Spleen tyrosine kinase inhibitors

Abstract

# imgabs0. The invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: wherein R4 is a 5-membered cycloolefin or a 5-membered heteroaryl group, each optionally fused to form a 5: 6 or 5: 5 aromatic or heteroaromatic bicyclic ring; wherein each R4 is optionally substituted. The invention also relates to pharmaceutical compositions comprising said compounds, and uses of said compounds, in particular in the treatment of diseases, disorders or conditions associated with spleen tyrosine kinase activity.

Description

Technical Field

[0001] The present invention particularly relates to compounds, pharmaceutical compositions of said compounds, and uses of said compounds. Said compounds are particularly useful for inhibiting spleen tyrosine kinase. Background Art

[0002] It will be clearly understood that if a prior art publication is referred to herein, this reference does not constitute 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. After activation by membrane-bound receptors, Syk phosphorylates many downstream targets that are primarily responsible for 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 is a potential target for the treatment of the following diseases: glioblastoma (Moncayo et al., 2018), ovarian cancer (Yu et al., 2019), B-cell and T-cell lymphomas (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 (Mócsai, 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., 2013). 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 dysostosis with sclerosing leukoencephalopathy (Nasu-Hakola disease) (Mócsai, Ruland, and Tybulewicz 2010), trimethoprim-sulfamethoxazole allergy, fasciitis, Mycobacterium abscessus infection, autoimmune allergic diseases, hemorrhagic disorders, chromoblastomycosis, carbapenem allergy, Waldenstrom's macroglobulinemia (Munshi et al., 2020), thrombocytopenia (Bussel et al., 2018), Mei-Niesel syndrome, nail diseases, oto-palatal-digital syndrome spectrum disorders, bone metabolism disorders (Shao et al., 2021), fungal infectious diseases / fungal diseases, chronic mucocutaneous candidiasis and dermatitis (Pavel et al., 2019) and cardiovascular thrombotic diseases (Andre et al., 2011).

[0005] Syk inhibitors are currently marketed (Fostamatinib) or are being advanced in the clinic (Entospletinib) for peripheral indications, including inflammatory diseases and oncology, providing strong evidence for the applicability of Syk inhibitors as potential drugs. Syk is highly conserved across species, and current clinical compounds have shown similar in vitro activity against Syk orthologs from humans, mice, and rats (Lamb et al., 2016; Currie et al., 2014), confirming the conservation of Syk structure and the ability to explore using multiple species.

[0006] Marketed and clinical Syk inhibitors (fostatinib and entostinib) support the safety profile of Syk inhibition. Fostatinib has been extensively tested in long-term studies for several disease indications, and adverse events are mild or manageable with dose reduction, interruption, or adjunctive medications (Bussel et al., 2018; Kang et al., 2019). Although Syk is expressed in most cell types, including neurons, astrocytes, and microglia (Hatterer et al., 2011; Xu et al., 2019; Lee and Suk 2018), 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 inducible knockout of Syk, which show some reduced inflammatory responses but otherwise no apparent effects on basic physical function (Wex et al., 2011).

[0007] Clinical trials of antibodies against Syk-related pathways have also been studied, further supporting the safety and efficacy of direct Syk inhibitors. For example, TREM2 is a receptor associated with increased risk of Alzheimer's disease (AD), and is also known to signal via Syk. Phase II trials of antibodies against TREM2 are in the process of being initiated. Phase 1 clinical trials of antibodies against two receptors (TREM2 and Siglec-3) in the same inflammatory pathway as Syk are underway (Alector, AL002 and AL003). The advantage of direct Syk inhibitors is that they target multiple pathways, rather than one or two receptors. Combined with the positive clinical safety characteristics of peripherally restricted Syk inhibitors established with marketed drugs (fotatinib) and clinical inhibitors (such as entosterinib), direct Syk inhibition is highly desirable and can provide significant advantages over other untested preclinical drug targets. SUMMARY OF THE INVENTION

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

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

[0011] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:

[0012] Formula (I)

[0013] in:

[0014] Z is CR 1 or N;

[0015] Y is CH or N;

[0016] X is CR 2 or N; and

[0017] No more than one of X, Y or Z is N;

[0018] in:

[0019] R 1 Selected from: 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, halogen, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 2-6 Alkenyl, -OC 2-6 Fluoroolefin, -OC 2-6 Alkynyl, -OC 2-6 Fluoroalkynyl and cyano groups;

[0020] R 2 Selected from: 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, halogen, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 2-6 Alkenyl, -OC 2-6 Fluoroolefin, -OC 2-6 Alkynyl, -OC 2-6 Fluoroalkynyl and cyano groups;

[0021] R 4is a 5-membered cycloalkene or a 5-membered heteroaryl, each of which is optionally fused to form a 5:6 or 5:5 aromatic or heteroaromatic bicyclic ring; wherein each R 4 is optionally substituted;

[0022] m is 0 or 1;

[0023] R 6 Selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl;

[0024] R 7 and R 7 'Independently selected from: H, fluorine, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 7 With 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;

[0025] R 8 and R 9 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 8 With R 9 Together they 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;

[0026] R 10 and R 11 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 10 With R 11 Together they 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;

[0027] R 12 and R 13 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 12 With R 13 Together they 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;

[0028] R 15 and R 16 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 15 With R 16 Together they 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;

[0029] or where:

[0030] -R 7 or R 7 'One 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;

[0031] -R 7 or R 7 'One and R 6 Together they 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;

[0032] -R 6 With 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;

[0033] -R 6 With R 10 or R 11 One of them together forms a 4- to 6-membered heterocyclyl ring or a 4- to 6-membered fluoroheterocyclyl ring;

[0034] -R 8 or R 9 One and R 12 or R 13 One of them together form a 4- to 7-membered heterocyclyl ring or a 4- to 7-membered fluoroheterocyclyl ring;

[0035] -R 8 or R 9 One and R 15 or R 16 One of them together forms a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring;

[0036] -R 10 or R 11 One and R 12 or R 13 One of them together forms a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring;

[0037] -R 10 or R 11 One 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;

[0038] -R 8 or R 9 One and R 10 or R 11 together form a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring; and / or

[0039] -R 12 or R 13 One and R 15 or R 16 One of them together forms a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring.

[0040] In one embodiment of the first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof:

[0041]

[0042] in:

[0043] Z is CR 1 or N;

[0044] Y is CH or N;

[0045] X is CR 2 or N; and

[0046] No more than one of X, Y or Z is N;

[0047] in:

[0048] R 1 Selected from: 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, halogen, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 2-6 Alkenyl, -OC 2-6 Fluoroolefin, -OC 2-6 Alkynyl, -OC 2-6 Fluoroalkynyl and cyano groups;

[0049] R 2 Selected from: 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, halogen, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 2-6 Alkenyl, -OC 2-6 Fluoroolefin, -OC 2-6 Alkynyl, -OC 2-6 Fluoroalkynyl and cyano groups;

[0050] R 4 is a 5-membered cycloalkene or a 5-membered heteroaryl, each of which is optionally fused to form a 5:6 or 5:5 aromatic or heteroaromatic bicyclic ring; wherein each R 4 Optionally one or more R 5 Replace; wherein each R 5 Independently selected from: -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -Cyclofluoroalkyl-R 19 , -R 14 -Heterocyclyl-R 19 , -R 14-Fluorinated heterocyclic group-R 19 , -R 14 -heteroaryl-R 19 , -R 14 -Aryl-R 19 , -cycloalkyl-R 19 ,-cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 ,-fluoroheterocyclic-R 19 , -heteroaryl-R 19 , -Aryl-R 19 , -R 14 -OR 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 and = O; where each R 14 Independently selected from 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; wherein each R 19 Independently selected from 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;

[0051] m is 0 or 1;

[0052] R 6 Selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl;

[0053] R 7 and R 7 'Independently selected from: H, fluorine, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 7 With 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;

[0054] R 8 and R 9 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 8 With R 9 Together they 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;

[0055] R 10 and R 11 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 10 With R 11 Together they 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;

[0056] R 12 and R 13 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 12 With R 13 Together they 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;

[0057] R 15 and R 16 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 15 With R 16 Together they 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;

[0058] or where:

[0059] -R 7 or R 7 'One 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;

[0060] -R 7 or R 7 'One and R 6 Together they 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;

[0061] -R 6 With 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;

[0062] -R 6 With R 10 or R 11 One of them together forms a 4- to 6-membered heterocyclyl ring or a 4- to 6-membered fluoroheterocyclyl ring;

[0063] -R 8 or R 9 One and R 12 or R 13 One of them together form a 4- to 7-membered heterocyclyl ring or a 4- to 7-membered fluoroheterocyclyl ring;

[0064] -R 8 or R 9 One and R 15 or R 16 One of them together forms a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring;

[0065] -R 10 or R 11 One and R 12 or R 13 One of them together forms a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring;

[0066] -R 10 or R 11 One 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;

[0067] -R 8 or R 9 One and R 10 or R 11 together form a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring; and / or

[0068] -R 12 or R 13 One and R 15 or R 16 One of them together forms a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring.

[0069] In one embodiment, the compound of formula (I) is a compound of formula (II):

[0070]

[0071] In another embodiment, the compound of formula (I) is a compound of formula (III):

[0072]

[0073] Advantageously, the present inventors have found that compounds of formula (I) can provide potent Syk inhibitors.

[0074] Syk is known to play multiple roles in Alzheimer's disease (AD) pathology, primarily in microglia (immune cells of the brain). Neuroinflammation is a key driver of AD pathology. Syk promotes neuroinflammation (Ye et al., 2020; Zeng et al., 2014) and acts as a pro-inflammatory signaling mediator for receptors such as TREM2, DAP12, Toll-like receptors (TLRs), and Fc receptors, all of which are associated with or upregulated in AD brain (Fuller, Stavenhagen, and Teeling 2014; Nizami et al., 2019; Mielcarska et al., 2019; Guerreiro et al., 2013). Amyloid-β plaques and Tau hyperphosphorylation in neurons are major 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 chronic proinflammatory microglial responses to amyloid-β and can also increase amyloid-β production in neurons. Syk directly phosphorylates Tau and colocalizes with Tau in mouse neurons. Thus, in addition to its key role in neuroinflammation, Syk is involved in the generation and activation of amyloid-β and Tau, leading to typical AD pathology.

[0075] Syk is also involved in other neuroinflammation-driven diseases, including other types of dementia, Parkinson's disease (PD), multiple sclerosis (MS), stroke, craniocerebral injury (TBI), and subarachnoid hemorrhage (SAH). In MS, Syk has a dual effect of regulating both peripheral (T cells, B cells) and CNS (B cells, microglia, macrophages, T cells) immune responses, which is indispensable in the pathology of MS (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 early inflammation after reperfusion, leading to improved recovery after infarction (Ye et al., 2020). In a TBI rat model, Syk inhibition has also been shown to improve neurological function (He et al., 2015). In animal models, Syk is involved in both TBI (Morin, Front Aging Neurosci, 2018) and SAH (He, Stroke, 2015).

[0076] Through genome-wide association studies, Syk is associated with AD, vascular dementia, and other neuroinflammation-related diseases such as multiple sclerosis (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 the fundamental role of Syk in neuroinflammation. Further validation of Syk as a target of AD, Syk expression and activation are increased in the brains of AD patients (particularly in degenerated neurites associated with beta-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 reflected in mouse models of the disease. Three AD mouse models (one focused on Tau pathology and the other two based on β-amyloid pathology) showed age-dependent increases in Syk expression and activation in neurons, dystrophic neurites, or microglia in the brain (Schweig et al., 2017; Sierksma et al., 2020), a situation relevant to human disease.

[0077] Syk kinase signaling has been found to regulate neuroinflammatory responses and immune activation in response to pathological protein aggregates present in PD and AD. Therefore, selective inhibition of the Syk kinase pathway could provide a multi-pronged approach for the treatment of PD and AD; targeting disease-modifying pathways of 1) tau phosphorylation, 2) amyloid-β production, and 3) neuroinflammation. The potential to inhibit the Syk kinase pathway could have therapeutic benefits for other neuroinflammatory diseases such as stroke and multiple sclerosis.

[0078] PD and AD are extremely debilitating due to significant disability, functional impairment, and duration, and there is an urgent unmet need for therapeutics that can modify disease progression. Currently approved treatments for PD and AD provide only symptomatic benefit, and no disease-modifying drugs are available for patients. For agents targeting a single pathway in AD, most notably β-amyloid-targeted antibodies and β-secretase (BACE) inhibitors, there is a high failure rate. Due to the heterogeneity of these diseases, addressing the mechanisms of action of multiple pathogenic pathways in the target population has high translational potential.

[0079] 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.

[0080] However, to the best of the inventors' knowledge, Syk has not been pursued for central nervous system (CNS) disorders, and based on its broad base, current clinical compounds do not reach sufficient concentrations in the brain to inhibit Syk. In addition, to the best of the inventors' knowledge, sufficiently potent and brain-penetrating small molecule Syk inhibitors have not been described in the literature.

[0081] To the best of the inventors' knowledge, there are few, if any, disclosures in the literature of brain-penetrant small molecule Syk inhibitors for the treatment of AD. Syk has compelling advantages over other, largely unsuccessful targets tested in AD, such as beta-amyloid or Tau-targeted biologics. Syk does not just target one pathological process implicated in AD, but is implicated in multiple disease pathways. In addition to directly alleviating neuroinflammation, Syk inhibition also reduces beta-amyloid production and Tau hyperphosphorylation.

[0082] In one embodiment, the compounds of formula (I) are capable of penetrating the blood-brain barrier. In one embodiment, the compounds of formula (I) are capable of acting on the central nervous system in vivo.

[0083] Small molecule Syk inhibitors that can cross the blood-brain barrier when administered orally have clear advantages in terms of direct mechanism of action to combat AD, PD and MS pathology, ease of use, patient compliance and cost. However, the design and synthesis of brain-penetrating kinase inhibitors has traditionally been very difficult to achieve due to the nature of the types of molecules that effectively bind to the kinase active site. The types of molecules that are typically found to be effective kinase inhibitors have high molecular weight, high polar surface area and too many H-bond donors or acceptors. For a good CNS drug, it is necessary to have a low molecular weight (less than 500, preferably less than 450 and most preferably less than 400 Daltons), a low polar surface area (less than Preferably less than and most preferably less than ), a logP between 2 and 5 (most preferably between 2 and 4) and three or fewer H-bond donors (preferably two or fewer, more preferably one or fewer H-bond donors) and less than 10 H-bond acceptors (preferably less than 8 and most preferably less than 6 H-bond acceptors) (Hitchcock et al., 2006). To the best of the inventors' knowledge, Syk inhibitors that meet the above criteria to achieve adequate brain penetration of the free drug have not been described in the literature. In some embodiments of compounds of formula (I), (II) or (III), the inventors were surprisingly able to achieve potent brain penetrant small molecule Syk inhibitors that are directly applicable to the treatment of AD and many other neurological diseases and peripheral disorders.

[0084] In one embodiment, the compounds of the invention provide CNS-permeable selective antagonists suitable for oral administration, which can be used to treat neurological diseases or disorders, such as AD, PD or MS.

[0085] By inhibiting Syk, the present invention can provide the advantage of regulating multiple pathways in AD at the same time, the most important of which is to reduce neuroinflammation, and has additional effects on Tau activation and beta amyloid formation. The proposed therapy is intended to reduce the possibility of progression of the disease to more advanced diseases. In AD, the difference from approved drugs (for example, Aricept and Exelon, which only address symptoms) is the improved efficacy and potential for improvement of the condition. The difference from beta amyloid and Tau targeting agents in clinical development is to improve efficacy by targeting multiple disease pathologies. Oral administration also provides advantages over biologics.

[0086] In some embodiments of compounds of Formula (I), Formula (II) or Formula (III), one or more features of paragraphs

[0028] to

[0059] may apply (features of paragraphs

[0028] to

[0059] may apply alone or in combination with any other features of paragraphs

[0028] to

[0059] ). 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 definition in may be combined with 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 in combination with any other definition.

[0087] In one embodiment, Z is CR 1In another embodiment, Z is N.

[0088] In another embodiment, Y is CH. In another embodiment, Y is N.

[0089] In one embodiment, X is CR 2 In another embodiment, X is N.

[0090] In one embodiment, R 1 Selected from: 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 1 H or C 1-6 Alkyl; especially R 1 H or CH 3 ; more particularly R 1 For H.

[0091] In one embodiment, R 2 Selected from: hydrogen, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 2-6 Alkenyl and C 2-6 Fluoroalkenyl; especially R 2 H, C 1-6 Alkyl or C 2-6 alkenyl; more particularly R 2 H, CH 3 or -CH=CH 2 ; most especially R 2 For H.

[0092] In one embodiment, Z is N, Y is CH and X is CR 2 ; in particular, Z is N, Y is CH, and X is CH, CC 1-6 Alkyl or CC 2-6 alkenyl; more particularly Z is N, Y is CH, and X is CH.

[0093] In another embodiment, Y is N and Z is CR 1 and X is CR 2 ; In particular, Y is N, X is CH, CC 1-6 Alkyl or CC 2-6 alkenyl, and 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=CH 2 , and Z is CH, C-CF 3 、C-CH 3 、C-CH 2 -CH 3 or CO-CH 3 ; most particularly Y is N, X is CH, and Z is CH.

[0094] In another embodiment, X is N, Y is CH and Z is CR 1 ; 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-CH 3 ; most particularly X is N, Y is CH, and Z is CH.

[0095] In another embodiment, X is CR 2 , 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-CH 3 or C-CH=CH 2 , Y is CH, and Z is CH or C-CH 3 ; most particularly X is CH, Y is CH, and Z is CH.

[0096] In one embodiment, R 4 is a 5-membered heteroaryl group, which is optionally fused to form a 5:6 or 5:5 aromatic bicyclic ring; wherein R 4 Optionally one or more R 5 replace.

[0097] In one embodiment, R 4 is a 5-membered cycloalkene or a 5-membered heteroaryl, each of which is optionally fused to form a 5:6 or 5:5 aromatic or heteroaromatic bicyclic ring; wherein each R 4 Optionally one or more R 5 replace.

[0098] In another embodiment, R 4 Selected from: cyclopentenyl, pyrrolyl, 2,3-dihydro-pyrrolizinyl, pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thienyl, 1,2-oxazolyl, 1,3-thiazolyl and 1,2-thiazolyl; wherein R 4 The group is optionally replaced by one or more R 5In another embodiment, R 4 Selected from: pyrrolyl and pyrazolyl; wherein said R 4 The group is optionally replaced by one or more R 5 replace.

[0099] In another embodiment, R 4 Selected from: In another embodiment, R 4 Selected from: Especially R 4 Selected from: In the foregoing embodiments, u is an integer from 0 to the maximum number of substitution positions on the group (particularly 0, 1 or 2; more particularly 0 or 1).

[0101] In one embodiment, each R 5 Independently selected from: -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -Cyclofluoroalkyl-R 19 , -R 14 -Heterocyclyl-R 19 , -R 14 -Fluorinated heterocyclic group-R 19 , -R 14 -heteroaryl-R 19 , -R 14 -Aryl-R 19 , -cycloalkyl-R 19 ,-cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 ,-fluoroheterocyclic-R 19 , -heteroaryl-R 19 , -Aryl-R 19 , -R 14 -OR 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 )COOR19 、-OCON(R 19 ) 2 、-N(R 19 )SO 2 R 19 、-SO 2 N(R 19 ) 2 and = O; where each R 14 Independently selected from 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; wherein each R 19 Independently selected from 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 In another embodiment, each R 5 Independently selected from: -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -Cyclofluoroalkyl-R 19 , -R 14 -Heterocyclyl-R 19 , -R 14 -Fluorinated heterocyclic group-R 19 , -R 14 -heteroaryl-R 19 , -R 14 -Aryl-R 19 , -cycloalkyl-R 19 ,-cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 ,-fluoroheterocyclic-R 19 , -heteroaryl-R 19 , -Aryl-R 19 , -R 14 -OR 19 、Cl、F、cyano、-OR 19 、-SR 19 and = O; where each R 14 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Fluoroalkyl, C 2-6Fluoroalkenyl and C 2-6 Fluoroalkynyl; wherein each R 19 Independently selected from 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 Fluoroalkynyl.

[0102] In another embodiment, each R 5 Independently selected from: -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -Cyclofluoroalkyl-R 19 , -R 14 -Heterocyclyl-R 19 , -R 14 -Fluorinated heterocyclic group-R 19 , -cycloalkyl-R 19 ,-cyclofluoroalkyl-R 19 , -heterocyclyl-R 19 ,-fluoroheterocyclic-R 19 , -R 14 -OR 19 、Cl、F、cyano、-OR 19 、-SR 19 and = O; where each R 14 Independently selected from 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; wherein each R 19 Independently selected from 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 another embodiment, each R 5 Independently selected from: -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; wherein each R 14 Independently selected from 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; wherein each R 19 Independently selected from 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 5 Independently selected from: -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; wherein each R 14 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Fluoroalkyl and C 2-6 Fluoroalkenyl; wherein each R 19 Independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Fluoroalkyl and C 2-6 Fluoroalkenyl.

[0103] In one embodiment, each R 5 Independently selected from: -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-heterocyclic, -cycloalkyl, -cyclofluoroalkyl, -cycloalkyl-C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -heterocyclyl, -heterocyclyl-C1-6 In another embodiment, each R 5 Independently selected from: -C 1-6 Alkyl and -heterocyclyl.

[0104] In one embodiment, R 4 Selected from:

[0106] In another embodiment, R 4 Selected from:

[0107] In one embodiment, R 6 Selected from 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 selected from H, C 1-6 Alkyl and C 1-6 Fluoroalkyl; most particularly selected from H and C 1-6 In one embodiment, R 6 Selected from H, CH 3 and CH 2 -CH 3 In another embodiment, R 6 For H.

[0108] In one embodiment, R 7 and R 7 'Independently selected from: 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 7 and R 7 'Independently selected from: H, fluorine, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, 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 1-6In another embodiment, R 7 and R 7 'Independently selected from: H, CH 3 and CF 3 ; more particularly H and CH 3 ; most particularly H. In one embodiment, R 7 and R 7 'At least one of them is H.

[0109] In one embodiment, R 8 and R 9 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 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 another embodiment, R 8 and R 9 Independently selected from: H, C 1-6 Alkyl and C 1-6 Fluoroalkyl groups; especially H and C 1-6 In one embodiment, R 8 and R 9 Independently selected from: H, CH 3 and CF 3 ; more particularly H and CH 3 ; most particularly H. In one embodiment, R 8 and R 9 At least one of them is H.

[0110] In one embodiment, R 10 and R 11 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl and C 3-6 Fluorinated cycloalkyl; or R 10 With R 11 Together they form a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 4- to 6-membered oxygen-containing heterocycle (such as oxetane, tetrahydrofuran, or pyran). 10 and R11 Independently selected from: H, C 1-6 Alkyl, fluorine and C 1-6 Fluoroalkyl; or R 10 With R 11 Together they 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 Independently selected from: H, C 1-6 Alkyl and fluorine; or R 10 With R 11 Together they form a 3 to 6 membered cycloalkyl ring, or an oxetane, tetrahydrofuran or pyran ring. 10 and R 11 Independently selected from: H, CH 3 、-CH 2 -CH 3 , F, CH 2 F. CHF 2 and CF 3 ; or R 10 With R 11 Together they form a cyclopropyl, cyclobutyl or oxetanyl ring. In another embodiment, R 10 and R 11 Independently selected from: H, CH 3 、-CH 2 -CH 3 、-CH-(CH 3 ) 2 、-C-(CH 3 ) 3 , F, cyclopropyl, CHF 2 and CF 3 ; or R 10 With R 11 Together they form a cyclopropyl, cyclobutyl or oxetanyl ring. In another embodiment, R 10 and R 11 Independently selected from: H, CH 3 、-CH 2 -CH 3 and CHF 2 ; or R 10 With R 11 Together they form a cyclopropyl or cyclobutyl ring. In one embodiment, R 10 and R 11 All CH 3 In another embodiment, R 10 and R 11 Both are H.

