Compounds as sort1 inhibitors

Abstract

Disclosed are compounds, or salts thereof, with sortilin-binding inhibitory activity, medical use thereof for treating, preventing, and / or diagnosing diseases or disorders associated with sortilin ligands, and methods of preparing said compounds or salts thereof. Provided are a compound of formula (I): or a salt thereof, wherein substituents are those as defined in the specification; and related aspects.

Description

DESCRIPTIONTitle of the InventionCOMPOUNDS AS SORT1 INHIBITORSTechnical Field

[0001] This invention relates to novel compounds, pharmaceutical compositions containing them and their use as medicaments, in particular in the prophylaxis or treatment of diseases or disorders benefiting from inhibition of sortilin.Background Art

[0002] Sortilin is a multifunctional receptor predominantly expressed in neurons of the central and peripheral nervous systems, but also in metabolic tissues including liver. This type I receptor, belonging to the VpslQ domain family, plays multiple roles in the cellular transport and signaling of a variety of ligands which interact with its luminal / extracellularVPS 10 domain. The C-terminal cytoplasmic tail of sortilin is known to associate with adaptor molecules which can determine whether sortilin trafficking occurs via the anterograde or retrograde pathway. Sortilin has been demonstrated to be responsible for trafficking ligands between secretory and lysosomal protein pathways (NPL1). At the cell surface sortilin acts as a receptor of neurotrophic factors and neuropeptides.Following endocytosis of bound ligands sortilin releases its cargo upon entering acidic endosomal compartments. Fusion of these compartments with lysosomes ultimately degrades the endocytosed ligand, however sortilin can, possibly through dimerization(NPL2), be recycled to the Golgi by the retromer pathway and back to the plasmamembrane.

[0003] The interaction between progranulin (PGRN) and sortilin (SORT1) was originally identified in a ligand, binding screen of an expression library (NPL3). Lysosomal trafficking of PGRN was found to be mediated through the binding of its C-terminal domain to sortilin in a similar fashion as previously described for neurotensin (NTS).Unsurprisingly NTS interferes with PGRN binding of sortilin (NPL3). Likewise, a small molecular weight sortilin inhibitor, AF38496, was also shown to interfere with NTS binding, indicating that small molecular weight compounds could be developed to similarly inhibit PGRN-sortilin binding as a potential means to elevate PGRN levels(NPL4). The ability of sortilin to regulate PGRN levels by impacting lysosomal trafficking and thereby PGRN turnover, has been demonstrated in cellular and mouse sortilin deficient models. Mice lacking sortilin demonstrated elevations of brain and serum PGRN levels by 2.5- to 5-fold. PGRN decreases observed in GRN+ / - mice were normalized by genetic ablation of the gene encoding sortilin, Sortl (NPL3). In vivo administration of sortilin targeting antibodies have also been described which deplete sortilin giving rise to a similar elevation in PGRN as observed with genetic ablation(NPL5). The ability of sortilin to act as a regulator of PGRN levels has furthermore been observed through genome-wide association studies where genetic variants, single nucleotide polymorphisms (SNPs) rs646776 and rs611917, were associated with increased SORT1 mRNA levels and decreased plasma PGRN (NPL6).

[0004] PGRN is a secreted pleiotropic growth factor associated with multiple biological processes including regulation of cell growth, survival inflammation, and wound healing(NPL9). Within the central nervous system (CNS) PGRN is attributed with neurotrophicand anti-inflammatory properties (NPL10; NPL11). The clinical significance of PGRN to neurodegenerative disease was made clear in 2006 with the discovery that missense mutations in one allele of the PGRN encoding gene, GRN, resulting in GRN haploinsufficiency, are causal for the development of frontotemporal lobar degeneration(FTLD) (NPL12; NPL13). Mutations in both GRN alleles result in neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease (NPL15). These PGRN insufficiency diseases are both associated with neuroinflammation and lysosomal dysfunction.Markers of inflammation and lysosomal functions were both improved in a GRN deficient mouse model by lentiviral expression of GRN (NPL14). Neither GRN+ / - or Sortl- / - mouse models exhibit the pathological phenotypes observed in the GRN deficient mouse.While sortilin appears to be the major lysosomal trafficking receptor for PGRN, other sortilin independent trafficking routes have been identified (NPL15). Overall, the evidence suggests pharmacological interference of PGRN-sortilin interaction, by brain penetrant small molecular weight inhibitors, has the potential to deliver clinical benefit inFTLD and other diseases characterised by PGRN insufficiency.

[0005] In addition to FTLD, SORT1 polymorphisms have also been linked to alteredAlzheimer’s disease (AD) susceptibility (NPL16). Potentially pathogenic GRN missense mutations have also been identified in neurodegenerative diseases, including Alzheimer’s disease (AD) (NPL17; NPL18; NPL19; NPL20; NPL21; NPL22), Parkinson’s disease(PD) (NPL23), and amyotrophic lateral sclerosis (ALS) (NPL24). A beneficial impact from progranulin modulation has been further validated in animal models of neurodegenerative disease. Direct injection of PGRN into the brains of 5xFAD mice leads to a reduction of A0 plaques, downregulation of beta-secretase 1 (BACE1), and enhanced microglia A0 phagocytosis (NPL25). Lentiviral introduction of PGRN in theAPP AD mouse model was demonstrated to be beneficial to reduce plaque load, enhance survival of hippocampal neurons and prevent memory deficits (NPL26). Lentiviral mediated GRN expression also protected dopaminergic (DA) neurons from the parkinsonian toxin MPTP (NPL27). A key histopathological hallmark of FTLD withGRN mutations is the presence of ubiquitinated TDP-43 inclusions. This pathology is shared with ALS and suggests potential common pathological mechanism across the two diseases (NPL28). In zebrafish models, overexpression of human PGRN mRNA is protective against mutant TDP-43 induced axonopathy (NPL29). PGRN overexpression has also been shown to reduce insoluble TDP-43 levels in TDP-43(A315T) mice (NPL30).Inversely PGRN insufficiency has been associated with the increased generation of pathological forms of TDP-43 (NPL31). Reduction of TDP-43 may be benefit in CNS pathologies including spinocerebellar ataxia 3 (SCA3) (NPL69), Huntington's diseases(HD) (NPL64) and limbic-predominant age-related TDP-43 encephalopathy (LATE)(NPL9) which show the cytoplasmic accumulations of TDP-43. GWAS studies have also implicated GRN as a risk factor for LATE (NPL32).

[0006] PGRN has been demonstrated to exert a protective effect against photoreceptor cell damage in mouse models (NPL33). PGRN attenuated neuronal injury induced by cerebral ischemia (NPL11). PGRN also protected axonal loss and astrogliosis following traumatic brain injury which was exaggerated in GRN- / - mice (NPL34).

[0007] Possible pathological overlap between FTLD with other CNS diseases has also been suggested. Schizophrenia-like psychosis was observed in patients, years before a dementia diagnosis consistent with TDP-43 positive FTD was made (NPL35). A study of siblings presenting with either FTD or schizophrenia while both carried a loss offunction GRN mutation has been reported (NPL36). Schizophrenia has previously been linked to mutations on a region of chromosome 17q21 shared by the GRN gene (NPL37).There is additional evidence of a clinical overlap between FTD and bipolar disorder(BPD). Plasma PGRN levels were observed to be significantly decreased relative to controls in a small study of patients with BPD (NPL38).

[0008] PGRN overexpression in sensory neurons of transgenic mice attenuates neuropathic pain after sciatic nerve injury (NPL39). PGRN-deficient mice models were demonstrated to develop more intense nociceptive hypersensitivity after nerve injury. RecombinantPGRN rescued primary dorsal root ganglia neurons from cell death induced by nerve growth factor withdrawal suggesting raised PGRN levels have the potential for therapeutic use in the treatment of injury associated chronic pain (NPL40). The sortilin ligand neurotensin, has also been demonstrated to effect peripheral neuropathic pain.Sortilin inhibition by antibodies or the small molecular weight inhibitor AF38469 blockedBDNF-induced pain and alleviated injury-induced neuropathic pain mechanical allodynia in a spared nerve injury model (NPL5).

[0009] Progranulin modulation could protect against acute focal cerebral ischemia by a variety of mechanisms including attenuation of blood-brain barrier disruption, neuroinflammation suppression, and neuroprotection. Progranulin could regulate vascular permeability via vascular endothelial growth factor, suppress neuroinflammation after ischemia via anti-inflammatory interleukin 10 in the microglia, and render neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA-binding protein-43. Administered recombinant progranulin has been shown to reduce cerebral infarct and oedema, suppress haemorrhagic transformation, and improved motoroutcomes (NPL41). Decreased progranulin levels, potentially associated with suppressed neutrophil recruitment, has been observed in patients, and rats, with subarachnoid hemorrhage (NPL42). The ability of sortilin to impact neuroinflammation is not restricted however to its influence on PGRN alone. Neurotensin has also been demonstrated to affect chemotaxis of microglia which could be blocked in cell models through the addition of the sortilin pro-peptide which competes for neurotensin binding on sortilin (NPL43). Cells carrying the GRN rs5848 variant, obtained from idiopathic normal pressure hydrocephalus (iNPH) patients also demonstrate an increased proinflammatory response. Suggesting that modulation of PGRN may have a beneficial effect for iNPH (NPL44).

[0010] In addition to the numerous neurological effects already listed, modulation of sortilin ligands has the potential to impact a variety of systemic diseases as well.

[0011] Retinal degeneration has been demonstrated in GRN deficient mice resulting in thinner retinas and increased lipofuscin deposits relative to controls which could be rescued through intravitreal injection of PGRN (NPL45). PGRN has also demonstrated protective effects on photoreceptors against excessive light exposure (NPL33; NPL46), suggesting that PGRN modulation may be therapeutic for age-related macular degeneration and other neurodegenerative disease of the eye.

[0012] PGRN levels have been reported to impact TNFR signalling and other immune function regulated pathways with suggested beneficial effects of modulating PGRN levels in a number of inflammatory diseases including but not restricted to rheumatoid arthritis (RA), osteoarthritis (OA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc),inflammatory bowel disease (IBD), psoriasis, type 1 diabetes mellitus (T1DM) and MS(NPL47).

[0013] ProNGF and proBDNF are known apoptotic ligands that bind to the receptor complex of p75NTR and sortilin. Thus, inhibition of sortilin is believed to be beneficial in preventing neurodegeneration (NPL5).

[0014] Modulation of sortilin also has the potential to influence other inflammatory cytokines.Sortilin has been demonstrated to aid the intracellular trafficking of IFN-g and IL-6, but not IL- 5 or MCP-1 (NPL48). In addition to reducing systemic markers of inflammation, the transfer of sortilin-deficient bone marrow into irradiated atherosclerotic mice also reduced atherosclerosis. Agents which impact the ability of sortilin to effectively transport IFN-g also have the potential to regulate autoimmune functions and could be of therapeutic benefit in the treatment of autoimmune disorders such as inflammatory bowel disease.

[0015] PGRN modulation may also be therapeutically relevant for inflammation-related osteoporosis. PGRN inhibited TNF-a-induced osteoclastogenesis from spleen cells ofPGRN-KO mice. Moreover, PGRN significantly promoted ALP activity, osteoblast- related mRNA (ALP, osteocalcin) expression in a dose-dependent manner and up- regulated osteoblastic differentiation by down-regulating phosphorylation of ERK1 / 2 in mouse calvarial cells (NPL49; NPL50; NPL51). PGRN also suppresses neutrophil recruitment into the ischemia-reperfusion brain (NPL52).

[0016] Sortilin regulates multiple ligands associated with atherogenesis mechanisms includinginflammation, dyslipidemia, vascular calcification and insulin resistance (NPL53).Progranulin in the hematopoietic compartment has been demonstrated to protect mice from atherosclerosis. The size of atherosclerotic lesions in bone marrow progranulin KO mice, in a Ldlr- / - genetic background, was increased by 47% in aortic roots and by 62% in whole aortas. Progranulin-deficient macrophages also exhibit increased cholesterol uptake and foam cell formation (NPL54). Sortilin KO mice have been observed to decrease plasma cholesterol levels by 20% on the wild-type LDL receptor background and by 30% in Ldlr- / - animals (NPL55). Sortilin hepatocyte deficiency also attenuates diet induced hypercholesterolemia in mice. AF38469 treatment also was shown to reduce hepatic VLDL secretion (NPL56). Sortilin also aids secretion of PCSK9, which leads toLDLR turnover and elevated LDL-C (NPL57). Elevated PCSK9 levels are correlated with increased risk of coronary artery disease, therefore targeting sortilin has the therapeutic potential to affect multiple ligands which impact coronary artery disease.Sortilin inhibition is also possibly a target for treatment of major depression, as it has been proved to have effect on depressive symptoms through TREK-1 channel (NPL65), brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor(VEGF) (NPL66; NPL67).

[0017] While PGRN is often associated with tumorigenic potential there are examples of particular tumour types where sortilin directed inhibitors have the potential to be antioncogenic. Inhibition of progranulin binding to sortilin was shown to block progranulin- induced metastatic breast cancer using a triple-negative in vivo xenograft model (NPL58).Xenograft models also indicate that a sortilin inhibitor, AF38469, which blocks interaction with PGRN blocked lung metastases (NPL59) and pancreatic cancer cell invasion (NPL60).

[0018] Methods of screening for sortilin binding antagonists (PTL1) and for treating and monitoring progranulin-associated disorders (PTL2) have been described.

