4-carboxylate (4.2 g, 15.4 mmol, 64% yield) as a pale yellow oil. 1H NMR (400MHz, DMSO-d6) δ 4.68(d,1H),3.86-3.49(m,4H),3.38-3.27(m,1H),3.12(ddd,1H),2.89-2.63(m,2H),1.40(s,9H),1.02(d,3H). LCMS (Method 8 - Column 3): Retention time = 10.82 min, [(M-56)H]+=176.

[0306] Synthesis of tert-butyl (2S)-2-[(1R)-1-hydroxyethyl]morpholine-4-carboxylate [ka] To a solution of tert-butyl (2S)-2-[(1R)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate (11.0 g, 29.0 mmol) in methanol (120 mL) was added potassium carbonate (6.0 g, 43.5 mmol). The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure, the reaction was poured into water, and the pH of the solution was adjusted to pH = 7 using 1N aqueous hydrochloric acid. The product was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 30% methyl tert-butyl ether in n-heptane to afford tert-butyl (2S)-2-[(1R)-1-hydroxyethyl]morpholine-4-carboxylate (4.7 g, 19.5 mmol, 67% yield) as a pale yellow oil. 1H NMR(400MHz,DMSO-d6) δ 4.78(d,1H),4.01(d,1H),3.80(d,1H),3.69(d,1H),3.47-3.39(m,1H),3.3 9-3.28(m,1H),2.96(ddd,1H),2.90-2.67(m,2H),1.40(s,9H),1.08(d,3H). LCMS (Method 8 - Column 3): Retention time = 11.48 min, [MH]+ = 232.

[0307] Synthesis of (2S)-4-benzyl-6,6-dimethylmorpholine-2-carbaldehyde [ka] To a solution of oxalyl chloride (10.0 mL, 116.9 mmol) in dichloromethane (100 mL) cooled to −78° C. was added dimethyl sulfoxide (16.6 mL, 233.7 mmol) dropwise over 15 minutes. The reaction was stirred at −78° C. for an additional 15 minutes. A solution of [(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]methanol (25.0 g, 106.2 mmol) in dichloromethane (100 mL) was then added over 10 minutes. The reaction mixture was stirred at −78° C. for 30 minutes, and then triethylamine (74.0 mL, 531.2 mmol) was added over 10 minutes. Stirring was continued at −78° C. for an additional 30 minutes. The reaction mixture was quenched with water, and the product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give (2S)-4-benzyl-6,6-dimethylmorpholine-2-carbaldehyde (26.0 g, 111.4 mmol, 105% yield), which was immediately carried to the next step without purification. LCMS (Method 5): Retention time = 1.16 min, [MH] + = 234.

[0308] (1S)-1-[(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol and (1R)-1-[(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol [ka] To a solution of (S)-4-benzyl-6,6-dimethylmorpholine-2-carbaldehyde (25.0 g, 107.2 mmol) in tetrahydrofuran (250 mL) cooled to -78 °C under nitrogen was added methylmagnesium bromide (1.4 M in tetrahydrofuran, 115.0 mL, 160.7 mmol). The reaction mixture was stirred at 0 °C for 1-2 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 10-16% ethyl acetate in petroleum ether to give (1S)-1-[(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol (6.0 g, 24.1 mmol, 23% yield) as a syrupy liquid as the first eluent, (1R)-1-[(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol (5.7 g, 22.9 mmol, 21% yield) as a syrupy liquid as the second eluent, and a 3.5 g mixed fraction.

[0309] (1S)-1-[(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol 1H NMR(400MHz,DMSO-d6): δ 7.33-7.31(m,4H),7.27-7.24(m,1H),4.37(d,1H),3.58-3.57(m,1H),3.54-3.51(m,1H),3.49-3.47(m,1H) ),3.39(s,1H),2.67(d,1H),2.50-2.44(m,1H),1.77-1.68(m,2H),1.25(s,3H),1.06(s,3H),0.97(d,3H). LCMS (Method 5): Retention time = 1.27 min, [MH]+=250.

[0310] (1R)-1-[(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol 1H NMR(400MHz,DMSO-d6): δ 7.33-7.31(m,4H),7.27-7.24(m,1H),4.49(d,1H),3.49-3.30(m,4H),2.94( d, 1H), 2.50-2.46 (m, 1H), 1.73-1.59 (m, 2H), 1.25 (s, 3H), 1.05-1.03 (m, 6H). LCMS (Method 5): Retention time = 1.32 min, [MH]+=250.

[0311] Synthesis of (1R)-1-[(2S)-6,6-dimethylmorpholin-2-yl]ethan-1-ol [ka] To a solution of (1R)-1-[(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol (5.7 g, 22.9 mmol) in methanol (100 mL) under nitrogen, palladium hydroxide on carbon (20% supported wet, 0.9 g, 0.64 mmol) was added, and the reaction was placed under a hydrogen atmosphere for 2-3 hours. The reaction mixture was filtered through a pad of Celite®, washed with methanol, and the filtrate was concentrated under reduced pressure to give (1R)-1-[(2S)-6,6-dimethylmorpholin-2-yl]ethan-1-ol (3.3 g, 20.7 mmol, 91% yield), which was carried on to the next step without further purification. 1H NMR(400MHz,MeOD): δ 3.54-3.48(m,1H),3.47-3.43(m,1H),3.05-3.01(m,1H),2.65(dd,1H), 2.51(d,1H),2.43-2.37(m,1H),1.29(s,3H),1.17(s,3H),1.15(d,3H). LCMS (Method 7): Retention time = 0.22 min, [MH]+=160.

[0312] Synthesis of tert-butyl (6S)-6-[(1R)-1-hydroxyethyl]-2,2-dimethylmorpholine-4-carboxylate [ka] To a solution of (1R)-1-[(2S)-6,6-dimethylmorpholin-2-yl]ethan-1-ol (3.3 g, 20.7 mmol) in dichloromethane (100 mL) and water (60 mL) was added sodium hydroxide (2N, 10.3 mL, 20.7 mmol), followed by a solution of di-tert-butyl dicarbonate (4.5 g, 20.7 mmol) in dichloromethane (30 mL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and dichloromethane, the aqueous layer was further extracted with dichloromethane, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of ethyl acetate in petroleum ether to give tert-butyl (S)-6-((R)-1-hydroxyethyl)-2,2-dimethylmorpholine-4-carboxylate (4.7 g, 17.9 mmol, 87% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 4.67 (d, 1H), 4.16-3.99 (m, 1H), 3.71-3.54 (m, 1H), 3.44-3.28 (m, 1H), 3.21 (ddd, 1H), 2.72-2.27 (m, 2H), 1.40 (s, 9H), 1.10 (s, 3H), 1.08 (s, 3H), 1.05 (d, 3H). LCMS (Method 5): Retention time = 2.68 min, [(M-100)H]+=160.

[0313] Synthesis of (1S)-1-[(2S)-6,6-dimethylmorpholin-2-yl]ethan-1-ol [ka] To a solution of (1S)-1-[(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol (6.0 g, 24.1 mmol) in methanol (100 mL) under nitrogen, palladium hydroxide on carbon (20% supported wet, 1.0 g, 0.71 mmol) was added, and the reaction was placed under a hydrogen atmosphere for 2-3 hours. The reaction mixture was filtered through a pad of Celite®, washed with methanol, and the filtrate was concentrated under reduced pressure to give (1S)-1-[(2S)-6,6-dimethylmorpholin-2-yl]ethan-1-ol (3.7 g, 23.2 mmol, 97% yield). This intermediate was carried on to the next step without further purification. 1H NMR(400MHz,MeOD): δ 3.59-3.50(m,2H),2.83-2.79(m,1H),2.67-2.64(m,1H),2.53-2.50(m,1H),2.50-2.41(m,1H),1.30(s,3H),1.17(s,3H),1.13(d,3H). LCMS (Method 5): Retention time = 0.64 min, [MH]+=160.

[0314] Synthesis of tert-butyl (6S)-6-[(1S)-1-hydroxyethyl]-2,2-dimethylmorpholine-4-carboxylate [ka] To a solution of (1S)-1-[(2S)-6,6-dimethylmorpholin-2-yl]ethan-1-ol (3.7 g, 23.2 mmol) in dichloromethane (100 mL) and water (70 mL) was added sodium hydroxide (2N, 11.5 mL, 23.2 mmol), followed by a solution of di-tert-butyl dicarbonate (5.1 g, 23.2 mmol) in dichloromethane (40 mL). The reaction was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and dichloromethane, the aqueous layer was further extracted with dichloromethane, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of ethyl acetate in petroleum ether to give tert-butyl (6S)-6-[(1S)-1-hydroxyethyl]-2,2-dimethylmorpholine-4-carboxylate (4.5 g, 17.4 mmol, 75% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 4.51 (d, 1H), 3.88-3.73 (m, 1H), 3.72-3.57 (m, 1H), 3.57-3.48 (m, 1H), 3.43 (ddd, 1H), 2.70-2.52 (m, 2H), 1.40 (s, 10H), 1.12 (s, 3H), 1.09 (s, 3H), 1.00 (d, 3H). LCMS (Method 5): Retention time = 2.65 min, [(M-100)H]+=160.

[0315] Synthesis of 4-methyl-2-[2-oxo-2-(propan-2-yloxy)ethyl]pyridine-3-carboxylic acid [ka] To a solution of potassium tert-butoxide (6.5 g, 57.7 mmol) in 2-propanol (43 mL) was added ethyl acetoacetate (5.0 g, 38.5 mmol) at room temperature. The reaction mixture was stirred for 1 hour. Copper(II) acetate (350 mg, 1.92 mmol) and 2-chloro-4-methylpyridine-3-carboxylic acid (3.3 g, 19.2 mmol) were added, and the reaction mixture was heated to 80° C. for 3 hours. The reaction mixture was acidified with acetic acid, and the volatiles were removed under reduced pressure. The residue was poured into water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was triturated with a mixture of hexane and diethyl ether to give 4-methyl-2-[2-oxo-2-(propan-2-yloxy)ethyl]pyridine-3-carboxylic acid (3.6 g, 13.7 mmol, 71% yield) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ 13.48 (br s, 1H), 8.37 (s, 1H), 7.25 (s, 1H), 4.88 (hept, 1H), 3.83 (s, 2H), 2.35 (s, 3H), 1.16 (d, 6H). LCMS (Method 4 - Column 7): Retention time = 0.90 min, [MH]+=238.