[0111] In one embodiment, R12 and R 13 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; in particular independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; more particularly independently selected from: H, C 1-6 Alkyl, fluorine and C 1-6 Fluoroalkyl; most particularly independently selected from: H, C 1-6 In one embodiment, R 12 and R 13 Independently selected from: H, CH 3 In another embodiment, R 12 and R 13 Both are H.

[0112] In one embodiment, m is 0. In another embodiment, m is 1.

[0113] In one embodiment, R 15 and R 16 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; in particular independently selected from: 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; more particularly independently selected from: H, C 1-6 Alkyl and C 1-6 Fluoroalkyl; most particularly independently selected from: H and C 1-6 In one embodiment, R 15 and R 16 Independently selected from: H and CH 3In another embodiment, R 15 and R 16 Both are H.

[0114] In one embodiment, R 10 or R 11 One and R 12 or R 13 One of them may together form a 3 to 6-membered cycloalkyl ring or a fluorocycloalkyl ring. 10 or R 11 One and R 12 or R 13 One of the two may together form a cyclopropyl, cyclobutyl or cyclopentyl ring; in particular a cyclopropyl or cyclopentyl ring.

[0115] In one embodiment, R 8 or R 9 One and R 10 or R 11 One of them may together form a 5- to 7-membered heterocyclyl ring or a fluoroheterocyclyl ring. 8 or R 9 One and R 10 or R 11 One of them can be -CH 2 -、-CH 2 -CH 2 -or-CH 2 -CH 2 -CH 2 -.

[0116] In one embodiment, R 8 or R 9 One and R 12 or R 13 One of them may together form a 4 to 7 membered heterocyclyl ring or a fluoroheterocyclyl ring. 8 or R 9 One and R 12 or R 13 One of them can be -CH 2 -、-CH 2 -CH 2 -or-CH 2 -CH 2 -CH 2 -; especially -CH 2 In one embodiment, if m is 1, then R 8 or R 9 One and R 12 or R 13 One of the two may be a bond together (this would form a four-membered ring).

[0117] In one embodiment, R 7 or R 7 'One and R 8 or R 9 One of them may together form a 5- or 6-membered cycloalkyl ring or a fluorocycloalkyl ring. 7 or R 7 'One and R 8 or R 9 One of the two may together form a cyclopentyl or cyclohexyl ring; in particular a cyclopentyl ring.

[0118] In one embodiment:

[0119] -R 7 or R 7 'One 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;

[0120] -R 7 or R 7 'One and R 6 Together they 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;

[0121] -R 6 With 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;

[0122] -R 6 With R 10 or R 11 One of them together forms a 4- to 6-membered heterocyclyl ring or a 4- to 6-membered fluoroheterocyclyl ring;

[0123] -R 8 or R 9 One and R 12 or R 13 One of them together form a 4- to 7-membered heterocyclyl ring or a 4- to 7-membered fluoroheterocyclyl ring;

[0124] -R 8 or R 9 One and R 15 or R 16 One of them together forms a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring;

[0125] -R 10 or R 11 One and R 12 or R 13One of them together forms a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring;

[0126] -R 10 or R 11 One 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;

[0127] -R 8 or R 9 One and R 10 or R 11 or

[0128] -R 12 or R 13 One and R 15 or R 16 One of them together forms a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring.

[0129] In one embodiment of the compound of formula (I), Selected from: In particular, selected from:

[0131] In one embodiment of the compound of formula (I), Selected from:

[0133] In particular, selected from:

[0134] In one embodiment, the compound of formula (I) is selected from the compounds of one of Tables 2-4, 6-8 and 10-15.

[0135] In another embodiment, the compound of formula (I) is selected from one of the following compounds or a pharmaceutically acceptable salt thereof:

[0136]

[0137]

[0138]

[0139]

[0140] In another embodiment, the compound of formula (I) is selected from one of the following compounds or a pharmaceutically acceptable salt thereof:

[0141] 7-(1-methyl-1H-pyrrol-3-yl)-5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]-1,6-naphthyridine

[0142] 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-(1-methyl-1H-pyrrol-3-yl)-1,6-naphthyridine

[0143] 7-(1-methyl-1H-pyrrol-3-yl)-5-{[(2S)-morpholin-2-yl]methoxy}-1,6-naphthyridine

[0144] 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-(1-methyl-1H-pyrrol-3-yl)quinoline

[0145] 5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]-7-[1-(propan-2-yl)-1H-pyrrol-3-yl]-1,6-naphthyridine

[0146] 7-(1-ethyl-1H-pyrrol-3-yl)-5-{[(2S)-1,4-oxazepan-2-yl]methoxy}-1,6-naphthyridine

[0147] 7-(1-methyl-1H-pyrrol-3-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline

[0148] 7-(1-tert-Butyl-1H-pyrazol-4-yl)-5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-1,6-naphthyridine

[0149] 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-[1-(propan-2-yl)-1H-pyrrol-3-yl]-1,6-naphthyridine

[0150] 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-(1-ethyl-1H-pyrrol-3-yl)-1,6-naphthyridine

[0151] 7-(1-tert-Butyl-1H-pyrazol-4-yl)-5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]-1,6-naphthyridine

[0152] 5-{[(2S)-Morpholin-2-yl]methoxy}-7-[1-(Propan-2-yl)-1H-pyrrol-3-yl]-1,6-naphthyridine

[0153] 7-(1-tert-Butyl-1H-pyrazol-4-yl)-5-[(6,6-dimethylmorpholin-2-yl)methoxy]-4-methyl-1,6-naphthyridine

[0154] 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-[1-(propan-2-yl)-1H-pyrazol-4-yl]quinoline

[0155] 5-{[(2S)-6,6-dimethylmorpholin-2-yl]methoxy}-7-[1-(oxetan-3-yl)-1H-pyrrol-3-yl]quinoline

[0156] 7-(1-methyl-1H-pyrazol-4-yl)-5-{[(6S)-5-oxa-8-azaspiro[3.5]non-6-yl]methoxy}-1,6-naphthyridine

[0157] 5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]-7-[1-(propan-2-yl)-1H-pyrazol-4-yl]-1,6-naphthyridine

[0158] 7-(1-tert-Butyl-1H-pyrrol-3-yl)-5-{[(2S,6R)-6-methylmorpholin-2-yl]methoxy}quinoxaline

[0159] 7-(2,3-Dihydro-1H-pyrrolizin-6-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline

[0160] 7-(1-tert-Butyl-1H-pyrazol-4-yl)-5-[(1R)-1-[(2S)-morpholin-2-yl]ethoxy]quinoline

[0161] 7-(1-tert-Butyl-1H-pyrazol-4-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline

[0162] 5-{[(5S)-4-oxa-7-azaspiro[2.5]octan-5-yl]methoxy}-7-[1-(propan-2-yl)-1H-pyrrol-3-yl]-1,6-naphthyridine

[0163] 7-(1-tert-Butyl-1H-pyrazol-4-yl)-5-{[(2S,6S)-6-(difluoromethyl)morpholin-2-yl]methoxy}-1,6-naphthyridine.

[0164] The compound names in the previous paragraph were derived using ChemAxon Instant JChem 19.8.0.

[0165] 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).

[0166] The compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof has an EC of 1. 50 It may be less than 500 nM, specifically less than 250 nM, more specifically less than 100 nM, and most specifically less than 50 nM.

[0167] In one embodiment, the compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof may have a molecular weight of more than 10×10 -6 cm / s, especially exceeding 15×10 -6 cm / s, most notably exceeding 20×10 -6 cm / sP app Permeability of AB. 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.

[0168] The compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof may have a K of more than 0.05, particularly more than 0.1, more particularly more than 0.2, most particularly more than 0.3. pu,u The compound of the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, may have a free brain level of greater than 10 nM, particularly greater than 25 nM, or greater than 50 nM after an oral dose of 10 mg / kg.

[0169] As used herein, terms such as Means u R 5 Substituents may be attached to the ring system and may be located at any position, including on the nitrogen atom (e.g., pyrrole N) or on either ring (e.g., in 2,3-dihydropyrrolizine, R 5 can be attached to the pyrrole moiety or the pyrrolidine moiety). For example, if the pyrrole N is not R 5 substituted, then the pyrrole N is NH.

[0170] Unless defined otherwise, 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.

[0171] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" 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.

[0172] The term "alkyl" refers to a straight or branched chain 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 alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, hexyl, heptyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, octyl, nonyl, decyl, undecyl, dodecyl, etc. The carbon numbers mentioned relate to the carbon backbone and the carbon branches, but do not include carbon atoms belonging to any substituent, such as carbon atoms of alkoxy substituents branched from the main carbon chain.

[0173] 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 are replaced by 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 by 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 by fluorine. The fluoroalkyl group may contain, for example, only one fluorine atom, or may be a perfluoroalkyl group. For example, the cyclofluoroalkyl group may be a 3- to 8-membered cyclofluoroalkyl ring; in particular a 3- to 7-membered cyclofluoroalkyl ring.

[0174] The term "alkenyl" refers to a straight or branched alkenyl substituent containing, for example, 2 to about 12 carbon atoms, preferably 2 to about 8 carbon atoms, more preferably 2 to about 6 carbon atoms. The example of suitable alkenyl includes, but is not limited to, vinyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, etc. Branched alkenyl can be branched at any suitable position, and exemplary branched alkenyl can include, for example, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 2-methyl-2-pentenyl, 2-methyl-3-pentenyl, 2-methyl-4-pentenyl, etc. The carbon number mentioned relates to a carbon backbone and a carbon branch, but does not include the carbon atom belonging to any substituent, for example, the carbon atom of the alkoxy substituent branched from the main carbon chain.

[0175] The term "alkynyl" refers to a straight or branched alkynyl substituent containing, for example, 2 to about 12 carbon atoms, preferably 2 to about 8 carbon atoms, more preferably 2 to about 6 carbon atoms. The example of suitable alkynyl includes, but is not limited to, ethynyl, propynyl (such as prop-2-ynyl or prop-1-ynyl), butynyl, di-butadiynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, etc. Branched alkynyl can be branched at any suitable position, and exemplary branched alkynyl can include, for example, 3-methyl-1-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, etc. The carbon number mentioned relates to a carbon backbone and a carbon branch, but does not include the carbon atom belonging to any substituent, such as the carbon atom of the alkoxy substituent branched from the main carbon chain.

[0176] 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 contains 3, 4, 5, 6, 7 or 8 carbon atoms. The cycloalkyl may be a monocyclic, bicyclic or tricyclic ring. When there is more than one ring, the rings are fused together (for example, if two rings have two atoms, the bicyclic ring is fused) or connected by a common atom (for example, a spirocyclic compound). Non-limiting examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Cycloalkyl may be, for example, a 3 to 8-membered cycloalkyl ring; particularly a 3 to 7-membered cycloalkyl ring.

[0177] The term "cycloalkenyl" or "cycloolefin" refers to a non-aromatic cyclic hydrocarbon having at least one double bond. The cycloalkenyl ring may contain a specified number of carbon atoms. For example, a 5-membered cycloalkenyl contains 5 carbon atoms. The cycloalkenyl may be a monocyclic, bicyclic or tricyclic ring. When there is more than one ring, the rings are fused together (for example, if two rings have two atoms in common, the bicyclic rings are fused) or connected by a common atom (for example, a spirocyclic compound). Non-limiting examples may include cyclopentenyl and cyclopenta-1,3-dienyl.

[0178] The term "aryl" or "aromatic" refers to an aromatic carbocyclic substituent, as generally understood in the art. It should be understood that, according to Huckel's rule, the term aryl applies to cyclic substituents in which at least one ring is planar and contains 4n+2 π electrons. The aryl group may be monocyclic, bicyclic or tricyclic. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Cycloalkyl groups are not encompassed by aryl groups, and aryl groups have a ring system in which at least one ring is aromatic (e.g., monocyclic, bicyclic or tricyclic). For example, naphthyl and 1,2,3,4-tetrahydronaphthyl are both aryl or aromatic groups. When there is more than one ring, the rings are fused together (e.g., if two rings have two atoms in common, the bicyclic ring is fused) or connected by a common atom (e.g., a spirocyclic compound that may exist as a non-aromatic ring).

[0179] As used herein, the term "heterocycle" or "heterocyclic group" refers to a cycloalkyl or cycloalkenyl group in which one or more carbon atoms are replaced by heteroatoms independently selected from N, S and O. For example, 1 to 4 carbon atoms in each ring can be replaced by heteroatoms independently selected from N, S and O. The heterocyclic group can be a monocyclic, bicyclic or tricyclic ring, wherein at least one ring contains a heteroatom. When there is more than one ring, the rings are fused together (for example, if two rings have two atoms in common, the bicyclic ring is fused) or connected by a common atom (for example, a spirocyclic compound). Each ring of the heterocyclic group can contain, for example, 5 to 7 atoms. Examples of heterocyclic groups include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolinyl, dithiolyl, 1,3-dioxanyl, dioxinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, 1,4-dithianyl and decahydroisoquinolinyl. In a bicyclic or tricyclic heterocyclyl, neither ring is aromatic. In one embodiment, the heterocyclyl may be optionally substituted with =0.

[0180] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a monocyclic, bicyclic, or tricyclic ring having up to 7 atoms in each ring, wherein at least one ring is aromatic, and at least one ring contains 1 to 4 heteroatoms selected from O, N, and S. When more than one ring is present, the rings are fused together (e.g., a bicyclic ring is fused if two rings have two atoms in common) or connected by a common atom (e.g., a spirocyclic compound may exist as a non-aromatic ring). For example, when determining whether a ring is a heterocyclyl or heteroaryl ring, tautomers of heteroatom-containing ring systems containing carbonyl groups must be considered. Heteroaryl groups include, but are not limited to, 5-membered heteroaryl groups with one heteroatom (e.g., thiophene, pyrrole, furan); 5-membered heteroaryl groups with two heteroatoms at the 1,2 or 1,3 positions (e.g., oxazole, pyrazole, imidazole, thiazole); 5-membered heteroaryl groups with three heteroatoms (e.g., triazole, thiadiazole, oxadiazole, furazan); 5-membered heteroaryl groups with four heteroatoms (e.g., tetrazole); 6-membered heteroaryl groups with one heteroatom (e.g., pyridine); 6-membered heteroaryl groups with two heteroatoms (e.g., pyridazines, cinnoline, phthalazine, pyrazine, pyrimidine, quinazoline, quinoxaline); 6-membered heteroaryl groups with three heteroatoms (e.g., 1,3,5-triazine); and 6-membered heteroaryl groups with four heteroatoms. Examples of heteroaryl groups 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. Other exemplary heteroaryl groups can include, for example, dihydroindole or 2,3-dihydrobenzofuran. In one embodiment, heteroaryl groups can be optionally substituted with =O.

[0181] Whenever a range of atoms in a structure is specified (e.g., C 1-12 , C 1-6 alkyl, etc.), it is specifically contemplated that any subrange or individual number of carbon atoms falling within the specified range may also be used. Thus, for example, as used with respect to any chemical group (e.g., alkyl, etc.) mentioned herein, 1-12 carbon atoms (e.g., C 1-12 ), 1-6 carbon atoms (e.g., C 1-6) ranges encompass and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and / or 12 carbon atoms, as appropriate, and 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 12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms and / or 4-12 carbon atoms, as the case may be).

[0182] As used herein, "halogen" refers to a halogen atom, particularly F, Cl or Br; more particularly F or Cl; most particularly F.

[0183] As used herein, the term "optionally substituted" means that any number of hydrogen atoms on the optionally substituted group are replaced with another moiety. Exemplary optional substituents are discussed above, for example, in R 5 middle.

[0184] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are toxicologically safe for systemic or topical administration, such as salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic or organic bases and inorganic or organic acids); in particular, salts prepared from pharmaceutically acceptable inorganic or organic acids.

[0185] As used herein, the term "4- to 6-membered oxygen-containing heterocycle" may include, for example, oxetanyl, tetrahydrofuranyl or pyranyl ring systems. Oxetanyl ring systems may be preferred.

[0186] 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 also be considered to include C 1 -C 20 ester, or containing a cycloalkyl or aryl moiety (e.g., from a substituent R 4The ester of hydroxyl radical (OH group in hydroxyl radical). The aryl moiety may include a substituted phenyl or a fused 2-3 ring aromatic ring. Suitable prodrugs may include those defined in Simplício, 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).

[0187] According to the second aspect of the present invention, a pharmaceutical composition is provided, comprising an effective amount of the compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof. The composition may further comprise a pharmaceutically acceptable carrier, diluent and / or excipient.

[0188] While the compounds of formula (I) (or pharmaceutically acceptable salts or prodrugs thereof) can be administered as the pure chemical, they can also be administered as part of a pharmaceutical composition comprising at least one carrier or excipient.

[0189] The type of pharmaceutical composition can depend on the absorption, distribution, metabolism and excretion (ADME) characteristics of the compound of formula (I) (or its pharmaceutical salt or prodrug). For example, the compound of formula (I) (or its pharmaceutical salt or prodrug) may be most suitable for parenteral (particularly intravenous) administration, so the pharmaceutical composition can be formulated for parenteral or intravenous administration. However, and preferably, the pharmaceutical composition can include those suitable for oral or rectal administration or for administration by non-intravenous route. Oral compositions for oral administration may be preferred.

[0190] Parenteral administration can include administration by one or more of the following approaches: intravenous, intrathecal, percutaneous, subcutaneous, nasal, intramuscular, intraocular, epithelial, vaginal, intraperitoneal and local. Topical administration includes oral administration, sublingual, skin, eye, rectum, nose, and administration by suction or aerosol mode. For intravenous, percutaneous or subcutaneous injection or injection at the position of the desired treatment, the activating agent can be a pyrogen-free and parenteral acceptable aqueous solution form with suitable pH, isotonicity and stability. Those skilled in the art will be able to prepare suitable solution.

[0191] The properties of pharmaceutical composition and carrier or excipient will depend on the properties of route of administration and illness and the patient to be treated. It is believed that those skilled in the art can easily determine the selection of specific carriers, excipients or delivery systems, and route of administration. In some cases, it may be necessary to protect the compound (or its pharmaceutically acceptable salt or prodrug) of formula (I) by means known in the art (for example, by microencapsulation). The route of administration should also be selected so that the activating agent reaches its site of action. The pharmaceutical composition can include any suitable activating agent in an effective amount, which is commensurate with the expected dosage range to be adopted.

[0192] The pharmaceutical composition may be in solid form (including tablets, filled capsules, powders, cachets, capsules, lozenges, suppositories, wafers, dispersible granules and vaginal suppositories), or in liquid form (including solutions, suspensions, syrups, emulsions, gels, elixirs, creams, gels and foams). In one embodiment, the pharmaceutical composition may be in the form of a sterile injectable solution for parenteral use.

[0193] One or more pharmaceutically acceptable carriers or one or more excipients must be acceptable in the sense that they are compatible with other components in the composition and will not be harmful to the patient. Pharmaceutically acceptable carriers or excipients can be solid or liquid. Carriers or excipients can serve as diluents, buffers, stabilizers, isotonic agents, flavoring agents, antioxidants, solubilizers, lubricants, suspending agents, binding agents, preservatives, tablet disintegrating agents or encapsulating materials. Suitable carriers and excipients are known to the technician. Regarding buffers, aqueous compositions can include buffers for maintaining the composition close to physiological pH or at least about pH 6.0 to 9.0.

[0194] If the pharmaceutical composition is a powder, the active agent (compound of formula (I) or a pharmaceutically acceptable salt thereof) and the carrier or excipient may both be finely divided powders which are mixed together, for example, using methods known in the art such as dry blending or wet granulation.

[0195] If the pharmaceutical composition is a tablet, the active agent can be mixed with a suitable amount of a carrier or excipient having necessary binding capacity and then compressed into tablets of desired shape and size.

[0196] The powder or tablet may contain any suitable amount of the active agent, and exemplary amounts of the active agent in the powder or tablet may range from about 5% or 10% to about 70%. Exemplary carriers or excipients for powders and tablets may include, for example, magnesium carbonate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, low melting wax, cocoa butter, and the like.

[0197] Liquid form preparations can include, for example, water, saline, water-dextrose, water-propylene glycol, petroleum or oil (including animal, plant mineral or synthetic oil) solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Such liquid form preparations can contain at least 0.1% by weight of the active compound.

[0198] Liquid pharmaceutical compositions can be formulated into unit dosage forms. For example, the composition can be provided in an ampoule, a prefilled syringe, a small volume infusion set or a multi-dose container. Such compositions can include preservatives. The composition can also include formulation agents, such as suspending agents, stabilizers and / or dispersants. The composition can also be in powder form for construction with a suitable vehicle (such as sterile water) before use. Liquid carriers and excipients can include colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, suspending agents, etc.

[0199] Aqueous solutions for oral use can be prepared by dissolving the active agent in water and adding colorants, thickeners, flavoring agents and stabilizers as needed. Aqueous suspensions for oral use can be prepared by dispersing the active agent in water containing a viscous material such as a natural or synthetic gum, resin, methylcellulose or other suspending agent.

[0200] For topical administration to the epidermis, the compounds may be formulated as ointments, creams or lotions, or as a transdermal patch.

[0201] The composition can also be administered by inhalation in the form of a spray from a pressurized dispenser or container containing a propellant such as carbon dioxide gas, hydrofluoroalkane, nitrogen, propane or other suitable gas or gas combination. The pharmaceutical composition can be in a form suitable for administration by inhalation or insufflation.

[0202] The pharmaceutical composition may be adapted to provide sustained release of the active agent.

[0203] The pharmaceutical composition can be in unit dosage form. In this form, the pharmaceutical composition can be prepared as a unit dose containing an appropriate amount of the active agent. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0204] According to a third aspect of the invention, a method for treating or preventing a disease, disorder or condition associated with spleen tyrosine kinase activity in an individual is provided, the method comprising administering to the individual 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 the central nervous system or be in the central nervous system. In another embodiment, the disease, disorder or condition associated with spleen tyrosine kinase activity may affect the peripheral nervous system or be in the peripheral nervous system. The disease, disorder or condition associated with spleen tyrosine kinase activity may be associated with the brain of the individual. The disease, disorder or condition associated with spleen tyrosine kinase activity may be associated with an area outside the brain of the individual.

[0205] According to a fourth aspect of the invention, a method for treating or preventing one or more of the following is provided: 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 I diabetes), inflammation (particularly dermatitis, fasciitis or lung inflammation), Graves' disease, lung disease or disorder (including Hantavirus pulmonary syndrome), kidney disease (including glomerulonephritis), acquired bullous epidermolysis bullosa lysis, Wiskott-Aldrich syndrome, agammaglobulinemia, Nasu-Hakola disease, allergies (including drug allergies, especially co-trimoxazole allergies and carbapenem allergies), microbial infections (especially bacterial infections, more especially Mycobacterium abscessus infections), fungal infections (including chromoblastomycosis and mycosis), autoimmune allergic diseases, bleeding disorders, thrombocytopenia, bone or skeletal disorders (including Mei-Nielsen syndrome and oto-palatine-digital (toe) syndrome spectrum disorders), nail diseases, chronic mucocutaneous candidiasis, nervous system diseases or disorders (including Alzheimer's disease, dementia, multiple sclerosis and Parkinson's disease), neuroinflammatory diseases, stroke, craniocerebral injury and subarachnoid hemorrhage); the method comprises administering to the individual an effective amount of the compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of the second aspect.

[0206] According to a fifth aspect of the present invention, there is provided a compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof for use in the preparation of a medicament for treating or preventing a disease, disorder or condition associated with spleen tyrosine kinase activity in an individual. The disease, disorder or condition associated with spleen tyrosine kinase activity may affect the central nervous system or be in the central nervous system. In another embodiment, the disease, disorder or condition associated with spleen tyrosine kinase activity may affect the peripheral nervous system or be in the peripheral nervous system. The disease, disorder or condition associated with spleen tyrosine kinase activity may be associated with the brain of the individual. The disease, disorder or condition associated with spleen tyrosine kinase activity may be associated with an area outside the brain of the individual.