[0019] Sortlin antagonists have also been described (NPL61; PTL3).Citation List

[0020] Patent Literature[PTL 1] WO2016 / 164608[PTL 2] W02020 / 081575[PTL 3] WO2021 / 186054

[0021] Non Patent Literature[NPL 1] Nykjaer and Wilnow Trends in Neurosciences 35: 2012, 261-270[NPL 2] Itoh, S et al. J. Biol. Chem. (2018) 293(12) 4532-4544[NPL 3] Hu F et al. Neuron. 2010; 68: 654-667[NPL 4] Schroeder TJ et al. Bioorg Med Chem Lett 2014 Jan 1; 24(1): 177-80[NPL 5] Miyakawa S et al. Front Neurosci. 2020 Dec 15; 14: 586107[NPL 6] Carrasquillo MM et al. Am J Hum Genet. 2010 Dec 10; 87(6): 890-7[NPL 7] Liu C et al. Antiinflamm Antiallergy Agents Med Chem. 2020; 19(2): 88-10[NPL 8] Yang D et al. Am J Cancer Res. 2015 Sep 15; 5(10): 3085-97[NPL 9] Rhinn H et al. Trends in Pharmacological Sciences. 2022 Aug; 43(8): 641-652[NPL 10] van Damme P, et at J Cell Biol. 2008; 181(1): 37-41[NPL 11] Ahmed Z et al. J Neuroinflammation. 2007 Feb 11; 4: 7[NPL 12] Cruts, M et al. (2006) Nature 442, 920-92[NPL 13] Baker, M et al. (2006) Nature 442, 916-919[NPL 14] Arrant AB et al. J Neurosci. 2018 Feb 28; 38(9): 2341-2358[NPL 15] Zhou X et al. J Cell Biol. 2015; 210(6): 991-1002[NPL 16] Andersson CH et al. Alzheimers Dis. 2016 Jul 1; 53(4): 1353-63[NPL 17] Brouwers N et al. Neurology. 2008; 26; 656-664.[NPL 18] Viswanathan I et al. Am. J. Med. Genet. B. Neuropsychiatr. Genet 2009;150B: 747-750[NPL 19] Kamalainen A et al. J Alzheimers Dis. 2013; 33(1): 23-7[NPL 20] Sheng J et al. Gene 2014 542:2 (141-145)[NPL 21] Xu HM et al. Mol Neurobiol. 2017 Mar; 54(2): 1187-1195[NPL 22] Bellenguez C et al. Nat Genet. 2022 Apr; 54(4): 412-436[NPL 23] Nalls MA et al. Lancet Neurol. 2019 Dec; 18(12): 1091-1102[NPL 24] Sleegers K et al. Neurology. 2008; 71: 253-259[NPL 25] Guan Z et al. Front Cell Neurosci. 2020; 14: 260[NPL 26] Minami SS et al. Nat Med. 2014 Oct; 20(10): 1157-64[NPL 27] Van Kampen JM et al. PLoS One. 2014 May 7; 9(5): e97032[NPL 28] Irwin D et ah J Neurol Sci. 2009 Jan 15; 276(1-2): 9-13[NPL 29] Laird AS et al. PLoS One. 2010; 5(10): el3368. Published 2010 Oct 13[NPL 30] Beel S et al. Mol Neurodegener. 2018; 13(1): 55[NPL 31] Robinson S et al. bioRxiv preprint. January 16, 2024[NPL 32] Dugan AJ et al. ActaNeuropathol Commun. 2021 Sep 15; 9(1): 152[NPL 33] Tanaka M et al. Mol Vis. 2019; 25: 902-911[NPL 34] Menzel L et al. Glia. 2017; 65(2): 278-292[NPL 35] Velakoulis D et al. Br J Psychiatry. 2009 Apr; 194(4): 298-305[NPL 36] Momeni P et al. Neurocase. 2010 Jun; 16(3): 273-9[NPL 37] Escamilla M et al. Am J Psychiatry. 2009 Apr; 166(4): 442-9[NPL 38] Galimberti D et al. PLoS One. 2012; 7(4): e32164[NPL 39] Altmann C et al. Neurobiol Dis. 2016; 96: 294-311[NPL 40] Lim et. al. J Cell Mol Med 2012 Apr; 16(4): 708-21[NPL 41] Kanazawa et al. Brain, Volume 138, Issue 7, July 2015, Pages 1932-1948[NPL 42] Zhou C et al. J Neuroinflammation. 2015; 12: 200[NPL 43] Martin S et al. J Neurosci. 2003 Feb 15; 23(4): 1198-1205[NPL 44] Jeskanen H et al. Neuroscience Meeting 2022. 276.16 / D41[NPL 45] Zin et. al. Mol Ther Methods Clin Dev. 2021[NPL 46] Tsuruma K, et al. Stem Cells Transl Med 2014 Jan; 3(1): 42-53[NPL 47] Lan YJ et al. J Inflamm Res. 2021; 14: 6543-6556. Published 2021 Dec 4[NPL 48] Mortenson et al. J Clin Invest. 2014; 124(12): 5317-5322[NPL 49] Noguchi et al. Biochem Biophys Res Commun. 2015 Sep 25; 465(3): 638-43[NPL 50] Wei et al. Ann N Y Acad Sci. 2020 Jan; 1460(1): 43-56[NPL 51] Yu et al. J Int Med Res. 2021 Aug; 49(8): 3000605211032508[NPL 52] Tao et. Al. Brain Research Volume 1436, 3 February 2012, Pages 130-136[NPL 53] Goettsch et al. Arterioscler Thromb Vase Biol. 2017 May; 37(5): 1005-1011[NPL 54] Nguyen et al. Atherosclerosis 2018 Oct; 277: 145-154[NPL 55] Kjolby M et al. Cell Metabolism, 2010; 12 (3): 213-223[NPL 56] Chen C et al. J Lipid Res 2019 Mar; 60(3): 539-549[NPL 57] Gustafsen, C et al. Cell Met. 2014; 19: 310-318[NPL 58] Berger K et al. J Med Chem. 2021; 64(17): 12865-12876[NPL 59] Rhost S et al. Breast Cancer Res. 2018; 20(1): 137[NPL 60] Gao F et al. Am J Pathol. 2020; 190(9): 1931-1942[NPL 61] Satchel SJ et al. Bioorganic & Medicinal Chemistry Letters 30 (2020) 127403[NPL 62] Jian et al. EBioMedicine 2016 Sep; 11: 127-137[NPL 63] Tan CF et al. ActaNeuropathol. 2009 Oct; 118(4): 553-560[NPL 64] Schwab et al. J Neuropathol Exp Neurol. 2008 Dec; 67(12): 1159-1165[NPL 65] Mazella J et al. Front Pharmacol 2019 Jan 8:9:1541[NPL 66] Buttenschon NH et al. Transl Psychiatry. 2015 Nov 10; 5(11): e677[NPL 67] Zhou Li et al. J Affect Disord. 2013 Sep 25; 150(3): 776-784Summary of Invention

[0022] There remains a need for the identification of modulators of sortilin. Such modulators may demonstrate enhanced in vivo potency, selectivity, acceptable safely profile, or desirable pharmacokinetic parameters, including acceptable brain penetration.

[0023] Provided is a compound of formula (I):or a salt thereof, wherein:R1is:1) H,2) halo,3) OH,4) R11optionally substituted with the same or different one or more R12, or5) - L1-R11optionally substituted with the same or different one or more R12;L1is O or S;R11is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl;R12i each independently halo, -OH, -N(Ra)(Rb), -O-C1-6alkyl, -O-C1-6alkyl-N(Ra)(Rb), C3-8 cycloalkyl, or saturated 3- to 8-membered monocyclic heterocyclyl comprising at least one heteroatom independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R12is optionally substituted with the same or different one or more halo, C1-6alkyl, or CN;Rais H or C1-6alkyl;Rbis H, C1-6alkyl, or C(=O)OC1-6alkyl;R2is:1) C1-6alkyl optionally substituted with the same or different one or more halo orCN,2) C3-8 cycloalkyl optionally substituted with the same or different one or more C1-6alkyl, halo or CN, or3) Si(C1-6alkyl)3;R3is CH2 or O;R4is H or C1-6alkyl;Ring A is 5- or 6-membered heteroaryl or 6-membered aryl;Ring A may be optionally substituted with the same or different one or more A1selected from the group consisting of halo, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkyl-O-,C1-6haloalkyl-O-, C1-6alkylene(C3-6 cycloalkyl), C1-6alkylene(3- to 10-membered heterocyclyl), C1-6alkylene(C6-10aryl), C1-6alkylene-0-(C6-10aryl), C1-6alkylene(5- to 12- membered heteroaryl), C0-6alkyleneOH, C0-3 alkyleneOC2-3 alkylene(OH), C0-6alkylene(N(Rc)(Rd)), -OC0-6alkylene(OC1-6alkyl), -OC0-6alkylene(N(Rc)(Rd)), and C0-3 alkyleneOCi-3 alkylene(N(Rc)(Rd));Rcis H or C1-6alkyl;Rdis H or C1-6alkyl, C1-6haloalkyl, or C(=O)OC1-6alkyl;Ring A may be optionally substituted with the same or different one or two RingG;Ring G is a monocyclic or bicyclic 6- to 10-membered aryl, a monocyclic or bicyclic 5- to 12-membered heteroaryl, C3-8 cycloalkyl, or a saturated or partially unsaturated monocyclic or bicyclic 3- to 16-membered heterocyclyl; wherein the bicyclic aryl comprises a 6-membered aryl attached to Ring A, and the bicyclic heteroaryl comprises a 5- or 6-membered heteroaryl attached to Ring A;Ring G may be independently optionally substituted with the same or different one or more G1A;G1Ais halo, C1-6alkyl, C1-6halo alkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, -(CRxRy)v-CN, -(CH2)v-NRxRy, -(CH2)v-C3-8cycloalkyl, -(CH2)v-C3-8 cycloalkenyl, -(CH2)v-(3- to 10-membered heterocyclyl), -(CH2)v-C6-10aryl, -(CH2)v-(5- to 12- membered heteroaryl), -(CRxRy)v-O-Rz, -O-(CRxRy)n-ORz, nitro, Si(Rx)4, -S(O)q-Rx, -C(=O)RX, -(CRxRy)v-C(=O)ORz, -(CRxRy)v-O-C(=O)-Rz, -(CRxRy)v-C(=O)NRxRy, - (CH2)v-NRxC(=O)Ry, -(CH2)v-OC(=O)NRxRy, -(CH2)v-NRxC(=O)ORy, -NRx-(CH2)v-Rz,-(CH2)v-O-C(=O)-C1-4alkyl-NRxRy, -(CH2)v-NRx-(CH2)n-O-C(=O)-Rz, -(CH2)v-NRx- (CH2)v-SO2-Ry, -(CH2)v-NH-SO2-NRxRy, -(CH2)v-SO2NRxRygroups, and -P(=O)(RX)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C6-10aryl, 3- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl groups may be optionally substituted with the same or different one or more Rxgroups and the two Rxmay join to form a 3- to 7-membered ring optionally containing one or two additional heteroatoms selected from O, N, S, and oxidized forms of N or S;Rx, Ryand Rzeach independently represent halo, H, C1-6alkyl, C1-6alkenyl, C2-6alkynyl, -(CH2)v-C3-8 cycloalkyl, -(CH2)v-C3-8 cycloalkenyl, -(CH2)V-C6-IO aryl, -(CH2)5- to 12-membered heteroaryl, -(CH2)v-(3- to 10-membered heterocyclyl), -(CH2)VOH optionally substituted with the same or different one or more halo, -C(=0)0C1-6alkyl,OH, =0, C1-6alkyl-O-, C1-6halo alkyl, -(CH2)n-O-C1-6alkyl, -C(=O)-(CH2)n-C1-6alkyl-O-,-C(=0)-C1-6alkyl, -(CH2)VC(=O)(OG2A), -(CH2)V-CN, C1-6alkyl-N(H)2-q(Rh)q, -N(H)2. q(Rh)q, -C(=O)-N(H)2<](C1-6alkyl)q, -(CH2)v-NH-SO2-N(H)2-q(C1-6alkyl)q, -(CH2)V-N(CI.4 alkyl)-SO2-N(H)2.q(C1-6alkyl)q, and -(CH2)V-O-C(=O)-C1-4alkyl-N(H)2-q(C1-6alkyl)q; and when attached to nitrogen, carbon, silicon, or phosphorus atom, Rxand Rymay join to form a 3- to 7-membered ring optionally containing one or two additional heteroatoms selected from O, N, S, and oxidized forms of N or S;G2Ais H, C1-6alkyl, C0-3 alkylene(C6-10aryl) or C0-3 alkylene(5- to 12-membered heteroaryl), wherein said aryl or heteroaryl may be optionally substituted with the same or different one or more groups selected from the group consisting of halo, CN, OH, Ci-6 alkyl, C1-6haloalkyl, C1-6alkyl-O-, C1-6haloalkyl-O-, and C3-6 cycloalkyl;Rhis C1-6alkyl, C1-6haloalky 1, or C(=0)0 C1-6alkyl; v independently represents an integer from 0-4; n independently represents an integer from 1-4; p independently represents an integer from 0-4; and q represents an integer from 0-2.

[0024] The compound of formula (I), or a salt thereof, may be used as medicaments, for example sortilin inhibitors, in particular for use in increasing PGRN levels, inhibiting neurotensin signaling, inhibiting BDNF signaling, inhibiting proNGF signaling, or inhibiting proBDNF signaling.

[0025] Also provided is a method of treatment, prophylaxis, or diagnosis of a disease or disorder associated with sortilin ligands, the method which comprises administering to a subject in need thereof a compound of formula (I), or a salt thereof.

[0026] Also provided are pharmaceutical compositions comprising a compound of formula (I) or a salt thereof and a pharmaceutically acceptable carrier or excipient.

[0027] Also provided are processes for preparing a compound of formula (I) or a salt thereof and novel intermediates of use in the preparation of compounds of formula (I) or a salt thereof.Description of Embodiments

[0028] The phrases and terms used in this specification are explained in detail below.

[0029] The term "halo" or "halogen" used herein is fluorine, chlorine, bromine, or iodine.Particular examples include fluorine, chlorine, and bromine, for example fluorine and chlorine, for example fluorine.

[0030] The term "C1-6alkyl" used herein, whether alone or forming part of a larger group such as an "Oalkyl" group or "alkyl-O-" group, is a straight or a branched hydrocarbon groupcontaining 1 to 6 carbon atoms (C1-6), and examples of "C1-6alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, 1- ethylpropyl, neopentyl, 1,1 -dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2- dimethylbutyl, and 2,3 -dimethylbutyl. "C1-6alkyl" also includes C1-6alkyl having 1 to 7 deuterium atoms substituted for 1 to 7 hydrogen atoms, and examples include methyl-d13, ethyl-d1-5, propyl-d1-7, and isopropyl-d1-7, and further examples include methyl-d1, methyl-d2, methyl-d3, ethyl-d3, ethyl-d5, propyl-d3, propyl-d7, isopropyl-di, isopropyl-d3, isopropyl-d6, and isopropyl-d7. The alkyl group may be C1-4alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0031] The term "C1-6haloalkyl" used herein, whether alone or forming part of a larger group such as an "Ohaloalkyl" group or "haloalkyl-O-" group, is the above-defined "C1-6alkyl" that is substituted with at least one halogen atom, such as 1 to 7 halogen atoms, independently selected from the group of the above-defined "halo". Examples of "C1-6haloalkyl" include monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 1 -fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1- difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difhioroethyl, 1- fluoro- 1 -methylethyl, 2,2,2-trifhioro- 1 -methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl. 3 -fluoropropyl, 3 -chloropropyl, 1 , 1 -difluoropropyl, 3,3,3- trifluoropropyl, 3,3,3-trifluoro-2-methylpropyl, 3-chloro-2,2-difhioropropyl, 4,4,4- trifluorobutyl, 3-methyl-4,4,4-trifhiorobutyl, and 3-chloro-4-fhioropentyl.