[0316] Synthesis of 4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-5,7-dione [ka] To a solution of 4-methyl-2-[2-oxo-2-(propan-2-yloxy)ethyl]pyridine-3-carboxylic acid (1.5 g, 5.7 mmol) in tetrahydrofuran (10 mL) cooled to 0 °C, triethylamine (1.2 mL, 8.0 mmol) was added, and the reaction was stirred for 20 minutes. Ethyl chloroformate (0.7 mL, 7.4 mmol) was added dropwise while maintaining the temperature at 0 °C, and the reaction was stirred at room temperature for 48 hours. The reaction mixture was cooled to 0 °C, and ammonium hydroxide (25-30% in water, 10.0 mL, 5.7 mmol) was added dropwise. The reaction was stirred at room temperature for an additional 2 hours. The reaction mixture was neutralized with dilute aqueous hydrochloric acid, and the volatiles were removed under reduced pressure. The crude material was purified by reverse-phase column chromatography eluting with water and acetonitrile to give 4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-5,7-dione (250 mg, 1.18 mmol, 21% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.78 (s, 1H), 6.24 (s, 1H), 4.98 (s, 1H), 4.05 (s, 1H), 2.61 (s, 3H). LCMS (Method 4 - Column 7): Retention time = 0.73 min, [MH]+ = 177.

[0317] Synthesis of 5,7-dichloro-4-methyl-1,6-naphthyridine [ka] To a mixture of 4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-5,7-dione (250 mg, 1.4 mmol) and tetramethylammonium chloride (160 g, 1.5 mmol) was added phosphoryl chloride (2.4 mL, 18.4 mmol). The reaction mixture was heated to 110° C. for 16 hours. The cooled reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The residue was poured into cold water, made basic with saturated aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of ethyl acetate in hexane to give 5,7-dichloro-4-methyl-1,6-naphthyridine (30 mg, 0.13 mmol, 9% yield) as a colorless solid. 1H NMR (400MHz, DMSO-d6) δ 8.99 (d, 1H), 8.08 (s, 1H), 7.64 (d, 1H), 3.01 (s, 3H). LCMS (Method 4 - Column 7): Retention time = 1.78 min, [MH]+ = 213. HPLC: Retention time = 7.98 minutes.

[0318] Synthesis of 2-[2-oxo-2-(propan-2-yloxy)ethyl]-4-(trifluoromethyl)pyridine-3-carboxylic acid [ka] To a solution of potassium tert-butoxide (7.2 g, 63.8 mmol) in 2-propanol (80 mL) was added ethyl acetoacetate (5.4 mL, 42.6 mmol) at room temperature. The reaction mixture was stirred for 30 minutes. Copper(II) acetate (390 mg, 2.13 mmol) and 2-chloro-4-(trifluoromethyl)pyridine-3-carboxylic acid (4.8 g, 21.3 mmol) were added, and the reaction mixture was heated to 80° C. for 16 hours. The reaction mixture was acidified with acetic acid, and the volatiles were removed under reduced pressure. The residue was poured into water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by reverse-phase column chromatography eluting with a gradient of 5 to 100% acetonitrile in water to give 2-[2-oxo-2-(propan-2-yloxy)ethyl]-4-(trifluoromethyl)pyridine-3-carboxylic acid (3.6 g, 11.3 mmol, 53% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 14.34 (s, 1H), 8.87 (d, 1H), 7.80 (d, 1H), 4.90 (hept, 1H), 3.95 (s, 2H), 1.17 (d, 6H). LCMS (Method 4 - Column 8): Retention time = 3.51 min, [MH] = 292.

[0319] Synthesis of 4-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5,7-dione [ka] To a solution of 2-[2-oxo-2-(propan-2-yloxy)ethyl]-4-(trifluoromethyl)pyridine-3-carboxylic acid (3.0 g, 10.3 mmol) in tetrahydrofuran (30 mL) cooled to 0 °C, triethylamine (2.2 mL, 15.4 mmol) was added, and the reaction was stirred for 20 minutes. Ethyl chloroformate (1.5 mL, 15.4 mmol) was added dropwise while maintaining the temperature at 0 °C, and the reaction was stirred at room temperature for 4 days. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting intermediate was dissolved in tetrahydrofuran (45 mL), the reaction mixture was cooled to 0 °C, and ammonium hydroxide (25-30% in water, 25.7 mL, 164.8 mmol) was added dropwise. The reaction was stirred at room temperature for an additional 2 hours. The reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate, which was discarded. The aqueous layer was then neutralized with dilute aqueous hydrochloric acid, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5,7-dione (1.7 g, 7.2 mmol, 69% yield) as a brick-red solid. H NMR (400 MHz, DMSO-d) δ 11.59 (s, 1H), 9.02 (d, 1H), 7.88 (d, 1H), 4.17 (s, 2H). LCMS (Method 4 - Column 7): Retention time = 1.20 min, [MH] = 231.

[0320] Synthesis of 5,7-dichloro-4-(trifluoromethyl)-1,6-naphthyridine [ka] To a mixture of 4-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5,7-dione (1.6 g, 6.7 mmol) and tetramethylammonium chloride (770 g, 7.0 mmol) was added phosphoryl chloride (8.1 mL, 97.1 mmol). The reaction mixture was heated to 130° C. for 24 hours. The cooled reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The residue was poured into cold water, made basic with saturated aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of ethyl acetate in hexane to give 5,7-dichloro-4-(trifluoromethyl)-1,6-naphthyridine (960 mg, 3.6 mmol, 54% yield) as a light orange solid. 1H NMR (400MHz, DMSO-d6) δ 9.40(d,1H), 8.35(s,1H), 8.28(d,1H). LCMS (Method 4 - Column 7): Retention time = 2.38 min, [MH]+ = 268. HPLC: Retention time = 8.32 minutes.

[0321] Synthesis of 5,7-dichloro-3-iodo-1,6-naphthyridine [ka] To a solution of 5,7-dichloro-1,6-naphthyridine (200 mg, 1.0 mmol) in acetic acid (10 mL) was added N-iodosuccinimide (230 mg, 1.0 mmol), and the reaction mixture was heated to reflux for 24 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with 2 N aqueous sodium hydroxide solution followed by brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 0 to 50% ethyl acetate in heptane to give 5,7-dichloro-3-iodo-1,6-naphthyridine (43 mg, 0.13 mmol, 13% yield) as a white solid. H NMR (400 MHz, chloroform-d) δ 9.23 (d, 1H), 8.95 (dd, 1H), 7.90 (d, 1H). LCMS (Method 2): Retention time = 3.02 min, [MH]+=325.

[0322] Synthesis of 5,7-dichloro-3-ethenyl-1,6-naphthyridine [ka] To a suspension of 5,7-dichloro-3-iodo-1,6-naphthyridine (43 mg, 0.13 mmol), 2,4,6-trivinylcyclotriboroxane pyridine complex (16 mg, 0.07 mmol), and potassium carbonate (35 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL), tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol) was added, and the reaction mixture was heated to 100 °C under microwave irradiation for 1 h. The cooled reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5,7-dichloro-3-ethenyl-1,6-naphthyridine (23 mg, 0.10 mmol, 77% yield). 1H NMR (400MHz, chloroform-d) δ 9.20(d,1H),8.44(dd,1H),7.91(d,1H),6.91(dddd,1H),6.10(d,1H),5.63(d,1H). LCMS (Method 2): Retention time = 2.85 min, [MH]+=225.

[0323] Synthesis of 5,7-dichloro-3-methyl-1,6-naphthyridine [ka] To a suspension of 5,7-dichloro-3-iodo-1,6-naphthyridine (137 mg, 0.42 mmol), trimethylboroxine (70 μL, 0.48 mmol), and potassium carbonate (120 mg, 0.87 mmol) in 1,4-dioxane (2 mL) was added tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol). The reaction mixture was heated to 120° C. under microwave irradiation for 12 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 0 to 50% ethyl acetate in heptane to afford 5,7-dichloro-3-methyl-1,6-naphthyridine (68 mg, 0.32 mmol, 76% yield) as a white solid. LCMS (Method 2): Retention time = 2.71 min, [MH]+ = 213.

[0324] Synthesis of 4-bromo-2-methoxy-6-nitroaniline [ka] To a solution of 2-methoxy-6-nitroaniline (18.0 g, 107.0 mmol) in acetic acid (260 mL) was added sodium acetate (14.1 g, 171.3 mmol) and bromine (5.9 mL, 117.8 mmol), and the reaction was stirred at room temperature for 30 minutes. The resulting orange solid was collected by filtration, washed with cold water, and dried under vacuum to give 4-bromo-2-methoxy-6-nitroaniline (25.4 g, 102.8 mmol, 96% yield). 1H NMR (400 MHz, DMSO) δ 7.71 (d, 1H), 7.27 (s, 2H), 7.19 (d, 1H), 3.90 (s, 3H). LCMS (Method 4 - Column 7): Retention time = 2.23 min, [MH]+ = 246 / 248.

[0325] Synthesis of 5-bromo-3-methoxybenzene-1,2-diamine [ka] To a solution of 4-bromo-2-methoxy-6-nitroaniline (20.0 g, 81.0 mmol) in a mixture of tetrahydrofuran (400 mL) and acetic acid (400 mL), zinc dust (79.4 g, 1.2 mol) was added portionwise, and the reaction was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to pH 7 by the addition of 10% aqueous potassium carbonate. The resulting salts were removed by filtration, and the filtrate was partitioned between water and ethyl acetate. The product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 5-bromo-3-methoxybenzene-1,2-diamine (18.0 g, 80.8 mmol, 100% yield) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ 6.40 (d, 1H), 6.34 (d, 1H), 4.78 (s, 2H), 4.11 (s, 2H), 3.71 (s, 3H). LCMS (Method 4 - Column 7): Retention time = 1.41 min, [MH]+=217.