[0207] According to the sixth aspect of the present invention, there is provided a use of the compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for treating or preventing one or more of the following in an individual: 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 fatty liver disease and hepatocellular carcinoma), fibrosis (especially peritoneal fibrosis), periodontal disease (for example, diseases associated with alveolar bone resorption), diabetes (especially type I diabetes), inflammation (especially dermatitis, fasciitis or lung inflammation), Graves disease, The invention also includes, but is not limited to, pulmonary diseases or disorders (including Hantavirus pulmonary syndrome), renal diseases (including glomerulonephritis), epidermolysis bullosa acquired, Wiskott-Aldrich syndrome, agammaglobulinemia, Nasu-Hakola disease, allergies (including drug allergies, in particular trimethoprim-sulfamethoxazole allergy and carbapenem allergy), microbial infections (in particular bacterial infections, more particularly Mycobacterium abscessus infections), fungal infections (including chromoblastomycosis and mycosis fungoides), autoimmune allergic diseases, bleeding disorders, thrombocytopenia, bone or skeletal disorders (including Meissler-Nietzschitz syndrome and oto-palatal-digital syndrome spectrum disorders), nail diseases, chronic mucocutaneous candidiasis, nervous system diseases or disorders (including Alzheimer's disease, dementia and Parkinson's disease), neuroinflammatory diseases, stroke, head injury and subarachnoid hemorrhage.

[0208] According to a seventh aspect of the present invention, a compound of the first aspect or a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutical composition of the second aspect is provided for treating or preventing a disease, disorder or condition associated with spleen tyrosine kinase activity. A disease, disorder or condition associated with spleen tyrosine kinase activity may affect the central nervous system or be in the central nervous system. In another embodiment, a disease, disorder or condition associated with spleen tyrosine kinase activity may affect the peripheral nervous system or be in the peripheral nervous system. A disease, disorder or condition associated with spleen tyrosine kinase activity may be associated with the brain of an individual. A disease, disorder or condition associated with spleen tyrosine kinase activity may be associated with an area outside the brain of an individual.

[0209] According to the eighth 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 treating or preventing one or more of the following: 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 fatty liver disease and hepatocellular carcinoma), fibrosis (especially peritoneal fibrosis), periodontal disease (for example, diseases associated with alveolar bone resorption), diabetes (especially type I diabetes), inflammation (especially dermatitis, fasciitis or lung inflammation), Graves disease, The invention also includes, but is not limited to, pulmonary diseases or disorders (including Hantavirus pulmonary syndrome), renal diseases (including glomerulonephritis), epidermolysis bullosa acquired, Wiskott-Aldrich syndrome, agammaglobulinemia, Nasu-Hakola disease, allergies (including drug allergies, in particular trimethoprim-sulfamethoxazole allergy and carbapenem allergy), microbial infections (in particular bacterial infections, more particularly Mycobacterium abscessus infections), fungal infections (including chromoblastomycosis and mycosis fungoides), autoimmune allergic diseases, bleeding disorders, thrombocytopenia, bone or skeletal disorders (including Meissler-Nietzschitz syndrome and oto-palatal-digital syndrome spectrum disorders), nail diseases, chronic mucocutaneous candidiasis, nervous system diseases or disorders (including Alzheimer's disease, dementia and Parkinson's disease), neuroinflammatory diseases, stroke, head injury and subarachnoid hemorrhage.

[0210] The disease, disorder or condition associated with spleen tyrosine kinase activity may be selected from one or more of the following: 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 I diabetes), inflammation (particularly dermatitis, fasciitis or lung inflammation), Graves' disease, lung diseases or disorders (including Hantan Viral pulmonary syndrome), renal disease (including glomerulonephritis), acquired epidermolysis bullosa, Wiskott-Aldrich syndrome, agammaglobulinemia, Nasu-Hakola disease, allergies (including drug allergies, especially trimethoprim-sulfamethoxazole allergies and carbapenem allergies), microbial infections (especially bacterial infections, more especially Mycobacterium abscessus infections), fungal infections (including chromoblastomycosis and mycosis), autoimmune allergic diseases, bleeding disorders, thrombocytopenia, bone or skeletal disorders (including Mei-Nielsen syndrome and oto-palatal-digital (toe) syndrome spectrum disorders), nail diseases, chronic mucocutaneous candidiasis, nervous system diseases or disorders (including Alzheimer's disease, dementia and Parkinson's disease), neuroinflammatory diseases, stroke, craniocerebral injury and subarachnoid hemorrhage. Diseases, disorders or conditions associated with spleen tyrosine kinase activity may affect the central nervous system or be in the central nervous system.

[0211] In this specification and claims, the word "comprising" and its derivatives (including "comprises" and "comprise") include each stated integer, but do not exclude the inclusion of one or more additional integers.

[0212] 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 to complete recovery. The term "treatment" includes ameliorating the symptoms of a disease, disorder or condition, or lessening the severity of a disease, disorder or condition. Similarly, "prevention" does not necessarily mean that an individual will never be infected with a disease, disorder or condition. "Prevention" can be considered to reduce the likelihood of an onset of a disease, disorder or condition, or to prevent or otherwise reduce the risk of developing a disease, disorder or condition.

[0213] As used herein, the term "subject" or "individual" or "patient" may refer to any individual for whom treatment is desired, particularly a vertebrate individual, and even more particularly a mammalian individual. Suitable vertebrates include, but are not limited to, primates, avian, livestock animals (e.g., sheep, cattle, 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 individual is a human.

[0214] As used herein, "effective amount" refers to the amount of the relevant active agent administered that is sufficient to at least partially achieve the desired response, or prevent the occurrence of symptoms of the disease, disorder or condition being treated, or cause the deterioration of the symptoms to stop, or treat and alleviate or at least reduce the severity of the symptoms. The amount may vary depending on the following factors: 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 desired degree of treatment / prevention, the formulation of the composition, and the assessment of the medical condition. It is expected that the "effective amount" will fall within a wide range that can be determined by conventional tests. For example, the effective amount associated with human patients can be in the range of about 0.1ng / kg body weight to 1g / kg body weight per dose, or in the range of about 100ng to 100mg per kg body weight per dose. The dosage regimen can be adjusted to provide the best therapeutic response. For example, several doses can be administered every day, every two weeks or every week, or at other suitable time intervals, or the dosage can be reduced proportionally as indicated by the situation. Decisions about dosage, etc. will be within the skill range of the practicing physician or veterinarian responsible for the care of the patient.

[0215] The compound of formula (I) (or a pharmaceutically acceptable salt or prodrug thereof) can be administered together with another active agent. For example, if the disease, disorder or condition being treated or prevented is cancer, the compound of formula (I) can be administered together with other cancer drugs (such as docetaxel, 5-fluorouracil, etc.).

[0216] In a ninth aspect, the present invention relates to a method for synthesizing a compound of formula (I) of the first aspect, the method comprising the following steps:

[0217] (a) Make and Coupled to provide

[0218] (b) in the presence of a catalyst With R 23 -R 4 Coupled to provide

[0219] (c) From Removing PG to provide a compound of formula (I);

[0220] in:

[0221] 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 As defined in the first aspect;

[0222] R 20 and R 22 One of them is OH, and the other is a leaving group;

[0223] PG is a protecting group; and:

[0224] οR 21 is a leaving group; and R 23 is in R 4 Middle connection R 23 a group providing an activated carbon at the carbon of

[0225] οR 23 is a leaving group; and R 21 Is connecting R 21 Provide an activated carbon group at the carbon of.

[0226] As used herein, the term "leaving group" may refer to, for example, a halogen (such as F, Cl, Br or I) or an active oxygen group (such as a sulfonyloxy group, including tosyloxy, trifluoromethylsulfonyloxy or methylsulfonyloxy).

[0227] As used herein, the term "protecting group" in relation to the above PG refers to an atomic group that masks, reduces or prevents the reactivity of the nitrogen atom to which the PG is attached. Examples of protecting groups can be found in "Greene's Protective Groups in Organic Synthesis", (Wiley, 4th edition, 2007). In one embodiment, PG may be a Boc or Cbz group.

[0228] In one embodiment, R 20 and R 22One of them is OH and the other is Cl, Br, I, or an active oxygen group (such as a sulfonyloxy group including toluenesulfonyloxy, trifluoromethylsulfonyloxy or methylsulfonyloxy).

[0229] In one embodiment of step (b), the catalyst is a palladium catalyst. Exemplary palladium catalysts may include palladium catalysts with phosphine ligands. Exemplary catalysts may include tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II), or (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0230] 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 a sp2-sp2 coupling reaction.

[0231] In one embodiment, R 23 is with R 4 The metal or metalloid may be selected from a boron, zinc or tin group or a Grignard reagent, in particular a boron group (such as a boronic acid or a boric ester). In one embodiment, R 21 is a metal or metalloid attached to a carbon atom. The metal or metalloid may be selected from a boron, zinc or tin group or a Grignard reagent, in particular a boron group (such as a boronic acid or a boric ester).

[0232] In step (c), the skilled person will be able to determine the appropriate conditions for removing the protecting group. For example, if PG is Boc, step (c) may include treatment with trifluoroacetic acid. If PG is Cbz, step (c) may include treatment with hydrobromic acid.

[0233] In one embodiment, step (b) may comprise making R 24 -R 5 and Coupling, where R 24 is a leaving group (such as a halogen (including fluorine, chlorine, bromine or iodine) or an active oxygen group (such as a sulfonyloxy group, including toluenesulfonyloxy, trifluoromethylsulfonyloxy or methylsulfonyloxy)), and wherein R 5 Via R 4 The nitrogen atom in R 4 In this embodiment, R in step (c) 4 Is R 5 Replaced by R 4 .

[0234] 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 medicaments of the fifth and sixth aspects of the present invention may be pharmaceutical compositions as described above.

[0235] Within the scope of the present invention, any feature described herein may be combined with any one or more other features described herein, in any combination.

[0236] Preferred features, embodiments and variants of the present invention can be seen from the following examples, which provide sufficient information for those skilled in the art to implement the present invention. The following examples should not be considered to limit the scope of the foregoing summary of the invention in any way. Example

[0237] Compound synthesis

[0238] abbreviation

[0239] Throughout the Examples section, various abbreviations are used. Although most abbreviations are understood by those skilled in the art, some are explained below.

[0240] -Bn: benzyl

[0241] -Boc: tert-butyloxycarbonyl

[0242] -Cbz: carboxybenzyl

[0243] -DMSO: dimethyl sulfoxide

[0244] -HPLC: High Performance Liquid Chromatography

[0245] -H 2 O: Water

[0246] -Hz: Hertz

[0247] -LCMS: Liquid chromatography-mass spectrometry

[0248] -MeCN: acetonitrile

[0249] -PG: Protective group

[0250] -Prep: Preparation

[0251] -Rac: racemic

[0252] -Rel: relative

[0253] -UPLC: Ultra-Performance Liquid Chromatography

[0254] General approach:

[0255] Purification method:

[0256] Method 1:

[0257] Silica gel chromatography techniques include automated techniques, or manual chromatography on prepacked columns, hand-packed flash columns, or ionic solid phase extraction cartridges.

[0258] Method 2:

[0259] Preparative HPLC was performed using the following conditions: Shimadzu UFLC XR. Column: Xterra Prep MS C18OBD, 19×150 mm, 10 μm. Column temperature: ambient temperature. Mobile phase A: H 2 O + 0.05% formic acid. Mobile phase B: MeCN. Flow rate: 15 mL / min. Mobile phase gradient and run time varied depending on the compound.

[0260] Method 3:

[0261] Preparative HPLC was performed using the following conditions: Shimadzu UFLC XR. Column: Xterra Prep MS C18OBD, 19×150 mm, 10 μm. Column temperature: ambient temperature. Mobile phase A: H 2 O + 10 mM ammonium bicarbonate. Mobile phase B: MeCN. Flow rate: 15 mL / min. Mobile phase gradient and run time varied depending on the compound.

[0262] 1 H NMR method:

[0263] 1H 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 the residual solvent signal (1H: δ 7.26 for chloroform-d; 1H: δ 2.50 for DMSO-d6; 1H: δ 3.31 for methanol-d4, 1H: δ 4.79 for deuterium oxide). The 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.

[0264] LC-MS method:

[0265] Method 1:

[0266] Shimadzu LCMS-2020Nexera UHPLC, column: Xterra MS-C18, 2.1×50 mm, 2.5 μm. Column temperature: 40°C. Mobile phase A: H 2O + 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); run end 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 Shimadzu LCMS-2020.

[0267] Method 2:

[0268] Shimadzu LCMS-2020Nexera UHPLC, column: Xterra MS-C18, 2.1×50 mm, 3.5 μm. Column temperature: 40°C. Mobile phase A: H 2 O + 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); run end 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 Shimadzu LCMS-2020.

[0269] Method 3:

[0270] Shimadzu LCMS-2020 Nexera UHPLC. Column: X-Bridge BEH C18, 2.1×50 mm, 2.5 microns. 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 electrospray ionization in positive / negative mode on Shimadzu LCMS-2020.

[0271] Method 4:

[0272] Water Acquity UPLC with binary solvent manager, and PDA detector and Acquity QDA high performance mass spectrometer. 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; run ended at T = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, analysis time 4 min. Column 1: X-Bridge C18 50×2.1mm, 2.5 micron; Column 2: YMC tri-art C18 50×2.0mm, 1.9 micron; Column 3: X-Bridge C18 50×4.6mm, 3.5 micron; Column 4: Sunfire C18 150×4.6mm, 3.5 micron; Column 5: YMC C1850×2.0mm, 1.9 micron; Column 6: X-Bridge C18 250×4.6mm, 5.0 micron; Column 7: X-Bridge BEH C18 50×2.1mm, 2.5 micron; Column 8: X-Bridge C1850×2.5mm, 2.5 micron; Column 9: Xtimate C18 50×2.1, 1.8 micron.

[0273] Method 5:

[0274] Agilent 1200 LCMS 6130, column: Atlantis dC18, 4.6×50 mm, 5 μm. Column temperature: 25°C. Mobile phase A: H 2 O + 0.1% formic acid, mobile phase B: MeCN. Mobile phase gradient details: T = 0 minutes (95% A, 5% B); T = 2.5 minutes (5% A, 95% B); gradient to T = 4 minutes (5% A, 95% B); run end at T = 4.5 minutes (95% A, 5% B). Flow rate: 1.5 mL / min, analysis time 6.0 minutes. UV detection: maximum absorption.

[0275] Method 6:

[0276] Agilent 1290 Infinity II LCMS 6130, column: X-Bridge C8, 4.6×50 mm, 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); run ended at T=8.5 min (95% A, 5% B). Flow rate: 1.0 mL / min, analysis time 10.0 min. UV detection: maximum absorption.

[0277] Method 7:

[0278] Agilent 1200 series. Column: X-Bridge C18 50×4.6 mm, 3.5 microns. 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, analysis time 10 min. UV detection: maximum absorption.

[0279] Method 8:

[0280] Waters Alliance 2690 and 996PDA detector with 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, analysis time 17 min. Column 1: Welch C18 4.6 x 150 mM, 5 micron; Column 2: Sunfire C18, 150 x 4.6 mM, 3.5 micron; Column 3: X-Bridge C18, 250 x 4.6 mM, 5 micron.

[0281] Method 9:

[0282] Aquity, with PDA detector and SQ detector. Column: X-Bridge C18, 50×2.1 mM, 2.5 micron. 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); run ended at T=4 min (97% A, 3% B). Flow rate: 0.5 mL / min, analysis time 4 min.

[0283] HPLC Method:

[0284] Waters HPLC-e2695 with Waters 2998-PDA detector. Column: X-Bridge C18, 150×4.6 mm, 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); run ended at T=17 min (90% A, 10% B), flow rate: 1 mL / min, analysis time 17 min.

[0285] General route

[0286] General route overview

[0287] The compounds of formula (I) can be prepared by the following general methods. 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 configure R 4 Before removing the protecting group (PG) on nitrogen, R 4 The group is modified (for example, to provide R 5 group).

[0288]

[0289] Various compounds of formula (I) can be prepared using readily available starting materials employing techniques available in the art using the synthetic routes described below. The methods described can be readily adapted to provide other compounds falling within the scope of formula (I).

[0290] The following examples are intended to illustrate embodiments and should not be construed as limiting in any way.Additional compounds can be prepared using similar reaction schemes and methods.

[0291] General Route 1 - Naphthyridine

[0292]

[0293] For example, in the above schemes, the steps labeled "A" are the following general procedure A. Similarly, the steps labeled "B" are the following general procedure B, and so on. The substituents are as defined above. PG is a protecting group.

[0294] General Route 2 - Quinoxaline and Quinoline

[0295]

[0296] For example, in the above schemes, steps labeled "E" are the following General Procedure E. Similarly, steps labeled "F" are the following General Procedure F, and so on. Substituents are as defined above. PG is a protecting group.

[0297] General Route 3 - Quinazoline

[0298]

[0299] For example, in the above schemes, the steps labeled "J" are the following General Procedure J. The substituents are as defined above. PG is a protecting group.

[0300] General Procedure A

[0301]

[0302] To a solution of the alcohol (1.2 eq) in acetonitrile (0.05-0.1 M) cooled to 0° C., sodium hydride (57-63% oil dispersion) (2.0 eq) was added portionwise and the reaction was stirred for 5 min. After this, the appropriate heteroaryl chloride (1.0 eq) was added and the reaction was stirred at room temperature for 1-5 h.

[0303] 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.

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314] General Procedure B

[0315]

[0316] Tetrakis(triphenylphosphine)palladium (0.1 equivalent), sodium carbonate (3.0 equivalents), appropriate boronic acid / boronic ester (1.2-1.5 equivalents) and appropriately substituted heteroaryl halide (1.0 equivalents) are added to a microwave vial. The vial is evacuated and backfilled with nitrogen. This is repeated twice above, and then a degassed solution of 1,4-dioxane / water (0.1-0.4M, 10:1 ratio) is added. The reaction is heated at 135 ° C for 30 minutes to 1 hour under microwave radiation. The cooled reaction mixture is distributed between water and ethyl acetate. The water layer is further extracted with ethyl acetate, and the combined organic matter is washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate and concentrated. The residue is purified by standard purification methods 1, 2 or 3, or enters the next step as a crude product, wherein the protecting group is removed using any of the following conditions:

[0317] Boc deprotection

[0318] Condition 1: To a solution of the protected intermediate (1.0 equiv) in dichloromethane (0.05-0.2 M) was added trifluoroacetic acid (6-60 equiv). The reaction mixture was stirred at room temperature for 1-24 hours. After the starting material was consumed, the reaction mixture was purified using one of the standard purification methods.

[0319] Condition 2: A solution of the intermediate (1.0 eq.) 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 hours. The solvent was removed under reduced pressure and the reaction mixture was purified using one of the standard purification methods.

[0320] Cbz deprotection

[0321] To the protected intermediate (1.0 equiv.) was added a solution of hydrobromic acid (30 wt. % in acetic acid, 25-50 equiv.) and the resulting solution was stirred at room temperature for 10 minutes. After this, the reaction mixture was treated with hydrochloric acid (1M 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.

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347] General Procedure C

[0348]

[0349] In a microwave vial, a solution of the appropriate heteroaryl halide (1.0 eq.) in 1,4-dioxane / water (0.1-0.4 M, ratio 1:5–1:10) was degassed with nitrogen for 5 minutes. Sodium carbonate (3.0 eq.), tetrakis(triphenylphosphine)palladium (0.1 eq.), and the appropriate pinacol boronate (1.5 eq.) were added. The reaction was heated at 130-135° C. for 1 hour under microwave irradiation. 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 crude material was purified using Purification Method 1.

[0350]

[0351]

[0352]

[0353]

[0354] General Procedure D

[0355]

[0356] When using alkyl halide starting materials:

[0357] To a solution of the heterocyclic starting material (1.0 equiv) and the appropriate alkyl halide (5.0-10.0 equiv) in N,N-dimethylformamide (0.05-0.3 M) was added sodium hydride (57-63% oil dispersant) (1.0-3.0 equiv) and the reaction mixture was stirred at room temperature for 1-24 hours. 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 purified by standard purification methods 1, 2 or 3 or the crude product was taken to the deprotection step.

[0358] When using an alkyl tosylate or alkyl methanesulfonate starting material:

[0359] Cesium carbonate (1.0-3.0 equivalents) is added to a solution of the heterocyclic starting material (1.0 equivalents) and the appropriate alkyl tosylate or alkyl methanesulfonate (1.0-10.0 equivalents) in dimethyl sulfoxide (0.05-0.3M). The reaction is heated to 110°C for 1-24 hours. Water is added and the product is extracted with ethyl acetate. The combined organics are washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate and concentrated. The residue is purified by standard purification methods 1, 2 or 3, or is used crude and the protecting group is removed using any of the following conditions:

[0360] Boc deprotection conditions 1: To a solution of the protected intermediate (1.0 equiv) in dichloromethane (0.05-0.2 M) was added trifluoroacetic acid (6-60 equiv). The reaction mixture was stirred at room temperature for 1-24 hours. After the starting material was consumed, the reaction mixture was purified using one of the standard purification methods.

[0361] Boc deprotection conditions 2: A solution of the intermediate (1.0 eq.) 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 hours. The solvent was removed under reduced pressure and the reaction mixture was purified using one of the standard purification methods.

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379] General ProcedureE

[0380]

[0381] Triethylamine (2.5 eq.) and methanesulfonyl chloride (1.2 eq.) were added to a solution of alcohol (1.0 eq.) in dichloromethane (0.1-0.2 M) at room temperature. After 2-15 hours, the reaction mixture was partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate, and concentrated. Purification method 1 was used to purify the crude material.

[0382] General Procedure F

[0383]

[0384] To a solution of heteroaryl bromide (7-bromoquinoxaline-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) (0.1-0.4 M) is added cesium carbonate (3.0 equiv). The reaction mixture is heated at 100°C for 4-16 hours. The cooled reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is extracted with ethyl acetate, and the combined organics are washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate and concentrated in vacuo. The residue is purified using Purification Method 1.

[0385]

[0386]

[0387]

[0388] General Procedure G:

[0389]

[0390] 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 (0.1-0.5 M, 4:1 ratio) was added potassium phosphate (3.0 equiv) followed by [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (Pd(dppf)Cl 2 ·CH 2 Cl 2 ) (5-10 mol %). The reaction mixture was sealed and heated to 90-120° C. over 30 minutes to 4 hours. The cooled reaction mixture was diluted with 2M aqueous sodium hydroxide solution or saturated brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate / magnesium sulfate and concentrated. The residue was purified by standard purification methods 1, 2 or 3, or used crude, and the protecting group was removed using any of the following conditions:

[0391] To a solution of the protected intermediate (1.0 equiv) in dichloromethane (0.05-0.2 M) is added trifluoroacetic acid (6.0-60 equiv). The reaction mixture is stirred at room temperature for 1-24 hours. After the starting material is consumed, the reaction mixture is purified using one of the standard purification methods.

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399] General Procedure H:

[0400]

[0401] To a degassed solution of heteroaryl halide (1.0 equiv) and aryl boronic acid / ester (1.1-1.25 equiv) in tetrahydrofuran / 2M aqueous sodium carbonate solution (0.1-0.5 M, 10:1 ratio) was added methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos Pd G3) (2-10 mol%). The reaction mixture was sealed and heated to 135° C. for 1 hour. The cooled reaction mixture was diluted with 2M aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate / magnesium sulfate and concentrated. The residue was purified by standard purification methods 1, 2 or 3, or by taking it as a crude product and the protecting groups were removed using any of the following conditions:

[0402] Condition 1: To a solution of the protected intermediate (1.0 equiv) in dichloromethane (0.05-0.2 M) was added trifluoroacetic acid (6.0-60 equiv). The reaction mixture was stirred at room temperature for 1-24 hours. After the starting material was consumed, the reaction mixture was purified using one of the standard purification methods.

[0403] Condition 2: A solution of the intermediate (1.0 eq.) 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 hours. The solvent was removed under reduced pressure and the reaction mixture was purified using one of the standard purification methods.

[0404]

[0405]

[0406]

[0407]

[0408]

[0409] General Procedure I:

[0410]

[0411] Boc deprotection

[0412] Condition 1: To a solution of the protected intermediate (1.0 equiv) in dichloromethane (0.05-0.2 M) was added trifluoroacetic acid (6.0-60 equiv). The reaction mixture was stirred at room temperature for 1-24 hours. After the starting material was consumed, the reaction mixture was purified using one of the standard purification methods.