[0032] The term "alkylene" used herein, whether alone or forming part of a larger group such as"C0-6alkyleneOH", is a bifunctional straight or branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of C0-3 alkylene groupsinclude C0-3 alkylene, C1-3 alkylene, and C2-3 alkylene, such as where the group is absent / a bond (i.e., Co), methylene (Ci), ethylene (C2), propylene (C3), -CH(Me)-, and -C(Me)2-.

[0033] The term "C2-6alkenyl" used herein is a straight or branched hydrocarbon group containing 2 to 6 carbon atoms (C2-6) and at least one carbon-carbon double bond, such as one or two double bonds. Examples of "C2-6alkenyl" include CH=CH2, CH2CH=2CH,2CH=CHCH3, CH2CH2CH=CH2, CH=CHCH2CH3, CH2CHCHCH3,CH2CH2CH2CH=CH2, CH=CHCH2CH2CH3, CH2CH=CHCH2CH3,CH2CH2CH=CHCH3, CH(CH3)CH=CH2, CH=C(CH3)2, CH2CH2CH2CH=CH2,CH=CHCH2CH2CH3, CH2CH=CHCH2CH3, CH2CH2CH=CHCH3, CH=CHCH=CHCH3, and CH2CH=CHCH=CH2.

[0034] The term "C2-6haloalkenyl" used herein is the above-defined " C2-6alkenyl" that is substituted with at least one halogen atom, such as 1 to 7 halogen atoms, independently selected from the group of the above-defined "halo".

[0035] The term "C2-6alkynyl" used herein is a straight or branched hydrocarbon group containing 2 to 6 carbon atoms (C2-6) and at least one carbon-carbon triple bond.Examples of "C2-6alkynyl" include C≡CH, CH2OCH, C≡CCH3, CH2CH2C≡CH, C≡CCH2CH3, CH2C≡CCH3, CH(CH3)C≡CH, CH2CH2CH2C≡CH, C≡CCH2CH2CH3,CH2C≡CCH2CH3, CH2CH2 C≡CC H3, C≡CC≡CCH3, and CH2C≡CC≡CCH.

[0036] The term "C3-8 cycloalkyl" used herein, whether alone or forming part of a larger group such as "-(CH2)V-C3-8 cycloalkyl", is a saturated mono- or poly-cyclic hydrocarbon ring group containing 3 to 8 carbon atoms. In some embodiments, the cycloalkyl group maybe a bridged ring group. In other embodiments, the cycloalkyl group may be a spirocyclic group, i.e., a bicyclic cycloalkyl group wherein the two rings are connected through just one atom and the two rings can be different or can be the same. Examples of "C3-8 cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, and bicyclo[l.l.l]pentyl. The cycloalkyl group may be C3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[l,l.l]pentyl.

[0037] The term "C3-8 cycloalkenyl" used herein is a mono or polycyclic hydrocarbon ring system containing 3 to 8 carbon atoms and at least one carbon-carbon double bond., such as one or two double bonds, for example one double bond. Examples of "C3-8 cycloalkenyl" include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0038] The term "aryl" used herein is a mono or polycyclic ring system (e.g., comprising one or two, such as one, additional ring) containing at least one phenyl ring. Examples of "aryl" include an aryl group containing 6-10 ring members, i.e., C6-10aryl. The additional ring in a polycylic ring system may be a saturated (e.g., forming indanyl or tetralinyl) or partially unsaturated (e.g., forming indenyl), or fully unsaturated (e.g., forming naphthalenyl) hydrocarbon ring, or the additional ring may be a saturated or partially unsaturated heterocycle (e.g., forming chromanyl). Suitably aryl refers to a "monocyclic or bicyclic aryl", i.e., a mono (i.e., phenyl) or a bicyclic ring system containing at least one phenyl ring (and no heteroaryl rings), such as C7-10 bicyclic aryl, including indanyl.

[0039] The term "6-membered aryl" used herein is Ce aryl, i.e., phenyl.

[0040] The term "heteroaryl" used herein is a mono or polycyclic ring system (e.g., bicyclic,tricyclic, and tetracyclic) with at least one ring having aromatic character and containing at least one heteroatom selected from N, O, and S, for example N. Examples of"heteroaryl" include a heteroaryl containing 5-12 ring members. Where a heteroaryl group contains more than one ring, not all rings must contain a heteroatom, and not all rings must be aromatic in character. In some embodiments, heteroaryl is monocyclic, such as a 5- or 6-membered, heteroaryl ring (e.g., containing at least one, such as one and two, heteroatoms selected fromN, O, and S). In other embodiments, heteroaryl is bicyclic, such as a 5 / 5, 5 / 6, 5 / 7, 6 / 6, 6 / 7, and 7 / 7 bicyclic system (e.g., containing at least one, such as one, two, and three, heteroatoms selected from N, O, and S). In some embodiments, heteroaryl may contain one heteroatom selected from N, O, and S, for example N and 0. In other embodiments, heteroaryl may contain two heteroatoms selected from N, O, andS. In further embodiments, heteroaryl may contain three heteroatoms selected from N,O, and S, for example N and O. Examples of "heteroaryl" include monocyclic heteroaryl such as pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; and polycyclic heteroaryl such as furopyrrolyl, pyrrolopyrrolyl, indazolyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiophenyl, benzothiazolyl, benzoisothiazolyl, imidazopyridinyl, imidazopyrazinyl, pyrazolopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, furopyridinyl, benzotriazolyl, thienopyridinyl, thiazolopyridinyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthaladinyl, naphthyridinyl, benzoazepinyl, and benzoxazepinyl. Examples of 5- or 6-membered heteroaryl include pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.

[0041] The term "heterocyclyl" used herein is a fully saturated or partially unsaturated 3- to 16- membered ring system containing the specified number of carbon and non-carbon ring atoms (i.e., not including any aromatic rings), wherein at least one of the ring atoms is a heteroatom selected from as N, O, S, or B. Suitably, heteroatoms are selected from N, O, and S. As required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. In some embodiments, a heterocyclyl group may contain one heteroatom selected from N, 0, and S, for example N and O. In other examples a heterocyclyl group may contain two heteroatoms selected fromN, O, and S, for exampleN and O, for example N and S, or for example the two are N. In other embodiments, a heterocyclyl group may contain three heteroatoms selected fromN, O, and S, for exampleN and O, for example N and S, or for example the three are N. In some embodiments, the heterocyclyl group may be substituted with oxo (=O). When a ring heteroatom is S, the heterocyclyl group includes an oxo-substituted heterocyclyl group wherein the S atom(s) is substituted (such as one S atom is substituted) with one or two oxygen atoms(i.e., S(O) or S(O)a) to form a sulfone or sulfoxide. Alternatively, any sulfur atom(s) in the heterocycle ring are not substituted. A heterocyclyl group may be monocyclic.Examples of a monocyclic heterocyclyl group include saturated monocyclic heterocyclyl such as aziridinyl, oxylanyl, thiylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolanyl, piperidinyl, piperazinyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, and azocanyl; and partially unsaturated monocyclic heterocyclyl such as dihydropyridinyl, tetrahydropyridinyl, imidazolidinyl, pyrazolidinyl, azepinyl, oxetanyl, dihydropyranyl, pyranyl, thiopyranyl, thiazinyl, thiazolinyl (dihydrothiazolyl), and thiazolidinyl. Alternatively, a heterocyclyl group may be polycyclic (e.g., bicyclic,tricyclic, and tetracyclic) such as a fused bicyclic or a bridged bicyclic ring system wherein the fused bicyclic ring may include an aromatic ring such as benzene. Examples of a fused heterocyclic group include pyrrolidinopyrrolidinyl, dihydrobenzoimidazolyl, indolyl, isoindolyl, indazolinyl (dihydroindazolyl), tetrahydroimidazopyrazinyl, tetrahydropyridoindolyl, tetrahydrobenzoazepinyl, hexahydropyrrolopyrrolyl, dihydrobenzoxazolyl, oxaazabicycloheptanyl, tetrahydrofiiropyrrolyl, benzoxazinyl, dihydrobenzoxazinyl, chromenyl, isochromenyl, dihydroimidazooxazinyl, dihydropyrazolooxazinyl, tetrahydrobenzoxazepinyl, dihydropyrano[4,3-d]thiazolyl, octahydropyrrolo[l,2-a]pyrazinyl, and benzodiazepinyl. Examples of a bridged heterocyclic group include 2-oxabicyclo[2.1.1]hexanyl, azabicycloocctane (for example, azabicyclo[3.2.1]octanyl), and diazabicyclo [3. l.l]heptanyl. In some embodiments, a bicyclic heterocyclic group is spirocyclic, i.e., a bicyclic group wherein the two rings are connected through just one atom and the two rings can be different or identical. At least one of the two rings comprises at least one heteroatom. Examples of a spiro-heterocyclic group include 2-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxa-6- azaspiro[3.3]heptanyl, oxaazaspirooctanyl, and 2,6-diazaspiro[3.4]octanyl.

[0042] Examples of "saturated 3- to 8-membered monocyclic heterocyclyl" used herein include azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azocanyl, and diazepanyl.

[0043] Examples of "3- to 10-membered heterocyclyl" used herein include azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azocanyl, diazepanyl, and the following groups:H NN H

[0044] Examples of "saturated or partially unsaturated monocyclic or bicyclic heterocyclyl" used herein include pyrrolidinyl, azepanyl, and isoindolyl.

[0045] Examples of "3- to 7-membered ring optionally containing one or two additional heteroatoms selected from N, O, S, and oxidized forms of N or S" used herein include cyclopropane.

[0046] Various substituents in the compound represented by formula (I) (herein also referred to as "Compound (I)") are explained below. A bond with a wavy line in a chemical formula as used herein refers to a binding site of the moiety, group, or ring system represented by the chemical formula to the remainder of Compound (I).

[0047] In some embodiments, Ring A is selected from the following groups:

[0048] In further embodiments, Ring A is 5- or 6-membered heteroaryl, preferably selected from the following groups:

[0049] In still further embodiments, Ring A is selected from the following groups:

[0050] In still further embodiments, Ring A is selected from:(A-XV)(A-XIII) (A-XVI)(A-XIV)(A-XVII) (A-XVIII) (A-XIX) wherein the ringmeans Ring G.

[0051] In still further embodiments, Ring A is isoxazolyl, thiazolyl, pyridinyl, or phenyl.

[0052] In Compound (I), Ring A may be optionally substituted with the same or different one or more, such as 1 to 4, 1 to 3, 1 to 2, and one, A1.

[0053] In some embodiments, A1is each independently selected from the group consisting of halo, CN, C1-6alkyl, C1-6alkyl-O-, C1-6alkyleneOH, -OC1-6alkylene-O(C1-6alkyl), -OCi-6 alkylene-N(C1-6alkyl)2, C1-6alkylene(C6-10aryl), and C1-6alkylene-0(C6-10aryl).

[0054] In other embodiments, A1is each independently C1-6alkyl or -OC1-6alkylene-N(C1-6alkyl)2.

[0055] In some embodiments, Ring A is substituted with the same or different one or two RingG.

[0056] In some embodiments, Ring G is a monocyclic or bicyclic 6- to 10-membered aryl, a monocyclic or bicyclic 5- to 12-membered heteroaryl, or a saturated or partially unsaturated monocyclic or bicyclic 3- to 16-membered heterocyclyl.

[0057] In further embodiments, Ring G is selected from the following groups:In still further embodiments, Ring G is selected from the following groups:wherein is a binding point to Ring A.

[0059] In still further embodiments, Ring G is pyrazolyl, phenyl, or pyridyl.

[0060] In Compound (I), Ring G may be optionally substituted with the same or different one or more, such as 1 to 4, 1 to 3, 1 to 2, and one, G1A.

[0061] In some embodiments, G1Ais each independently and preferably halo; OH; ON; C1-6alkyl; C1-6haloalkyl; -(C1-6alkylene)OH; -(C1-6alkylene)CN; (C1-6alkylene)NHz; (C1-6alkylene)NH(C1-6alkyl); (C1-6alkylene)N(C1-6alkyl)z; (C1-6alkylene)NHC(=O)C1-6alkyl; (C1-6alkylene)NHC(=0)0C1-6alkyl; (C1-6alkylene)N(C1-6alkyl)C(=O)OC1-6alkyl; (C1-6alkylene)(C3-6 cycloalkyl); (C1-6alkylene)(5- or 6-membered heteroaryl); (Ci-6 alkylene)(saturated 3- to 8-membered monocyclic heterocyclyl); C(=O)C1-6alkyl; OCi-6 alkyl; OC1-6haloalkyl; O(C1-6alkylene)OH; O(C1-6alkylene)O(C1-6alkyl); O(Ci-$ alkylene)N(C1-6alkyl)z; OC1-6alkylene-(C3-6 cycloalkyl); NHz; N(CI-6 alkyl)z; C3^ cycloalkyl; 5- or 6-membered heteroaryl; saturated 3- to 8-membered monocyclic heterocyclyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, OH, CN, oxo, C1-6alkyl, C1-6haloalkyl, (C1-6alkylene)C(=O)OH, (Ci-6alkylene)C(=O)O(C1-6alkyl), C(=O)O(C1-6alkyl), C(=O)O(Ci-6 alkylene)(C6-10aryl)O(C1-6alkyl), NHz, N(CI-6 alkyl)z, NHC(=0)0(CI-6 alkyl), C3-6 cycloalkyl, and saturated 3- to 8-membered monocyclic heterocyclyl; partially unsaturated 5- or 6-membered monocyclic heterocyclyl optionally substituted with C1-6alkyl; or any one of the following groups:NH NH NN xN / NNHNH NH / N N optionally substituted with C1-6alkyl

[0062] In other embodiments, G1Ais each independently halo, CN, OC1-6haloalkyl, 5- or 6- membered heteroaryl, or saturated 3- to 8-membered monocyclic heterocyclyl optionally substituted with one or more groups independently selected from the group consisting ofhalo and C1-6alkyl. In other embodiments, G1Ais each independently halo, CN, OC1-6haloalkyl, 5- or 6-membered heteroaryl, or saturated 3- to 8-membered monocyclic heterocyclyl optionally substituted with halo or C1-6alkyl.