[0326] Synthesis of 7-bromo-5-methoxyquinoxaline [ka] To a solution of 5-bromo-3-methoxybenzene-1,2-diamine (18.0 g, 82.9 mmol) in methanol (900 mL) was added glyoxal (40% aqueous solution, 36.1 g, 248.8 mmol). The reaction was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure, and the crude material was purified by silica gel column chromatography eluting with 30% ethyl acetate in n-hexane. The product was further purified by trituration with diethyl ether to give 7-bromo-5-methoxyquinoxaline (10.0 g, 41.8 mmol, 50% yield) as a light brown solid. 1H NMR (400 MHz, chloroform-d) δ 8.86 (d, 1H), 8.83 (d, 1H), 7.89 (d, 1H), 7.20 (d, 1H), 4.11 (s, 3H). LCMS (Method 4 - Column 7): Retention time = 1.58 min, [MH]+ = 239.

[0327] Synthesis of 7-bromoquinoxalin-5-ol [ka] To a solution of 7-bromo-5-methoxyquinoxaline (10.0 g, 41.8 mmol) in dichloromethane (1.0 L) cooled to 0 °C, boron tribromide (1 M in dichloromethane, 418 mL, 418.3 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into cold water, and the aqueous layer was made basic with saturated sodium bicarbonate solution. The product was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was triturated with diethyl ether and dried under vacuum to give 7-bromoquinoxalin-5-ol (5.4 g, 24.0 mmol, 57% yield) as a light brown solid. 1H NMR (400MHz, DMSO-d6) δ 11.05 (br s, 1H), 8.95 (s, 1H), 8.89 (s, 1H), 7.73 (s, 1H), 7.29 (s, 1H). LCMS (Method 4 - Column 7): Retention time = 1.38 min, [MH]+ = 225. HPLC: Retention time = 3.79 minutes.

[0328] Synthesis of 7-bromo-5-methoxyquinoline [ka] The reaction was carried out in eight batches of 10 g of 3-bromo-5-methoxyaniline, each combined after workup.

[0329] To a solution of glycerol (74 mL, 1 mol) in nitrobenzene (40 mL) were added 3-bromo-5-methoxyaniline (80 g, 0.4 mol) and sulfuric acid (14 M aqueous solution, 26 mL, 0.4 mol), and the reaction mixture was heated to 100° C. for 16 h. The reaction was quenched by the addition of ice and sodium hydroxide (6 M aqueous solution), and the product was extracted with ethyl acetate followed by 10% methanol in dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 15% ethyl acetate in n-hexane to give 7-bromo-5-methoxyquinoline (21.0 g, 81.1 mmol, 21% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.95-8.89 (m, 1H), 8.49 (dd, 1H), 7.80 (d, 1H), 7.55 (dd, 1H), 7.22 (d, 1H), 4.02 (s, 3H). LCMS (Method 4 - Column 2): Retention time = 2.08 min, [MH]+ = 238.

[0330] Synthesis of 7-bromoquinolin-5-ol [ka] To a solution of 7-bromo-5-methoxyquinoline (21.0 g, 88.2 mmol) in dichloromethane (400 mL) cooled to 0 °C, boron tribromide (1 M in dichloromethane, 882 mL, 882.1 mmol) was added, and the reaction was stirred at room temperature for 1 day. The reaction mixture was cooled to 0 °C and quenched by the addition of water, and the pH of the mixture was adjusted to pH = 8-9 by the addition of solid sodium carbonate. The product was extracted with butanol, and the combined organic layers were then concentrated. The crude material was purified by silica gel column chromatography eluting with 6% methanol in dichloromethane to give 7-bromoquinolin-5-ol (13.5 g, 60.3 mmol, 68% yield) as a light brown solid. 1H NMR (400MHz, DMSO-d6) δ 11.09(s,1H),8.87(dd,1H),8.47(dd,1H),7.65(d,1H),7.50(dd,1H),7.04(d,1H). LCMS (Method 4 - Column 7): Retention time = 1.47 min, [MH]+ = 224. HPLC: Retention time = 3.79 minutes.

[0331] Synthesis of 7-bromo-5-methoxy-4-methylquinoline [ka] To a solution of 3-bromo-5-methoxyaniline (5.0 g, 24.8 mmol) in 1,4-dioxane (50 mL) was added concentrated sulfuric acid (2.0 mL, 37.1 mmol), and the mixture was heated to reflux for 30 minutes. A solution of but-3-en-2-one (2.6 g, 37.1 mmol) in 1,4-dioxane (5 mL) was then added, and the reaction mixture was heated at 100° C. for 4 hours. The reaction mixture was quenched by the addition of aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 10% ethyl acetate in petroleum ether to give 7-bromo-5-methoxy-4-methylquinoline (1.35 g, 5.35 mmol, 22% yield) as a brown solid. 1H NMR (400MHz, chloroform-d): δ 8.68(d,1H),7.93(d,1H),7.17-7.15(m,1H),6.97(d,1H),3.98(s,3H),2.89(d,3H). LCMS (Method 5): Retention time = 1.97 min, [MH]+=252.

[0332] Synthesis of 7-bromo-4-methylquinolin-5-ol [ka] To a solution of 7-bromo-5-methoxy-4-methylquinoline (1.1 g, 4.4 mmol) in dichloromethane (20 mL) cooled to -78 °C, boron tribromide (1.1 mL, 10.9 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was quenched with aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by trituration with n-hexane to give 7-bromo-4-methylquinolin-5-ol (520 mg, 2.2 mmol, 50% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 10.90(s,1H),8.63(d,1H),7.58(d,1H),7.22(d,1H),7.03(d,1H),3.84(s,3H). LCMS (Method 5): Retention time = 1.47 min, [MH]+=240.

[0333] Synthesis of 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-methoxyquinoline [ka] To a solution of 7-bromo-5-methoxyquinoline (550 mg, 2.3 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added 1-t-butylpyrazole-4-boronic acid, pinacol ester (690 mg, 2.8 mmol) and sodium carbonate (730 mg, 6.9 mmol). The reaction mixture was purged with nitrogen gas for 30 minutes, followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80 mg, 0.12 mmol). The reaction mixture was then heated to 80°C for 3 hours. The reaction mixture was poured into water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 2% methanol in dichloromethane to give 7-(1-tert-butylpyrazol-4-yl)-5-methoxyquinoline (550 mg, 1.8 mmol, 78% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (dd, 1H), 8.56 (d, 1H), 8.42 (ddd, 1H), 8.12 (d, 1H), 7.82 (s, 1H), 7.39 (dd, 1H), 7.33 (d, 1H), 4.07 (s, 3H), 1.59 (s, 9H). LCMS (Method 4 - Column 2): Retention time = 1.66 min, [MH]+ = 282.

[0334] Synthesis of 7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-ol [ka] To a solution of 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-methoxyquinoline (550 mg, 2.0 mmol) in dichloromethane (40 mL) cooled to 0 °C was added boron tribromide (1 M solution in dichloromethane, 39 mL, 39.1 mmol) dropwise. The reaction mixture was warmed to room temperature and stirring was continued for 1 day. The reaction mixture was quenched by the dropwise addition of 1 M aqueous sodium hydroxide (50 mL) and adjusted to pH = 8-9. The product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by column chromatography on silica eluting with 2% methanol in dichloromethane to give 7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-ol (320 mg, 1.2 mmol, 61% yield) as a brown solid. 1H NMR(400MHz,DMSO-d6) δ 10.46(s,1H),8.80(dd,1H),8.41(ddd,1H),8.38(d,1H),7.94(d,1H),7.71(app t,1H),7.35(dd,1H),7.15(d,1H),1.58(s,9H). LCMS (Method 4 - Column 2): Retention time = 1.43 min, [MH]+ = 268.

[0335] 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline (1) [ka] To a solution of 7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-ol (93 mg, 0.26 mmol) in N,N-dimethylformamide (3.0 mL) cooled to 0 °C was added sodium hydride (57-63% w / w oil dispersion, 6 mg, 0.26 mmol). The reaction mixture was warmed to room temperature and stirred for 10 min. tert-butyl (2S)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate (50 mg, 0.17 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was cooled in an ice bath and quenched by the addition of water. The reaction mixture was partitioned between ethyl acetate and water. The product was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated.

[0336] To a solution of the crude intermediate in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (purification method 2) to give 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline (38 mg, 0.99 mmol, 38% yield) as a colorless solid. 1H NMR(400MHz,DMSO-d6) δ 8.84(dd,1H),8.55(d,1H),8.42(ddd,1H),8.11(d,1H),7.82(app t,1H),7.41(dd,1H),7.33(d,1H),4.30-4.15(m,2H),3.87(dddd,1H),3.84 -3.77(m,1H),3.55(ddd,1H),3.02(dd,1H),2.77-2.62(m,3H),1.59(s,9H). LCMS (Method 2): Retention time = 1.51 min, [MH]+=367.

[0337] Synthesis of 5-methoxy-7-(1-methyl-1H-pyrazol-4-yl)quinoline [ka] To a solution of 1-methyl-1H-pyrazole-4-boronic acid (630 mg, 5.0 mmol) and 7-bromo-5-methoxyquinoline (0.8 g, 3.4 mmol) in 1,4-dioxane (10 mL) was added potassium carbonate (1.2 g, 8.4 mmol). Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (246 mg, 0.34 mmol) was added, and the reaction mixture was heated to 70 °C for 16 hours. The reaction mixture was then treated with water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 5-methoxy-7-(1-methyl-1H-pyrazol-4-yl)quinoline (720 mg, 2.6 mmol, 77% yield) as a red oil. 1H NMR (400MHz, DMSO-d6) δ 8.84(dd,1H),8.46-8.38(m,2H),8.11(s,1H),7.77(s,1H),7.40(dd,1H),7.27(d,1H),4.05(s,3H),3.91(s,3H). LCMS (Method 4 - Column 2): Retention time = 1.35 min, [MH]+ = 240.