[0413] Condition 2: A solution of the intermediate (1.0 eq.) 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 hours. The solvent was removed under reduced pressure and the reaction mixture was purified using one of the standard purification methods.

[0414] Cbz deprotection

[0415] To the protected intermediate (1.0 eq.) was added hydrobromic acid solution (30 wt. %, 25-50 eq.) and the resulting solution was stirred at 20° C. for 10 minutes. After this, the reaction mixture was treated with hydrochloric acid (1M aqueous solution) and the resulting mixture was extracted with dichloromethane. The aqueous phase was neutralized with aqueous sodium hydroxide solution 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.

[0416]

[0417]

[0418] General ProcedureJ

[0419]

[0420] To a solution of alcohol (1.2 eq) in acetonitrile (0.05-0.1 M) cooled to 0°C, sodium hydride (57-63% oil dispersant, 2.0 eq) was added in portions and the reaction was stirred for 5 minutes. After this, the appropriate heteroaryl chloride (1.0 eq) was added and the reaction was stirred at room temperature for 1-5 hours. The reaction mixture was quenched by slowly adding 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. Purification method 1 was used to purify the crude material.

[0421] Table 15 - Analytical data for compounds synthesized by General Method J:

[0422]

[0423] Synthesis of key building blocks

[0424] Synthesis of 1-[(Dibenzylamino)methyl]cyclopropan-1-ol

[0425]

[0426] Under nitrogen, tetraisopropyl titanate (4.0 mL, 13.4 mmol) and (ethyl) magnesium bromine (2 M in tetrahydrofuran, 100 mL, 201.2 mmol) were added dropwise to a suspension of ethyl 2-(dibenzylamino)acetate (19.0 g, 67.1 mmol) in tetrahydrofuran (60 mL) cooled to 0 ° C. The reaction was stirred at room temperature for 2 hours. 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 column chromatography on silica gel with a gradient elution of 10-15% ethyl acetate / petroleum ether to obtain 1-[(dibenzylamino)methyl]cyclopropane-1-ol (14.0 g, 52.4 mmol, 78% yield) as a colorless solid. LCMS (method 5): retention time = 1.44 minutes, [MH] + = 268.

[0427] Synthesis of 1-[(Benzylamino)methyl]cyclopropan-1-ol

[0428]

[0429] 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) was added palladium (II) hydroxide (20% loading on wet support, 640 mg, 0.46 mmol) under nitrogen. A hydrogen balloon was attached and the reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through 1% paraffin wax using methanol. The filtrate was concentrated. The reaction was repeated on the same scale, filtered and combined with the first reaction. The crude reaction mixture was basified with 28% ammonia solution, 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]cyclopropane-1-ol (8.0 g, 45.1 mmol, 94% yield) as a light yellow liquid. No purification was performed, and the product was used crude in the next step. LCMS (method 5): retention time = 0.92 minutes, [MH] + = 178.

[0430] Synthesis of [(5S)-7-Benzyl-4-oxa-7-azaspiro[2.5]octan-5-yl]methanol

[0431]

[0432] To a suspension of 1-[(benzylamino)methyl]cyclopropane-1-ol (8.0g, 45.1mmol) in toluene (30mL), (R)-(-)-epichlorohydrin (5.4mL, 69.2mmol) and lithium perchlorate (4.8g, 45.1mmol) were added. The reaction was stirred at room temperature for 72 hours. Then sodium methoxide (6.1g, 112.8mmol) was added, and the reaction was stirred at room temperature for another 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with 40-50% ethyl acetate / petroleum ether gradient elution to obtain [(5S)-7-benzyl-4-oxa-7-azaspiro [2.5] octan-5-yl] methanol (4.2g, 18.0mmol, 40% yield) in a light brown jelly. 1H NMR (400 MHz, 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, 1H), 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 minutes, [MH]+ = 234.

[0433] Synthesis of [(5S)-4-oxa-7-azaspiro[2.5]octan-5-yl]methanol

[0434]

[0435] 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) was added palladium(II) hydroxide (20% loading on wet support, 400 mg, 0.29 mmol) under nitrogen, a hydrogen balloon was attached, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through 4% paraffin wax with methanol wash. 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 (400 MHz, methanol-d4) δ 3.69-3.61 (m, 1H), 3.45 (dd, 2H), 3.19 (dd, 1H), 2.91 (ddd, 1H), 2.57 (dd, 1H), 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 minutes, [MH] + = 144.

[0436] Synthesis of tert-butyl (5S)-5-(hydroxymethyl)-4-oxa-7-azaspiro[2.5]octane-7-carboxylate

[0437]

[0438] To [(5S) -4- oxa -7- azaspiro [2.5] octan -5- yl] methanol (1.4g, 9.8mmol) in a solution of dichloromethane (10mL) and water (20mL) sodium hydroxide (390mg, 9.8mmol) was added. Dichloromethane (10mL) solution of di-tert-butyl dicarbonate (2.1g, 9.8mmol) 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 layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with 10-15% ethyl acetate / petroleum ether gradient elution to obtain (5S) -5- (hydroxymethyl) -4- oxa -7- azaspiro [2.5] octane -7- carboxylic acid tert-butyl ester (1.1g, 4.5mmol, 46% yield) in a slurry 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 minutes, [(M-100)H]+ = 144.

[0439] Synthesis of tert-butyl (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylate

[0440]

[0441] To the dichloromethane (30mL) solution of (S)-N-boc-2-hydroxymethylmorpholine (3.4g, 15.7mmol) cooled to 0 DEG C, add Dess-Martin oxidant (8.0g, 18.8mmol), and the reaction is stirred at room temperature for 16 hours. The reaction mixture is quenched with saturated sodium bicarbonate aqueous solution and diluted with dichloromethane. The resulting precipitation is removed by filtration. The product is extracted with dichloromethane. The combined organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated. Residue is purified by column chromatography on silica gel with 5-80% tert-butyl methyl ether / heptane gradient elution to obtain (2S)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (2.2g, 7.5mmol, 48% yield) as colorless residue.

[0442] Methylmagnesium chloride (3M in tetrahydrofuran, 3.9 mL, 11.7 mmol) was added to a solution of (2S)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (2.1 g, 9.8 mmol) in tetrahydrofuran (30 mL) cooled to 0 ° C, and the reaction was stirred at room temperature for 16 hours. The crude reaction mixture was quenched with saturated aqueous ammonium chloride, and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with a gradient elution of 5-60% tert-butyl methyl ether / heptane to obtain (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylic acid tert-butyl ester (999 mg, 4.1 mmol, 42% yield) as a diastereoisomer mixture of 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). 3:2 ratio of diastereoisomer mixture, but the signal assignment was 1:1 ratio.

[0443] Synthesis of 1-(Benzylamino)-2-methylpropan-2-ol

[0444]

[0445] 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 in batches. 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 layer was dried over anhydrous sodium sulfate and concentrated to obtain 1- (benzylamino) -2-methylpropan-2-ol (14.6 g, 81.4 mmol, 86% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 7.36-7.27 (m, 4H), 7.26-7.17 (m, 1H), 4.20 (br s, 1H), 3.72 (s, 2H), 2.36 (s, 2H), 1.09 (s, 6H). LCMS (Method 5): Retention time = 1.46 minutes, [MH]+ = 180.

[0446] Synthesis of [(2S)-4-Benzyl-6,6-dimethylmorpholin-2-yl]methanol

[0447]

[0448] 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 methanol solution, 14.2 mL, 66.9 mmol) was added and the reaction 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 column chromatography on silica gel with a gradient elution of 30-50% ethyl acetate / 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. NMR (400 MHz, DMSO-d6): δ7.33-7.25 (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), 2.81–2.79 (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.

[0449] Synthesis of [(2S)-6,6-dimethylmorpholin-2-yl]methanol

[0450]

[0451] To a solution of [(2S)-4-benzyl-6,6-dimethylmorpholin-2-yl]methanol (13.5 g, 57.4 mmol) in methanol (200 mL) was added palladium (II) hydroxide (20% loading on wet support, 1.4 g, 1.0 mmol) under nitrogen, a hydrogen balloon was attached, and the reaction was stirred at room temperature for 2-3 hours. The reaction mixture was filtered through eluting with methanol. 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 and the product was used crude in the next step. 1H NMR (400 MHz, DMSO-d6): δ 4.49 (br s1H), 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 minutes, [MH] + = 146.

[0452] Synthesis of tert-butyl (6S)-6-(hydroxymethyl)-2,2-dimethylmorpholine-4-carboxylate

[0453]

[0454] To a solution of [(2S)-6,6-dimethylmorpholine-2-yl]methanol (8.3g, 57.2mmol) in a mixture of dichloromethane (100mL) and water (50mL), ditert-butyl dicarbonate (12.5g, 57.2mmol) and aqueous sodium hydroxide solution (2N, 28.6mL, 57.2mmol) were added. The reaction was stirred at room temperature for 4-5 hours. The reaction mixture was quenched with ice-cold water, and the product was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with 10-20% ethyl acetate / petroleum ether gradient elution to obtain (6S)-6-(hydroxymethyl)-2,2-dimethylmorpholine-4-carboxylic acid tert-butyl ester (11.2g, 45.7mmol, 80% yield) in a slurry liquid. 1H NMR (400 MHz, 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 minutes, [(M-56)H]+ = 190.

[0455] Synthesis of (2S)-1-amino-3-(benzyloxy)propan-2-ol

[0456]

[0457] 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 hours. 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). 1H 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 minutes, [MH]+ = 182.

[0458] Synthesis of (2R)-N-[(2S)-3-(Benzyloxy)-2-hydroxypropyl]-2-chloropropionamide

[0459]

[0460] (2S) -1- amino -3- phenylmethoxy propan-2-ol (11.0g, 60.7mmol) in ethanol (90mL) solution was added dropwise (2R) -2- chloropropionic acid methyl ester (8.2g, 66.8mmol). 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 column chromatography on silica gel with 25% ethyl acetate / hexane elution to obtain (2R) -N- [(2S) -3- (benzyloxy) -2- hydroxypropyl] -2- chloropropionamide (6.2g, 22.8mmol, 38% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 272.

[0461] Synthesis of (2S,6S)-6-[(Benzyloxy)methyl]-2-methylmorpholin-3-one

[0462]

[0463] 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 wt / wt% oil dispersion, 3.7 g, 91.3 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was quenched with isopropanol (14 mL) and the mixture was stirred for 3 hours. The ... 50H + Resin (1.5g) was acidified and filtered. The filtrate was washed with water and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with 2% methanol / dichloromethane to obtain (2S, 6S)-6-[(benzyloxy)methyl]-2-methylmorpholine-3-one (3.9g, 16.6mmol, 73% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 236.

[0464] Synthesis of (2S,6S)-2-[(Benzyloxy)methyl]-6-methylmorpholine

[0465]

[0466] Under nitrogen, lithium aluminum hydride (1M solution in tetrahydrofuran, 48.5mL, 48.5mmol) was added to a solution of (2S, 6S)-2-methyl-6-(phenylmethoxymethyl)morpholine-3-one (3.8g, 16.1mmol) in tetrahydrofuran (30mL) cooled to 0°C. 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 column chromatography on silica gel eluting with 8% methanol / dichloromethane to obtain (2S, 6S)-2-[(benzyloxy)methyl]-6-methylmorpholine (2.8g, 12.7mmol, 78% yield) as a yellow oil. 1H NMR (400 MHz, 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.

[0467] Synthesis of tert-butyl (2S,6S)-2-[(Benzyloxy)methyl]-6-methylmorpholine-4-carboxylate

[0468]

[0469] To a solution of (2S, 6S)-2-methyl-6-(phenylmethoxymethyl)morpholine (2.8g, 12.7mmol) in dichloromethane (50mL) was added ditert-butyl dicarbonate (6.8g, 31.6mmol), 4-(dimethylamino)pyridine (0.1g, 0.82mmol) and triethylamine (4.2mL, 31.6mmol). The reaction was stirred at room temperature for 3 hours. The reaction mixture was poured onto water, and the product was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 8% ethyl acetate / hexane to obtain (2S, 6S)-2-[(benzyloxy)methyl]-6-methylmorpholine-4-carboxylic acid tert-butyl ester (3.2g, 9.6mmol, 76% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 266.

[0470] Synthesis of tert-butyl (2S,6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate

[0471]

[0472] 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% wet support, 1.0 g, 0.71 mmol) and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was filtered through The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel with 15-25% ethyl acetate / hexane gradient elution to obtain (2S, 6S)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester (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 minutes, [(M-56) H] + = 177.

[0473] Synthesis of (2S)-N-[(2S)-3-(Benzyloxy)-2-hydroxypropyl]-2-chloropropionamide

[0474]

[0475] In 15 minutes, (2S)-1-amino-3-phenylmethoxypropan-2-ol (10.5g, 57.9mmol) in ethanol (34mL) solution was added dropwise (2S)-2-chloropropionic acid methyl ester (7.8g, 63.7mmol). 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 column chromatography on silica gel with 2-5% methanol / dichloromethane gradient elution to obtain (2S)-N-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropionamide (8.0g, 25.9mmol, 45% yield) as a yellow liquid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 272.

[0476] Synthesis of (2R,6S)-6-[(Benzyloxy)methyl]-2-methylmorpholin-3-one

[0477]

[0478] 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 was added sodium hydride (57-63 wt / wt% oil dispersant, 4.7 g, 117.8 mmol) in portions. The reaction was stirred at 0°C for 5 minutes and then at room temperature for 6 hours. The reaction mixture was quenched with isopropanol (30 mL) and the mixture was stirred by adding in portions. 50H +The resin (50 g) was acidified. 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 column chromatography on silica gel eluting with 2-5% methanol / 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, [MH] + = 236.

[0479] Synthesis of (2S,6R)-2-[(Benzyloxy)methyl]-6-methylmorpholine

[0480]

[0481] 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 was added lithium aluminum hydride (1 M solution in tetrahydrofuran, 25.7 mL, 25.7 mmol) under nitrogen. The reaction was stirred at room temperature for 2.5 hours. The reaction was cooled to 0°C and quenched with water and then sodium hydroxide solution (1 N aqueous solution, 1 mL). The reaction was then filtered through 4% paraffin wax with dichloromethane washing thoroughly. The combined organics were washed with water, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with a 2-5% methanol / dichloromethane gradient to give (2S,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine (3.6 g, 16.3 mmol, 70% yield) as a yellow liquid. 1H NMR (400 MHz, DMSO-d6) 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.

[0482] Synthesis of tert-butyl (2S,6R)-2-[(Benzyloxy)methyl]-6-methylmorpholine-4-carboxylate

[0483]

[0484] To a solution of (2S, 6R)-2-methyl-6-(phenylmethoxymethyl)morpholine (3.6g, 16.3mmol) in dichloromethane (25mL) was added ditert-butyl dicarbonate (9.2g, 42.3mmol), 4-(dimethylamino)pyridine (120mg, 0.98mmol) and triethylamine (4.3mL, 42.3mmol). The reaction was stirred at room temperature for 3 hours. The reaction was poured onto water, and the product was extracted with ethyl acetate. The combined organic matter was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with 6-8% ethyl acetate / hexane elution to obtain (2S, 6R)-2-[(benzyloxy)methyl]-6-methylmorpholine-4-carboxylic acid tert-butyl ester (4.0g, 12.1mmol, 74% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [(M-56)H]+ = 266.

[0485] Synthesis of tert-butyl (2S,6R)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate

[0486]

[0487] 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% wet support, 1.0 g, 0.71 mmol) and the reaction was stirred at room temperature for 1.5 hours. The reaction was filtered through The filtrate was concentrated. The crude material was purified by column chromatography on silica gel with a gradient elution of 15-25% ethyl acetate / hexane to give (2S, 6R)-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylic acid tert-butyl ester (3.3 g, 14.0 mmol, 92% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 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 minutes, [(M-100) H] + = 132.

[0488] Synthesis of 3-(Benzylamino)-2,2-dimethylpropan-1-ol

[0489]

[0490] 3-amino-2,2-dimethylpropan-1-ol (10.0g, 96.9mmol) and benzaldehyde (10.8g, 101.7mmol) in benzene (170mL) solution were refluxed for 4 hours using Dean-Stark apparatus to remove water. The reaction was evaporated to obtain an oily intermediate. Sodium borohydride (5.5g, 145.1mmol) was added in three batches to a methanol (150mL) solution of the imine intermediate cooled to 0°C. The reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched with sodium hydroxide solution (6N aqueous solution, 25mL), and the solvent was evaporated. Water was added to the residue, and the product was extracted with diethyl ether. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on neutral alumina eluting with a 15-20% ethyl acetate / hexanes gradient to afford 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.

[0491] Synthesis of 3-{Benzyl[(2S)-3-(Benzyloxy)-2-hydroxypropyl]amino}-2,2-dimethylpropan-1-ol

[0492]

[0493] 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 hours. The volatiles were removed under reduced pressure and the crude material was purified by column chromatography on silica gel eluting with a 15-20% ethyl acetate / hexanes gradient 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 (400 MHz, 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 minutes, [MH]+ = 358.

[0494] Synthesis of 3-{Benzyl[(2S)-3-(Benzyloxy)-2-hydroxypropyl]amino}-2,2-dimethylpropyl methanesulfonate

[0495]

[0496] Note: The reaction was performed as 6×1 g parallel experiments. N,N-diisopropylamine (0.5 mL, 2.8 mmol) and methanesulfonyl chloride (217 μL, 2.8 mmol) were slowly added 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. The reaction was stirred at 0°C for 45 minutes, then poured onto saturated aqueous sodium bicarbonate solution, and the product was extracted with dichloromethane. The combined organic layers from 6 independent reactions were dried over anhydrous sodium sulfate and concentrated to give methanesulfonic acid 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}-2,2-dimethylpropyl ester (7.5 g, 17.2 mmol, 102% yield) as a viscous oil. Without purification, the material was used crude in the next step. LCMS (Method 4 - Column 7): Retention time = 1.89 min, [MH]+ = 436.

[0497] Synthesis of (2S)-4-Benzyl-2-[(Benzyloxy)methyl]-6,6-dimethyl-1,4-oxazepane

[0498]

[0499] Note: The reaction was performed as 7×1 g parallel experiments. Sodium hydride (57-63 wt / wt% oil dispersant, 129 mg, 3.2 mmol) was added in batches 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. The reaction was stirred at room temperature for 16 hours. The reaction mixture was poured onto 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 column chromatography on silica gel eluting with 1% ethyl acetate / hexane to give (2S)-4-benzyl-2-[(benzyloxy)methyl]-6,6-dimethyl-1,4-oxaazepine (0.9 g, 2.7 mmol, 17% yield) as a viscous oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 340.

[0500] Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-6,6-dimethyl-1,4-oxaazepane-4-carboxylate

[0501]

[0502] 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 at 200 psi in a hydrogenator for 24 hours. The reaction was filtered through eluting with methanol. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 25% ethyl acetate / hexanes to give ((2S)-2-(hydroxymethyl)-6,6-dimethyl-1,4-oxazepane-4-carboxylic acid tert-butyl ester (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 minutes, [(M-56)H]+ = 204.

[0503] Synthesis of 2-vinyl-3-phenyloxirane

[0504]

[0505] During workup, the reactions were performed in five parallel batches.

[0506] To a solution of benzaldehyde (960 μL, 9.4mmol) in tert-butanol (7mL) was added allyl bromide (2.4mL, 28.3mmol), potassium carbonate (6.5g, 47.1mmol) and tetrahydrothiophene (84 μL, 0.94mmol). 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 layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-vinyl-3-phenyl oxirane (6.0g, 41.0mmol, 87% yield) as a mixture of cis and trans isomers in a light 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).

[0507] Synthesis of rel-(1R,2R)-2-aminocyclopentan-1-ol

[0508]

[0509] 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 hours. 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 light yellow oil. No purification was performed, and the material was used crude in the next step. 1H NMR (400 MHz, 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.

[0510] Synthesis of N-[rel-(1R,2R)-2-Hydroxycyclopentyl]acetamide

[0511]

[0512] Triethylamine (7.3 mL, 52.4 mmol) was added 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, and then a solution of acetyl chloride (4.1 g, 52.4 mmol) in tetrahydrofuran (50 mL) was added dropwise. The reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered and the volatiles were removed under reduced pressure to obtain N-[rel-(1R, 2R)-2-hydroxycyclopentyl] acetamide (8.3 g, 48.7 mmol, 93% yield) as a light yellow oil. No purification was performed, and the material was used as a crude product 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.

[0513] Synthesis of rel-(3aS,6aR)-2-methyl-3aH,4H,5H,6H,6aH-cyclopenta[d][1,3]oxazole

[0514]

[0515] Under nitrogen atmosphere, maintaining the temperature between -10°C and -5°C, 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). The reaction was stirred at room temperature for 16 hours. 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). The crude material was used in the next step. 1H NMR (400MHz, DMSO-d6) δ5.66(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.

[0516] Synthesis of rel-(1R,2S)-2-aminocyclopentan-1-ol hydrochloride

[0517]

[0518] 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 to 100 °C for 1 hour. 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 light 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.

[0519] Synthesis of N-[rel-(1S,2R)-2-hydroxycyclopentyl]-4-methylbenzene-1-sulfonamide

[0520]

[0521] To a solution of rel-(1R, 2S)-2-aminocyclopent-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 column chromatography on silica gel eluting with 2% methanol / dichloromethane to obtain N-[rel-(1S, 2R)-2-hydroxycyclopentyl]-4-methylbenzenesulfonamide (10.4 g, 39.1 mmol, 57% yield) as a light yellow solid. 1H NMR (400 MHz, 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.

[0522] Synthesis of rel-(2R,4aS,7aR)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylvinyl]-octahydrocyclopenta[b][1,4]oxazine and rel-(2R,4aR,7aS)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylvinyl]-octahydrocyclopenta[b][1,4]oxazine

[0523]

[0524] To a degassed solution of 2-vinyl-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) was added palladium-tetrakis(triphenylphosphine) (450 mg, 0.39 mmol) 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 another 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 obtained was purified by column chromatography on silica gel eluting with 6% ethyl acetate / n-hexane to give a mixture of two diastereoisomeric 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-phenylvinyl]-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-phenylvinyl]-octahydrocyclopenta[b][1,4]oxazine (6.2 g, 13.6 mmol, 35% yield) as a yellow oil.

[0525] Isomer 1: rel-(2R,4aS,7aR)-4-(4-methylphenylsulfonyl)-2-[(1E)-2-phenylvinyl]-octahydrocyclopenta[b][1,4]oxazine

[0526] 1H NMR (400 MHz, 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 minutes, [MH]+ = 384.

[0527] Isomer 2: rel-(2R,4aR,7aS)-4-(4-methylphenylsulfonyl)-2-[(1E)-2-phenylvinyl]-octahydrocyclopenta[b][1,4]oxazine

[0528] 1H NMR (400 MHz, 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 minutes, [MH]+ = 384.

[0529] Synthesis of [rel-(2S,4aR,7aS)-4-(4-methylbenzenesulfonyl)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol

[0530]

[0531] To a solution of rel-(2R,4aR,7aS)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylvinyl]-octahydrocyclopenta[b][1,4]oxazine (5.5 g, 14.3 mmol) in water (10 mL) and acetone (80 mL) was added N-methylmorpholine N-oxide (3.4 g, 28.7 mmol) 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 solution (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 is poured into water, and the product is extracted with diethyl ether. The combined organic layer is dried over anhydrous sodium sulfate and concentrated. The obtained residue is dissolved in ethanol (50mL), and sodium borohydride (2.2g, 57.4mmol) is added. The reaction mixture is stirred at room temperature for 16 hours. Volatiles are removed under reduced pressure, and the residue is poured into water and extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate and concentrated. The obtained crude material is purified by column chromatography on silica gel with 25% ethyl acetate / n-hexane elution to obtain [rel-(2S, 4aR, 7aS)-4-(4-methylbenzenesulfonyl)-octahydrocyclopentadiene [b] [1,4] oxazine-2-yl] methanol (2.5g, 7.7mmol, 54% yield) as a colorless oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 312.