[0063] In other embodiments, G1Ais each independently halo, CN, -O-C1-6haloalkyl, pyridyl, azetidinyl optionally substituted with one or more groups independently selected from the group consisting of halo and C1-6alkyl, or piperazinyl optionally substituted with Ci-6 alkyl.

[0064] In some embodiments, R1is:1) H;2) fluoro;3) OH;4) methyl, methoxymethyl, ethoxymethyl, isopropoxymethyl, 2,2- difluoroethoxymethyl, ethyl, ethyl-dg, monofluoroethyl, , 2,2-difluoroethyl, methoxyethyl, ethoxyethyl, 2,2,2-trifluoroethoxymethyl, propyl, propyl-da, propyl-d?, isopropyl, monofluoropropyl, 2,2-difluoropropyl, 3 ,3 -difluoropropyl, 3-chloro-3,3- difluoropropyl, methoxypropyl, butyl, isobutyl, 3 -methylbutyl, 3 -trifluoromethylbutyl, 4- fluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, 3 -chloro-2,2-difluoro- propylaminomethyl, CH2-N(Me)2, C2H4-N(Me)2, CgH6-N(Me)2, cyclopropylmethyl, monofluorocyclpropylmethyl, difluorocyclopropylmethyl, cyanocyclcopropylmethyl, difluoroazetidinylmethyl, monofluorooxetanylmethyl, (monofluoropyrrolidinyl)methyl, tetrahydrofuranylmethyl, monofluorotetrahydrofuranylmethyl, tetrahydropyranylmethyl, monofluorotetrahydropyranylmethyl, cyclopropylethyl, (difluorocyclobutyl)methyl, difluoroazetidinylethyl, morpholinylethyl, tetrahydropyranylethyl, cyclohexylpropyl,tetrahydropyranylpropyl, 3,3-difhioroprop-2-enyl, or but-2-ynyl; or5) methoxy, cyclopropylmethoxy, monofluorooxetanylmethoxy, ethoxy, hydroxyethoxy, methoxyethoxy, propoxy, 2-methylpropoxy, 2-fluoro2-methylpropoxy,2-propenyloxy, butoxy, but-2-ynyloxy, -S-CH3, or -S-C2H5.

[0065] In other embodiments, Rlis H,R11optionally substituted with the same or different one or more R12, or-V-R11optionally substituted with the same or different one or more R12;V is O;R11is C1-6alkyl;R12is each independently halo or C3-8 cycloalkyl.

[0066] In other embodiments, R1is H, cyclopropylmethyl, ethyl, propyl, 3, 3 -difluoropropyl, propoxy, or isobutyloxy.

[0067] In other embodiments, R1is halo, OH, R11optionally substituted with the same or different one or more R12, or -V-R11optionally substituted with the same or different one or more R12.

[0068] In other embodiments, R1is R11optionally substituted with the same or different one or more R12, or-O-R11optionally substituted with the same or different one or more R12;R11is C1-6alkyl; andR12is each independently halo or C3-8 cycloalkyl.

[0069] In some embodiments, when R12is saturated 3- to 8-membered monocyclic heterocyclyl, the heterocyclyl group is preferably azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl tetrahydropyranyl, or morpholinyl.

[0070] In some embodiments, R2is attached to the nitrogen-containing ring:(R) NJVV in formula (I) in a trans-configuration manner to the carboxy group that is attached to the nitrogen-containing ring to have any of the following structures (IA), (IB), and / or their mixture, for example when R2is optionally substituted C1-6alkyl.In some embodiments, a compound of formula (I) has the following structure (IA):. In further embodiments, a compound of formula (I) has the structure (IA) wherein R2is optionally substituted C1-6alkyl.

[0072] In further embodiments, R2is:1) C2-6alkyl optionally substituted with the same or different one or more halo orCN,2) C3-8 cycloalkyl optionally substituted with the same or different one or more C1-6alkyl, halo or CN, or3) Si(Ci -6 alkyl)a.

[0073] In still further embodiments, R2is C2-6alkyl optionally substituted with the same or different one or more halo or CN. In still further embodiments, R2is preferably C2-4 alkyl, such as ethyl, isopropyl, and tert-butyl.

[0074] In some embodiments, R3is CH2.

[0075] In some embodiments, Compound (I) or a salt thereof is selected from compounds 1 to804 of Examples herein, or any salts thereof. In further embodiments, Compound (I) or a salt thereof is selected from compounds 1 to 799 of Examples herein, or any salts thereof.

[0076] In the present specification, the options and preferred embodiments for the different features of the compound, medicament, method, use, and composition of the present invention as presented include all possible combinations of the options and preferred embodiments for these different features as long as they are consistent combinations.

[0077] Compound (I) may also exist as any salts thereof, such as any pharmaceutically acceptable salts thereof. The phrase "pharmaceutically acceptable" is used herein to referto those compounds, materials, compositions, dosage forms, and the like which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals, for example human beings, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. It will be appreciated that for use in medicine salts of theCompound (I) may be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, PA, 1985, p.1418. In some embodiments, Compound (I) may form an acid addition salt or a salt with a base depending on substituent(s) that are present inCompound (I). Examples of the "acid" herein include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid, formic acid and the like. Examples of the "base" herein include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; organic bases such as methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, and choline; and ammonium salts, and the like. These inorganic bases may generate a salt, such as sodium salt, potassium salt, and calcium salt, of Compound (I). Compound (I) may also form a salt with an amino acid such as lysine, arginine, aspartic acid, glutamic acid, and the like.

[0078] The present invention also encompasses various hydrates, solvates, and crystal polymorphs of Compound (I) and any salts thereof.

[0079] Compound (I) also includes compounds in which one or more isotope atoms have been substituted for any one or more atoms in any proportions. Examples of isotope atoms include deuterium (2H or D), tritium (3H),nC,13C,14C,13N,1SN,150,17O,18O,32P,35S,36C1,37C1,18F,1231,125I, and the like.

[0080] In one embodiment, Compound (I), or a salt thereof, may be useful as a Positron EmissionTopography (PET) tracer, preferably a PET imaging agent, that may be useful for in vitro, exo vivo, in vivo, or clinical trial tests and diagnostic imaging in humans and / or non- humans. Substitution with positron emitting isotopes, such asnC,18F,15O, and13N, can be useful in PET studies for examining target occupancy. For example, compounds labeled withnC or18F may be used for a PET tracer.

[0081] One embodiment of the present invention includes pharmaceutically acceptable prodrugs of Compound (I). Compound (I) may be modified on any group(s) including any reactive functional groups of Compound (I) such as -OH, -COOH, amino, and the like, so as to provide prodrugs of Compound (I). These functional groups may be modified with any group(s) selected appropriately from the protecting groups of hydroxy, carboxy, and amino.

[0082] Compound (I), or a salt thereof, may be in the form of a pharmaceutically acceptable cocrystal. The co-crystal herein means a crystalline substance composed of two or more independent substances each having different physical properties at room temperature,such as structures, melting points, heat of fusion, and the like. Co-crystals and co-crystal salts may be manufactured appropriately by well-known co-crystallization methods.

[0083] Medical useCompound (I), or a salt thereof, may show sortilin-binding inhibitory activity in a subject including mammals. In some embodiments, Compound (I), or a salt thereof, may preferably demonstrate an ICso value in the TRF assay of Biological Activity, TestExample 1, of 5 pM or lower, for example 0.1 pM or lower, such as 0.01 pM or lower.In other embodiments, Compound (I), or a salt thereof, may preferably demonstrate anECiso value in the PGRN modulation assay of Biological Activity, Test Example 2, of 1 pM or lower. In other embodiments, Compound (I), or a salt thereof, may preferably demonstrate acceptable brain penetration and an increase in PGRN level in the assay ofBiological Activity, Test Example 3.

[0084] Compound (I), or a salt thereof, may be useful for treating, preventing, and / or diagnosing a disease or disorder that is associated with sortilin ligands, such as PGRN, neurotensin, proNGF, and proBDNF. In some embodiments, the disease or disorder may be mediated by PGRN-sortilin binding, neurotensin-sortilin binding, proNGF-sortilin binding, or proBDNF-sortilin binding. ProNGF and proBDNF are known apoptotic ligands that bind to the receptor complex of p75NTR and sortilin. The term "prophylaxis", "prevention", or "preventing" is used herein to mean the provision in advance, and as such may involve preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction. The term "treatment" or "treating" as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms. Theterm "diagnosis" or "diagnosing" as used herein includes detection or monitoring of a disease or disorder in a subject. A subject will typically be a subject in need of treatment or prophylaxis according to the invention. A subject is typically a mammal. Suitably, the subject is a human.

[0085] Non-limiting examples of a disease or disorder associated with sortilin ligands herein include inflammatory diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), psoriasis, type 1 diabetes mellitus (T1DM), and multiple sclerosis (MS); cancers including progranulin-induced metastatic breast cancer, lung metastases, and pancreatic cancer cell invasion; wounds (i.e., wound healing) and traumatic brain injury; CNS diseases such as stroke, schizophrenia-like psychosis, schizophrenia, or bipolar disorder(BPD); atypical parkinsonism, such as corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP); spinocerebellar ataxia 3 (SCA3), limbic-predominant age- related TDP-43 encephalopathy (LATE), and Huntington's diseases (HD); age-related macular degeneration (AMD), retinal degeneration, and other neurodegenerative diseases of the eye; atherosclerosis; neurodegenerative diseases such as frontotemporal dementia(FTD), frontotemporal lobar degeneration (FTLD), neuronal ceroid lipofuscinosis (NCL, a lysosomal storage disease), Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC), amyotrophic lateral sclerosis (ALS),C9ORF72-associated ALS / FTD, sporadic ALS, Alzheimer’s disease (AD), Gaucher disease types 2 and 3, Parkinson’s disease (PD), and major depression; pain; and hearing loss.

[0086] In some embodiments, Compound (I), or a salt thereof, may increase PGRN levels. Insome embodiments, PGRN levels may be increased in the central nervous system. In other embodiments, PGRN levels may be increased in the serum. PGRN is a secreted pleiotropic growth factor associated with multiple biological processes, and Compound(I), or a salt thereof, may be useful for treating, preventing, and / or diagnosing a disease or disorder involving regulation of cell growth, migration, transformation, cell cycle, inflammation, neuroinflammation, lysosomal dysfunction and characterised by PGRN insufficiency.

[0087] In some embodiments, Compound (I), or a salt thereof, may be beneficial to treat, prevent, and / or diagnose inflammatory diseases. In one embodiment, the inflammatory diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), psoriasis, type 1 diabetes mellitus(T1DM), and multiple sclerosis (MS).

[0088] PGRN may be a promising target for inflammation-related osteoporosis. PGRN inhibitedTNF-a-induced osteoclastogenesis from spleen cells of PGRN-KO mice. Moreover,PGRN significantly promoted ALP activity, osteoblast-related mRNA (ALP, osteocalcin) expression in a dose-dependent manner and up-regulated osteoblastic differentiation by down-regulating phosphorylation of ERK.1 / 2 in mouse calvarial cells. PGRN is a ligand of TNFR, an antagonist of TNFa signaling and plays a critical role in the pathogenesis of inflammatory arthritis in mice. Progranulin (PGRN), an anti-inflammatory molecule with therapeutic effect in inflammatory arthritis, was identified as an endogenous antagonist of TNFa by competitively binding to NFR. rhPGRN and Atsttrin also inhibited theTNFa-induced phosphorylation of p38, JNK and ERK1 / 2, mitogen activated protein kinase (MAPK) family members known to play an important role in TNFa-mediatedinflammation. PGRN prevented inflammation in multiple arthritis mouse models and inhibited TNFa-activated intracellular signaling. In one embodiment, Compound (I), or a salt thereof, may be beneficial for use in the treatment or prophylaxis of cancer including progranulin-induced metastatic breast cancer, lung metastases, and pancreatic cancer cell invasion.

[0089] In some embodiments, Compound (I), or a salt thereof, may also be beneficial to treat and / or prevent wounds (i.e., wound healing) and traumatic brain injury.

[0090] Progranulin could protect against acute focal cerebral ischemia by a variety of mechanisms including attenuation of blood-brain barrier disruption, neuroinflammation suppression, and neuroprotection. Progranulin could regulate vascular permeability via vascular endothelial growth factor, suppress neuroinflammation after ischemia via antiinflammatory interleukin 10 in the microglia, and render neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA-binding protein-43. Administered recombinant progranulin reduced cerebral infarct and oedema, suppressed haemorrhagic transformation, and improved motor outcomes. PGRN treatment suppressed neutrophil recruitment into the ischemia-reperfusion brain, and this led to a reduction of NF-KB andMMP-9 activation. In the in vitro inflammation models, PGRN suppressed both the neutrophil chemotaxis and ICAM-1 expression caused by TNF-a in endothelial cells. In one embodiment, Compound (I), or a salt thereof, may be beneficial for use in the treatment and / or prophylaxis of CNS diseases such as stroke, schizophrenia-like psychosis, schizophrenia, or bipolar disorder (BPD).

[0091] Intra-articular delivery of PGRN protects against osteoarthritis (OA) progression.Atsttrin, an engineered protein composed of three tumor necrosis factor receptor (TNFR)- binding fragments of progranulin, exhibited a preventative effect in OA by protecting articular cartilage and reducing OA-associated pain in both nonsurgically induced rat and surgically induced murine OA models. Mechanistic studies revealed that Atsttrin stimulated TNFR2-Akt-Erkl / 2-dependent chondrocyte anabolism, while inhibitingTNFo / TNFRl -mediated inflammatory catabolism.