[0338] Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)quinolin-5-ol [ka] To a solution of 5-methoxy-7-(1-methyl-1H-pyrazol-4-yl)quinoline (720 mg, 3.0 mmol) in dichloromethane (50 mL) cooled to 0° C., boron tribromide (1 M in dichloromethane, 60 mL, 60.1 mmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized by dropwise addition of sodium hydroxide (1 M aqueous solution), and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel column chromatography eluting with 4% methanol in dichloromethane to give 7-(1-methyl-1H-pyrazol-4-yl)quinolin-5-ol (370 mg, 1.6 mmol, 55% yield) as a light brown solid. 1H NMR(400MHz,DMSO-d6) δ 10.54(s,1H),8.80(dd,1H),8.42(dd,1H),8.24(s,1H),7.93(s,1H),7.70-7.59(m,1H),7.36(dd,1H),7.10(d,1H),3.90(s,3H). LCMS (Method 4 - Column 2): Retention time = 1.21 min, [MH]+ = 226.

[0339] 7-(1-methyl-1H-pyrazol-4-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline(2) [ka] To a solution of 7-(1-methyl-1H-pyrazol-4-yl)quinolin-5-ol (32 mg, 0.14 mmol) in N,N-dimethylformamide (2.5 mL) cooled to 0 °C was added sodium hydride (57-63% oil dispersion, 3.4 mg, 0.14 mmol). The reaction mixture was warmed to room temperature, and tert-butyl (2S)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate (50 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled in an ice bath and quenched by the addition of water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the Boc-protected intermediate.

[0340] To a solution of the above Boc-protected intermediate in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 1 h. Volatiles were removed under reduced pressure, and the crude material was purified by prep-HPLC to give 7-(1-methyl-1H-pyrazol-4-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline (30 mg, 0.09 mmol, 64% yield) as a colorless solid. 1H NMR (600MHz, methanol-d4) δ 8.80(dd,1H),8.63(dd,1H),8.19(s,1H),8.02(s,1H),7.75(s,1H),7.45(dd,1H),7.25(s,1H),4.35(dd,1H),4. 32(dd,1H),4.17-4.11(m,1H),4.07(dt,1H),3.98(s,3H),3.83(ddd,1H),3.35-3.32(m,1H),3.11-3.03(m,3H). LCMS (Method 2): Retention time = 1.36 min, [MH]+=325.

[0341] Synthesis of tert-butyl (2S)-2-[(1S)-1-{[7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylate (Isomer 1) and tert-butyl (2S)-2-[(1R)-1-{[7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylate (Isomer 2) [ka] To a suspension of sodium hydride (57-63% oil dispersion, 7 mg, 0.17 mmol) in acetonitrile (1.5 mL) was added 7-(1-tert-butylpyrazol-4-yl)quinolin-5-ol (30 mg, 0.11 mmol) and tert-butyl (2S)-2-(1-methylsulfonyloxyethyl)morpholine-4-carboxylate (52 mg, 0.17 mmol). The reaction mixture was stirred for 1 minute, followed by the addition of a solution of sodium iodide (2 mg, 0.01 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at room temperature for 5 minutes and then heated at 130 °C under microwave irradiation for 2 hours. The cooled reaction mixture was quenched by the slow addition of water, and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give a brown oil. The crude material was purified by silica gel column chromatography eluting with a gradient of 5 to 40% ethyl acetate in heptane to give a mixture of diastereoisomers, which were separated by prep-HPLC to give Isomer 1: tert-butyl (2S)-2-[(1S)-1-[7-(1-tert-butylpyrazol-4-yl)quinolin-5-yl]oxyethyl]morpholine-4-carboxylate (7 mg, 0.01 mmol, 11% yield) as a pale yellow residue and Isomer 2: tert-butyl (2S)-2-[(1R)-1-[7-(1-tert-butylpyrazol-4-yl)quinolin-5-yl]oxyethyl]morpholine-4-carboxylate (11 mg, 0.02 mmol, 19% yield) as a pale yellow residue.

[0342] tert-Butyl (2S)-2-[(1S)-1-{[7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylate 1H NMR (400MHz, methanol-d4) δ 8.77(dd,1H),8.62(d,1H),8.36(d,1H),8.04(d,1H),7.74(app t,1H),7.41(dd,1H),7.36-7.32(m,1H),5.01-4.91(m,1H),4.06(d,1H),3.96(d,1H),3.91-3 .83(m,1H),3.70(ddd,1H),3.57(td,1H),3.08-2.90(m,2H),1.66(s,9H),1.46-1.39(m,12H). LCMS (Method 2): Retention time = 2.73 min, [MH]+ = 481.

[0343] tert-Butyl (2S)-2-[(1R)-1-{[7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylate 1H NMR (400MHz, methanol-d4) δ 8.77(dd,1H),8.60(d,1H),8.37(d,1H),8.04(d,1H),7.75(app t,1H),7.42(dd,1H),7.35(dd,1H),4.92-4.85(m,1H),4.35-4.03(m,1H),3.94(d,1H), 3.90-3.73(m,1H),3.70-3.53(m,2H),3.04(ddd,2H),1.65(s,9H),1.53-1.34(m,12H). LCMS (Method 2): Retention time = 2.87 min, [MH]+ = 481.

[0344] Synthesis of tert-butyl (2S)-2-({[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-5-yl]oxy}methyl)morpholine-4-carboxylate [ka] To a microwave vial was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (10 mg, 0.01 mmol), potassium acetate (84 mg, 0.85 mmol), and bis(pinacolato)diboron (79 mg, 0.31 mmol). The vial was sealed, placed under vacuum, and backfilled with nitrogen. This was repeated two more times, followed by the addition of a degassed solution of tert-butyl (2S)-2-[(7-chloroquinolin-5-yl)oxymethyl]morpholine-4-carboxylate (120 mg, 0.28 mmol) in 1,4-dioxane (4 mL). The reaction mixture was heated at 130 °C under microwave irradiation for 1 hour. The cooled reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 0 to 100% in ethyl acetate (2:24:74 aqueous ammonia:ethanol:ethyl acetate mixture) to afford tert-butyl (2S)-2-({[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-5-yl]oxy}methyl)morpholine-4-carboxylate (131 mg, 0.21 mmol, 74% yield) as a beige residue, although impurities were still present. This intermediate was used in the next step without further purification. 1H NMR (400MHz, chloroform-d) δ 8.93(d,1H),8.61(d,1H),8.24(s,1H),7.41(dd,1H),7.20(s,1H),4.31(dd,1H),4.27-4. 06(m,2H),4.01-3.82(m,3H),3.65(td,1H),3.11-2.86(m,2H),1.49(s,9H),1.38(s,12H). LCMS (Method 2): Retention time = 2.08 min, [(M-82)H]+=389.

[0345] Synthesis of tert-butyl (2S)-2-[({7-[5-(difluoromethyl)thiophen-3-yl]quinolin-5-yl}oxy)methyl]morpholine-4-carboxylate [ka] To a microwave vial was added 4-bromo-2-(difluoromethyl)thiophene (25 mg, 0.12 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (4 mg, 0.01 mmol), and potassium acetate (35 mg, 0.35 mmol). The vial was sealed, evacuated, and backfilled with nitrogen. This was repeated two more times, followed by the addition of a degassed solution of tert-butyl (2S)-2-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-5-yl]oxymethyl]morpholine-4-carboxylate (40 mg, 0.06 mmol) in 1,4-dioxane (1 mL). The reaction was heated under microwave irradiation at 130 °C for 1 hour. The cooled reaction mixture was partitioned between water and ethyl acetate. The product was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give a brown residue. This residue was purified by silica gel column chromatography eluting with a gradient of 5 to 50% ethyl acetate in heptane to give tert-butyl (2S)-2-[({7-[5-(difluoromethyl)thiophen-3-yl]quinolin-5-yl}oxy)methyl]morpholine-4-carboxylate (18 mg, 0.04 mmol, 32% yield) as a light brown residue. This intermediate was used in the next step without further purification. 1H NMR (400MHz, methanol-d4) δ 8.84(d,1H),8.66(d,1H),8.10(s,1H),7.92(d,1H),7.86(s,1H),7.49(dd,1H),7.36(d,1H),7.09(t,1H),4.38(dd, 1H),4.32(dd,1H),4.22-4.11(m,1H),4.01-3.93(m,2H),3.89(d,1H),3.63(td,1H),3.16-2.88(m,2H),1.47(s,9H). LCMS (Method 2): Retention time = 3.03 min, [MH]+=477.

[0346] Synthesis of tert-butyl (2S)-2-[({7-[4-(difluoromethyl)thiophen-2-yl]quinolin-5-yl}oxy)methyl]morpholine-4-carboxylate [ka] To a microwave vial was added 2-bromo-4-(difluoromethyl)thiophene (18 mg, 0.09 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (3 mg, 0.004 mmol), and potassium acetate (25 mg, 0.26 mmol). The vial was sealed, evacuated, and backfilled with nitrogen two more times, after which a degassed solution of tert-butyl (2S)-2-({[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-5-yl]oxy}methyl)morpholine-4-carboxylate (40 mg, 0.09 mmol) in 1,4-dioxane (1 mL) / water (0.1 mL) was added. The reaction was heated at 130 °C under microwave irradiation for 1 h. The cooled reaction mixture was filtered through a pad of Celite®, and the filtrate was partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give a brown residue. This residue was purified by silica gel column chromatography eluting with a gradient of 0 to 50% ethyl acetate in heptane to give tert-butyl (2S)-2-[({7-[4-(difluoromethyl)thiophen-2-yl]quinolin-5-yl}oxy)methyl]morpholine-4-carboxylate (7.0 mg, 0.01 mmol, 12% yield) as a light brown residue, which was carried on to the next step without purification. 1H NMR (400MHz, chloroform-d) δ 8.96-8.88(m,1H),8.56(d,1H),7.96(s,1H),7.58-7.52(m,2H),7.41-7.32(m,1H),7.09(s,1H),6.71(t,1 H),4.32(dd,1H),4.27-4.11(m,2H),4.01-3.88(m,3H),3.70-3.61(m,1H),3.10-2.85(m,2H),1.49(s,9H). LCMS (Method 2): Retention time = 3.10 min, [MH]+=477.