[0532] Synthesis of [rel-(2R,4aS,7aR)-4-(4-methylbenzenesulfonyl)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol

[0533]

[0534] To a solution of rel-(2S,4aS,7aR)-4-(4-methylbenzenesulfonyl)-2-[(1E)-2-phenylvinyl]-octahydrocyclopenta[b][1,4]oxazine (2.5 g, 6.5 mmol) in water (5 mL) and acetone (40 mL) was added N-methylmorpholine N-oxide (1.5 g, 13.0 mmol) 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 adding saturated aqueous sodium thiosulfate solution (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 layer was dried over anhydrous sodium sulfate and concentrated. The obtained 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. 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 layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel eluted with 25% ethyl acetate / n-hexane to obtain [rel-(2R, 4aS, 7aR)-4-(4-methylbenzenesulfonyl)-octahydrocyclopenta[b][1,4]oxazine-2-yl]methanol (1.6 g, 4.7 mmol, 73% yield) as a colorless oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 312.

[0535] Synthesis of [rel-(2S,4aR,7aS)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol

[0536]

[0537] 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 hours. The reaction mixture was cooled to 0°C, basified to pH = 8 by adding solid sodium hydroxide in portions 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 the crude [rel-(2S,4aR,7aS)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol (1.3 g, 8.3 mmol, 107% yield) as a light yellow oil. The crude material was used in the next step without further purification. MS: [MH]+ = 158.

[0538] Synthesis of [rel-(2S,4aS,7aR)-octahydrocyclopenta[b][1,4]oxazin-2-yl]methanol

[0539]

[0540] 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 hours. 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. The crude material was used in the next step without further purification. MS: [MH]+ = 158.

[0541] Synthesis of tert-butyl rel-(2S,4aR,7aS)-2-(Hydroxymethyl)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate

[0542]

[0543] 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). The reaction mixture was stirred at room temperature for 5 minutes, then di-tert-butyl dicarbonate anhydride (1.7 g, 7.6 mmol) was added, and the reaction mixture was stirred at room temperature for another 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 on silica gel eluting with 20% ethyl acetate / n-hexane to give rel-(2S,4aR,7aS)-tert-butyl 2-(hydroxymethyl)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate (90 mg, 0.35 mmol, 5% yield) as a light 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.

[0544] Synthesis of tert-butyl rel-(2S,4aS,7aR)-2-(Hydroxymethyl)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate

[0545]

[0546] 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) was added triethylamine (2.1 mL, 15.3 mmol) and 4-dimethylaminopyridine (62 mg, 0.51 mmol), and the reaction mixture was stirred at room temperature for 5 minutes, then di-tert-butyl dicarbonate anhydride (1.1 g, 5.1 mmol) was added, and the reaction mixture was stirred at room temperature for another 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 / n-hexane to afford rel-(2S,4aS,7aR)-2-(hydroxymethyl)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (570 mg, 2.1 mmol, 41% yield) as a light yellow oil. 1HNMR (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 minutes, [(M-100)H] + = 158. HPLC: Retention time = 6.40 minutes.

[0547] Synthesis of Oxiran-2-ylmethoxy-tri(propyl-2-yl)silane

[0548]

[0549] Triisopropyl chlorosilane (58 mL, 270.0 mmol), triethylamine (45 mL, 323.8 mmol) and N, N-dimethylaminopyridine (1.7 g, 13.5 mmol) were added to a solution of oxirane-2-ylmethanol (20.0 g, 270.0 mmol) in N, N-dimethylformamide (150 mL), and the reaction was stirred at room temperature for 4 hours. The reaction mixture was distributed between water and diethyl ether. The product was extracted with diethyl ether, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 1% ethyl acetate / hexane to obtain oxirane-2-ylmethoxy-tri(propyl-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).

[0550] Synthesis of Benzyl(2,2-Dimethoxyethyl)Amine

[0551]

[0552] Benzaldehyde (14.6 mL, 142.7 mmol) was added to a solution of 2,2-dimethoxyethylamine (15.0 g, 142.7 mmol) in methanol (150 mL), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 ° C, and sodium borohydride (8.1 g, 214.0 mmol) was added, and the reaction was stirred at room temperature for another 16 hours. A 2M aqueous hydrochloric acid solution was added to adjust to pH = 9. The volatiles were removed under reduced pressure, and 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 give benzyl (2,2-dimethoxyethyl) amine (27.0 g, 138.3 mmol, 97% yield) as a colorless liquid. The material was used crude in the next step. 1H 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 minutes, [MH]+ = 196.

[0553] Synthesis of 5-Benzyl-3-methoxy-11-methyl-10,10-bis(propan-2-yl)-2,9-dioxa-5-aza-10-siladoca-7-ol

[0554]

[0555] Benzyl (2,2-dimethoxyethyl) amine (12.3 g, 62.9 mmol) was added to a solution of oxirane-2-ylmethoxy-tri (propyl-2-yl) silane (14.5 g, 62.9 mmol) in ethanol (150 mL). 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 (propyl-2-yl) -2,9-dioxa-5-aza-10-siladodecane-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 (400 MHz, 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 minutes, [MH]+ = 426.

[0556] Synthesis of 4-Benzyl-2-methoxy-6-({[tri(propyl-2-yl)silyl]oxy}methyl)morpholine

[0557]

[0558] A mixture of 5-benzyl-3-methoxy-11-methyl-10,10-bis(propan-2-yl)-2,9-dioxa-5-aza-10-siladodecane-7-ol (26.0 g, 61.1 mmol) and p-toluenesulfonic acid (4.2 g, 24.4 mmol) was heated to 115 ° C for 16 hours. The cooled reaction mixture was diluted with saturated sodium bicarbonate aqueous solution, 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 column chromatography on silica gel eluting with 10% ethyl acetate / n-hexane to obtain 4-benzyl-2-methoxy-6-({[tri(propan-2-yl)silyl]oxy}methyl)morpholine (23.0 g, 58.4 mmol, 96% yield) as a 5:7 diastereoisomer mixture of a light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) (5:7 diastereoisomer mixture, 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 time = 2.39 & 2.68 minutes, [MH]+ = 394.

[0559] Synthesis of Benzyl 2-({[Tri(propyl-2-yl)silyl]oxy}methyl)-3,4-dihydro-2H-oxazine-4-carboxylate

[0560]

[0561] To a solution of 4-benzyl-2-methoxy-6-({[tri(propyl-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 and 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 for 2 hours using a Dean-Stark apparatus. The cooled reaction mixture was quenched by adding 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 column chromatography on silica gel eluting with 5% ethyl acetate / hexanes to give benzyl 2-methoxy-6-({[tri(propan-2-yl)silyl]oxy}methyl)morpholine-4-carboxylate (4.8 g, 11.8 mmol, 49% yield) as a light yellow oil. NMR (400 MHz, 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.

[0562] Synthesis of Benzyl 3-({[Tri(propyl-2-yl)silyl]oxy}methyl)-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate

[0563]

[0564] To a solution of benzyl 2-({[tri(propyl-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 (1M 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 saturated aqueous sodium bicarbonate solution, 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 column chromatography on silica gel eluting with 5% ethyl acetate / hexanes to give benzyl 3-({[tri(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.

[0565] Synthesis of Benzyl 3-(Hydroxymethyl)-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylate

[0566]

[0567] To a solution of 3-({[tri(propyl-2-yl)silyl]oxy}methyl)-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylic acid benzyl ester (2.8 g, 6.7 mmol) in tetrahydrofuran (140 mL) cooled to 0° C. was added tetra-n-butylammonium fluoride (TBAF, 1 M solution in tetrahydrofuran, 6.8 mL, 23.4 mmol) dropwise. The reaction mixture was stirred for 3 hours and quenched by addition of saturated aqueous sodium bicarbonate 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 column chromatography on silica gel eluting with 35% ethyl acetate / hexanes to give 3-(hydroxymethyl)-2-oxa-5-azabicyclo[4.1.0]heptane-5-carboxylic acid benzyl ester (1.7 g, 6.5 mmol, 97% yield) as a colorless oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 264.

[0568] Synthesis of rel-(2S,3R)-3-aminobutan-2-ol

[0569]

[0570] 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 hours. The solvent was removed under reduced pressure to give the crude product rel-(2S,3R)-3-aminobutan-2-ol (2.0 g, 22.4 mmol, 74% yield) as a light yellow oil and 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.

[0571] Synthesis of N-[rel-(2S,3R)-3-hydroxybutan-2-yl]-4-methylbenzene-1-sulfonamide

[0572]

[0573] At 0 ° C, triethylamine (7.5 g, 74.0 mmol) was added to a solution of rel-(2S, 3R)-3-aminobutan-2-ol (6.0 g, 67.3 mmol) in dichloromethane (100 mL), and then p-toluenesulfonyl chloride (12.8 g, 67.3 mmol) was added after 15 minutes. The reaction mixture was then allowed to warm to room temperature and continued to stir for 48 hours. The reaction mixture was poured into water and the product was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by column chromatography with 15% ethyl acetate / hexane elution to obtain 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 (400 MHz, 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 minutes, [MH]+ = 244.

[0574] Synthesis of rel-(2S,3R,6S)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylvinyl]morpholine and rel-(2S,3R,6R)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylvinyl]morpholine

[0575]

[0576] 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-vinyl-3-phenyloxirane (4.7 g, 32.1 mmol) in dichloromethane (15 mL) was added tetrakis(triphenylphosphine)palladium (280 mg, 0.25 mmol) and the reaction was stirred at room temperature for 16 hours. After this, iron(III) chloride hexahydrate (670 mg, 2.5 mmol) was added and the reaction was stirred for another 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 column chromatography on silica gel eluting with 6-8% ethyl acetate / hexane to separate the two diastereomers.

[0577] Isomer 1: rel-(2S,3R,6S)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylvinyl]morpholine: obtained as a yellow liquid (3.0 g, 8.1 mmol, 33% yield)

[0578] 1H NMR (400 MHz, 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, 1H), 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 minutes, [MH]+ = 372.

[0579] Isomer 2: rel-(2S,3R,6R)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylvinyl]morpholine: obtained as a colorless solid (2.0 g, 5.4 mmol, 22% yield).

[0580] 1H NMR (400 MHz, 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 minutes, [MH]+ = 372.

[0581] Synthesis of rel-(2S,3R,6S)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylvinyl]morpholine

[0582]

[0583] To a solution of rel-(2S, 3R, 6S)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylvinyl]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 adding a saturated aqueous sodium thiosulfate solution, and the product was extracted with ethyl acetate. The combined organic layer was 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 layer was dried over anhydrous sodium sulfate and concentrated. The crude material is dissolved in ethanol (50mL), and sodium borohydride (1.2g, 32.3mmol) is added. The reaction mixture is stirred at room temperature for 16 hours. Volatiles are removed under reduced pressure, and the crude material is poured into a saturated aqueous ammonium chloride solution, and the product is extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate and concentrated. The crude residue is purified by column chromatography on silica gel with 19% ethyl acetate / hexane elution to obtain [(rel-2R, 5R, 6S) -5,6- dimethyl -4- (4- methylbenzenesulfonyl) morpholine -2- bases] methanol (1.8g, 6.0mmol, 74%). 1H NMR (400 MHz, 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 minutes, [MH]+ = 300.

[0584] Synthesis of rel-(2S,3R,6R)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylvinyl]morpholine

[0585]

[0586] To a solution of rel-(2S, 3R, 6R)-2,3-dimethyl-4-(4-methylbenzenesulfonyl)-6-[(1E)-2-phenylvinyl]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 adding a saturated aqueous sodium thiosulfate solution, and the product was extracted with ethyl acetate. The combined organic layer was 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 layer was dried over anhydrous sodium sulfate and concentrated. The crude material was then dissolved in ethanol (32 mL), and sodium borohydride (810 mg, 21.5 mmol) was added, and the reaction was stirred at room temperature for 16 hours. Volatiles were removed under reduced pressure, and the crude material was poured into a saturated aqueous ammonium chloride solution, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by column chromatography on silica gel with 21% ethyl acetate / hexane wash-out to obtain [rel-(2S, 5R, 6S)-5,6-dimethyl-4-(4-methylbenzenesulfonyl)morpholine-2-yl]methanol (1.2 g, 4.0 mmol, 74% yield) in a yellow oil. 1H NMR (400 MHz, 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, 2H), 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 minutes, [MH]+ = 300.

[0587] Synthesis of tert-butyl rel-(2S,3R,6R)-6-(hydroxymethyl)-2,3-dimethylmorpholine-4-carboxylate

[0588]

[0589] 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% 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 mixture of 10% 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 without purification. MS: [MH] + = 146.5

[0590] Triethylamine (1.8g, 18.0mmol) and 4-(dimethylamino)pyridine (70mg, 0.6mmol) are added to the dichloromethane (40mL) solution of the crude intermediate. The reaction is cooled to 0 ° C, and di-tert-butyl dicarbonate (1.3g, 6.0mmol) is added. The reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction mixture is poured into water, and the product is extracted with dichloromethane. The combined organic layer is dried over anhydrous sodium sulfate and concentrated. The crude residue is purified by column chromatography on silica gel eluted with 12% diethyl ether / petroleum ether to obtain rel-(2S, 3R, 6R)-6-(hydroxymethyl)-2,3-dimethylmorpholine-4-carboxylic acid tert-butyl ester (400mg, 1.6mmol, 27% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [MH] + = 146. HPLC: Retention time = 5.99 minutes.

[0591] Synthesis of tert-butyl rel-(2S,3R,6S)-6-(hydroxymethyl)-2,3-dimethylmorpholine-4-carboxylate

[0592]

[0593] 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. The intermediate was not purified. MS: [MH] + = 146.

[0594] Triethylamine (1.2g, 12.0mmol) and 4-(dimethylamino)pyridine (50.0mg, 0.40mmol) were added to a dichloromethane (40mL) solution of the crude intermediate. The reaction mixture was cooled to 0 ° C, and di-tert-butyl dicarbonate (870mg, 4.0mmol) was then added. After 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 layer was dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by column chromatography on silica gel eluted with 12% diethyl ether / petroleum ether to obtain rel-(2S, 3R, 6S)-6-(hydroxymethyl)-2,3-dimethylmorpholine-4-carboxylic acid tert-butyl tert-butyl ester (160mg, 0.65mmol, 16% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [MH] + = 146. HPLC: Retention time = 5.73 minutes.

[0595] Synthesis of Ethyl 3-(Benzylamino)-3-Methylbutyrate

[0596]

[0597] 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 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by column chromatography on silica gel eluting with 20% ethyl acetate / hexanes 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.

[0598] Synthesis of 3-(Benzylamino)-3-methylbutan-1-ol

[0599]

[0600] To a solution of ethyl 3-(benzylamino)-3-methylbutanoate (12.0 g, 51.0 mmol) in tetrahydrofuran (250 mL) cooled to 0°C was added a solution of lithium aluminum hydride (2.5 M in tetrahydrofuran, 41 mL, 82.0 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was allowed to slowly warm 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 ethyl acetate washing. 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.

[0601] Synthesis of 3-{Benzyl[(2S)-3-(Benzyloxy)-2-hydroxypropyl]amino}-3-methylbutan-1-ol

[0602]

[0603] 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 column chromatography on silica gel eluting with 2% methanol / dichloromethane to give 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 (400 MHz, 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.

[0604] Synthesis of (2S)-4-Benzyl-2-[(Benzyloxy)methyl]-5,5-dimethyl-1,4-oxazepane

[0605]

[0606] 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, 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.

[0607] Sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) was added in batches to a tetrahydrofuran (5 mL) solution of the mesylate intermediate cooled to 0 ° C. The reaction mixture was allowed to warm to room temperature and continued to stir for 16 hours. After completion, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The above two-step sequence was run in 16 parallel settings. The crude residue was merged and purified by column chromatography on neutral alumina eluted with 1% ethyl acetate / hexane to obtain (2S)-4-benzyl-2-[(benzyloxy)methyl]-5,5-dimethyl-1,4-oxa-azepane (2.0 g, 5.9 mmol, 24% yield) as a yellow liquid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 341.

[0608] Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-5,5-dimethyl-1,4-oxaazepane-4-carboxylate

[0609]

[0610] 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 decarbonate (1.6 g, 7.6 mmol). The reaction mixture was placed in a hydrogenator and stirred at room temperature under 200 psi of hydrogen for 96 hours. After this time, the reaction mixture was filtered through 4% paraffin wax with a methanol wash. The filtrate was concentrated under reduced pressure and the crude material was purified by column chromatography on silica gel eluting with 25% ethyl acetate / hexanes to give tert-butyl (2S)-2-(hydroxymethyl)-5,5-dimethyl-1,4-oxazepane-4-carboxylate (900 mg, 3.5 mmol, 59% yield) as a light yellow liquid. 1H NMR (400 MHz, 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 minutes, [(M-100)H]+ = 160. HPLC: Retention time = 6.72 minutes.

[0611] Synthesis of 4-Benzyl-2-Methylmorpholine-2-Carboxylic Acid Ethyl Ester

[0612]

[0613] Under nitrogen, diisopropyl lithium amide (2.0M THF / heptane / ethylbenzene solution, 14.4mL, 28.9mmol) is added to tetrahydrofuran (50mL) solution of 4-benzylmorpholine-2-carboxylic acid ethyl ester (4.8g, 19.3mmol) cooled to -78 DEG C, and react for 30 minutes, then add iodomethane (1.2mL, 19.3mmol). The reaction is stirred for another 1 hour at -78 DEG C, and quenched by adding saturated aqueous ammonium chloride solution. The product is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material is purified by column chromatography on silica gel with 5-10% ethyl acetate / petroleum ether wash-out to obtain 4-benzyl-2-methylmorpholine-2-carboxylic acid ethyl ester (3.6g, 13.7mmol, 71% yield) in an oily state. 1H NMR (400 MHz, 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 minutes, [MH]+ = 264.

[0614] Synthesis of [(2S)-4-Benzyl-2-methylmorpholin-2-yl]methanol and [(2R)-4-Benzyl-2-methylmorpholin-2-yl]methanol

[0615]

[0616] Sodium borohydride (1.0 g, 27.3 mmol) was added to a solution of 4-benzyl-2-methylmorpholine-2-carboxylic acid ethyl ester (3.6 g, 13.7 mmol) in ethanol (50 mL) cooled to 0°C. The reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding ice, and the product was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with a gradient elution of 20-50% ethyl acetate / petroleum ether to obtain the title compound as a mixture of enantiomers. The enantiomers were separated by chiral supercritical fluid chromatography (LUX A1 (250×30 mm), 5 micron column; mobile phase: CO 2 :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 specified.

[0617] Enantiomer 1: [(2S)-4-Benzyl-2-methylmorpholin-2-yl]methanol

[0618] 1H NMR (400 MHz, 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 minutes, [MH] + = 222. SFC: Retention time = 3.76 minutes, 99% ee.

[0619] Enantiomer 2: [(2R)-4-Benzyl-2-methylmorpholin-2-yl]methanol

[0620] 1H NMR (400 MHz, 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 minutes, [MH] + = 222. SFC: Retention time = 4.35 minutes, 99% ee.

[0621] Synthesis of [(2S)-2-Methylmorpholin-2-yl]methanol

[0622]

[0623] 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% loading on wet support, 317 mg, 0.22 mmol) under nitrogen. The reaction mixture was sealed, a hydrogen balloon was attached and stirring was continued for 6 hours. After this, the reaction mixture was filtered through 4% paraffin wax with methanol wash. The crude product [(2S)-2-methylmorpholin-2-yl]methanol (590 mg 4.5 mmol, 100% yield) was carried to the next step without purification. 1H NMR (400 MHz, 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 minutes, [MH] + = 132.

[0624] Synthesis of [(2R)-2-methylmorpholin-2-yl]methanol

[0625]

[0626] [(2R)-4-Benzyl-2-methylmorpholin-2-yl]methanol (1.0 g, 4.52 mmol) was debenzylated under similar conditions to Isomer 1 to give [(2R)-2-methylmorpholin-2-yl]methanol (600 mg, 4.6 mmol, 101% yield). The crude material was taken 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.

[0627] Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-2-methylmorpholine-4-carboxylate

[0628]

[0629] To a solution of [(2S)-2-methylmorpholine-2-yl]methanol (600mg, 4.6mmol) in dichloromethane (10mL) and water (10mL) was added sodium hydroxide solution (4M, 183mg, 4.6mmol), followed by a solution of di-tert-butyl dicarbonate (1.0g, 4.8mmol) in dichloromethane (10mL), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was distributed between water and dichloromethane, and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with ethyl acetate / petroleum ether gradient elution to obtain (2S)-2-(hydroxymethyl)-2-methylmorpholine-4-carboxylate (400mg, 1.7mmol, 38% yield) as a colorless oil. 1HNMR (400 MHz, 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 minutes, [(M-100)H]+ = 132.

[0630] Synthesis of tert-butyl (2R)-2-(hydroxymethyl)-2-methylmorpholine-4-carboxylate

[0631]

[0632] [(2R)-2-methylmorpholin-2-yl]methanol (600 mg, 4.6 mmol) was subjected to an analogous procedure to [(2S)-2-methylmorpholin-2-yl]methanol (Isomer 1) to afford 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.

[0633] Synthesis of 1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethan-1-one

[0634]

[0635] To a solution of (1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]ethane-1,2-diol (40.0 g, 152.5 mmol) in dichloromethane (200 mL) warmed to 30°C was added 10% aqueous sodium bicarbonate solution (20 mL), followed by addition of sodium metaperiodate (48.9 g, 228.8 mmol) in portions. The reaction mixture was stirred at 30°C for 2 hours. Thereafter, 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). The material was carried to the next step without purification.

[0636] Methylmagnesium bromide (3M in diethyl ether, 122 mL, 244.3 mmol) was added dropwise 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. The reaction mixture was stirred at -78°C for another 30 minutes, then warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was cooled to 0°C, 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-dioxolane-4-yl]ethan-1-ol (28.3 g, 193.6 mmol, 79% yield, collected at 30°C and 150 mbar). The material was carried forward to the next step without purification.

[0637] To a solution of dimethyl sulfoxide (71 mL, 997.0 mmol) in dichloromethane (250 mL) cooled to -78°C were added 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) in sequence, and the reaction mixture was warmed to -20°C and stirred at this temperature for 1 hour. After this, 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 forward to the next step without purification. 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).

[0638] Synthesis of Benzyl[(rel-1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]amine

[0639]

[0640] 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 in portions and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into an 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 column chromatography on silica gel eluting with 30% ethyl acetate / 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 light 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.

[0641] Synthesis of rel-(2S,3R)-3-(Benzylamino)butane-1,2-diol

[0642]

[0643] 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 hours. The cooled reaction mixture was neutralized with 10% aqueous sodium hydroxide solution, 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). The material was carried forward to the next step without purification. 1H NMR (300 MHz, 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 minutes, [MH]+ = 196.

[0644] Synthesis of rel-(2S,3R)-3-(Benzylamino)-1-[(tert-butyldimethylsilyl)oxy]butan-2-ol

[0645]

[0646] 1H-imidazole (10.9 g, 159.8 mmol) and tert-butyldimethylsilyl chloride (8.0 g, 53.3 mmol) were added 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. 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 layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 4% methanol / dichloromethane to obtain 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 (300 MHz, 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 minutes, [MH]+ = 310.

[0647] Synthesis of N-Benzyl-N-[rel-(2R,3S)-4-[(tert-butyldimethylsilyl)oxy]-3-hydroxybutan-2-yl]-2-chloroacetamide

[0648]

[0649] Chloroacetyl chloride (5.6 g, 49.6 mmol) was added dropwise 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, 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 column chromatography on silica gel eluting with 9% ethyl acetate / 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 (400 MHz, DMSO-d6) (mixture of rotamers 2:1) 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 minutes, [MH]+ = 386.

[0650] Synthesis of rel-(5S,6S)-4-benzyl-6-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylmorpholin-3-one

[0651]

[0652] 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 ammonium chloride solution, 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 column chromatography on silica gel eluting with 5% ethyl acetate / petroleum ether to give rel-(5S,6S)-4-benzyl-6-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylmorpholine-3-one (8.5 g, 24.3 mmol, 81% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 350.