[0092] Frontotemporal dementia (FTO) is a progressive neurodegenerative disorder. FTO includes a spectrum of clinically, pathologically, and genetically heterogeneous diseases presenting selective involvement of the frontal and temporal lobes. Clinical manifestations of FTO include alterations in behavior and personality, frontal executive deficits, and language dysfunction. Based on the diversity of clinical phenotypes, different presentations have been identified, such as behavioral variants of FTO (bvFTO) and primary progressive aphasia (PPA), which can either be the nonfluent / agrammatic variant PPA (avPPA) or the semantic variant PPA (svPPA). These clinical presentations can also overlap with atypical parkinsonism, such as corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). FTO is associated with various neuropathological hallmarks, including tau pathology in neurons and astrocytes or cytoplasmic ubiquitin inclusions in neurons. The Trans-activatingDNA-binding Protein with a molecular weight of 43 kDa (TOP-43) is the most prominent, ubiquitinated protein pathology accumulating in the majority of cases of FTO as well as in ALS. FTO is a significant cause of early-onset dementia with up to 80% of cases presenting between ages 45 and 64. The disease also presents a significant familial component, with about 30-50% of cases reporting family history of the disease.

[0093] While several genes have been linked to FTD, one of the most frequently mutated genes in FTD is GRN, which maps to human chromosome 17q21 and encodes the cysteine-rich protein PGRN (also known as proepithelin and acrogranin), Recent estimates suggest that GRN mutations account for 5-20% of FTD patients with positive family history and1-5% of sporadic cases). The precise molecular and cellular mechanisms underlying neurodegeneration and disease processes in GRN-associated FTD are unknown, although phenotypic characterization of Gm knockout mice combined with histological analyses of patients' brain suggests that both inflammation and lysosomal defects are central to the disease. Indeed, massive gliosis is present in cortical regions of patients and lipofuscin, a lysosomal pigment denoting lysosomal disorder, has been reported in the eye and cortex of mutated GRN carriers including both presymptomatic individuals and patients. More than seventy GRN disease mutations have been reported and mapped throughout the gene, where they result in confirmed or predicted loss of function (LOF) alleles. Most heterozygous mutations linked to FTD cause about 50% reduction in mRNA levels primarily as a result of non-sense mRNA decay and a comparable reduction in PGRN protein levels. Lower levels of PGRN are also found in the blood (serum) and cerebrospinal fluid (CSF) of carriers, including presymptomatic individuals. Therefore, haploinsufficiency is believed to be the main disease mechanism in GRN-associated FTD, suggesting that therapeutic approaches that elevate PGRN levels in carriers may delay the age of onset as well as the progression of FTD. This notion is supported by human genetic studies indicating that a variant of the gene TMEM106B both enhances the levels ofPGRN by 25% and delays the age of onset of GRN-associated FTD by 13 years.Homozygous GRN mutations have also been reported, although carriers present a vastly different clinical phenotype known as neuronal ceroid lipofuscinosis (NCL) (Batten disease; incidence 1-2.5 in 100,000 live births), which is a lysosomal storage disorder.GRN is in fact one of the 14 ceroid-lipofuscinosis neuronal (CLN) genes reported to be linked to NCL and GRN is also known as CLN11.

[0094] PGRN levels have also been associated with increased GBA activity and therefore modulation of PGRN has therapeutic potential in diseases driven by GBA as well as other lysosomal hydrolases (NPL62). Patients with Gaucher’s disease who carry homozygous mutations in the GBA gene have lower levels of PGRN in their serum. Parkinson’s disease patients with heterozygous mutations in GBA may also have lower levels ofPGRN. The invention may also provide a method comprising the steps of (i) determining if a subject has homozygous mutations in the GBA gene, and (ii) treating the subject by administering Compound (I), or a salt thereof. Variants in GRN have been linked to AD and the TDP-43 pathology is common in the brain of AD patients. PGRN gene delivery has also been shown to decrease amyloid burden in mouse models of AD.

[0095] Niemann-Pick disease types A and B (NPA and NPB) result from mutations in the gene encoding acid sphingomyelinase (SMPD1). Niemann-Pick disease type C (NPC) results from mutations in the genes involved in cholesterol transport, i.e., NPC1 and NPC2.

[0096] The vast majority of ALS cases present the TDP-43 pathology, which is also shared with patients harboring GRN mutations. Among all ALS cases, GGGGCC repeat expansions within the C9ORF72 gene are the most common cause of ALS and a significant cause ofFTD. The average mutation frequencies reported in North American and European populations are 37% for familial ALS, 6% for sporadic ALS, 21% for familial FTD, and6% for sporadic FTD patients. Additionally, the TMEM106B variant that is protective in GRN-associated FTD is also protective in FTD patients harboring repeat expansionsin the C9ORF72 gene. The invention may also provide a method comprising the steps of(i) determining if a subject has TDP-43 pathology, and (ii) treating the subject by administering Compound (I), or a salt thereof. Based on the cytoplasmic accumulations of TDP-43, Compound (I), or a salt thereof, may also be expected to be potent for spinocerebellar ataxia 3 (SCA3), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Huntington's diseases (HD).

[0097] Age-related macular degeneration (AMD) is a degenerative disease and a major cause of blindness in the developed world. It causes damage to the macula, a small spot near the center of the retina and the part of the eye needed for sharp, central vision. The degenerative changes in the eye and loss of vision may be caused by impaired function of lysosomes and harmful protein accumulations behind the retina. As the disease progresses, retinal sensory cells in the central vision area are damaged, leading to loss of central vision. In some embodiments, Compound (I), or a salt thereof, may also be expected to be effective for AMD, retinal degeneration, and other neurodegenerative disease of the eye.

[0098] In some embodiments, a disease or disorder where inhibition of PGRN-sortilin binding may be beneficial is a disorder related to PGRN expression, processing, glycosylation, cellular uptake, trafficking, and / or function. In other embodiments, a disease or disorder where inhibition of PGRN-sortilin binding may be beneficial is atherosclerosis, Gaucher disease, or AMD. In some embodiments, a subject has a decreased level of PGRN and / or a disorder associated with a decreased level of PGRN. In some embodiments, the subject has a mutation in a granulin (GRN) gene. In some embodiments, the mutation in theGRN gene decreases PGRN expression and / or activity.

[0099] Hematopoietic progranulin deficiency promotes diet-induced atherosclerosis in Ldlr- / - mice (mice prone to atherosclerosis because of low-density lipoprotein receptordeficient), possibly due to increased exophagy-mediated cholesterol uptake. Bone marrow transplanted from wild-type (WT) or Gm- / - (progranulin KO) mice to Ldlr- / - mice to generate mice in which the immune cells, such as lesion macrophages, either expressed or lacked endogenous progranulin. After feeding these mice a high-fat diet for10 weeks, despite abundant circulating levels of progranulin, the size of atherosclerotic lesions in bone marrow progranulin KO mice was increased by 47% in aortic roots and by 62% in whole aortas. Aortic root lesions in Tx-KO mice had increased macrophage content and larger necrotic cores, consistent with more advanced lesions. Cultured progranulin-deficient macrophages exhibited increased lysosome-mediated exophagy of aggregated low-density lipoproteins resulting in increased cholesterol uptake and foam cell formation.

[0100] In some embodiments, the disease or disorder where inhibition of PGRN-sortilin binding may be beneficial is Gaucher disease type 1. In further embodiments, the disease or disorder where inhibition of PGRN-sortilin binding may be beneficial is a disorder associated with TOP -43. In some embodiments the TDP-43 associated disorder is AD orALS. In still further embodiments, the disease or disorder where inhibition of PGRN- sortilin binding may be beneficial is a neurodegenerative disease. In still further embodiments, the neurodegenerative disease is selected from the group consisting of frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), neuronal ceroid lipofuscinosis (NCL, a lysosomal storage disease), Niemann-Pick disease type A(NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC),amyotrophic lateral sclerosis (ALS), C9ORF72-associated amyotrophic lateral sclerosis(ALS) / FTD, sporadic ALS, Alzheimer’s disease (AD), Gaucher disease types 2 and 3, Parkinson’s disease (PD), and major depression.

[0101] In some embodiments, the disease or disorder where increasing in PGRN levels and inhibition of neurotensin signaling may be beneficial is neuropathic pain.

[0102] Compound (I), or a salt thereof may be effective in the treatment, prevention, and / or diagnosis of any two or more diseases described above. Moreover, Compound (I), or a salt thereof, may be useful as active ingredients in pharmaceuticals, and for example may show enhanced in vivo potency, selectivity, acceptable safety profile, side effects, tolerability, stability (including storage stability, metabolic stability, etc.), pharmacokinetic parameters, for example, acceptable brain penetration, high brain availability, and / or low clearance rate that may reduce the dose required for effect in vivo, and the like.

[0103] Pharmaceutical compositions / FormulationsIn one embodiment, a medical preparation (herein also referred to as a "pharmaceutical composition") comprising Compound (I) or a salt thereof as an active ingredient is provided.

[0104] A medical preparation herein may be selected from various forms depending on therapeutic objectives. Any administration routes of a medical preparation may be chosen depending on dosage forms, the age and sex of a patient to be administered, disease status, and other conditions. A medical preparation may be administered orally, intravenously,intramuscularly, intradermally, subcutaneously, intraperitoneally, or rectally as necessary.Examples of the medical preparation include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions, etc.).Tablets include coated tablets such as sugar-coated tablets, gelatin-coated tablets, enteric- coated tablets, film-coated tablets, double tablets, and multilayered tablets.

[0105] Compound (I), or a salt thereof, may be combined with a pharmaceutically acceptable carrier to be formulated into any forms of a medical preparation. Examples of the carrier include commonly used substances for a component of a medical preparation, including excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption aids such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as colloidal silicic acid; and lubricants such as magnesium stearate and polyethylene glycol; diluents; fillers; bulking agents; and surfactants.

[0106] Pharmaceutically acceptable carriers to be used in formulating into a tablet specifically include excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption aids such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as colloidal silicic acid; and lubricants such as magnesium stearate and polyethylene glycol.

[0107] Pharmaceutically acceptable carriers to be used in formulating into a pill specifically include excipients such as glucose; binders such as gum arabic powder; and disintegrants such as laminaran.

[0108] Pharmaceutically acceptable diluents to be used in formulating into a liquid, emulsion, orsuspension specifically include water. Any ordinary solubilizing agents and / or buffers as well as colorants, preservatives, aromatics, flavorings, and sweeteners may also be comprised in the preparation, and other drugs may also be comprised as necessary.

[0109] Pharmaceutically acceptable carriers to be used in formulating into a suppository specifically include cocoa butter.

[0110] In some embodiments, Compound (I), or a salt thereof, may be formulated into the form of a liquid, emulsion, or suspension to prepare an injection. In one embodiment, the injection is preferably sterilized, and is also preferably isotonic with blood. The isotonic injection may comprise a sufficient amount of sodium chloride and soothing agents, and may also optionally comprise other drugs.

[0111] The amount (herein also referred to as "effective amount") of Compound (I), or a salt thereof, comprised in a medical preparation may be, but is not limited thereto, any amounts conventionally used in the art, and preferably includes any amounts of 1% to70% of the medical preparation. The dose of Compound (I), or a salt thereof, to be administered may be any doses selected depending on administration routes, the age and sex of a patient to be administered, the severity of diseases, and other conditions, and includes 0.01 to 100 mg, preferably 0.1 to 50 mg, per 1 kg of body weight per day. The dose may be administered once or separately in several times.

[0112] Compound (I), or a salt thereof, may be used or administered in combination with at least one therapeutic or preventive drug or standard-of-care agent, which may be referred to as a combined drug herein, useful for one of the above-mentioned diseases. WhenCompound (I), or a salt thereof, is used in combination with a combined drug, Compound(I), or a salt thereof, and the drug may be administered simultaneously or at the same time, separately or sequentially at about the same time, or separately or sequentially at different times with a suitable interval in between. Compound (I), or a salt thereof, and the combined drug may be formulated into separate preparations or mixed and formulated into a single preparation.

[0113] Methods of manufactureMethods of manufacturing Compound (I) are explained below. Compound (I) may be manufactured, but is not limited thereto, based on the methods described in the General syntheses and Examples below. Unless otherwise specified, reaction temperatures may be optionally adjusted depending on reactants, solvents, and other conditions used in each reaction herein.

[0114] An alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction etherification reaction, nucleophilic substitution reaction, addition reaction, oxidation reaction, reduction reaction, and the like in the General syntheses may be performed in accordance with any known methods. Examples of such methods include the methods described in Experimental Chemistry (Fifth Edition, edited by The ChemicalSociety of Japan, Maruzen Co., Ltd.); Organic Functional Group Preparations SecondEdition, Academic Press, Inc., 1989; Comprehensive Organic Transformations, VCHPublishers, Inc., 1989; and P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (Fourth Edition, 2006), and the like.

[0115] As used herein, the term “Ci-is alkanesulfonyl” is a linear or branched alkanesulfonylhaving 1 to 18 carbon atoms (Ci-is), and examples thereof include methanesulfonyl, 1- propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, and the like.

[0116] As used herein, the term “C1-6alkanesulfonyloxy” is a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C1-6), and examples thereof include methanesulfonyloxy, ethanesulfonyloxy, 1 -propanesulfonyloxy, 2-propanesulfonyloxy,1 -butanesulfonyloxy, 3-butanesulfonyloxy, 1 -pentanesulfonyloxy, 1 -hexanesulfonyloxy, and the like.

[0117] As used herein, the term “arylsulfonyloxy” is phenylsulfonyloxy, naphthylsulfonyloxy, and the like, that is optionally substituted with 1 to 3 groups selected from the group consisting of a linear or branched alkyl having 1 to 6 carbon atoms (C1-6), a linear or branched alkoxy having 1 to 6 carbon atoms (C1-6), nitro, and halogen, on the benzene or naphthalene ring. Examples of phenylsulfonyloxy optionally having substituents) include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4- nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3- chlorophenylsulfonyloxy, and the like. Specific examples of naphthylsulfonyloxy include a-naphthylsulfonyloxy, P-naphthylsulfonyloxy, and the like.

[0118] As used herein, the term “aralkylsulfonyloxy” is a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C1-6) that is substituted with phenyl optionally substituted with 1 to 3 groups selected from the group consisting of a linear or branched alkyl having1 to 6 carbon atoms (C1-6), a linear or branched alkoxy having 1 to 6 carbon atoms (C1-6), nitro, and halogen on the benzene ring; or a linear or branched alkanesulfonyloxy having1 to 6 carbon atoms (C1-6) that is substituted with naphthyl, and the like. Examples of alkanesulfonyloxy substituted with phenyl include benzylsulfonyloxy, 2- phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2- methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3- chlorobenzylsulfonyloxy, and the like. Specific examples of alkanesulfonyloxy substituted with naphthyl include a-naphthylmethylsulfonyloxy, P- naphthylmethylsulfonyloxy, and the like.