[0347] Synthesis of tert-butyl (2S)-2-({[7-(5-tert-butylthiophen-2-yl)quinolin-5-yl]oxy}methyl)morpholine-4-carboxylate [ka] To a microwave vial was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (3 mg, 0.004 mmol), 2-bromo-5-tert-butylthiophene (19 mg, 0.09 mmol), and potassium acetate (25 mg, 0.26 mmol). The vial was sealed, evacuated, and backfilled with nitrogen two more times, after which a degassed solution of tert-butyl (2S)-2-({[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-5-yl]oxy}methyl)morpholine-4-carboxylate (40 mg, 0.09 mmol) in 1,4-dioxane (1 mL) / water (0.1 mL) was added. The reaction was heated under microwave irradiation at 130 °C for 45 min. The cooled reaction mixture was filtered through a pad of Celite®, and the filtrate was partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give a brown residue. The crude material was purified by silica gel column chromatography eluting with a gradient of 0 to 50% ethyl acetate in heptane to give the intermediate tert-butyl (2S)-2-({[7-(5-tert-butylthiophen-2-yl)quinolin-5-yl]oxy}methyl)morpholine-4-carboxylate (10 mg, 0.02 mmol, 17% yield) as a light brown residue. This intermediate was used in the next step without further purification. 1H NMR (400MHz, chloroform-d) δ 8.87(dd,1H),8.52(d,1H),7.93(s,1H),7.35-7.29(m,2H),7.08(d,1H),6.86(d,1H),4.31(dd,1H) ,4.26-4.16(m,2H),4.02-3.86(m,3H),3.65(td,1H),3.12-2.87(m,2H),1.49(s,9H),1.43(s,9H). LCMS (Method 2): Retention time = 3.49 min, [MH]+=483.

[0348] Synthesis of 6-(5-{[(2S)-morpholin-2-yl]methoxy}quinolin-7-yl)-2,3-dihydro-1H-pyrrolidin-1-one (3) [ka] To a solution of tert-butyl (2S)-2-[[7-(7-oxo-5,6-dihydropyrrolidin-2-yl)quinolin-5-yl]oxymethyl]morpholine-4-carboxylate (50 mg, 0.11 mmol) in dichloromethane (0.9 mL) was added triethylsilane (50 μL, 0.31 mmol) and trifluoroacetic acid (0.1 mL, 1.3 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane, and the product was extracted with 1 M aqueous hydrochloric acid. The combined aqueous layers were neutralized with sodium hydroxide (10 mL of 2 M aqueous solution), and the product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 6-(5-{[(2S)-morpholin-2-yl]methoxy}quinolin-7-yl)-2,3-dihydro-1H-pyrrolidin-1-one (17 mg, 0.05 mmol, 43% yield) as a white solid. 1H NMR (600MHz, methanol-d4) δ 8.78(dd,1H),8.61(dd,1H),7.85(s,1H),7.77(s,1H),7.44(dd,1H),7.25(d,1H),7.18(d,1H),4.43(t,2H),4.28 (dd,1H),4.24(dd,1H),4.04-3.99(m,1H),3.98-3.92(m,1H),3.73(td,1H),3.15-3.07(m,3H),2.93-2.80(m,3H). LCMS (Method 2): Retention time = 1.34 min, [MH]+=364.

[0349] Synthesis of 7-(2,3-dihydro-1H-pyrrolidin-6-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline (4) [ka] To a solution of tert-butyl (2S)-2-({[7-(1-oxo-2,3-dihydro-1H-pyrrolidin-6-yl)quinolin-5-yl]oxy}methyl)morpholine-4-carboxylate (50 mg, 0.11 mmol) in methanol (1 mL) was added sodium borohydride (15 mg, 0.40 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of water, and the product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude alcohol intermediate. To a solution of this crude intermediate in dichloromethane (2 mL), triethylsilane (0.1 mL, 0.63 mmol) and trifluoroacetic acid (0.1 mL, 1.3 mmol) were added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between 1 M aqueous hydrochloric acid and dichloromethane. The aqueous layer was made basic with sodium hydroxide (2 M aqueous solution), and the product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 7-(2,3-dihydro-1H-pyrrolidin-6-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline (16 mg, 0.04 mmol, 38% yield) as a pale yellow oil. 1H NMR (400MHz, methanol-d4) δ 8.71(dd,1H),8.55(ddd,1H),7.64(app t,1H),7.35(dd,1H),7.22(d,1H),7.18(d,1H),6.27-6.25(m,1H),4.25(dd,1H),4.20(dd,1H),4.04 -3.97(m,3H),3.96-3.92(m,1H),3.72(ddd,1H),3.09(dd,1H),2.90-2.82(m,5H),2.57-2.45(m,2H). LCMS (Method 2): Retention time = 1.43 min, [MH]+=350.

[0350] Synthesis of tert-butyl (2S)-2-[(1R)-1-{[7-(1H-pyrrol-3-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylate [ka] Pyrrole-3-boronic acid, pinacol ester (132 mg, 0.69 mmol), tert-butyl (2S)-2-[(1R)-1-(7-bromoquinolin-5-yl)oxyethyl]morpholine-4-carboxylate (250 mg, 0.57 mmol), potassium phosphate (364 mg, 1.7 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (42 mg, 0.06 mmol) were weighed into a 5 mL thick-walled glass vial. Degassed 1,4-dioxane (2.8 mL) and water (0.7 mL) were added, and the reaction mixture was heated at 100 °C for 1 h. The cooled reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 0 to 100% ethyl acetate in heptane to give tert-butyl (2S)-2-[(1R)-1-{[7-(1H-pyrrol-3-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylate (180 mg, 0.35 mmol, 61% yield) as a beige solid. LCMS (Method 2): Retention time = 2.17 min, [MH]+ = 424.

[0351] Synthesis of rel-(1R,2S,5R)-2-(benzyloxy)-6-oxabicyclo[3.1.0]hexane and rel-(1R,2R,5R)-2-(benzyloxy)-6-oxabicyclo[3.1.0]hexane [ka] To a solution of cyclopent-2-en-1-yloxymethylbenzene (8.5 g, 48.8 mmol) in dichloromethane (50 mL) cooled to 0°C, 3-chloroperoxybenzoic acid (16.8 g, 97.6 mmol) was added portionwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, and the organic layer was washed successively with 10% sodium sulfate solution, saturated aqueous sodium bicarbonate solution, and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 6-8% ethyl acetate in hexane to give rel-(1R,2R,5R)-2-phenylmethoxy-6-oxabicyclo[3.1.0]hexane (3.8 g, 20.0 mmol, 41% yield) as a colorless liquid and rel-(1R,2S,5R)-2-phenylmethoxy-6-oxabicyclo[3.1.0]hexane (1.5 g, 7.9 mmol, 16% yield) as a pale yellow liquid.

[0352] rel-(1R,2R,5R)-2-phenylmethoxy-6-oxabicyclo[3.1.0]hexane: 1H NMR (400 MHz, chloroform-d) δ 7.40-7.29 (m, 4H), 7.32-7.24 (m, 1H), 4.60 (d, 1H), 4.52 (d, 1H), 4.10 (d, 1H), 3.55 (d, 1H), 3.49 (d, 1H), 1.98 (dd, 1H), 1.92-1.72 (m, 2H), 1.58-1.46 (m, 1H).

[0353] rel-(1R,2S,5R)-2-phenylmethoxy-6-oxabicyclo[3.1.0]hexane: 1H NMR (400 MHz, chloroform-d) δ 7.42-7.27 (m, 5H), 4.64 (s, 2H), 4.05 (t, 1H), 3.50 (d, 1H), 3.43 (d, 1H), 2.10 (dd, 1H), 1.91-1.79 (m, 1H), 1.67-1.55 (m, 1H), 1.52-1.40 (m, 1H).

[0354] Synthesis of rel-(1R,2S,5R)-2-azido-5-(benzyloxy)cyclopentan-1-ol [ka] To a solution of rel-(1R,2R,5R)-2-phenylmethoxy-6-oxabicyclo[3.1.0]hexane (3.8 g, 20.0 mmol) and ammonium chloride (2.5 g, 45.9 mmol) in methanol (8 mL):water (1 mL) was added sodium azide (6.5 g, 99.9 mmol), and the reaction mixture was heated to 80 °C for 16 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and dichloromethane. The aqueous layer was further extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give rel-(1R,2S,5R)-2-azido-5-phenylmethoxycyclopentan-1-ol (4.2 g, 18.0 mmol, 90% yield) as a brown liquid. 1H NMR (400 MHz, chloroform-d) δ 7.42-7.27 (m, 5H), 4.59 (d, 1H), 4.53 (d, 1H), 3.97 (t, 1H), 3.84-3.70 (m, 1H), 3.69-3.56 (m, 1H), 2.50 (s, 1H), 2.09-1.93 (m, 2H), 1.85-1.68 (m, 2H).