[0653] Synthesis of rel-(2S,3S)-4-benzyl-2-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methylmorpholine

[0654]

[0655] Borane dimethyl sulfide (4.6 mL, 48.6 mmol) was added dropwise to a solution of rel-(5S, 6S)-4-benzyl-6-{[(tert-butyldimethylsilyl)oxy]methyl}-5-methylmorpholine-3-one (8.5 g, 24.3 mmol) in tetrahydrofuran (30 mL) cooled to 0 ° C. 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, and then heated to reflux for 30 minutes. After completion, the reaction mixture was cooled to room temperature and concentrated. The crude residue was purified by column chromatography on silica gel eluted with 2% ethyl acetate / petroleum ether to obtain 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 (400 MHz, 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 minutes, [MH]+ = 336.

[0656] Synthesis of [(2S,3S)-4-Benzyl-3-methylmorpholin-2-yl]methanol and [(2R,3S)-4-Benzyl-3-methylmorpholin-2-yl]methanol

[0657]

[0658] 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, tetrabutylammonium fluoride solution (1M in tetrahydrofuran, 33 mL, 33.1 mmol) was added. 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 layer was 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 / petroleum ether to obtain the desired product (4.3 g) as a racemic mixture in the form of a red oil. The enantiomers were separated by chiral supercritical fluid chromatography (LUX A1 (250×30 mm) 5 micron column; mobile phase: CO 2: isopropanol (60:40) containing 0.5% isopropylamine) 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.

[0659] Isomer 1:

[0660] 1H NMR (400 MHz, 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 minutes, [MH]+ = 222.

[0661] Isomer 2:

[0662] 1H NMR (400 MHz, 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 minutes, [MH]+ = 222.

[0663] Synthesis of [(2S,3S)-3-methylmorpholin-2-yl]methanol

[0664]

[0665] 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% loading on wet support, 550 mg, 0.39 mmol) and the reaction was stirred at room temperature for 16 hours. After this time, the reaction mixture was filtered through 4% paraffin wax with methanol wash. 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 (300 MHz, 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.

[0666] Synthesis of tert-butyl (2S,3S)-2-(hydroxymethyl)-3-methylmorpholine-4-carboxylate

[0667]

[0668] Triethylamine (1.4 g, 13.6 mmol) was added to a solution of [(2S, 3S)-3-methylmorpholine-2-yl] methanol (1.3 g, 9.9 mmol) in dichloromethane (60 mL), 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, the reaction mixture was poured into water, and the product was extracted with dichloromethane. The combined organic layer was washed with water, dried over sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 23% ethyl acetate / petroleum ether to obtain (2S, 3S)-2-(hydroxymethyl)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (1.9 g, 8.2 mmol, 83% yield) as a colorless oil. 1H NMR (300 MHz, 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 minutes, [(M-100)H]+ = 132.

[0669] Synthesis of 3-Bromo-1-tert-butyl-1H-pyrrole

[0670]

[0671] N-bromosuccinimide (2.3 g, 13.0 mmol) was added to a solution of 1-tert-butyl-1H-pyrrole (2.0 g, 16.2 mmol) in tetrahydrofuran (30 mL) cooled to -78 ° C. After 2 hours, 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 column chromatography on silica gel eluting with 2% ethyl acetate / n-hexane to obtain 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 minutes, [MH]+ = 202 / 204.

[0672] Synthesis of 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole

[0673]

[0674] 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 11.9 mmol), bis(acetonitrile)palladium(II)dichloride (77 mg, 0.03 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (365 mg, 0.09 mmol) and triethylamine (3.5 mL, 24.7 mmol) were added to a solution of 3-bromo-1-tert-butylpyrrole (2.0 g, 9.9 mmol) in toluene (3 mL). The reaction 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 column chromatography on silica gel eluting with 2% ethyl acetate / n-hexane to afford 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 light 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.

[0675] Synthesis of 3-[2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propionitrile

[0676]

[0677] Trichloroacetyl chloride (5.7 mL, 49.9 mmol) was added to a solution of 3-(1H-pyrrole-1-yl)propionitrile (5.0 g, 41.6 mmol) in dichloromethane (100 mL) cooled to 0 ° C, and the reaction was stirred for 2 hours. 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 solution and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel with a gradient elution of 10-20% ethyl acetate / petroleum ether to obtain 3-[2-(2,2,2-trichloroacetyl)-1H-pyrrole-1-yl]propionitrile (4.3 g, 16.2 mmol, 39% yield) as a colorless solid. 1H NMR (400 MHz, chloroform-d) δ7.65-7.63 (m, 1H), 7.20-7.18 (m, 1H), 6.37-6.35 (m, 1H), 4.60 (t, 2H), 2.94 (t, 2H).

[0678] Synthesis of 3-[4-bromo-2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propionitrile

[0679]

[0680] N-bromosuccinimide (3.4 g, 18.8 mmol) was added to a solution of 3-[2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propionitrile (5.0 g, 18.8 mmol) in dichloromethane (500 mL) cooled to -20 ° C, 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 layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with a gradient elution of 10-20% ethyl acetate / petroleum ether to obtain 3-[4-bromo-2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]propionitrile (4.6 g, 13.4 mmol, 71% yield) as a colorless solid. 1H NMR (400MHz, DMSO-d6): δ7.79(s,1H),7.52(s,1H),4.59(t,2H),3.04(t,2H).

[0681] Synthesis of 4-bromo-1-(2-cyanoethyl)-1H-pyrrole-2-carboxylic acid methyl ester

[0682]

[0683] To a solution of 3-[4-bromo-2-(2,2,2-trichloroacetyl)-1H-pyrrole-1-yl]propionitrile (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 layer was washed with water and brine, then dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with a gradient elution of 5-15% ethyl acetate / petroleum ether to obtain 4-bromo-1-(2-cyanoethyl)-1H-pyrrole-2-carboxylic acid methyl ester (3.6 g, 14.0 mmol, 93% yield) as a colorless solid. 1H NMR (400MHz, DMSO-d6): δ7.44(s,1H),6.94(s,1H),4.54(t,2H),3.76(s,3H),3.02(t,2H).

[0684] Synthesis of 4-bromo-1-(3-methoxy-3-oxopropyl)-1H-pyrrole-2-carboxylic acid methyl ester

[0685]

[0686] In a sealed container, a solution of 4-bromo-1-(2-cyanoethyl)-1H-pyrrole-2-carboxylic acid methyl ester (3.5 g, 13.6 mmol) in a mixture (1:5) of sulfuric acid (15 mL, 13.6 mmol) and methanol (75 mL) was heated to 80 ° C for 5 hours. A mixture of ice and water was added, and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with a gradient elution of 5-10% ethyl acetate / petroleum ether to obtain 4-bromo-1-(3-methoxy-3-oxopropyl)-1H-pyrrole-2-carboxylic acid methyl ester (2.3 g, 7.9 mmol, 58% yield) in a liquid. 1H NMR (400MHz, DMSO-d6): δ7.33(s,1H),6.88(s,1H),4.50(t,2H),3.75(s,3H),3.59(s,3H),2.80(t,2H).

[0687] Synthesis of 4-bromo-1-(2-carboxyethyl)-1H-pyrrole-2-carboxylic acid

[0688]

[0689] To a solution of 4-bromo-1-(3-methoxy-3-oxopropyl)-1H-pyrrole-2-carboxylic acid methyl ester (4.6 g, 15.9 mmol) in tetrahydrofuran (100 mL) cooled to 0 ° C, a solution of lithium hydroxide (950 mg, 39.6 mmol) in water (50 mL) was added. The reaction was stirred at room temperature for 4 hours. The reaction mixture was acidified to pH = 3 by dropping 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. The intermediate was used in the next step without purification. 1H NMR (400 MHz, 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 minutes, [M-2H]- = 260.

[0690] Synthesis of 6-bromo-2,3-dihydro-1H-pyrrolizin-1-one

[0691]

[0692] Sodium acetate (154 mg, 1.9 mmol) was added 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), and the reaction mixture was heated to 100 ° C for 15 hours. The cooled reaction mixture was cooled and treated with ice-cold water, and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography on silica with a gradient elution of 20-40% ethyl acetate / petroleum ether to obtain 6-bromo-2,3-dihydro-1H-pyrrolizine-1-one (290 mg, 1.5 mmol, 63% yield) as a light yellow solid. 1H NMR (400 MHz, 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 minutes, [MH] + = 201.

[0693] Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolizin-1-one

[0694]

[0695] To a degassed solution of 6-bromo-2,3-dihydropyrrolizine-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 and evacuated and backfilled with nitrogen, which was repeated twice more and the reaction mixture was heated to 100° C. under microwave irradiation for 2 hours. 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 column chromatography on silica gel eluting with a gradient of 30-50% ethyl acetate / petroleum ether to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolizin-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.

[0696] Synthesis of Benzyl N-(But-3-en-1-yl)carbamate

[0697]

[0698] Sodium carbonate (4M aqueous solution, 90mL, 360.0mmol) is added to a dichloromethane (1L) solution of but-3-ene-1-amine hydrochloride (10g, 93.0mmol) cooled to 0°C, and the reaction is stirred at 0°C for 15 minutes, and then benzyl chloroformate (15.9g, 93.0mmol) is added dropwise. The reaction mixture is stirred at room temperature for 16 hours. After this, the reaction mixture is poured into water, and each layer is separated, and the product is extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate and concentrated. The crude material is purified by column chromatography on silica gel with 20-30% ethyl acetate / n-hexane gradient elution to obtain N- (but-3-ene-1-yl) benzyl carbamate (6.0g, 29.2mmol, 31% yield) as a yellow oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 206.

[0699] Synthesis of (1R,5S,7S)-7-(Hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylic acid benzyl ester (Isomer 1) and (1S,5R,7S)-7-(Hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylic acid benzyl ester (Isomer 2)

[0700]

[0701] 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, 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 hours, the volatiles were removed under reduced pressure and the crude material was purified by preparative HPLC eluting with isopropanol and heptane to give Isomer 1: (1R,5S,7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylic acid benzyl ester (280 mg, 1.0 mmol, 7% yield) and Isomer 2: (1S,5R,7S)-7-(hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylic acid benzyl ester (560 mg, 2.0 mmol, 14% yield) as a clear oil. Relative stereochemistry is arbitrarily assigned.

[0702] Isomer 1: ((1R,5S,7S)-7-(Hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylic acid benzyl ester)

[0703] 1H NMR (400 MHz, 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 minutes, [MH]+ = 278.

[0704] Isomer 2: (1S,5R,7S)-7-(Hydroxymethyl)-6-oxa-2-azabicyclo[3.2.1]octane-2-carboxylic acid benzyl ester

[0705] 1H NMR (400 MHz, 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.

[0706] Synthesis of 1-[(Benzylamino)methyl]cyclobutan-1-ol

[0707]

[0708] 1- (aminomethyl) cyclobutanol (4.3g, 42.4mmol) was added to a solution of benzaldehyde (4.5g, 42.4mmol) in ethanol (150mL), and the reaction mixture was stirred at room temperature for 2 hours. After this, the reaction mixture was cooled to 0 ° C, and sodium borohydride (1.8g, 46.6mmol) was added in batches. The reaction mixture was warmed to room temperature and continued to stir for 16 hours. The reaction mixture was quenched by adding ice water, and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to obtain 1- [(benzylamino) methyl] cyclobutan-1-ol (5.2g, 27.2mmol, 64% yield) as a colorless solid. The intermediate was used in the next step without further purification. 1H NMR (300 MHz, 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 minutes, [MH+] = 192.

[0709] Synthesis of [(6S)-8-Benzyl-5-oxa-8-azaspiro[3.5]nonan-6-yl]methanol

[0710]

[0711] (R)-(-)-epichlorohydrin (6.9g, 74.5mmol) and lithium perchlorate (5.3g, 49.7mmol) were added to a solution of 1-[(benzylamino)methyl]cyclobutane-1-ol (9.5g, 49.7mmol) in toluene (200mL), and the reaction mixture was stirred at room temperature for 3 days. Sodium methoxide (25 weight / weight% methanol solution, 16mL, 74.5mmol) was added and the reaction was stirred at room temperature for another 1 day. The reaction mixture was quenched by adding ice-cold water, and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with 20-60% ethyl acetate / petroleum ether gradient elution to obtain [(6S)-8-benzyl-5-oxa-8-azaspiro[3.5]nonyl-6-yl]methanol (10.0g, 40.4mmol, 81% yield) in an oily state. LCMS (Method 5): Retention time = 1.64 min, [MH]+ = 248.

[0712] Synthesis of [(6S)-5-oxa-8-azaspiro[3.5]nonan-6-yl]methanol

[0713]

[0714] 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) was added palladium hydroxide on carbon (20% loading wet support, 2.0 g, 1.4 mmol) under nitrogen. The reaction flask was evacuated and refilled with hydrogen. After 6 hours, the reaction mixture was filtered through 4% paraffin wax with additional methanol wash. The combined filtrates were 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.

[0715] Synthesis of tert-butyl (6S)-6-(hydroxymethyl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate

[0716]

[0717] To a solution of [(6S)-5-oxa-8-azaspiro [3.5] nonane-6-yl] methanol (5.6 g, 35.6 mmol) in dichloromethane (100 mL) and water (50 mL), sodium hydroxide solution (2M aqueous solution, 18 mL, 36.0 mmol) and ditert-butyl dicarbonate (7.8 g, 35.6 mmol) were added, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was distributed between water and dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with 10-20% ethyl acetate / n-heptane gradient elution to obtain (6S)-6-(hydroxymethyl)-5-oxa-8-azaspiro [3.5] nonane-8-carboxylic acid tert-butyl esters (4.5 g, 17.5 mmol, 49% yield) in an oily state. 1HNMR (400 MHz, 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 minutes, [(M-100)H]+ = 158.

[0718] Synthesis of 3-{Benzyl[(2S)-3-(Benzyloxy)-2-hydroxypropyl]amino}propan-1-ol

[0719]

[0720] 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 / dichloromethane to give 3-{benzyl[(2S)-3-(benzyloxy)-2-hydroxypropyl]amino}propan-1-ol (31.0 g, 94.1 mmol, 78% yield) as a colloidal liquid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 330.

[0721] Synthesis of 3-{Benzyl[(2S)-3-(Benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate

[0722]

[0723] 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 was added N,N-diisopropylethylamine (16.0 mL, 91.1 mmol), followed by methanesulfonyl chloride (7.1 mL, 91.1 mmol) 5 minutes later. The reaction mixture was stirred at -6°C for another 30 minutes. The reaction mixture was poured onto ice, then diluted with saturated aqueous sodium bicarbonate solution, 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 (400 MHz, 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 minutes, [MH]+ = 408.

[0724] Synthesis of (2S)-4-Benzyl-2-[(Benzyloxy)methyl]-1,4-oxazepane

[0725]

[0726] To a suspension of sodium hydride (57-63 wt / wt% oil dispersant, 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 hours. The reaction mixture was cooled to 0°C and quenched by adding saturated aqueous sodium bicarbonate 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 column chromatography on silica gel eluting with 20% ethyl acetate / hexane to obtain (2S)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxaazepine (12.3 g, 39.5 mmol, 43% yield). 1H NMR (400MHz, DMSO-d6) δ7.54-6.92 (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 minutes, [MH] + = 312. The sample was analyzed using the following method: Waters Alliance 2690 and 996 PDA detectors with Micro mass ZQ LCMS. Column: Sunfire C18, 150 x 4.6 mM, 3.5 micron. Column temperature: 35°C. Mobile phase A: 5 mM ammonium acetate and 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); run ended at T = 17 min (90% A, 10% B). Flow rate: 1 mL / min, analysis time 17 min.

[0727] Synthesis of tert-butyl (2S)-2-(hydroxymethyl)-1,4-oxaazepane-4-carboxylate

[0728]

[0729] 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 4% paraffin wax with ethanol (500 mL) washing. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 2% methanol / 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 (400 MHz, 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, 1H), 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 minutes, [(M-100)H]+ = 132. HPLC: Retention time = 5.21 minutes.

[0730] Synthesis of 3-{Benzyl[(2R)-3-(Benzyloxy)-2-hydroxypropyl]amino}propan-1-ol

[0731]

[0732] 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 (400 MHz, 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 minutes, [MH]+ = 330.

[0733] Synthesis of 3-{Benzyl[(2R)-3-(Benzyloxy)-2-hydroxypropyl]amino}propyl methanesulfonate

[0734]

[0735] 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 was added N,N-diisopropylethylamine (6.8 mL, 48.6 mmol), followed by methanesulfonyl chloride (3.8 mL, 48.6 mmol) 5 minutes later. The reaction was stirred at -6 ° C for another 30 minutes. The reaction mixture was poured onto ice and then diluted with saturated aqueous sodium bicarbonate solution. 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 (400 MHz, 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 minutes, [MH]+ = 408.

[0736] Synthesis of (2R)-4-Benzyl-2-[(Benzyloxy)methyl]-1,4-oxazepane

[0737]

[0738] Sodium hydride (2.4 g, 60.1 mmol) was added in batches 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. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by adding a saturated aqueous sodium bicarbonate solution, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by reverse phase column chromatography with a 50-75% acetonitrile / water gradient elution. The separated material was further purified by column chromatography on silica gel with a 10-40% ethyl acetate / hexane gradient elution to obtain (2R)-4-benzyl-2-[(benzyloxy)methyl]-1,4-oxaazepine (3.1 g, 9.4 mmol, 22% yield) as a colorless liquid. 1H NMR (400 MHz, 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), 3.24 (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 minutes, [MH]+ = 312.

[0739] Synthesis of tert-butyl (2R)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate

[0740]

[0741] 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 at 200 psi of hydrogen at room temperature for 14 hours. The reaction mixture was filtered through 4% paraffin wax with ethyl acetate washing. The resulting filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel with a 2-4% methanol / dichloromethane gradient elution to give (2R)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylic acid tert-butyl ester (0.97 g, 3.9 mmol, 44% yield) as a colorless liquid. 1H NMR (400 MHz, 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 minutes, [MNa] + = 254. HPLC: Retention time = 5.18 minutes.

[0742] Synthesis of tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate

[0743]

[0744] To a solution of (S)-4-(tert-butyloxycarbonyl)morpholine-2-carboxylic acid (60.0 g, 259.5 mmol) in dichloromethane (1.0 L) was added 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) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, 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 a saturated aqueous sodium bicarbonate solution, and the product was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give (2S)-tert-butyl 2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate (165.0 g, 246.6 mmol, 95% yield) as a light yellow oil. The material was used crude in the next step without purification. LCMS (Method 4 - Column 7): Retention time = 1.56 min, [MNa]+ = 297.

[0745] Synthesis of tert-butyl (2S)-2-acetylmorpholine-4-carboxylate

[0746]

[0747] Under nitrogen atmosphere, methylmagnesium bromide (3M in diethyl ether, 275mL, 825.0mmol) was added dropwise to a solution of (2S)-2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylic acid tert-butyl ester (165.0g, 601.5mmol) in tetrahydrofuran (800mL) cooled to 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C and quenched by adding 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 column chromatography on silica gel eluting with 20% ethyl acetate / n-hexane to obtain (2S)-2-acetylmorpholine-4-carboxylic acid tert-butyl ester (50.0g, 218.1mmol, 36% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 230.

[0748] Synthesis of tert-butyl (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylate

[0749]

[0750] Sodium borohydride (13.1 g, 343.5 mmol) was added in batches to a methanol (500 mL) solution of (2S)-2-acetylmorpholine-4-carboxylic acid tert-butyl ester (52.5 g, 229.0 mmol) cooled to 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and volatiles were removed under reduced pressure. The product was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylic acid tert-butyl ester (51.0 g, 220.5 mmol, 96% yield) as a 1:1 diastereoisomer mixture as a light yellow oil. Without purification, the material was used as a crude product in the next step.

[0751] Isomer 1

[0752] LCMS (Method 8 - Column 3): Retention time = 10.72 min, [MH]+ = 232.

[0753] Isomer 2

[0754] LCMS (Method 8 - Column 3): Retention time = 11.41 min, [MH]+ = 232.

[0755] 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

[0756]

[0757] (2R)-2-methoxy-2-phenylacetic acid (40.3 g, 242.6 mmol) and N, N'-dimethylaminopyridine (6.7 g, 55.1 mmol) were added to a solution of (2S)-2-(1-hydroxyethyl)morpholine-4-carboxylic acid tert-butyl ester (51.0 g, 220.5 mmol) in dichloromethane (800 mL). The reaction mixture was cooled to 0 ° C, and N, N'-dicyclohexylcarbodiimide (54.5 g, 264.6 mmol) was added in batches. 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 layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with a gradient of 8-20% ethyl acetate / n-hexane to give Isomer 1: (2S)-tert-butyl 2-[(1R)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate (16.0 g, 42.2 mMol, 19% yield) and Isomer 2: (2S)-tert-butyl 2-[(1S)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylate (10.3 g, 27.1 mMol, 12% yield).

[0758] Isomer 1: (2S)-2-[(1R)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylic acid tert-butyl ester

[0759] 1H NMR (400 MHz, 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 minutes, [MH]+ = 380.

[0760] Isomer 2: (2S)-2-[(1S)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylic acid tert-butyl ester

[0761] 1H NMR (400 MHz, 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 minutes, [MH]+ = 380.

[0762] Synthesis of tert-butyl (2S)-2-[(1S)-1-hydroxyethyl]morpholine-4-carboxylate

[0763]

[0764] Potassium carbonate (5.0 g, 36.4 mmol) was added to a solution of (2S)-2-[(1S)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylic acid tert-butyl ester (9.2 g, 24.3 mmol) in methanol (100 mL). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure, and the reaction was poured into water, and the pH of the solution was adjusted to pH=7 using 1N aqueous hydrochloric acid solution. The product was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material obtained was purified by column chromatography on silica gel eluting with 36% methyl tert-butyl ether / n-heptane to obtain (2S)-2-[(1S)-1-hydroxyethyl]morpholine-4-carboxylic acid tert-butyl ester (4.2 g, 15.4 mmol, 64% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [(M-56)H]+ = 176.

[0765] Synthesis of tert-butyl (2S)-2-[(1R)-1-hydroxyethyl]morpholine-4-carboxylate

[0766]

[0767] To a solution of (2S)-2-[(1R)-1-{[(2R)-2-methoxy-2-phenylacetyl]oxy}ethyl]morpholine-4-carboxylic acid tert-butyl ester (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, and the reaction was poured into water, and the pH of the solution was adjusted to pH=7 using 1N aqueous hydrochloric acid solution. 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 column chromatography on silica gel eluting with 30% methyl tert-butyl ether / n-heptane to obtain (2S)-2-[(1R)-1-hydroxyethyl]morpholine-4-carboxylic acid tert-butyl ester (4.7 g, 19.5 mmol, 67% yield) as a light yellow oil. 1H NMR (400 MHz, 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), 3.39-3.28 (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 minutes, [MH]+ = 232.

[0768] Synthesis of (2S)-4-Benzyl-6,6-dimethylmorpholine-2-carbaldehyde

[0769]

[0770] In 15 minutes, dimethyl sulfoxide (16.6 mL, 233.7 mmol) was added dropwise to a solution of oxalyl chloride (10.0 mL, 116.9 mmol) in dichloromethane (100 mL) cooled to -78 ° C. The reaction was stirred for another 15 minutes at -78 ° C. Then, a solution of [(2S)-4-benzyl-6,6-dimethylmorpholine-2-yl] methanol (25.0 g, 106.2 mmol) in dichloromethane (100 mL) was added over a 10-minute period. The reaction mixture was stirred at -78 ° C for 30 minutes, and triethylamine (74.0 mL, 531.2 mmol) was then added over 10 minutes. Stirring was continued for another 30 minutes at -78 ° C. 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 directly carried into the next step without purification. LCMS (Method 5): Retention time = 1.16 min, [MH]+ = 234.