[0119] Examples of the term “perhaloalkanesulfonyloxy” used herein include trifluoromethanesulfbnyloxy and the like.

[0120] Examples of the term “sulfonic” used herein include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, di-(2-cyanoethyl)sulfonio, di-(2-nitroethyl)sulfonio, di-(aminoethyl)sulfonio, di-(2-methylaminoethyl)sulfonio, di-(2- dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio, di-(3- hydroxypropyl)sulfonio, di-(2-methoxyethyl)sulfonio, di-(2-carbamoylethyl)sulfbnio, di-(2-carbamoylethyl)sulfonio, di-(2-carboxyethyl)sulfonio, di-(2- methoxycarbonylethyl)sulfonio, diphenylsulfonio, and the like.

[0121] As used herein, the term “solvent” may be an inert solvent in a reaction described herein, and examples thereof include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether,1,2-dimethoxy ethane, cyclopentyl methyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether), hydrocarbons, halogenated hydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, and carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, and xylene), alcohols (e.g., methanol, ethanol, andisopropanol), esters, ketones, amides, nitriles, sulfoxides, and polar solvents (e.g., N,N- dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile). These solvents may be used alone or as a mixture of any two or more of them with optional ratios. Examples of "hydrocarbons" herein include, for example, aliphatic hydrocarbons such as hexane and pentane; alicyclic hydrocarbons such as cyclopentane and cyclohexane; and aromatic hydrocarbons such as benzene and toluene. Examples of "alcohols" herein include, for example, methanol, ethanol, 2-propanol, propanol, and tert-butanol. Examples of "ethers" herein include, for example, chained ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, and diphenyl ether; and circular ethers such as 1,4-dioxane and tetrahydrofuran. Examples of "esters" herein include, for example, ethyl acetate and ethyl propionate. Examples of "ketones" herein include, for example, acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of "amides" herein include, for example,N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone.Examples of "nitriles" herein include, for example, acetonitrile and propionitrile.Examples of "sulfoxides" herein include, for example, dimethyl sulfoxide.

[0122] As used herein, the term “catalyst” to be used in reduction reactions is not particularly limited to examples used herein, but examples thereof include palladium on carbon(Pd / C), platinum on carbon (Pt / C), platinum oxide (PtCh), and the like.

[0123] As used herein, the term “halogenating agent” is not particularly limited to examples used herein, but examples thereof include fluorinating agents, chlorinating agents, brominating agents, and iodinating agents, such as potassium fluoride, tetrabutylammonium fluoride,(diethylamino)sulfur trifluoride, phosphorus oxychloride, phosphorus trichloride,phosphorus pentachloride, thionyl chloride, oxalyl chloride, trichlorophosphoric acid, bromine, phosphorus oxybromide, phosphorus tribromide, iodine, sodium iodide, N- chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and the like.

[0124] As used herein, the term “acid” is not particularly limited to examples used herein, but includes an inorganic acid, an organic acid, and the like. Examples of the “inorganic acid” include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, and the like. Examples of the “organic acid” include acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and the like.These acids may be used alone or as a mixture of any two or more of them.

[0125] As used herein, the term “base” is not particularly limited to examples used herein, but includes an inorganic base, an organic base, and the like. Examples of the “inorganic base” include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, and barium hydroxide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, and barium carbonate), alkali metal carboxylates (e.g., sodium acetate, potassium acetate, and sodium butyrate), alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate), alkali metal phosphates(e.g., sodium phosphate, potassium phosphate, and cerium phosphate), alkaline earth metal phosphates (e.g., magnesium phosphate and calcium phosphate), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, andpotassium tert-butoxide), alkali metal hydride (e.g., sodium hydride, potassium hydride, and cesium hydride), and the like. Examples of the “organic base” include aromatic amines (e.g., pyridine arid lutidine), trialkylamines (e.g., trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine (DIPEA)), cyclohexyldimethylamine, 4-dimethylaminopyridine (DMAP), N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorphiline, tetramethylethylenediamine, tetramethylpropylenediamine, picoline, 1,5- diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), dialkylamine (e.g., diethylamine and diisopropylamine), metal amides (e.g., lithium diisopropylamide and lithium hexamethyldisilazide), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium phenoxide), and the like.These bases may be used alone or as a mixture of any two or more of them. The organic base herein is preferably DMAP or TEA.

[0126] As used herein, the term “palladium catalyst" is not particularly limited to examples used herein, and examples thereof include tetravalent palladium catalysts such as sodium hexachloropalladium (IV) acid tetrahydrate and potassium hexachloropalladium (TV) acid; divalent palladium catalysts such as [1,1’- bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct(PdCh(dppf) • DCM), (2-dicyclohexylphosphino-2’, 4’ ,6’ -triisopropyl- 1,1’ -biphenyl) [2-(2’-amino-l,r-biphenyl)]palladium (II) methanesulfonate (XPhos Pd G3), palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palladium (II) acetylacetonate, dichlorobis(benzonitrile)palladium (II), dichlorobis(acetonitrile)palladium (II), dichlorobis(triphenylphosphine)palladium (II), dichlorotetraammine palladium (II),dichloro(cycloocta-l,5-diene)palladium (II), and palladium (II) trifluoroacetate; and zerovalent palladium catalysts such as tris(dibenzylideneacetone)dipalladium (0)(Pd2(dba)3), tris(dibenzylideneacetone)dipalladium (O)-chloroform complex, and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4). These palladium compounds may be used alone or as a mixture of any two or more of them.

[0127] As used herein, the term “leaving group” is not particularly limited to examples used herein, and examples thereof include halogen (e.g., fluorine, chlorine, bromine, and iodine), Ci-ig alkylsulfonyl, alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy, and trifluoromethylsulfonyloxy), phenyloxy (e.g., 4-nitrophenyloxy), arylsulfonyloxy(e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2- nitrobenzenesulfonyloxy, and 4-nitrobenzenesulfonyloxy), aralkylsulfonyloxy, perhaloalkanesulfonyloxy, sulfonio, toluenesulfoxy, nitrophenylcarbonate, imidazolecarbonate, and the like.

[0128] Examples of a condensation agent used herein include, but not limited to:T3P; PyBOP; DMT-MM; COMU; HBTU; HATU; DCC; N-cyclohexyl-N’ - morpholinoethylcarbodiimide; N-cyclohexyl-N’ -(4- diethylaminocyclohexyl)carbodiimide; N,N’ -diethylcarbodiimide; N,N’- diisopropylcarbodiimide; N,N-diisopropylethylamine; WSC or a hydrochloride salt thereof; N,N’ -carbonylbis(2-methylimidazole); pentamethyleneketene-N- cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene, 1-alkoxy-l- chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphoryl chloride; phosphorus trichloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; alkyl haloformate such as ethyl chloroformate and isopropylchloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hy dioxide inner salt; benzotriazol- 1 -yloxy- tris(dimethylamino)phosphonium hexafluorophosphate; l-(p- chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole; and so-called Vilsmeier agents prepared by reactions of DMF with thionyl chloride, phosgene, trichloromethyl chlorofonnate, or phosphorus oxychloride.

[0129] In addition to a condensation agent, a condensation accelerator may be added. Examples of a condensation accelerator used herein include, but not limited to, 1- hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), l-hydroxy-7- azabenzotriazole (HOAt), and hydroxy-3 ,4-dihydro-4-oxo- 1,2, 3 -benzotriazine (HOOBt).

[0130] Examples of a reducing agent used herein include, but not limited to, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium triethylborohydride, lithium triethylborohydride, lithium aluminum hydride, sodium dihydridobis(2-methoxyethoxy)aluminate, borane-tetrahydrofuran complex, diisobutylaluminium hydride, and hydrosilane such as triethylsilane and phenylsilane.

[0131] Examples of a reducing agent for the reductive amination reaction herein include, but not limited to: sodium borohydride (NaBHt), lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride (NaBH(OAc)3), sodium triethylborohydride, lithium triethylborohydride, lithium aluminum hydride, sodium dihydridobis(2-methoxyethoxy)- aluminate, borane-tetrahydrofuran complex, diisobutylaluminium hydride, formic acid, sodium formate, ammonium formate, and phenylsilane.

[0132] Examples of a catalyst for the reductive amination reaction herein include, but not limited to: Iridium catalysts such as chloro(pentamethylcyclopentadienyl)(8- quinolinolato)iridium (HI), chlorido(8-quinolinolato-K2N,O)(T]5 - pentamethylcyclopentadienyl)iridium (III), [5,5'-bis(trifluoromethyl)-2,2'-bipyridine-KN,xN]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-KN]phenyl] iridium hexafluorophosphate and (4,4'-di-tert-butyl-2,2'-bipyridine)bis [3 ,5 -difluoro-2- [5 - trifluoromethyl-2-pyridinyl-kappaN)phenyl-kappaC] iridium (HI) hexafluorophosphate.

[0133] Examples of a "protecting group of hydroxy" used herein include, but not limited to, any protecting groups of hydroxy used in the field of synthetic organic chemistry, and include, for example, alkyl groups (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, acetylmethyl); alkenyl groups (e.g., ethenyl, 1 -propenyl,2-propenyl, l-methyl-2-propenyl); alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, l-methyl-2-propynyl); formyl; alkyl (alkenyl) carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E)-2-methyl-2-butenoyl); arylcarbonyl groups (e.g., benzoyl, a- naphthoyl, fl-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4- toluoyl, 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl, 4- phenylbenzoyl); alkoxycarbonyl groups (e.g., methoxycarbonyl, tert-butoxycarbonyl,2, 2, 2-trichloroethoxy carbonyl, 2-trimethylsilylethoxy carbonyl, 9- fluorenylmethyloxycarbonyl); tetrahydro (thio) pyranyl (furanyl) groups (e.g., tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl, tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl); silyl groups (e.g., trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethyl silyl, methyldiisopropyl silyl, methyl di-tert-butylsilyl, triisopropylsilyl, diphenylmethyl silyl, diphenylbutyl silyl, diphenylisopropyl silyl, phenyldiisopropyl silyl); alkoxymethyl groups (e.g., methoxymethyl, 1, 1 -dimethyl- 1- methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tertbutoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl); alkoxyethyl groups (e.g., 1-ethoxyethyl, l-(isopropoxy)ethyl); halogenated ethyl groups (e.g., 2,2,2-trichloroethyl); aralkyl groups (e.g., benzyl, a- naphthylmethyl, 0-naphthylmethyl, diphenylmethyl, triphenylmethyl, a- naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5- trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4- nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl); alkenyloxycarbonyl groups (e.g., vinyloxycarbonyl, allyloxycarbonyl); and aralkyloxycarbonyl groups (e.g., benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2- nitrobenzyloxy carbonyl, 4-nitrobenzyloxy carbonyl).

[0134] Examples of a "protecting group of carboxy" used herein include, but not limited to, any protecting groups of carboxy used in the field of synthetic organic chemistry, and include, for example, the "alkyl groups", "alkenyl groups", "alkynyl groups", "aralkyl groups", and "silyl groups" as above listed in the examples of the "protecting group of hydroxy" and similar groups thereof.

[0135] Examples of a "protecting group of amino" used herein include, but not limited to, any protecting groups of amino used in the field of synthetic organic chemistry, and include, for example, the "alkyl (alkenyl) carbonyl groups", "arylcarbonyl groups","alkoxycarbonyl groups", "silyl groups", "aralkyl groups", "alkenyloxycarbonyl groups",and "aralkyloxycarbonyl groups" as above listed in the "protecting group of hydroxy" and similar groups thereof.

[0136] The reaction temperature in each step in the General syntheses herein typically ranges from -80 to 150°C. The reaction time in each step typically ranges from 0.1 to 200 hours.

[0137] General synthesesIn general, the compounds of the invention and intermediates of use in the synthesis of such compounds may be made according to synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in theExamples and the Reference Examples, and any modifications thereof. In the following schemes, reactive groups can, as appropriate, be protected with protecting groups and deprotected according to established techniques well known to the skilled person. The processes of the invention include any individual step of a multi-step scheme.

[0138] General synthesis 1 :In an aspect of the invention, there is provided a method of preparing a compound of formula (I):or a salt thereof,wherein R1, R2, R3, R4, and Ring A are as defined above, the method which comprises reacting a compound of formula (Pl):or a salt thereof, wherein R1, R2, and R3are as defined above and Q1is either a suitable protecting group, such as alkyl groups and aralkyl groups (e.g., benzyl), or is hydrogen; with a compound of formula (P2):or a protected derivative or salt thereof, wherein Ring A and R4are as defined above and Q2is a suitable leaving group, such as halogen, methylsulfonyloxy, or trifluoromethylsulfonyloxy.

[0139] Where Q1is other than hydrogen, by a deprotection reaction suitable to remove the protecting group Q1. Reaction may be performed in the presence of a base, such asDIPEA or K2CO3, in a suitable solvent, e.g., acetonitrile, at an appropriate temperature, e.g., room temperature. Where Q1is hydrogen, the compound (Pl) may optionally be used in the form of a salt, such as that formed with an inorganic base, e.g., an alkali metal salt such as a sodium or potassium salt. Removal of the protecting group Q1may be effected using acid or base hydrolysis using a suitable inorganic acid (e.g., hydrochloric acid) or inorganic base (e.g., lithium hydroxide), under aqueous conditions, optionally inthe presence of an organic co-solvent such as dioxane or methanol or THE.

[0140] General synthesis 2:In a further aspect of the invention, there is provided a method of preparing a compound of formula (I):or a salt thereof, wherein R1, R2, R3, R4, and Ring A are as defined above, the method which comprises reacting a compound of formula (Pl):or a salt thereof, wherein R1, R2, and R3are as defined above and Q1is either a suitable protecting group, such as alkyl groups and aralkyl groups (e.g., benzyl), or is hydrogen; with a compound of formula (P3):or a protected derivative or salt thereof, wherein Ring A and R4are as defined above.