[0355] Synthesis of rel-(1R,2S,5S)-2-azido-5-(benzyloxy)cyclopentan-1-ol [ka] To a solution of rel-(1R,2R,5R)-2-(benzyloxy)-6-oxabicyclo[3.1.0]hexane (2.0 g, 10.5 mmol) in a mixture of methanol (8 mL) and water (1 mL) was added sodium azide (3.4 g, 52.6 mmol) and ammonium chloride (1.3 g, 24.2 mmol), and the reaction mixture was heated to 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude material was partitioned between water and dichloromethane, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give rel-(1R,2S,5S)-2-azido-5-(benzyloxy)cyclopentan-1-ol (2.4 g, 9.3 mmol, 88% yield) as a brown liquid. 1H NMR (400 MHz, chloroform-d) δ 7.41-7.28 (m, 5H), 4.62 (d, 1H), 4.49 (d, 1H), 4.01-3.92 (m, 1H), 3.92-3.79 (m, 2H), 2.74 (br s, 1H), 2.23-2.08 (m, 1H), 2.08-1.92 (m, 1H), 1.87-1.74 (m, 1H), 1.58-1.45 (m, 1H).

[0356] Synthesis of rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentyl 4-nitrobenzoate [ka] To a solution of rel-(1R,2S,5R)-2-azido-5-phenylmethoxycyclopentan-1-ol (4.2 g, 18.0 mmol) in tetrahydrofuran (5 mL) was added 4-nitrobenzoic acid (0.54 g, 3.2 mmol) and triphenylphosphine (0.84 g, 3.2 mmol). The reaction mixture was cooled to 0 °C, and diisopropyl azodicarboxylate (0.69 g, 3.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated aqueous ammonium chloride, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentyl 4-nitrobenzoate (2.4 g, 6.3 mmol, 35% yield) as a brown oil. 1H NMR (400 MHz, chloroform-d) δ 8.31 (d, 2H), 8.18 (d, 2H), 7.38-7.26 (m, 5H), 5.37 (t, 1H), 4.65 (d, 1H), 4.60 (d, 1H), 4.05 (dd, 1H), 3.98-3.89 (m, 1H), 2.20-1.94 (m, 4H).

[0357] Synthesis of rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentyl 4-nitrobenzoate [ka] To a solution of triphenylphosphine (5.4 g, 20.5 mmol) and 4-nitrobenzoic acid (3.6 g, 21.2 mmol) in tetrahydrofuran (70 mL) was added dropwise a solution of rel-(1R,2S,5S)-2-azido-5-(benzyloxy)cyclopentan-1-ol (3.3 g, 14.2 mmol) in tetrahydrofuran (20 mL), and the reaction mixture was stirred at room temperature for 15 minutes. After the reaction mixture was cooled to 0° C., diisopropyl azodicarboxylate (4.6 g, 22.6 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 5–15% ethyl acetate in hexane to give rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentyl 4-nitrobenzoate (3.0 g, 7.9 mmol, 56% yield) as a yellow liquid. 1H NMR (400 MHz, chloroform-d) δ 8.35–8.27 (m, 2H), 8.22 (d, 2H), 7.41–7.28 (m, 5H), 5.39 (t, 1H), 4.62 (s, 2H), 4.22–4.08 (m, 2H), 2.37–2.11 (m, 2H), 2.02–1.86 (m, 1H), 1.86–1.69 (m, 1H).

[0358] Synthesis of rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentan-1-ol [ka] To a solution of rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentyl 4-nitrobenzoate (2.4 g, 6.3 mmol) in methanol (25 mL) was added potassium carbonate (2.6 g, 18.8 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the crude material was diluted with saturated aqueous ammonium chloride. The product was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography on neutral alumina eluting with 40% ethyl acetate in hexane to give rel-(1S,2S,5R)-2-azido-5-phenylmethoxycyclopentan-1-ol (1.4 g, 6.0 mmol, 96% yield) as a brown liquid. 1H NMR (400 MHz, chloroform-d) δ 7.44-7.28 (m, 5H), 4.60 (d, 1H), 4.54 (d, 1H), 3.99 (t, 1H), 3.84-3.71 (m, 1H), 3.71-3.57 (m, 1H), 2.12-1.95 (m, 2H), 1.85-1.67 (m, 2H).

[0359] Synthesis of rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentan-1-ol [ka] To a stirred solution of rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentyl 4-nitrobenzoate (3.0 g, 7.9 mmol) in methanol (30 mL) was added potassium carbonate (3.3 g, 23.5 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 0 to 30% ethyl acetate in hexane to give rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentan-1-ol (1.4 g, 5.8 mmol, 74% yield) as a pale yellow liquid. 1H NMR (400 MHz, chloroform-d) δ 7.38-7.27 (m, 5H), 4.55 (s, 2H), 4.10 (t, 1H), 4.06-3.99 (m, 1H), 3.92-3.83 (m, 1H), 2.26-2.04 (m, 2H), 1.88-1.76 (m, 1H), 1.73-1.62 (m, 1H).

[0360] Synthesis of methyl 2-{[rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentyl]oxy}acetate [ka] To a solution of rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentan-1-ol (1.4 g, 6.0 mmol) in N,N-dimethylformamide (45 mL) cooled to 0 °C was added sodium hydride (60% dispersion in mineral oil, 1.9 g, 48.0 mmol). After stirring for 10 minutes, methyl 2-bromoacetate (4.6 g, 30.0 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by the slow addition of water, and the product was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 0–20% ethyl acetate in hexane to give methyl 2-{[rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentyl]oxy}acetate (1.0 g, 3.3 mmol, 55% yield) as a yellow liquid. 1H NMR (400 MHz, chloroform-d) δ 7.39–7.27 (m, 5H), 4.55 (d, 1H), 4.51 (d, 1H), 4.28 (d, 1H), 4.22 (d, 1H), 3.98–3.89 (m, 1H), 3.84–3.76 (m, 2H), 3.73 (s, 3H), 2.09–1.92 (m, 2H), 1.86–1.72 (m, 2H). LCMS (Method 4 - Column 1): Retention time = 2.51 min, [MH]+ = 306.

[0361] Synthesis of methyl 2-{[rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentyl]oxy}acetate [ka] To a solution of rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentan-1-ol (1.4 g, 6.0 mmol) in N,N-dimethylformamide (50 mL) cooled to 0 °C, sodium hydride (60% dispersion in mineral oil, 1.9 g, 48.0 mmol) was added portionwise. After stirring for 15 minutes, methyl 2-bromoacetate (4.6 g, 30.0 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by the slow addition of ice-cold water, and the product was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 0–20% ethyl acetate in hexane to give methyl 2-{[rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentyl]oxy}acetate (1.5 g, 4.9 mmol, 82% yield) as a pale yellow liquid. 1H NMR (400MHz, chloroform-d) δ 7.40-7.27(m,5H),4.55(s,2H),4.32(d,1H),4.24(d,1H),4.13-4.04(m,1H),4.00-3.90(m,2 H),3.74(s,3H),2.25-2.13(m,1H),2.08-1.95(m,1H),1.86-1.73(m,1H),1.69-1.60(m,1H). LCMS (Method 4 - Column 1): Retention time = 2.56 min, [MH]+ = 306.

[0362] Synthesis of rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazin-3-one [ka] To a solution of methyl 2-{[rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentyl]oxy}acetate (0.7 g, 2.3 mmol) in ethyl acetate (20 mL) was added palladium on carbon (10% w / w, 0.3 g, 0.28 mmol), and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through a Celite® bed, and the filtrate was concentrated under reduced pressure. The crude material was triturated with hexane (3 mL) to give rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazin-3-one (0.6 g, 2.4 mmol, 106% yield) as a light brown solid. 1H NMR(400MHz,DMSO-d6) δ 8.38(s,1H),7.42-7.22(m,5H),4.58-4.45(m,2H),4.13(s,2H),3.95-3.87(m,1 H),3.72-3.52(m,2H),2.22-2.03(m,1H),1.83-1.58(m,2H),1.58-1.35(m,1H). LCMS (Method 4 - Column 9): Retention time = 1.67 min, [MH]+ = 248.

[0363] Synthesis of rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazin-3-one [ka] To a solution of methyl 2-{[rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentyl]oxy}acetate (1.5 g, 4.9 mmol) in ethyl acetate (50 mL) was added palladium on carbon (10% w / w, 0.78 g, 0.73 mmol), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through a Celite® plug and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude material was triturated with n-hexane and dried under vacuum to give rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazin-3-one (1.1 g, 4.4 mmol, 89% yield) as a brown solid. 1H NMR (400MHz, chloroform-d) δ 7.42-7.26(m,5H),6.39(s,1H),4.54(s,2H),4.18(d,1H),4.08(d,1H),4.01(d,1H),3.98 -3.93(m,1H),3.82-3.73(m,1H),2.32-2.19(m,1H),2.18-2.08(m,1H),1.82-1.62(m,2H). LCMS (Method 4 - Column 1): Retention time = 1.84 min, [MH]+ = 248.

[0364] Synthesis of rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine [ka] To a solution of lithium aluminum hydride (1 M in tetrahydrofuran, 6.0 mL, 6.0 mmol) in tetrahydrofuran (30 mL) cooled to 0 °C was added dropwise a solution of rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazin-3-one (0.6 g, 2.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to room temperature, and stirring was continued for 16 h. The reaction mixture was quenched by the slow addition of water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by trituration with hexane (5 mL) to give rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine (470 mg, 2.0 mmol, 83% yield) as a light brown liquid. 1H NMR(400MHz,DMSO-d6) δ 7.37-7.19(m,5H),4.56-4.43(m,2H),3.84-3.72(m,1H),3.50-3.37(m,1H),3.15-3.06(m,1H),2.74-2.6 1(m,2H),2.47-2.31(m,1H),2.07-1.89(m,1H),1.71-1.57(m,1H),1.57-1.43(m,1H),1.43-1.31(m,2H). LCMS (Method 9): Retention time = 2.25 min, [MH]+=234.