[0771] Synthesis of (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

[0772]

[0773] Under nitrogen, methylmagnesium bromide (1.4M in tetrahydrofuran, 115.0 mL, 160.7 mmol) was added 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. The reaction mixture was stirred at 0°C for 1-2 hours. The reaction mixture was quenched by adding 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 column chromatography in silica gel eluting with a 10-16% ethyl acetate / petroleum ether gradient 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 and (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 3.5 g of mixed fractions.

[0774] (1S)-1-[(2S)-4-Benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol

[0775] 1H NMR (400 MHz, DMSO-d6): δ7.33-7.31 (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 minutes, [MH]+ = 250.

[0776] (1R)-1-[(2S)-4-Benzyl-6,6-dimethylmorpholin-2-yl]ethan-1-ol

[0777] 1H NMR (400 MHz, 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 minutes, [MH]+ = 250.

[0778] Synthesis of (1R)-1-[(2S)-6,6-dimethylmorpholin-2-yl]ethan-1-ol

[0779]

[0780] 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) was added palladium hydroxide on carbon (20% loading wet support, 0.9 g, 0.64 mmol) under nitrogen and the reaction was placed under a hydrogen atmosphere for 2-3 hours. The reaction mixture was filtered through a methanol wash. The mixture was stirred for 2 h at 40 ℃ for 1 h 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). The intermediate was taken to the next step without further purification. 1H NMR (400 MHz, 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 minutes, [MH] + = 160.

[0781] Synthesis of tert-butyl (6S)-6-[(1R)-1-hydroxyethyl]-2,2-dimethylmorpholine-4-carboxylate

[0782]

[0783] 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 column chromatography on silica gel eluting with an ethyl acetate / petroleum ether gradient to afford (S)-tert-butyl 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 minutes, [(M-100)H]+ = 160.

[0784] Synthesis of (1S)-1-[(2S)-6,6-dimethylmorpholin-2-yl]ethan-1-ol

[0785]

[0786] 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) was added palladium hydroxide on carbon (20% wet support, 1.0 g, 0.71 mmol) under nitrogen and the reaction was placed under a hydrogen atmosphere for 2-3 hours. The reaction mixture was filtered through a methanol wash. The mixture was stirred for 2 h at 40 ℃ for 1 h 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). The intermediate was taken to the next step without any further purification. 1H NMR (400 MHz, 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.

[0787] Synthesis of tert-butyl (6S)-6-[(1S)-1-hydroxyethyl]-2,2-dimethylmorpholine-4-carboxylate

[0788]

[0789] 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 column chromatography on silica gel eluting with an ethyl acetate / petroleum ether gradient 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 minutes, [(M-100)H]+ = 160.

[0790] Synthesis of 4-methyl-2-[2-oxo-2-(propan-2-yloxy)ethyl]pyridine-3-carboxylic acid

[0791]

[0792] At room temperature, ethyl acetoacetate (5.0 g, 38.5 mmol) was added to a solution of potassium tert-butoxide (6.5 g, 57.7 mmol) in 2-propanol (43 mL). 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 volatiles were removed under reduced pressure. The residue was poured into water, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was ground with a mixture of hexane and diethyl ether to obtain 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 (400 MHz, 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.

[0793] Synthesis of 4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-5,7-dione

[0794]

[0795] 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 was added triethylamine (1.2 mL, 8.0 mmol) and the reaction was stirred for 20 minutes. The temperature was maintained at 0°C, ethyl chloroformate (0.7 mL, 7.4 mmol) was added dropwise, 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 as mobile phases 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.

[0796] Synthesis of 5,7-dichloro-4-methyl-1,6-naphthyridine

[0797]

[0798] Phosphorus oxychloride (2.4 mL, 18.4 mmol) was added 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). 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, alkalized with saturated sodium bicarbonate aqueous solution, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with ethyl acetate / hexane gradient elution to obtain 5,7-dichloro-4-methyl-1,6-naphthyridine (30 mg, 0.13 mmol, 9% yield) as a colorless solid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 213. HPLC: Retention time = 7.98 minutes.

[0799] Synthesis of 2-[2-oxo-2-(propan-2-yloxy)ethyl]-4-(trifluoromethyl)pyridine-3-carboxylic acid

[0800]

[0801] At room temperature, ethyl acetoacetate (5.4mL, 42.6mmol) was added to a 2-propanol (80mL) solution of potassium tert-butoxide (7.2g, 63.8mmol). The reaction mixture was stirred for 30 minutes. Copper (II) acetate (390mg, 2.13mmol) and 2-chloro-4-(trifluoromethyl)pyridine-3-carboxylic acid (4.8g, 21.3mmol) were added, and the reaction mixture was heated to 80°C for 16 hours. The reaction mixture was acidified with acetic acid, and volatiles were removed under reduced pressure. The residue was poured into water, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by reverse phase column chromatography with 5-100% acetonitrile / water gradient elution to obtain 2-[2-oxo-2-(propan-2-yloxy)ethyl]-4-(trifluoromethyl)pyridine-3-carboxylic acid (3.6g, 11.3mmol, 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.

[0802] Synthesis of 4-(Trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-5,7-dione

[0803]

[0804] Triethylamine (2.2 mL, 15.4 mmol) was added 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, and the reaction was stirred for 20 minutes. The temperature was maintained at 0°C, ethyl chloroformate (1.5 mL, 15.4 mmol) was added dropwise, and the reaction was stirred at room temperature for 4 days. The reaction mixture was quenched by adding a 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 obtained intermediate was dissolved in tetrahydrofuran (45 mL), and 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 another 2 hours. The reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate, and the ethyl acetate was discarded. The aqueous layer was then neutralized with dilute aqueous hydrochloric acid and the product was extracted with ethyl acetate, and the combined organics 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. 1H NMR (400 MHz, DMSO-d6) 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.

[0805] Synthesis of 5,7-dichloro-4-(trifluoromethyl)-1,6-naphthyridine

[0806]

[0807] Phosphorus oxychloride (8.1 mL, 97.1 mmol) was added 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). 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, alkalized with saturated sodium bicarbonate aqueous solution, and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel with ethyl acetate / hexane gradient elution to obtain 5,7-dichloro-4-(trifluoromethyl)-1,6-naphthyridine (960 mg, 3.6 mmol, 54% yield) as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, 1H), 8.35 (s, 1H), 8.28 (d, 1H). LCMS (Method 4-Column 7): Retention time = 2.38 minutes, [MH]+ = 268. HPLC: Retention time = 8.32 minutes.

[0808] Synthesis of 5,7-dichloro-3-iodo-1,6-naphthyridine

[0809]

[0810] N-iodosuccinimide (230 mg, 1.0 mmol) was added to a solution of 5,7-dichloro-1,6-naphthyridine (200 mg, 1.0 mmol) in acetic acid (10 mL), and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with 2N aqueous sodium hydroxide solution, then washed with brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel with a gradient elution of 0-50% ethyl acetate / heptane to obtain 5,7-dichloro-3-iodo-1,6-naphthyridine (43 mg, 0.13 mmol, 13% yield) as a white solid. 1H 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 minutes, [MH] + = 325.

[0811] Synthesis of 5,7-dichloro-3-vinyl-1,6-naphthyridine

[0812]

[0813] To a suspension of 5,7-dichloro-3-iodo-1,6-naphthyridine (43 mg, 0.13 mmol), 2,4,6-trivinylcyclotriborane 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 for 1 hour under microwave irradiation. The cooled reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5,7-dichloro-3-vinyl-1,6-naphthyridine (23 mg, 0.10 mmol, 77% yield). 1H NMR (400 MHz, 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 minutes, [MH] + = 225.

[0814] Synthesis of 5,7-dichloro-3-methyl-1,6-naphthyridine

[0815]

[0816] Tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol) was added to a suspension of 5,7-dichloro-3-iodo-1,6-naphthyridine (137 mg, 0.42 mmol), trimethylcyclotriboroxane (70 μL, 0.48 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,4-dioxane (2 mL). The reaction mixture was heated to 120 ° C for 12 hours under microwave irradiation. The reaction mixture was distributed 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 column chromatography on silica gel with a gradient elution of 0-50% ethyl acetate / heptane to obtain 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 minutes, [MH] + = 213.

[0817] Synthesis of 4-bromo-2-methoxy-6-nitroaniline

[0818]

[0819] 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 and washed with cold water and dried in vacuo 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 minutes, [MH] + = 246 / 248.

[0820] Synthesis of 5-bromo-3-methoxybenzene-1,2-diamine

[0821]

[0822] Zinc powder (79.4 g, 1.2 mol) was added in batches 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), and the reaction was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to pH~7 by adding 10% aqueous potassium carbonate solution. The resulting salt was 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 (400 MHz, 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 minutes, [MH]+ = 217.

[0823] Synthesis of 7-Bromo-5-methoxyquinoxaline

[0824]

[0825] 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 hours. Volatiles were removed under reduced pressure, and the crude material was purified by column chromatography on silica gel eluting with 30% ethyl acetate / n-hexane. The product was further purified by grinding with diethyl ether to obtain 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 minutes, [MH] + = 239.

[0826] Synthesis of 7-bromoquinoxalin-5-ol

[0827]

[0828] Boron tribromide (1M in dichloromethane, 418 mL, 418.3 mmol) was added to a solution of 7-bromo-5-methoxyquinoxaline (10.0 g, 41.8 mmol) in dichloromethane (1.0 L) cooled to 0 ° C, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into cold water, and the aqueous layer was basified 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 in vacuo to give 7-bromoquinoxaline-5-ol (5.4 g, 24.0 mmol, 57% yield) as a light brown solid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 225. HPLC: Retention time = 3.79 minutes.

[0829] Synthesis of 7-bromo-5-methoxyquinoline

[0830]

[0831] The reaction was carried out in 8 batches of 10 g of 3-bromo-5-methoxyaniline, which were combined after work-up.

[0832] 3-bromo-5-methoxyaniline (80 g, 0.4 mol) and sulfuric acid (14 M aqueous solution, 26 mL, 0.4 mol) were added to a solution of glycerol (74 mL, 1 mol) in nitrobenzene (40 mL), and the reaction mixture was heated to 100 ° C for 16 hours. The reaction was quenched by adding ice and sodium hydroxide (6 M aqueous solution), and the product was extracted with ethyl acetate and then with dichloromethane containing 10% methanol. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 15% ethyl acetate / n-hexane to obtain 7-bromo-5-methoxyquinoline (21.0 g, 81.1 mmol, 21% yield) as a yellow solid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 238.

[0833] Synthesis of 7-bromoquinolin-5-ol

[0834]

[0835] Boron tribromide (1M in dichloromethane, 882mL, 882.1mmol) was added to a solution of 7-bromo-5-methoxyquinoline (21.0g, 88.2mmol) in dichloromethane (400mL) cooled to 0°C, and the reaction was stirred at room temperature for 1 day. The reaction mixture was cooled to 0°C and quenched by adding water, and the pH of the mixture was adjusted to pH=8-9 by adding solid sodium carbonate. The product was extracted with butane 1-alcohol, and the combined organic layer was then concentrated. The crude material was purified by column chromatography on silica gel eluting with 6% methanol / dichloromethane to obtain 7-bromoquinoline-5-ol (13.5g, 60.3mmol, 68% yield) as a light brown solid. 1H NMR (400 MHz, 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 minutes, [MH] + = 224. HPLC: Retention time = 3.79 minutes.

[0836] Synthesis of 7-bromo-5-methoxy-4-methylquinoline

[0837]

[0838] Concentrated sulfuric acid (2.0 mL, 37.1 mmol) was added to a solution of 3-bromo-5-methoxyaniline (5.0 g, 24.8 mmol) in 1,4-dioxane (50 mL), and the mixture was heated to reflux for 30 minutes. Then, a solution of 1,4-dioxane (5 mL) of but-3-ene-2-one (2.6 g, 37.1 mmol) was added, and the reaction mixture was heated at 100 ° C for 4 hours. The reaction mixture was quenched by adding an aqueous sodium bicarbonate solution, and the product was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluted with 10% ethyl acetate / petroleum ether to obtain 7-bromo-5-methoxy-4-methylquinoline (1.35 g, 5.35 mmol, 22% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d): δ8.68 (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 minutes, [MH]+ = 252.

[0839] Synthesis of 7-Bromo-4-methylquinolin-5-ol

[0840]

[0841] Boron tribromide (1.1 mL, 10.9 mmol) was added to a solution of 7-bromo-5-methoxy-4-methylquinoline (1.1 g, 4.4 mmol) in dichloromethane (20 mL) cooled to -78 °C, and the reaction was stirred at room temperature overnight. The reaction mixture was quenched with sodium bicarbonate aqueous solution, and the product was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by grinding with n-hexane to obtain 7-bromo-4-methylquinoline-5-ol (520 mg, 2.2 mmol, 50% yield) as a white solid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 240.

[0842] Synthesis of 7-(1-tert-butyl-1H-pyrazol-4-yl)-5-methoxyquinoline

[0843]

[0844] 1-tert-butylpyrazole-4-boronic acid pinacol ester (690 mg, 2.8 mmol) and sodium carbonate (730 mg, 6.9 mmol) were added to a solution of 7-bromo-5-methoxyquinoline (550 mg, 2.3 mmol) in 1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was purged with nitrogen for 30 minutes, and then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (80 mg, 0.12 mmol) was added. Then, the reaction mixture was 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 column chromatography on silica gel eluting with 2% methanol / dichloromethane to obtain 7-(1-tert-butylpyrazole-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 minutes, [MH]+ = 282.

[0845] Synthesis of 7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-ol

[0846]

[0847] Boron tribromide (1M in dichloromethane, 39 mL, 39.1 mmol) was added dropwise 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. The reaction mixture was allowed to warm to room temperature and continued to stir for one day. The reaction mixture was quenched by adding 1M aqueous sodium hydroxide solution (50 mL) to adjust 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 crude material obtained was purified by column chromatography on silica eluting with 2% methanol / dichloromethane to give 7-(1-tert-butyl-1H-pyrazol-4-yl)quinoline-5-ol (320 mg, 1.2 mmol, 61% yield) as a brown solid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 268.

[0848] 7-(1-tert-Butyl-1H-pyrazol-4-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline (1)

[0849]

[0850] Sodium hydride (57-63 weight / weight % oil dispersant, 6 mg, 0.26 mmol) was added to a solution of 7-(1-tert-butyl-1H-pyrazol-4-yl)quinoline-5-ol (93 mg, 0.26 mmol) in N,N-dimethylformamide (3.0 mL) cooled to 0 ° C. The reaction mixture was warmed to room temperature and stirred for 10 minutes, and (2S)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylic acid tert-butyl ester (50 mg, 0.17 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice bath and quenched by adding water. The reaction mixture was distributed between ethyl acetate and water. The product was extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated.

[0851] Trifluoroacetic acid (0.5 mL) was added to a solution of the crude intermediate in dichloromethane (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 preparative HPLC (purification method 2) to obtain 7- (1- tert-butyl -1H- pyrazole -4- bases) -5- { [(2S) -morpholine -2- bases] methoxy} quinoline (38 mg, 0.99 mmol, 38% yield) as a colorless solid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 367.

[0852] Synthesis of 5-methoxy-7-(1-methyl-1H-pyrazol-4-yl)quinoline

[0853]

[0854] Potassium carbonate (1.2 g, 8.4 mmol) was added 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). Nitrogen was bubbled through the reaction mixture for 15 minutes. After this, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (246 mg, 0.34 mmol) was added, and the reaction mixture was heated to 70 ° C for 16 hours. After this, the reaction mixture was 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 (400 MHz, 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 minutes, [MH]+ = 240.

[0855] Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)quinolin-5-ol

[0856]

[0857] Boron tribromide (1M in dichloromethane, 60mL, 60.1mmol) was added to a solution of 5-methoxy-7-(1-methyl-1H-pyrazol-4-yl)quinoline (720mg, 3.0mmol) in dichloromethane (50mL) cooled to 0°C, and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized by dropping sodium hydroxide (1M 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 column chromatography on silica gel eluting with 4% methanol / dichloromethane to obtain 7-(1-methyl-1H-pyrazol-4-yl)quinoline-5-ol (370mg, 1.6mmol, 55% yield) as a light brown solid. 1H NMR (400 MHz, 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 minutes, [MH]+ = 226.

[0858] 7-(1-Methyl-1H-pyrazol-4-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline (2)

[0859]

[0860] Sodium hydride (57-63% oil dispersant, 3.4 mg, 0.14 mmol) was added to a solution of 7-(1-methyl-1H-pyrazol-4-yl)quinoline-5-ol (32 mg, 0.14 mmol) in N,N-dimethylformamide (2.5 mL) cooled to 0 ° C. The reaction mixture was warmed to room temperature and then (2S)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylic acid tert-butyl ester (50 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice bath and quenched by adding water, and the product was extracted with ethyl acetate. The combined organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a Boc-protected intermediate.

[0861] To a solution of the 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 hour. The volatiles were removed under reduced pressure, and the crude material was purified by preparative HPLC to afford 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 (600 MHz, 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 minutes, [MH]+ = 325.

[0862] Synthesis of (2S)-2-[(1S)-1-{[7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylic acid tert-butyl ester (Isomer 1) and (2S)-2-[(1R)-1-{[7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylic acid tert-butyl ester (Isomer 2)

[0863]

[0864] 7-(1-tert-butylpyrazole-4-yl)quinoline-5-ol (30 mg, 0.11 mmol) and (2S)-2-(1-methylsulfonyloxyethyl)morpholine-4-carboxylic acid tert-butyl ester (52 mg, 0.17 mmol) were added to a suspension of sodium hydride (57-63% oil dispersant, 7 mg, 0.17 mmol) in acetonitrile (1.5 mL). The reaction mixture was stirred for 1 minute, and then a solution of sodium iodide (2 mg, 0.01 mmol) in acetonitrile (0.5 mL) was added. The reaction mixture was stirred at room temperature for 5 minutes, and then heated at 130 ° C for 2 hours under microwave radiation. The cooled reaction mixture was quenched by slowly adding water, and the reaction mixture was distributed between water and ethyl acetate. The water layer was further extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain a brown oil. The crude material was purified by column chromatography on silica gel eluting with a 5-40% ethyl acetate / heptane gradient to give a mixture of diastereomers. The diastereomers were separated by preparative HPLC to give Isomer 1: (2S)-tert-butyl 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 light yellow residue and Isomer 2: (2S)-tert-butyl 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 light yellow residue.

[0865] (2S)-tert-Butyl 2-[(1S)-1-{[7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylate

[0866] 1H NMR (400 MHz, 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 minutes, [MH]+ = 481.

[0867] (2S)-tert-Butyl 2-[(1R)-1-{[7-(1-tert-butyl-1H-pyrazol-4-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylate

[0868] 1H NMR (400 MHz, 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 minutes, [MH]+ = 481.

[0869] 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

[0870]

[0871] 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (10mg, 0.01mmol), potassium acetate (84mg, 0.85mmol) and bis(pinacol)diboron (79mg, 0.31mmol) were added to a microwave vial. The vial was sealed and placed under vacuum and backfilled with nitrogen. It was repeated twice above, and then a degassed solution of (2S)-2-[(7-chloroquinoline-5-yl)oxymethyl]morpholine-4-carboxylic acid tert-butyl ester (120mg, 0.28mmol) in 1,4-dioxane (4mL) was added. The reaction mixture was heated at 130 °C for 1 hour under microwave radiation. The cooled reaction mixture was distributed between water and ethyl acetate. The water layer was extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel with a 0-100% (2:24:74 ammonia:ethanol:ethyl acetate mixture) / ethyl acetate gradient elution to give (2S)-tert-butyl 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 with impurities still present. This intermediate was used in the next step without further purification. 1H NMR (400 MHz, 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 minutes, [(M-82)H]+ = 389.

[0872] Synthesis of tert-butyl (2S)-2-[({7-[5-(difluoromethyl)thiophen-3-yl]quinolin-5-yl}oxy)methyl]morpholine-4-carboxylate

[0873]

[0874] 4-bromo-2-(difluoromethyl)thiophene (25 mg, 0.12 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (4 mg, 0.01 mmol) and potassium acetate (35 mg, 0.35 mmol) were added to a microwave vial. The vial was sealed and evacuated and backfilled with nitrogen. This was repeated twice, and then a degassed solution of (2S)-2-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)quinoline-5-yl]oxymethyl]morpholine-4-carboxylic acid tert-butyl ester (40 mg, 0.06 mmol) in 1,4-dioxane (1 mL) was added. The reaction was heated at 130 ° C for 1 hour under microwave irradiation. The cooled reaction mixture was distributed between water and ethyl acetate. The product was extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain a brown residue. The residue was purified by column chromatography on silica gel eluting with a 5-50% ethyl acetate / heptane gradient to give (2S)-tert-butyl 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 (400 MHz, 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 minutes, [MH]+ = 477.

[0875] Synthesis of tert-butyl (2S)-2-[({7-[4-(difluoromethyl)thiophen-2-yl]quinolin-5-yl}oxy)methyl]morpholine-4-carboxylate

[0876]

[0877] 2-Bromo-4-(difluoromethyl)thiophene (18 mg, 0.09 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (3 mg, 0.004 mmol) and potassium acetate (25 mg, 0.26 mmol) were added to a microwave vial. The vial was sealed and evacuated and backfilled with nitrogen, which was repeated twice, and then a solution of a degassed solution of (2S)-2-({[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)quinoline-5-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (40 mg, 0.09 mmol) in 1,4-dioxane (1 mL) / water (0.1 mL) was added. The reaction was heated at 130 ° C for 1 hour under microwave irradiation. The cooled reaction mixture was filtered through The mixture was stirred for 2 hours at 4 ℃ for 10 minutes and then stirred for 2 hours.Then the mixture was stirred for 3 hours at 4 ℃ for 10 minutes.Then the mixture was stirred for 2 ... 1H NMR (400 MHz, 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, 1H), 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 minutes, [MH]+ = 477.

[0878] Synthesis of tert-butyl (2S)-2-({[7-(5-tert-butylthiophen-2-yl)quinolin-5-yl]oxy}methyl)morpholine-4-carboxylate

[0879]

[0880] 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (3mg, 0.004mmol), 2-bromo-5-tert-butylthiophene (19mg, 0.09mmol) and potassium acetate (25mg, 0.26mmol) were added to a microwave vial. The vial was sealed and evacuated and backfilled with nitrogen, which was repeated twice, and then a degassed solution of 1,4-dioxane (1mL) / water (0.1mL) solution of tert-butyl 2-({[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)quinoline-5-yl]oxy}methyl)morpholine-4-carboxylate (40mg, 0.09mmol) was added. The reaction was heated at 130°C for 45 minutes under microwave irradiation. The cooled reaction mixture was filtered through The mixture was stirred for 2 hours at 4 ℃ for 10 minutes, and the filtrate was distributed between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain brown residue. The crude material was purified by column chromatography on silica gel with 0-50% ethyl acetate / heptane gradient elution to obtain the intermediate (2S)-2-({[7-(5-tert-butylthiophene-2-yl)quinoline-5-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (10mg, 0.02mmol, 17% yield) as a light brown residue. The intermediate is used for the next step without further purification. 1H NMR (400 MHz, 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 minutes, [MH]+ = 483.

[0881] Synthesis of 6-(5-{[(2S)-morpholin-2-yl]methoxy}quinolin-7-yl)-2,3-dihydro-1H-pyrrolizin-1-one (3)

[0882]

[0883] Triethylsilane (50 μL, 0.31 mmol) and trifluoroacetic acid (0.1 mL, 1.3 mmol) were added to a solution of (2S)-2-[[7-(7-oxo-5,6-dihydropyrrolizine-2-yl)quinoline-5-yl]oxymethyl]morpholine-4-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol) in dichloromethane (0.9 mL). 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 solution. The combined aqueous layer was 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-pyrrolizin-1-one (17 mg, 0.05 mmol, 43% yield) as a white solid. 1H NMR (600 MHz, 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 minutes, [MH]+ = 364.