[0141] Where Q1is other than hydrogen, by a deprotection reaction suitable to remove the protecting group Q1. Reaction typically requires the presence of a suitable reducing agent, such as NaBH(OAc)3, phenylsilane or formic acid, in a suitable solvent, e.g., 2- methyltetrahydrofuran, DCM or acetonitrile, at an appropriate temperature, e.g., 65°C or room temperature; and is optionally carried out in the presence of an additive and / or catalyst, such as pentamethylcyclopentadienyl iridium (8-quinolinolate) chloride or triethylamine. Where Q1is hydrogen, the compound (Pl) may optionally be used in the form of a salt, such as that formed with an inorganic base, e.g., an alkali metal salt such as a sodium or potassium salt. Again, removal of the protecting group Q1may be effected using acid or base hydrolysis using a suitable inorganic acid (e.g., hydrochloric acid) or inorganic base (e.g., lithium hydroxide), under aqueous conditions, optionally in the presence of an organic co-solvent such as dioxane or methanol or THF.

[0142] General synthesis 3:In a still further aspect of the invention, there is provided a process for preparation of compound of formula (I) comprising the step of deprotection of a protected derivative of a compound of formula (I). Deprotection comprises any suitable deprotection reaction, the conditions of which will depend upon the nature of the protecting group. For example, an alkyl ester may be deprotected to the corresponding carboxylic acid by hydrolysis with a suitable aqueous inorganic acid, such as hydrochloric acid, or a suitable base such as lithium hydroxide or sodium hydroxide, optionally in the presence of an organic co- solvent, such as dioxane, methanol or THF. A number of deprotection reactions areillustrated in the Examples.

[0143] General synthesis 4:In a still further aspect of the invention, there is provided the conversion of a first compound of formula (I), or a protected derivative thereof to a second compound of formula (I), or a protected derivative thereof. For example, a compound of formula (I) in which R1represents a first substituent may be converted, such as by methods known to one skilled in the art, into other compounds of formula (I) in which R1represents a second substituent. A number of conversion reactions are illustrated in the Examples. In particular, optionally protected compounds of formula (I), in which R1is hydrogen, may be converted to optionally protected compounds of formula (I) in which R1is other than hydrogen.

[0144] General synthesis 5:In a still further aspect of the invention, there are also provided methods for the formation of a pharmaceutically acceptable salt of a compound of formula (I), comprising treatment with (as appropriate) a pharmaceutically acceptable acid or base, at a suitable temperature in an appropriate solvent or mixture of solvents. Resulting salts may be isolated by methods well known in the art, e.g., evaporation of solvent or solvents, or crystallization.

[0145] General synthesis 6:In a still further aspect of the invention, there is also provided a method of preparing a compound of formula (I), the method which comprises reacting a compound of formula(P4), or protected derivative thereof:where R1, R2, R3, R4, Q1, and Ring A are as defined above; with a compound of Formula (P5) or protected derivative thereofwherein Ring G is as defined above; and wherein one of Q3and Q4is a leaving group, such as halogen, and the other is the residue of a metal or metalloid, such as a boronic acid or boronate ester; alternatively, Q3can be converted from halogen to the corresponding boronic acid or boronate ester and reacted in situ with a compound of formula (P5) where Q4is a leaving group, such as halogen; in an analogous manner, Q4can be converted from halogen to the corresponding boronic acid or boronate ester and reacted in situ with a compound of formula (P4) where Q3is a leaving group such as halogen. Such reactions will be typically conducted using a suitable boron source such as bis(pinacolato)diboron in the presence of a suitable catalyst, e.g., a metal complex such as Pd(dppf)Ch, optionally in the presence of a suitable additive, such as a base, e.g., CS2CO3, in a suitable solvent, such as dioxane / water, and at a suitable temperature, e.g., 100°C.

[0146] General synthesis 7:In a still further aspect of the invention, there is also provided a further method of preparing a compound of formula [I], wherein L is oxygen; which method comprisesreacting a compound of formula (P6), or protected derivative thereof:where R1, R2, R3, R4, Ring A, Ring G, and Q1are as defined above; with a compound of formula R1-Q5, or protected derivative thereof, where R1is as defined above and Q5is a suitable leaving group, such as halogen, trifluoromethylsulfonyloxy or p-toluenesulfonyloxy. Such a reaction will be typically conducted using a suitable base, such as sodium hydride, in a suitable solvent, such as tetrahydrofuran or N,N- dimethylformamide, at an appropriate temperature, e.g., room temperature.

[0147] IntermediatesIn a further aspect of the present invention, there are provided novel intermediates in the synthesis of compounds of the invention, such as compounds of formulae (Pl), (P2), (P3),(P4), (P5) or (P6) and salts, such as pharmaceutically acceptable salts, of any thereof.

[0148] In a still further aspect of the present invention, there are also provided protected derivatives of compounds of formulae (I), (Pl), (P2), (P3), (P4), (P5) or (P6), and salts, such as pharmaceutically acceptable salts, of any thereof. Suitable protected derivatives of compounds of formula (I) include esters, such as C1-6alkyl esters, for example methyl esters.

[0149] In each of the reactions in the above synthetic schemes, the reaction product may be usedin the next reaction either as is in the form dissolved in the reaction solution or as a crude product, but it may also be isolated from the reaction mixture by ordinary methods and easily purified by ordinary separation techniques. Examples of ordinary separation techniques include recrystallization, distillation, and chromatography.

[0150] Any starting compounds, intermediate compounds, and product compounds in each of the above steps and Compound (I) include geometric isomers, stereoisomers, optical isomers, and tautomers thereof. Respective isomers may be separated by ordinary optical resolution methods. They may also be manufactured from raw material compounds having suitable optical activity.

[0151] Compound (I) may be manufactured according to any of the above synthetic schemes, or analogous methods thereof.

[0152] Unless otherwise specified, any starting compounds used in the manufacture ofCompound (I) are commercially available, or may be produced by known methods or analogous methods thereof.

[0153] Any starting compounds and product compounds in each step above may be used in the form of appropriate salts thereof. Examples of such salts include salts similar to those listed for salts of Compound (I) herein.

[0154] When any compounds obtained in each step or commercially available compounds used herein are in the free form, they may be converted to corresponding salts by known methods. When any compounds obtained in each step or commercially availablecompounds used herein are in the salt form, they may be converted to corresponding free forms or into other salts by known methods.

[0155] Disclosures of all literature cited herein are incorporated by reference in the present specification in their entireties.

[0156] EmbodimentsThe present invention is further illustrated by reference to the following clauses:Clause 1. A compound of formula (I):or a salt thereof, wherein:R1is:1) H,2) halo,3) OH,4) R11optionally substituted with the same or different one or more R12, or5) -I^-R11optionally substituted with the same or different one or more R12;L1is O or S;R11is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl;R12is each independently halo, -OH, -N(Ra)(Rb), -O-C1-6alkyl, -O-C1-6alkyl-N(Ra)(Rb), C3-8 cycloalkyl, or saturated 3- to 8-membered monocyclic heterocyclyl comprising at least one heteroatom independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R12is optionally substituted with the same or different one or more halo, C1-6alkyl, or CN;R“ is H or C1-6alkyl;Rbis H, C1-6alkyl, or C(=O)OC1-6alkyl;R2is:1) C1-6alkyl optionally substituted with the same or different one or more halo orCN,2) C3-8cycloalkyl optionally substituted with the same or different one or more C1-6alkyl, halo or CN, or3) Si(C1-6alkyl)3;R3is CH2 or O;R4is H or C1-6alkyl;Ring A is 5- or 6-membered heteroaryl or 6-membered aryl;Ring A may be optionally substituted with the same or different one or more A1selected from the group consisting of halo, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkyl-O-, C1-6haloalkyl-O-, C1-6alkylene(C3-6 cycloalkyl), C1-6alkylene(3- to 10-membered heterocyclyl), C1-6alkylene(C6-10aryl), C1-6alkylene-0-(C6-10aryl), C1-6alkylene(5-to 12- membered heteroaryl), C0-6alkyleneOH, C0-3 alkyleneOCz-3 alkylene(OH), C0-6alkylene(N(Rc)(Rd)), -OC0-6 alkylene(OC1-6alkyl), -OC0-6 alkylene(N(Rc)(Rd)), and C0-3 alkyleneOCi-3 alkylene(N(R°)(Rd));Rcis H or C1-6alkyl;Rdis H or C1-6alkyl, C1-6haloalkyl, or C(=O)OC1-6alkyl;Ring A may be optionally substituted with the same or different one or two RingG;Ring G is a monocyclic or bicyclic 6- to 10-membered aryl, a monocyclic or bicyclic 5- to 12-membered heteroaryl, C3-8cycloalkyl, or a saturated or partially unsaturated monocyclic or bicyclic 3- to 16-membered heterocyclyl; wherein the bicyclic aryl comprises a 6-membered aryl attached to Ring A, and the bicyclic heteroaryl comprises a 5- or 6-membered heteroaryl attached to Ring A;Ring G may be independently optionally substituted with the same or different one or more G1A;G1Ais halo, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, -(CR^-CN, -(CH2)v-NRxRy, -(CH2)v-C3-8cycloalkyl, -(CH2)v-C3-8cycloalkenyl, -(CH2)V-(3- to 10-membered heterocyclyl), -(CH2)V-C6-IO aryl, -(CH2)v-(5- to 12- membered heteroaryl), -(CRxRy)v-O-Rz, -O-(CRxRy)n-ORz, nitro, Si(RxX -S(O)q-Rx, -C(=O)RX, -(CRxRy)v-C(=O)ORz, -(CRxRy)v-0-C(=O)-Rz, -(CRxRy)v-C(=O)NRxRy, -(CH2)v-NRxC(=O)Ry, -(CH2)v-OC(=O)NRxRy, -(CH2)v-NRxC(=O)ORy, -NRX-(CH2)V-Rz,-(CH2)v-O-C(=O)-C1-4alkyl-NRxRy, -(CH2)v-NRx-(CH2)n-O-C(=O)-Rz, -(CH2)V-NRX- (CH2)v-SO2-Ry, -(CH2)v-NH-SO2-NRxRy, -(CH2)v-SO2NRxRygroups, and -P(=O)(RX)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.g cycloalkyl, C3.g cycloalkenyl, C6-10aryl, 3- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl groups may be optionally substituted with the same or different one or more Rxgroups and the two Rxmay join to form a 3- to 7-membered ring optionally containing one or two additional heteroatoms selected from O, N, S, and oxidized forms of N or S;Rx, Ryand Rzeach independently represent halo, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -(CH2)v-C3.g cycloalkyl, -(CH2)v-C3-8cycloalkenyl, -(CH2)v-C6-10aryl, -(CH2)5- to 12-membered heteroaryl, -(CH2)v-(3- to 10-membered heterocyclyl), -(CH2)vOHoptionally substituted with the same or different one or more halo, -C(=O)OC1-6alkyl,OH, =0, C1-6alkyl-O-, C1-6haloalkyl, -(CH2)n-O-C 1-6 alkyl, -C(=O)-(CH2)n-C1-6alkyl-O-,-C(=O)-C1-6alkyl, -(CH2)VC(=O)(OG2A), -(CH2)v-CN, C1-6alkyl-N(H)2-q(Rh)q, -N(H)2.q(Rh)q, -C(=O)-N(H)2-q(C1-6alkyl)q, -(CH2)v-NH-SO2-N(H)2^(Ci4alkyl)q, -(CH2)v-N(CI.4 alkyl)-SO2-N(H)2-q(C1-6alkyl)q, and -(CH2)V-O-C(=O)-C1-4alkyl-N(H)2^(C1-6alkyl)q; and when attached to nitrogen, carbon, silicon, or phosphorus atom, Rxand Rymay join to form a 3- to 7-membered ring optionally containing one or two additional heteroatoms selected from O, N, S, and oxidized forms of N or S;G2Ais H, C1-6alkyl, C0-3 alkylene(C6-10aryl) or C0-3 alkylene(5- to 12-membered heteroaryl), wherein said aryl or heteroaryl may be optionally substituted with the same or different one or more groups selected from the group consisting of halo, CN, OH, Ci-6 alkyl, C1-6haloalkyl, C1-6alkyl-O-, C1-6haloalkyl-O-, and C3-6 cycloalkyl;Rhis C1-6alkyl, C1-6haloalkyl, or C(=O)OC1-6alkyl; v independently represents an integer from 0-4; n independently represents an integer from 1-4; p independently represents an integer from 0-4; and q represents an integer from 0-2.

[0157] Clause 2. The compound according to clause 1, or a salt thereof, wherein R2is:1) C2-6alkyl optionally substituted with the same or different one or more halo orCN,2) C3-8 cycloalkyl optionally substituted with the same or different one or more C1-6alkyl, halo or CN, or3) Si(C1-6alkyl)3.

[0158] Clause 3. The compound according to clause 1 or 2, or a salt thereof, wherein RingA is substituted with the same or different one or two Ring G.

[0159] Clause 4. The compound according to any one of clauses 1 to 3, or a salt thereof, wherein Ring G is a monocyclic or bicyclic 6- to 10-membered aryl, a monocyclic or bicyclic 5- to 12-membered heteroaryl, or a saturated or partially unsaturated monocyclic or bicyclic 3- to 16-membered heterocyclyl.

[0160] Clause 5. The compound according to any one of clauses 1 to 4, or a salt thereof, wherein Ring A is pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or phenyl; or Ring A is 5- or 6-membered heteroaryl, for example, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0161] Clause 6. The compound according to any one of clauses 1 to 5, or a salt thereof, wherein Ring A is pyrazolyl, imidazolyl, furanyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 1,2,3 -triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or phenyl.

[0162] Clause 7. The compound according to any one of clauses 1 to 6, or a salt thereof, wherein Ring A is selected from the following groups:

[0163] Clause 8. The compound according to any one of clauses 1 to 7, or a salt thereof, wherein Ring A is selected from the following groups:

[0164] Clause 9. The compound according to any one of clauses 1 to 8, or a salt thereof, wherein Ring A is selected from the following groups:w ,herem . tHhe n .ng means Ring G.

[0165] Clause 10. The compound according to any one of clauses 1 to 9, or a salt thereof,wherein Ring A is isoxazolyl, thiazolyl, pyridinyl, or phenyl.

[0166] Clause 11. The compound according to any one of clauses 1 to 10, or a salt thereof, wherein Ring A is isoxazolyl, thiazolyl, or pyridinyl.