[0365] Synthesis of rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine [ka] To a solution of lithium aluminum hydride (1 M in tetrahydrofuran, 8.9 mL, 8.9 mmol) in tetrahydrofuran (50 mL) cooled to 0 °C under nitrogen, a solution of rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazin-3-one (1.1 g, 4.5 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the slow addition of water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine (1.0 g, 3.6 mmol, 82% yield) as a pale brown liquid. 1H NMR (400MHz, chloroform-d) δ 7.40-7.26(m,5H),4.58-4.49(m,2H),3.97-3.88(m,1H),3.88-3.82(m,1H),3.82-3.73(m,1H),3.5 4(ddd,1H),3.42-3.33(m,1H),3.05(ddd,1H),2.67(dt,1H),2.30-2.18(m,1H),1.96-1.60(m,4H). LCMS (Method 4 - Column 1): Retention time = 1.41 min, [MH]+ = 234.

[0366] Synthesis of tert-butyl rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate [ka] To a solution of rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine (470 mg, 2.0 mmol) and diisopropylethylamine (780 mg, 6.0 mmol) in dichloromethane (10 mL) cooled to 0 °C, di-tert-butyl dicarbonate (1.3 g, 6.0 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between water and dichloromethane. The aqueous layer was further extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give tert-butyl rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate (370 mg, 1.1 mmol, 55% yield) as a pale yellow liquid. 1H NMR(400MHz,DMSO-d6) δ 7.39-7.19(m,5H),4.57-4.43(m,2H),3.97-3.86(m,1H),3.84-3.75(m,1H),3.70(d,1H),3.52(td,1H),3.27(d d,1H),2.90-2.74(m,2H),2.28(dd,1H),2.07-1.93(m,1H),1.89-1.75(m,1H),1.64-1.47(m,1H),1.38(s,9H). LCMS (Method 4 - Column 1): Retention time = 2.70 min, [MH]+ = 334.

[0367] Synthesis of tert-butyl rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate [ka] To a solution of rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine (1.0 g, 4.3 mmol) in dichloromethane (25 mL) cooled to 0 °C, diisopropylethylamine (1.7 g, 12.9 mmol) was added, and the reaction mixture was stirred for 15 minutes, followed by the addition of di-tert-butyl dicarbonate (2.8 g, 12.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was partitioned between water and dichloromethane. The aqueous layer was further extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of 0–20% ethyl acetate in hexane to give tert-butyl rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate (1.0 g, 3.0 mmol, 70% yield) as a pale yellow liquid. 1H NMR (400MHz, chloroform-d) δ 7.42-7.27(m,5H),4.58-4.44(m,2H),4.44-4.11(m,1H),3.90-3.57(m,4H),3.53-3.35(m,1 H),3.17-2.94(m,1H),2.29-2.11(m,1H),2.02-1.81(m,1H),1.81-1.60(m,2H),1.47(s,9H). LCMS (Method 4 - Column 1): Retention time = 2.44 min, [(M-56)H]+ = 278.

[0368] Synthesis of tert-butyl rel-(4aS,7R,7aS)-7-hydroxy-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate [ka] To a solution of tert-butyl rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate (370 mg, 1.1 mmol) in methanol (15 mL) was added palladium hydroxide on carbon (20% supported wet, 0.2 g, 0.14 mmol), and the reaction was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was filtered through a pad of Celite®, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 50-60% ethyl acetate in hexane to give tert-butyl rel-(4aS,7R,7aS)-7-hydroxy-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate (240 mg, 0.99 mmol, 89% yield) as a white semisolid. 1H NMR(400MHz,DMSO-d6) δ 5.02(s,1H),3.89(ddd,1H),3.85-3.74(m,1H),3.67(d,1H),3.45(td,1H),3.02(dd,1H),2. 84-2.70(m,2H),2.29-2.14(m,1H),2.03-1.85(m,1H),1.87-1....

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, 【Chemistry 1】 During the ceremony, Z is CR １ or N, Y is CH or N, X is CR ２ or N, One or less of X, Y, or Z is N. During the ceremony, R １ is selected from the group consisting of hydrogen, C １～６ alkyl, C １～６ fluoroalkyl, C ２～６ alkenyl, C ２～６ fluoroalkenyl, C ２～６ alkynyl, C ２～６ fluoroalkynyl, C ３～６ cycloalkyl, halo, -O-C １～６ alkyl, -O-C １～６ fluoroalkyl, -O-C ２～６ alkenyl, -O-C ２～６ fluoroalkenyl, -O-C ２～６ alkynyl, -O-C ２～６ fluoroalkynyl and cyano R ２ is hydrogen, C １～６ Alkyl, C １～６ Fluoroalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl, C ２～６ Fluoroalkynyl, Halo, -O-C １～６ Alkyl, -O-C １～６ Fluoroalkyl, -O-C ２～６ Alkenyl, -O-C ２～６ Fluoroalkenyl, -O-C ２～６ Alkinyl, -O-C ２～６ Selected from the group consisting of fluoroalkynyls and cyanos, R ４ R is a five-membered cycloalkene or a five-membered heteroaryl, each of which may condense to form a 5:6 or 5:5 aromatic or heteroaromatic biring, and each R ４ It may be substituted, m is either 0 or 1. R ６ H, C １～６ Alkyl, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyls, R ７ and R ７ ' is independently H, fluoro, C １～６ Alkyl, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyl, or R ７ and R ７ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R ８ and R ９ H and C are independent of each other. １～６ Alkyl, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyl, or R ８ and R ９ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R １０ and R １１ H and C are independent of each other. １～６ Alkyl, fluoro, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyl, or R １０ and R １１ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R １２ and R １３ H and C are independent of each other. １～６ Alkyl, fluoro, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyl, or R １２ and R １３ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R １５ and R １６ are, independently, H, C １～６ alkyl, C １～６ fluoroalkyl, C ３～６ cycloalkyl, C ３～６ fluorocycloalkyl, C ２～６ alkenyl, C ２～６ fluoroalkenyl, C ２～６ alkynyl and C ２～６ fluoroalkynyl, or R １５ and R １６ together form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocyclic ring, or R ７ Or R ７ ' one of and R ８ Or R ９ One of them together forms a 5 or 6-membered cycloalkyl ring, a 5 or 6-membered fluorocycloalkyl ring, or a 5 or 6-membered oxygen-containing heterocyclic ring. R ７ Or R ７ ' one of and R ６ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R ６ and R ８ Or R ９ One of them together forms a 5 or 6-membered cycloalkyl ring, a 5 or 6-membered fluorocycloalkyl ring, or a 5 or 6-membered oxygen-containing heterocyclic ring. R ６ and R １０ Or R １１ One of them combines to form a 4-6 member heterocyclyl ring or a 4-6 member fluoroheterocyclyl ring. R ８ Or R ９ one of the and R １２ Or R １３ One of them combines to form a 4-7 member heterocyclyl ring or a 4-7 member fluoroheterocyclyl ring. R ８ Or R ９ one of the and R １５ Or R １６ One of them combines to form a 5-7 member heterocyclyl ring or a 5-7 member fluoroheterocyclyl ring. R １０ Or R １１ one of the and R １２ Or R １３ One of them combines to form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 5 or 6 membered oxygen-containing heterocyclic ring. R １０ Or R １１ one of the and R １５ Or R １６ One of them together forms a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered fluorocycloalkyl ring. R ８ Or R ９ one of the and R １０ Or R １１ One of them together forms a 5-7 member heterocyclyl ring or a 5-7 member fluoroheterocyclyl ring, and / or R １２ Or R １３ one of the and R １５ Or R １６ One of these groups together forms a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 5 or 6 membered oxygen-containing heterocyclic ring. A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

2. A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, 【Chemistry 2】 During the ceremony, Z is CR １ or N, Y is CH or N, X is CR ２ or N, One or less of X, Y, or Z is N. During the ceremony, R １ is hydrogen, C １～６ Alkyl, C １～６ Fluoroalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl, C ２～６ Fluoroalkynyl, C ３～６ Cycloalkyl, halo, -O-C １～６ Alkyl, -O-C １～６ Fluoroalkyl, -O-C ２～６ Alkenyl, -O-C ２～６ Fluoroalkenyl, -O-C ２～６ Alkinyl, -O-C ２～６ Selected from the group consisting of fluoroalkynyls and cyanos, R ２ is hydrogen, C １～６ Alkyl, C １～６ Fluoroalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl, C ２～６ Fluoroalkynyl, Halo, -O-C １～６ Alkyl, -O-C １～６ Fluoroalkyl, -O-C ２～６ Alkenyl, -O-C ２～６ Fluoroalkenyl, -O-C ２～６ Alkinyl, -O-C ２～６ Selected from the group consisting of fluoroalkynyls and cyanos, R ４ R is a five-membered cycloalkene or a five-membered heteroaryl, each of which may condense to form a 5:6 or 5:5 aromatic or heteroaromatic biring, and each R ４ is one or more R ５ It may be replaced by each R ５ Independently, -R １４ , -R １４ -Cycloalkyl-R １９ , -R １４ -Cyclofluoroalkyl-R １９ , -R １４ -Heterocyclyl-R １９ , -R １４ -Fluoroheterocyryl-R １９ , -R １４ - Heteroaryl - R １９ , -R １４ -Aryl-R １９ , -cycloalkyl-R １９ , -cyclofluoroalkyl-R １９ ,-heterocyclyl-R １９ ,-Fluoroheterocyryl-R １９ -heteroaryl-R １９ -aryl-R １９ , -R １４ -O-R １９ Cl, F, cyano, -OR １９ , -SR １９ , -SOR １９ , -SO ２ R １９ , -N(R １９ ) ２ , -N(R １９ ) COR １９ , -CON(R １９ ) ２ , -N(R １９ ) CON(R １９ ) ２ , -N(R １９ ) COOR １９ , -OCON(R １９ ) ２ , -N(R １９ ) SO ２ R １９ , -SO ２ N(R) １９ ) ２ Selected from the group consisting of , and = O, each R １４ Independently, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Fluoroalkyl, C ２～６ Fluoroalkenyl, C ２～６ Fluoroalkynyl and C ３～６ Selected from the group consisting of cycloalkyls, each R １９ H and C are independent of each other. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Fluoroalkyl, C ２～６ Fluoroalkenyl, C ２～６ Fluoroalkynyl and C ３～６ Selected from the group consisting of cycloalkyl groups, m is either 0 or 1. R ６ H, C １～６ Alkyl, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyls, R ７ and R ７ ' is independently H, fluoro, C １～６ Alkyl, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyl, or R ７ and R ７ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R ８ and R ９ H and C are independent of each other. １～６ Alkyl, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyl, or R ８ and R ９ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R １０ and R １１ H and C are independent of each other. １～６ Alkyl, fluoro, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyl, or R １０ and R １１ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R １２ and R １３ H and C are independent of each other. １～６ Alkyl, fluoro, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyl, or R １２ and R １３ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R １５ and R １６ H and C are independent of each other. １～６ Alkyl, C １～６ Fluoroalkyl, C ３～６ Cycloalkyl, C ３～６ Fluorocycloalkyl, C ２～６ Alkenil, C ２～６ Fluoroalkenyl, C ２～６ Alkinyl and C ２～６ Selected from the group consisting of fluoroalkynyl, or R １５ and R １６ They combine to form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring, or R ７ Or R ７ ' one of and R ８ Or R ９ One of them together forms a 5 or 6-membered cycloalkyl ring, a 5 or 6-membered fluorocycloalkyl ring, or a 5 or 6-membered oxygen-containing heterocyclic ring. R ７ Or R ７ ' one of and R ６ These together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring. R ６ and R ８ Or R ９ One of them together forms a 5 or 6-membered cycloalkyl ring, a 5 or 6-membered fluorocycloalkyl ring, or a 5 or 6-membered oxygen-containing heterocyclic ring. R ６ and R １０ Or R １１ One of them combines to form a 4-6 member heterocyclyl ring or a 4-6 member fluoroheterocyclyl ring. R ８ Or R ９ one of the and R １２ Or R １３ One of them combines to form a 4-7 member heterocyclyl ring or a 4-7 member fluoroheterocyclyl ring. R ８ Or R ９ one of the and R １５ Or R １６ One of them combines to form a 5-7 member heterocyclyl ring or a 5-7 member fluoroheterocyclyl ring. R １０ Or R １１ one of the and R １２ Or R １３ One of them combines to form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 5 or 6 membered oxygen-containing heterocyclic ring. R １０ Or R １１ one of the and R １５ Or R １６ One of them together forms a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered fluorocycloalkyl ring. R ８ Or R ９ one of the and R １０ Or R １１ One of them together forms a 5-7 member heterocyclyl ring or a 5-7 member fluoroheterocyclyl ring, and / or R １２ Or R １３ one of the and R １５ Or R １６ One of these groups together forms a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 5 or 6 membered oxygen-containing heterocyclic ring. A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