[0884] Synthesis of 7-(2,3-dihydro-1H-pyrrolizin-6-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline (4)

[0885]

[0886] Sodium borohydride (15 mg, 0.40 mmol) was added to a methanol (1 mL) solution of (2S)-2-({[7-(1-oxo-2,3-dihydro-1H-pyrrolizine-6-yl)quinoline-5-yl]oxy}methyl)morpholine-4-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by adding water, and the product was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude alcohol intermediate. Triethylsilane (0.1 mL, 0.63 mmol) and trifluoroacetic acid (0.1 mL, 1.3 mmol) were added to a dichloromethane (2 mL) solution of the crude intermediate, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was distributed between 1 M aqueous hydrochloric acid solution and dichloromethane. The water layer was alkalized 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-pyrrolizin-6-yl)-5-{[(2S)-morpholin-2-yl]methoxy}quinoline (16 mg, 0.04 mmol, 38% yield) as a light yellow oil. 1H NMR (400 MHz, 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 minutes, [MH]+ = 350.

[0887] Synthesis of tert-butyl (2S)-2-[(1R)-1-{[7-(1H-pyrrol-3-yl)quinolin-5-yl]oxy}ethyl]morpholine-4-carboxylate

[0888]

[0889] Pyrrole-3-boronic acid pinacol ester (132 mg, 0.69 mmol), (2S)-2-[(1R)-1-(7-bromoquinolin-5-yl)oxyethyl]morpholine-4-carboxylic acid tert-butyl ester (250 mg, 0.57 mmol), potassium phosphate (364 mg, 1.7 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (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 hour. 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 column chromatography on silica gel eluting with a 0-100% ethyl acetate / heptane gradient to give (2S)-tert-butyl 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.

[0890] 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

[0891]

[0892] 3-Chloroperoxybenzoic acid (16.8 g, 97.6 mmol) was added in portions to a solution of cyclopent-2-en-1-yloxymethylbenzene (8.5 g, 48.8 mmol) in dichloromethane (50 mL) cooled to 0°C, 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 with 10% sodium sulfate solution, saturated sodium bicarbonate aqueous solution and water in sequence. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 6-8% ethyl acetate / hexanes 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 light yellow liquid.

[0893] rel-(1R,2R,5R)-2-phenylmethoxy-6-oxabicyclo[3.1.0]hexane:

[0894] 1H NMR (400MHz, chloroform-d) δ7.40-7.29(m,4H),7.32-7.24(m,1H),4.60(d,1H),4.52(d,1H),4.1 0(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).

[0895] rel-(1R,2S,5R)-2-phenylmethoxy-6-oxabicyclo[3.1.0]hexane:

[0896] 1H NMR (400 MHz, chloroform-d) δ7.42-7.27 (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).

[0897] Synthesis of rel-(1R,2S,5R)-2-azido-5-(benzyloxy)cyclopentan-1-ol

[0898]

[0899] 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 hours. 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) δ7.42-7.27 (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).

[0900] Synthesis of rel-(1R,2S,5S)-2-azido-5-(benzyloxy)cyclopentan-1-ol

[0901]

[0902] 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 hours. 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).

[0903] Synthesis of rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentyl 4-nitrobenzoate

[0904]

[0905] 4-Nitrobenzoic acid (0.54 g, 3.2 mmol) and triphenylphosphine (0.84 g, 3.2 mmol) were added to a solution of rel-(1R, 2S, 5R)-2-azido-5-phenylmethoxycyclopent-1-ol (4.2 g, 18.0 mmol) in tetrahydrofuran (5 mL). 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 a saturated aqueous ammonium chloride 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 crude material was purified by column chromatography on silica gel eluting with 10% ethyl acetate / hexane to obtain 4-nitrobenzoic acid rel-(1S, 2S, 5R)-2-azido-5-(benzyloxy)cyclopentyl ester (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).

[0906] Synthesis of rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentyl 4-nitrobenzoate

[0907]

[0908] 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 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, and the reaction mixture was cooled to 0 ° C, and then diisopropyl azodicarboxylate (4.6 g, 22.6 mmol) was added dropwise. The reaction mixture was warmed 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 column chromatography on silica gel eluting with a 5-15% ethyl acetate / hexanes gradient 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).

[0909] Synthesis of rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentan-1-ol

[0910]

[0911] Potassium carbonate (2.6 g, 18.8 mmol) was added to a solution of 4-nitrobenzoic acid rel-(1S, 2S, 5R)-2-azido-5-(benzyloxy)cyclopentyl ester (2.4 g, 6.3 mmol) in methanol (25 mL), 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 solution. 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 / hexane to give rel-(1S, 2S, 5R)-2-azido-5-phenylmethoxycyclopent-1-ol (1.4 g, 6.0 mmol, 96% yield) as a brown liquid. 1H NMR (400 MHz, chloroform-d) δ7.44-7.28 (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).

[0912] Synthesis of rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentan-1-ol

[0913]

[0914] Potassium carbonate (3.3 g, 23.5 mmol) was added to a stirred solution of 4-nitrobenzoic acid rel-(1S, 2S, 5S)-2-azido-5-(benzyloxy)cyclopentyl ester (3.0 g, 7.9 mmol) in methanol (30 mL), 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 column chromatography on silica gel with a gradient elution of 0-30% ethyl acetate / hexane to obtain rel-(1S, 2S, 5S)-2-azido-5-(benzyloxy)cyclopent-1-ol (1.4 g, 5.8 mmol, 74% yield) as a light 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).

[0915] Synthesis of methyl 2-{[rel-(1S,2S,5R)-2-azido-5-(benzyloxy)cyclopentyl]oxy}acetate

[0916]

[0917] Sodium hydride (60% dispersion in mineral oil, 1.9 g, 48.0 mmol) was added to a solution of rel-(1S, 2S, 5R)-2-azido-5-(benzyloxy)cyclopent-1-ol (1.4 g, 6.0 mmol) in N, N-dimethylformamide (45 mL) cooled to 0 ° C. Methyl 2-bromoacetate (4.6 g, 30.0 mmol) was added after stirring for 10 minutes, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by slowly adding 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 column chromatography on silica gel with a gradient elution of 0-20% ethyl acetate / 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 minutes, [MH]+ = 306.

[0918] Synthesis of methyl 2-{[rel-(1S,2S,5S)-2-azido-5-(benzyloxy)cyclopentyl]oxy}acetate

[0919]

[0920] 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 was added sodium hydride (60% dispersion in mineral oil, 1.9 g, 48.0 mmol) in portions. 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 slowly adding 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 column chromatography on silica gel eluting with 0-20% ethyl acetate / hexanes 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 light yellow liquid. 1H NMR (400 MHz, 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, 2H), 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.

[0921] Synthesis of rel-(4aS,7R,7aS)-7-(Benzyloxy)-octahydrocyclopenta[b][1,4]oxazin-3-one

[0922]

[0923] 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 at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through The crude material was triturated with hexanes (3 mL) to afford 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 (400 MHz, 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, 1H), 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 minutes, [MH]+ = 248.

[0924] Synthesis of rel-(4aS,7S,7aS)-7-(Benzyloxy)-octahydrocyclopenta[b][1,4]oxazin-3-one

[0925]

[0926] 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 for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through 4% paraffin wax and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude material was triturated with n-hexane and dried in vacuo to afford 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 (400 MHz, 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 minutes, [MH]+ = 248.

[0927] Synthesis of rel-(4aS,7R,7aS)-7-(Benzyloxy)-octahydrocyclopenta[b][1,4]oxazine

[0928]

[0929] To a solution of lithium aluminum hydride (1M 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]oxazine-3-one (0.6 g, 2.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to room temperature and stirring continued for 16 hours. The reaction mixture was quenched by slowly adding 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 (400 MHz, 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), 2.74-2.61 (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 minutes, [MH]+ = 234.

[0930] Synthesis of rel-(4aS,7S,7aS)-7-(Benzyloxy)-octahydrocyclopenta[b][1,4]oxazine

[0931]

[0932] 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 was added a solution of rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-3-one (1.1 g, 4.5 mmol) in tetrahydrofuran (10 mL) dropwise, 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 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 light brown liquid. 1H NMR (400 MHz, 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), 3.54 (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 minutes, [MH]+ = 234.

[0933] Synthesis of tert-butyl rel-(4aS,7R,7aS)-7-(Benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate

[0934]

[0935] 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 column chromatography on silica gel eluting with 10% ethyl acetate / hexane to obtain rel-(4aS, 7R, 7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (370 mg, 1.1 mmol, 55% yield) as a light yellow liquid. 1H NMR (400 MHz, 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 (dd, 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.

[0936] Synthesis of tert-butyl rel-(4aS,7S,7aS)-7-(Benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate

[0937]

[0938] 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 was added diisopropylethylamine (1.7 g, 12.9 mmol) and the reaction mixture was stirred for 15 minutes before adding 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 column chromatography on silica gel eluting with a 0-20% ethyl acetate / hexanes gradient to afford rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (1.0 g, 3.0 mmol, 70% yield) as a light yellow liquid. 1H NMR (400 MHz, 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, 1H), 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 minutes, [(M-56)H]+ = 278.

[0939] Synthesis of tert-butyl rel-(4aS,7R,7aS)-7-hydroxy-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate

[0940]

[0941] To a solution of rel-(4aS,7R,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (370 mg, 1.1 mmol) in methanol (15 mL) was added palladium hydroxide on carbon (20% loading wet support, 0.2 g, 0.14 mmol) and the reaction was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through The crude material was purified by column chromatography on silica gel eluting with 50-60% ethyl acetate / hexanes to afford rel-(4aS,7R,7aS)-7-hydroxy-octahydrocyclopenta[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (240 mg, 0.99 mmol, 89% yield) as a white semisolid. 1H NMR (400 MHz, 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), 1.87-1.68 (m, 1H), 1.25-1.12 (m, 1H). LCMS (Method 4-Column 1): Retention time = 1.61 minutes, [MH]+ = 244.

[0942] Synthesis of tert-butyl rel-(4aS,7S,7aS)-7-hydroxy-octahydrocyclopenta[b][1,4]oxazine-4-carboxylate

[0943]

[0944] To a solution of rel-(4aS,7S,7aS)-7-(benzyloxy)-octahydrocyclopenta[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (1.0 g, 3.0 mmol) in methanol (30 mL) was added palladium hydroxide on carbon (20% wet support, 546 mg, 0.39 mmol) and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through The crude material was purified by column chromatography on silica gel eluting with a 25-30% ethyl acetate / hexanes gradient to afford rel-(4aS,7S,7aS)-7-hydroxy-octahydrocyclopenta[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (600 mg, 2.5 mmol, 82% yield) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.54-4.24 (m, 1H), 4.20-4.03 (m, 1H), 3.92-3.54 (m, 3H), 3.52-3.37 (m, 1H), 3.16-2.90 (m, 1H), 2.35-2.19 (m, 1H), 2.05-1.86 (m, 1H), 1.79-1.68 (m, 1H), 1.59-1.51 (m, 1H), 1.47 (s, 9H). LCMS (Method 4-Column 1): Retention time = 1.65 minutes, [(M-56)H]+ = 188.

[0945] Synthesis of [(2S,6S)-4-Benzyl-6-ethylmorpholin-2-yl]methanol and [(2S,6R)-4-Benzyl-6-ethylmorpholin-2-yl]methanol

[0946]

[0947] The reaction was performed in 3 parallel batches of 3.3 g of 1-(benzylamino)butan-2-ol per batch, which were combined after post-treatment. (R)-(-)-epichlorohydrin (7.7 g, 82.8 mmol) was added dropwise to a toluene (70 mL) solution of 1-(benzylamino)butan-2-ol (9.9 g, 55.2 mmol), followed by addition of lithium perchlorate (5.9 g, 55.2 mmol) in batches. The reaction was stirred at room temperature for 16 hours. Sodium methoxide (30% methanol solution, 27.9 mL, 165.7 mmol) was added dropwise after 16 hours, and the reaction mixture was stirred at room temperature for another 16 hours. The reaction mixture was distributed between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a 0-20% ethyl acetate / hexanes gradient to give [(2S,6S)-4-benzyl-6-ethylmorpholin-2-yl]methanol (3.6 g, 15.3 mmol, 28% yield) and [(2S,6R)-4-benzyl-6-ethylmorpholin-2-yl]methanol (3.0 g, 12.7 mmol, 23% yield).

[0948] [(2S,6S)-4-Benzyl-6-ethylmorpholin-2-yl]methanol

[0949] 1H NMR (400 MHz, DMSO-d6) δ 7.36-7.19 (m, 5H), 4.61 (t, 1H), 3.54-3.47 (m, 1H), 3.47-3.36 (m, 3H), 3.29-3.19 (m, 2H), 2.79-2.67 (m, 2H), 1.73-1.61 (m, 2H), 1.46-1.26 (m, 2H), 0.84 (t, 3H). LCMS (Method 8-Column 1): Retention time = 4.26 minutes, [MH]+ = 236.

[0950] [(2S,6R)-4-Benzyl-6-ethylmorpholin-2-yl]methanol

[0951] 1H NMR (400 MHz, DMSO-d6) δ 7.37-7.19 (m, 5H), 4.55 (t, 1H), 3.68-3.59 (m, 1H), 3.59-3.51 (m, 1H), 3.51-3.38 (m, 4H), 2.45-2.30 (m, 2H), 2.23-2.08 (m, 2H), 1.72-1.57 (m, 1H), 1.49-1.35 (m, 1H), 0.80 (t, 3H). LCMS (Method 8-Column 1): Retention time = 4.24 minutes, [MH]+ = 236.

[0952] Synthesis of tert-butyl (2S,6S)-2-ethyl-6-(hydroxymethyl)morpholine-4-carboxylate

[0953]

[0954] To a solution of [(2S,6S)-4-benzyl-6-ethylmorpholin-2-yl]methanol (3.4 g, 14.4 mmol) in methanol (68 mL) was added palladium hydroxide on carbon (20% wet support, 1.7 g, 1.2 mmol), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through The mixture was plugged with celite, and the filtrate was concentrated under reduced pressure to give the intermediate [(2S,6S)-6-ethylmorpholin-2-yl]methanol as a light yellow liquid.

[0955] To a solution of [(2S, 6S) -6- ethylmorpholine -2- bases] methanol (2.0 g, 13.8 mmol) in dichloromethane (55 mL): water (18 mL) cooled to 0 ° C, sodium hydroxide (550 mg, 13.8 mmol) was added, and the reaction mixture was stirred for 10 minutes, then di-tert-butyl dicarbonate (3.3 g, 15.2 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was distributed between water and dichloromethane, and the aqueous layer was further extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel with a gradient elution of 0-30% ethyl acetate / hexane to obtain (2S, 6S) -2- ethyl -6- (hydroxymethyl) morpholine -4- carboxylic acid tert-butyl ester (2.4 g, 9.6 mmol, 68% yield) as a colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.14-3.75 (m, 2H), 3.75-3.62 (m, 1H), 3.62-3.47 (m, 2H), 3.44-3.23 (m, 1H), 2.79-2.36 (m, 2H), 2.02-1.88 (m, 1H), 1.58-1.48 (m, 2H), 1.46 (s, 9H), 0.96 (t, 3H). LCMS (Method 4-Column 7): Retention time = 1.84 minutes, [MH]+ = 246.

[0956] Synthesis of tert-butyl (2R,6S)-2-ethyl-6-(hydroxymethyl)morpholine-4-carboxylate

[0957]

[0958] To a solution of [(2S,6R)-4-benzyl-6-ethylmorpholin-2-yl]methanol (2.8 g, 11.9 mmol) in methanol (56 mL) was added palladium hydroxide on carbon (20% wet support, 1.4 g, 1.0 mmol), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through The mixture was plugged with celite and the filtrate was concentrated under reduced pressure to give the intermediate [(2S,6R)-6-ethylmorpholin-2-yl]methanol.

[0959] To a solution of [(2S, 6R) -6- ethylmorpholine -2- bases] methanol (1.6 g, 11.0 mmol) in dichloromethane / water (42: 14 mL) cooled to 0 ° C, sodium hydroxide (440 mg, 11.0 mmol) was added, and the reaction mixture was stirred for 10 minutes, then di-ter...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: in: Z is CR 1 or N; Y is CH or N; X is CR 2 or N; and No more than one of X, Y or Z is N; in: R 1 Selected from: 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, halogen, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 2-6 Alkenyl, -OC 2-6 Fluoroolefin, -OC 2-6 Alkynyl, -OC 2-6 Fluoroalkynyl and cyano groups; R 2 Selected from: 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, halogen, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 2-6 Alkenyl, -OC 2-6 Fluoroolefin, -OC 2-6 Alkynyl, -OC 2-6 Fluoroalkynyl and cyano groups; R 4 is a 5-membered cycloalkene or a 5-membered heteroaryl, each of which is optionally fused to form a 5:6 or 5:5 aromatic or heteroaromatic bicyclic ring; wherein each R 4 is optionally substituted; m is 0 or 1; R 6 Selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; R 7 and R 7 'Independently selected from: H, fluorine, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 7 With 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 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 8 With R 9 Together they 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 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 10 With R 11 Together they 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 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 12 With R 13 Together they 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 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 15 With R 16 Together they 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 where: -R 7 or R 7 'One 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 heterocycle; -R 7 or R 7 'One and R 6 Together they 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 With 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 heterocycle; -R 6 With R 10 or R 11 One of them together forms a 4- to 6-membered heterocyclyl ring or a 4- to 6-membered fluoroheterocyclyl ring; -R 8 or R 9 One and R 12 or R 13 One of them together form a 4- to 7-membered heterocyclyl ring or a 4- to 7-membered fluoroheterocyclyl ring; -R 8 or R 9 One and R 15 or R 16 One of them together forms a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring; -R 10 or R 11 One and R 12 or R 13 One of them together forms 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 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 and R 10 or R 11 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 and R 15 or R 16 One of them together forms a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring.

2. A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: in: Z is CR 1 or N; Y is CH or N; X is CR 2 or N; and No more than one of X, Y or Z is N; in: R 1 Selected from: 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, halogen, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 2-6 Alkenyl, -OC 2-6 Fluoroolefin, -OC 2-6 Alkynyl, -OC 2-6 Fluoroalkynyl and cyano groups; R 2 Selected from: 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, halogen, -OC 1-6 Alkyl, -OC 1-6 Fluoroalkyl, -OC 2-6 Alkenyl, -OC 2-6 Fluoroolefin, -OC 2-6 Alkynyl, -OC 2-6 Fluoroalkynyl and cyano groups; R 4 is a 5-membered cycloalkene or a 5-membered heteroaryl, each of which is optionally fused to form a 5:6 or 5:5 aromatic or heteroaromatic bicyclic ring; wherein each R 4 Optionally one or more R 5 Replace; wherein each R 5 Independently selected from: -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -Cyclofluoroalkyl-R 19 , -R 14 -Heterocyclyl-R 19 , -R 14 -Fluorinated heterocyclic group-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; wherein each R 14 Independently selected from 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; wherein each R 19 Independently selected from 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 Selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; R 7 and R 7 'Independently selected from: H, fluorine, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 7 With 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 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 8 With R 9 Together they 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 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 10 With R 11 Together they 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 Independently selected from: H, C 1-6 Alkyl, Fluorine, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 12 With R 13 Together they 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 Independently selected from: H, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 3-6 Cycloalkyl, C 3-6 Fluorinated cycloalkyl, C 2-6 Alkenyl, C 2-6 Fluoroalkenyl, C 2-6 Alkynyl and C 2-6 Fluoroalkynyl; or R 15 With R 16 Together they 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 where: -R 7 or R 7 'One 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 heterocycle; -R 7 or R 7 'One and R 6 Together they 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 With 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 heterocycle; -R 6 With R 10 or R 11 One of them together forms a 4- to 6-membered heterocyclyl ring or a 4- to 6-membered fluoroheterocyclyl ring; -R 8 or R 9 One and R 12 or R 13 One of them together form a 4- to 7-membered heterocyclyl ring or a 4- to 7-membered fluoroheterocyclyl ring; -R 8 or R 9 One and R 15 or R 16 One of them together forms a 5- to 7-membered heterocyclyl ring or a 5- to 7-membered fluoroheterocyclyl ring; -R 10 or R 11 One and R 12 or R 13 One of them together forms 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 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 and R 10 or R 11 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 and R 15 or R 16 One of them together forms a 3- to 6-membered cycloalkyl ring, a 3- to 6-membered fluorocycloalkyl ring, or a 5- or 6-membered oxygen-containing heterocyclic ring.

3. A compound according to claim 1 or claim 2, wherein the compound is a compound of formula (II):

4. A compound according to claim 1 or claim 2, wherein the compound is a compound of formula (III):

5. The compound according to any one of claims 1 to 4, wherein Y is N, Z is CR 1 and X is CR 2 .

6. A compound according to any one of claims 1 to 4, wherein Z is N, Y is CH and X is CR 2 .

7. A compound according to any one of claims 1 to 4, wherein X is CR 2 , Y is CH and Z is CR 1 .

8. A compound according to any one of claims 1 to 7, wherein R 4 Selected from: cyclopentenyl, pyrrolyl, 2,3-dihydro-pyrrolizinyl, pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thienyl, 1,2-oxazolyl, 1,3-thiazolyl and 1,2-thiazolyl; wherein R 4 The group is optionally replaced by one or more R 5 Replace; wherein each R 5 Independently selected from: -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -Cyclofluoroalkyl-R 19 , -R 14 -Heterocyclyl-R 19 , -R 14 -Fluorinated heterocyclic group-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; wherein each R 14 Independently selected from 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; wherein each R 19 Independently selected from 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.

9. A compound according to any one of claims 1 to 7, wherein R 4 Selected from: wherein u is an integer from 0 to the maximum number of substituent positions on the group; Each R 5 Independently selected from: -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -Cyclofluoroalkyl-R 19 , -R 14 -Heterocyclyl-R 19 , -R 14 -Fluorinated heterocyclic group-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; wherein each R 14 Independently selected from 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; wherein each R 19 Independently selected from 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.

10. The compound according to claim 8 or claim 9, wherein each R 5 Independently selected from: -R 14 , -R 14 -cycloalkyl-R 19 , -R 14 -Cyclofluoroalkyl-R 19 , -R 14 -Heterocyclyl-R 19 , -R 14 -Fluorinated heterocyclic group-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; where each R 14 Independently selected from 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; wherein each R 19 Independently selected from 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 Fluoroalkynyl.

11. A compound according to any one of claims 1 to 10, wherein R 8 and R 9 Independently selected from: H, C 1-6 Alkyl and C 1-6 Fluoroalkyl.

12. A compound according to any one of claims 1 to 11, wherein R 10 and R 11 Independently selected from: H, C 1-6 Alkyl, fluorine and C 1-6 Fluoroalkyl; or R 10 With R 11 Together they 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.

13. A compound according to any one of claims 1 to 12, wherein R 12 and R 13 Independently selected from: H, C 1-6 Alkyl, fluorine and C 1-6 Fluoroalkyl.

14. The compound according to any one of claims 1 to 13, wherein m is 0.

15. A compound according to any one of claims 1 to 10, wherein in the compound of formula (I), Selected from:

16. The compound according to claim 1, wherein the compound of formula (I) is selected from:

17. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or prodrug thereof; wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent and / or excipient.

18. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or prodrug thereof, in the preparation of a medicament for treating or preventing a disease, disorder or condition associated with spleen tyrosine kinase activity in a subject.

19. A method for treating or preventing a disease, disorder or condition associated with spleen tyrosine kinase activity in an individual, the method comprising administering to the individual an effective amount of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 17.

20. The method of claim 19, wherein the disease, disorder or condition associated with spleen tyrosine kinase activity is selected from one or more of the following: glioblastoma, cancer, osteoporosis, rheumatoid arthritis, liver disease, fibrosis, periodontal disease, diabetes, inflammation, Graves' disease, lung disease or disorder, kidney disease, acquired epidermolysis bullosa, Wiskott-Aldrich syndrome, agammaglobulinemia, Nasu-Hakola disease, allergy, microbial infection, fungal infection, autoimmune allergic disease, bleeding disorder, thrombocytopenia, bone or skeletal disorder, nail disease, chronic mucocutaneous candidiasis, nervous system disease or disorder, neuroinflammatory disease, stroke, head injury and subarachnoid hemorrhage.

21. The method of claim 19 or claim 20, wherein the disease, disorder or condition associated with spleen tyrosine kinase activity is in the central nervous system.

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