3. The compound is a compound of formula (II). 【Transformation 3】 The compound according to claim 1 or claim 2.

4. The compound is a compound of formula (III). 【Chemistry 4】 The compound according to claim 1 or claim 2.

5. Y is N, and Z is CR １ And X is CR ２ The compound according to claim 1 or claim 2.

6. Z is N, Y is CH, and X is CR ２ The compound according to claim 1 or claim 2.

7. X is CR ２ And Y is CH, and Z is CR １ The compound according to claim 1 or claim 2.

8. R ４ The group is selected from cyclopentenyl, pyrrolyl, 2,3-dihydropyrrolidinyl, pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiophenyl, 1,2-oxazolyl, 1,3-thiazolyl, and 1,2-thiazolyl, and the R ４ The base is one or more R ５ It may be replaced by each R ５ Independently, -R １４ , -R １４ -Cycloalkyl-R １９ , -R １４ -Cyclofluoroalkyl-R １９ , -R １４ -Heterocyclyl-R １９ , -R １４ -Fluoroheterocyryl-R １９ , -R １４ - Heteroaryl - R １９ , -R １４ -Aryl-R １９ , -cycloalkyl-R １９ , -cyclofluoroalkyl-R １９ ,-heterocyclyl-R １９ ,-Fluoroheterocyryl-R １９ -heteroaryl-R １９ -aryl-R １９ , -R １４ -O-R １９ Cl, F, cyano, -OR １９ , -SR １９ , -SOR １９ , -SO ２ R １９ , -N(R １９ ) ２ , -N(R １９ ) COR １９ , -CON(R １９ ) ２ , -N(R １９ ) CON(R １９ ) ２ , -N(R １９ ) COOR １９ , -OCON(R １９ ) ２ , -N(R １９ ) SO ２ R １９ , -SO ２ N(R) １９ ) ２ Selected from the group consisting of , and = O, each R １４ Independently, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Fluoroalkyl, C ２～６ Fluoroalkenyl, C ２～６ Fluoroalkynyl and C ３～６ Selected from the group consisting of cycloalkyls, each R １９ H and C are independent of each other. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Fluoroalkyl, C ２～６ Fluoroalkenyl, C ２～６ Fluoroalkynyl and C ３～６ A compound according to claim 1 or claim 2, selected from the group consisting of cycloalkyls.

9. R ４ teeth, 【Transformation 5】 Selected from the group consisting of, u is an integer from 0 to the maximum number of substituent positions on the group, Each R ５ Independently, -R １４ , -R １４ -Cycloalkyl-R １９ , -R １４ -Cyclofluoroalkyl-R １９ , -R １４ -Heterocyclyl-R １９ , -R １４ -Fluoroheterocyryl-R １９ , -R １４ - Heteroaryl - R １９ , -R １４ -Aryl-R １９ , -cycloalkyl-R １９ , -cyclofluoroalkyl-R １９ ,-heterocyclyl-R １９ ,-Fluoroheterocyryl-R １９ -heteroaryl-R １９ -aryl-R １９ , -R １４ -O-R １９ Cl, F, cyano, -OR １９ , -SR １９ , -SOR １９ , -SO ２ R １９ , -N(R １９ ) ２ , -N(R １９ ) COR １９ , -CON(R １９ ) ２ , -N(R １９ ) CON(R １９ ) ２ , -N(R １９ ) COOR １９ , -OCON(R １９ ) ２ , -N(R １９ ) SO ２ R １９ , -SO ２ N(R) １９ ) ２ Selected from the group consisting of , and = O, each R １４ Independently, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Fluoroalkyl, C ２～６ Fluoroalkenyl, C ２～６ Fluoroalkynyl and C ３～６ Selected from the group consisting of cycloalkyls, each R １９ H and C are independent of each other. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Fluoroalkyl, C ２～６ Fluoroalkenyl, C ２～６ Fluoroalkynyl and C ３～６ Selected from the group consisting of cycloalkyl groups The compound according to claim 1 or claim 2.

10. Each R ５ Independently, -R １４ , -R １４ -Cycloalkyl-R １９ , -R １４ -Cyclofluoroalkyl-R １９ , -R １４ -Heterocyclyl-R １９ , -R １４ -Fluoroheterocyryl-R １９ , -R １４ - Heteroaryl - R １９ , -R １４ -Aryl-R １９ , -cycloalkyl-R １９ , -cyclofluoroalkyl-R １９ ,-heterocyclyl-R １９ ,-Fluoroheterocyryl-R １９ -heteroaryl-R １９ -aryl-R １９ , -R １４ -O-R １９ Cl, F, cyano, -OR １９ , -SR １９ Selected from the group consisting of and = O, each R １４ Independently, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Fluoroalkyl, C ２～６ Fluoroalkenyl and C ２～６ Selected from the group consisting of fluoroalkynyls, each R １９ H and C are independent of each other. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Fluoroalkyl, C ２～６ Fluoroalkenyl and C ２～６ The compound according to claim 8, selected from the group consisting of fluoroalkynyls.

11. R ８ and R ９ H and C are independent of each other. １～６ Alkyl and C １～６ A compound according to claim 1 or claim 2, selected from the group consisting of fluoroalkyls.

12. R １０ and R １１ H and C are independent of each other. １～６ Alkyl, fluoro, and C １～６ Selected from the group consisting of fluoroalkyls, or R １０ and R １１ The compound according to claim 1 or claim 2, wherein the compounds together form a 3-6 membered cycloalkyl ring, a 3-6 membered fluorocycloalkyl ring, or a 4-6 membered oxygen-containing heterocyclic ring.

13. R １２ and R １３ H and C are independent of each other. １～６ Alkyl, fluoro, and C １～６ A compound according to claim 1 or claim 2, selected from the group consisting of fluoroalkyls.

14. The compound according to claim 1 or claim 2, wherein m is 0.

15. In the compound of formula (I) above, 【Transformation 6】 teeth, 【Transformation 7】 A compound according to claim 1 or claim 2, selected from the group consisting of the following.

16. The compound of formula (I) is Table 1(1) 【Table 1(2)】 【Table 1(3)】 A compound according to claim 1, selected from the group consisting of the following.

17. A pharmaceutical composition comprising an effective amount of the compound described in claim 1 or claim 2, or a pharmaceutically acceptable salt or prodrug thereof, further comprising a pharmaceutically acceptable carrier, diluent and / or excipient.

18. Use of the compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a pharmaceutical for the treatment or prevention of a disease, disorder, or condition related to spleen tyrosine kinase activity in a subject.

19. The use according to claim 18, wherein the disease, disorder, or condition related to the spleen tyrosine kinase activity may be selected from one or more of the group consisting of glioblastoma, cancer, osteoporosis, rheumatoid arthritis, liver disease, fibrosis, periodontal disease, diabetes, inflammation, Graves' disease, lung disease or disorder, kidney disease, acquired epidermolysis bullosa, Wiscott-Aldrich syndrome, agammaglobulinemia, Nasu-Hakola disease, allergy, microbial infection, fungal infection, autoimmune hypersensitivity disease, blood coagulation disorder, thrombocytopenia, bone or skeletal disorder, nail disease, chronic mucocutaneous candidiasis, neurological disease or disorder, neuroinflammatory disease, stroke, traumatic brain injury, and subarachnoid hemorrhage.

20. The use according to claim 18, wherein the disease, disorder, or condition related to the spleen tyrosine kinase activity is in the central nervous system.

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