[0167] Clause 12. The compound according to any one of clauses 1 to 11, or a salt thereof, wherein A1is each independently selected from the group consisting of halo, CN, C1-6alkyl, C1-6alkyl-O-, C1-6alkyleneOH, -OC1-6alkylene-O(C1-6alkyl), -OC1-6alkylene-N(CI-6 alkyl)2, C1-6alkylene(C6-10aryl), and C1-6alkylene-0(C6-10aryl).

[0168] Clause 13. The compound according to any one of clauses 1 to 12, or a salt thereof, wherein A1is each independently C1-6alkyl or -OC1-6alkylene-N(C1-6alkyl)z.

[0169] Clause 14. The compound according to any one of clauses 1 to 3 and 5 to 13, or a salt thereof, wherein Ring G is selected from the following groups:Clause 15. The compound according to any one of clauses 1 to 3 and 5 to 14, or a salt thereof, wherein Ring G is selected from the following groups:

[0171] Clause 16. The compound according to any one of clauses 1 to 15, or a salt thereof, wherein Ring G is selected from the following groups:

[0172] Clause 17. The compound according to any one of clauses 1 to 16, or a salt thereof, wherein Ring G is selected from the following groups:Clause 18. The compound according to clause 17, or a salt thereof, wherein Ring G is selected from the following groups:wherein is a binding point to Ring A.

[0174] Clause 19. The compound according to any one of clauses 1 to 18, or a salt thereof, wherein Ring G is pyrazolyl, phenyl, or pyridyl.

[0175] Clause 20. The compound according to any one of clauses 1 to 19, or a salt thereof, wherein G1Ais each independently and preferably halo; OH; CN; C1-6alkyl; C1-6haloalkyl; -(C1-6alkylene)OH; -(C1-6alkylene)CN; (C1-6alkyleneJNHz; (C1-6alkylene)NH(C1-6alkyl); (C1-6alkylene)N(C1-6alkyl)?; (C1-6alkylene)NHC(=0)C1-6alkyl; (C1-6alkylene)NHC(=O)OC1-6alkyl; (C1-6alkylene)N(C1-6alky 1)C (=0)0 C1-6alkyl; (C1-6alkylene)(C3-6 cycloalkyl); (C1-6alkylene)(5- or 6-membered heteroaryl); (Ci-6 alkylene)(saturated 3- to 8-membered monocyclic heterocyclyl); C(=O)C1-6alkyl; OCi-6 alkyl; OC1-6haloalkyl; 0(C1-6alkylene)OH; 0(C1-6alkylene) O(C 1-6 alkyl); 0(C1-6alkylene)N(C1-6alkyl)?; OC1-6alkylene-(C3-6 cycloalkyl); NH?; N(C1-6alkyl)?; C3-6 cycloalkyl; 5- or 6-membered heteroaryl; saturated 3- to 8-membered monocyclic heterocyclyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, OH, CN, oxo, C1-6alkyl, C1-6haloalkyl, (C1-6alkylene)C(=O)OH, (C1-6alkylene)C(=O)O(C1-6alkyl), C(=O)O(C1-6alkyl), C(=O)O(Ci-6 alkylene)(C6-10aryl)O(C1-6alkyl), NHz, N(C1-6alkyl)?, NHC(=O)O(C1-6alkyl), C3-6 cycloalkyl, and saturated 3- to 8-membered monocyclic heterocyclyl; partially unsaturated 5- or 6-membered monocyclic heterocyclyl optionally substituted with C1-6alkyl; or any one of the following groups:NH xN xNNHNH NH / N N optionally substituted with C1-6alkyl.

[0176] Clause 21. The compound according to any one of clauses 1 to 20, or a salt thereof, wherein G1Ais each independently halo, CN, OC1-6haloalkyl, 5- or 6-membered heteroaryl, or saturated 3- to 8-membered monocyclic heterocyclyl optionally substituted with halo or C1-6alkyl.

[0177] Clause 22. The compound according to any one of clauses 1 to 21, or a salt thereof, wherein R4is H or methyl.

[0178] Clause 23. The compound according to any one of clauses 1 to 22, or a salt thereof, wherein R4is H.

[0179] Clause 24. The compound according to any one of clauses 1 to 23, or a salt thereof, wherein R2is C2-6alkyl, such as ethyl, isopropyl, 1,1 -dimethylpropyl, and tert-butyl, optionally substituted with one or two halo; C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, and bicyclo[l.l.l]pentyl, optionally substituted with at least one C1-6alkyl; or trimethylsilyl; for example, R2is 1,1 -difluoroethyl, isopropyl, 1,1 -dimethylpropyl, 2- fluoropropan-2-yl, tert-butyl, methylcyclopropyl, 1 -methylcyclobutyl, bicyclo[l.l.l]pentyl, or trimethylsilyl.

[0180] Clause 25. The compound according to any one of clauses 1 to 24, or a salt thereof, wherein R2is C2-6alkyl or C1-6alkyl-substituted C3-6 cycloalkyl.

[0181] Clause 26. The compound according to any one of clauses 1 to 24, or a salt thereof, wherein R2is C2-6alkyl optionally substituted with the same or different one or more halo or CN.

[0182] Clause 27. The compound according to any one of clauses 1 to 26, or a salt thereof, wherein R2is C2-6alkyl.

[0183] Clause 28. The compound according to any one of clauses 1 to 27, or a salt thereof, wherein R2is isopropyl or tert-butyl.

[0184] Clause 29. The compound according to any one of clauses 1 to 28, or a salt thereof, wherein R2is attached to the nitrogen-containing ring in formula (I) in a transconfiguration manner to the carboxy group that is attached to the nitrogen-containing ring.

[0185] Clause 30. The compound according to any one of clauses 1 to 29, or a salt thereof, wherein R12is each independently halo, C1-6alkyl-O-, C3-6 cycloalkyl, or saturated 3- to8-membered monocyclic heterocyclyl.

[0186] Clause 31. The compound according to any one of clauses 1 to 30, or a salt thereof, wherein R11is C1-6alkyl optionally substituted with the same or different one or more halo.

[0187] Clause 32. The compound according to any one of clauses 1 to 31, or a salt thereof, wherein R1is:1) halo,2) OH,3) R11optionally substituted with the same or different one or more R12, or4) -iJ-R11optionally substituted with the same or different one or more R12.

[0188] Clause 33. The compound according to any one of clauses 1 to 29, or a salt thereof, wherein R1is:1) H;2) fluoro;3) OH;4) (4-a) C1-6alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and 3- methylbutyl, optionally substituted with the same or different one or more R12; whereinR12is fluoro; chloro; -O-C1-6alkyl optionally substituted with the same or different one or more halo; -N(Ra)(Rb), wherein Rais H or C1-6alkyl and Rbis H or C1-6alkyl, optionally substituted with the same or different one or more halo; C3-8 cycloalkyl, such as cyclopropyl, cyclobutyl, and cyclohexyl, optionally substituted with the same or different one or more halo or CN; saturated 3- to 8-membered monocyclic heterocyclyl comprising at least one heteroatom independently selected from the group consisting of nitrogen and oxygen, such as azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, wherein the 3- to 8-membered monocyclic heterocyclyl is optionally substituted with the same or different one or more halo; (4-b) C2-6alkenyl, such as prop-2-enyl, optionally substituted with one or more fluoro; or (4-c) C2-6alkynyl, such as but-2-ynyl; or5) (5-a) -O-C1-6alkyl, such as methoxy, ethoxy, propoxy, 2-methylpropoxy, and butoxy, optionally substituted with one or two groups independently selected from the group consisting of halo, C3-8 cycloalkyl, such as cyclopropyl, saturated 3- to 8-membered monocyclic heterocyclyl comprising oxygen, such as oxetanyl, optionally substituted with the same or different one or two halo; (5-b) -O-C1-6alkenyl, such as 2-propenyloxy;(5-c) -O-C1-6alkynyl, such as but-2-ynyloxy; or (5-d) -S-C1-6alkyl, such as -S-CH3 and -S-C2H5.

[0189] Clause 34. The compound according to any one of clauses 1 to 33, or a salt thereof, wherein R3is CH2.

[0190] Clause 35. The compound according to any one of clauses 1 to 34, or a salt thereof, wherein:R1is H,R11optionally substituted with the same or different one or more R12, or-Ll-Rnoptionally substituted with the same or different one or more R12;L4s O;R11is C1-6alkyl;R12is each independently halo or C3-8 cycloalkyl;R2is C2-6alkyl;R3is CH2 or 0;R4is H;Ring A is isoxazolyl, thiazolyl, pyridinyl, or phenyl;Ring A may be optionally substituted with the same or different one or more A1selected from the group consisting of C1-6alkyl and -OC1-6alkylene(N(R°)(Rd));Rcis C1-6alkyl;Rdis C 1-6 alkyl;Ring A may be optionally substituted with Ring G;Ring G is phenyl, pyrazolyl, or pyridyl;Ring G may be independently optionally substituted with the same or different one or more G1A; andG1Ais each independently halo, CN, -O-C1-6haloalkyl, pyridyl, azetidinyl optionally substituted with one or more groups independently selected from the group consisting of halo and C1-6alkyl, or piperazinyl optionally substituted with C1-6alkyl.

[0191] Clause 36. The compound according to any one of clauses 1 to 35, or a salt thereof,whereinR1is R11optionally substituted with the same or different one or more R12, or-O-R11optionally substituted with the same or different one or more R12;R11is C1-6alkyl;R12is each independently halo or C3-8 cycloalkyl;R2is C2-6alkyl;R3is CH2or O;R4is H;Ring A is isoxazolyl, thiazolyl, pyridinyl, or phenyl;Ring A may be optionally substituted with the same or different one or more A1selected from the group consisting of C1-6alkyl and -OC1-6alkylene(N(Rc)(Rd));Rcis C1-6alkyl;Rdis C1-6alkyl;Ring A may be optionally substituted with Ring G;Ring G is phenyl, pyrazolyl, or pyridyl;Ring G may be independently optionally substituted with the same or different one or more G1A; andG1Ais each independently halo, CN, -O-C1-6haloalkyl, pyridyl, azetidinyl optionally substituted with one or more groups independently selected from the group consisting of halo and C1-6alkyl, or piperazinyl optionally substituted with C1-6alkyl.

[0192] Clause 37. The compound according to any one of clauses 1 to 36, or a salt thereof, having the following structure (IA):wherein R1, R2, R3, R4, and Ring A are those as defined in clause 1.

[0193] Clause 38. The compound according to any one of clauses 1 to 37, or a salt thereof, which is not l-(2-fluorobenzyl)-5-methylpiperidine-3-carboxylic acid.

[0194] Clause 39. The compound according to any one of clauses 1 to 38, or a salt thereof, which is not rel-(3R,5R)-5-(l , 1 -dimethylethyl)-! -[[2-(12M ,2, 4-triazol-l - yl)phenyl]methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-( 1,1 -dimethylethyl)- 1- [(6- oxo-1 ,6-dihydropyridin-3-yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-l -[3- acetamidobenzyl)-5-(l , 1 -dimethylethyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(1,1 -dimethylethyl)- 1 - [(3 ,5-dimethy 1- 1 -( 1 -methylethyl)- 1 H-pyrazol-4-y l)methy 1] -3 - piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)- 1 -[4-chloropyridin-3- yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5 -(1,1 -dimethylethyl)- 1 - [(3 ,5- dimethyl-4-pyridinyl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l- dimethylethyl)-l-[((4-cyanothiophen-2-yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-( 1 , 1 -dimethylethyl)- 1 -[3 -chloro-5 -hydroxyben2yl)-3 -piperidinecarboxylic acid, rel-(3R,5R)-5 -(1,1 -dimethylethyl)- 1 -[(3 -methoxy- 1 -methyl- 1 H-pyrazol-4- yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[[3-(l- methylethyl)-4-isoxazolyl]methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l- dimethylethyl)- 1 - [(3 -fluoro-2-pyridinyl)methyl]-3 -piperidinecarboxylic acid, rel-(3 R, 5R)-5 -( 1 , 1 -dimethylethyl)- 1 - [(2-cy clopropy 1- 1 H-imidazol-5 -y l)methy] -3 - piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)- 1 -[(4-fluoro-2- hydroxyphenyl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)-1 - [(4, 5 -dimethyl- 1 H-pyrazol-3-y l)methy 1] -3 -piperidinecarboxylic acid, 5-(l,l- dimethylethyl)-l-[l-[(5-chloro-2-thiazolyl)methyl]-3-piperidinecarboxylic acid, 5-(l,l- dimethylethyl)-l-[(5-ethyl-l-methyl-lH-pyrazol-4-yl)methyl]-3-piperidinecarboxylic acid, 5-(l,l-dimethylethyl)-l-[(l-cyclobutyl-lH-pyrazol-4-yl)methyl]-3- piperidinecarboxylic acid, 5-( 1 , 1 -dimethylethyl)- 1 - [(6-cy clobutyl-3 -pyridiny l)methy 1] -3 -piperidinecarboxylic acid, rel-(3R,5R)-5-( 1 , 1 -dimethylethyl)- 1 - [(3 -ethoxy-2- hydroxyphenyl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)- l-[[3-(dimethylamino)-5-fluoro-4-pyridinyl]methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)- 1 - [(4-chloro- 1 -methyl- 1 H-pyrazol-3 -yl)methyl]-3 - piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[[5-(trifluoromethyl)-2- furanyl]methyl]-3 -piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)- 1 -[3-(1,1 -dimethylethyl)- 1 -ethyl- lH-pyrazol-4-yl]methyl]-3 -piperidinecarboxylic acid, rel-(3R, 5R)-5-(l , 1 -dimethylethyl)- 1 - [[ 1 -(2,2-difluoroethy l)-3 -methyl- 1 H-pyrazol-4- yl]methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)-! -[(5-ethyl-l - methyl-lH-pyrazol-4-yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l- dimethylethyl)-l-[[l-(cyclopropylmethyl)-lH-pyrazol-5-yl]methyl]-3- piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)-! -[[! -(2,2,2- trifluoroethyl)-lH-pyrazol-4-yl]methyl]-3-piperidinecarboxy lie acid, rel-(3R,5R)-5-(l,l- dimethylethyl)- 1 - [(2-amino-3 -fluoropheny l)methyl]-3 -piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[[l-(2-propen-l-yl)-!H-pyrazol-4-yl]-3- piperidinecarboxylic acid, rel-(3R,5R)-5-(l ,1 -dimethylethyl)-! -[(5-ethyl-!H-imidazol-2- yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)- 1 -[(2-methoxy-5-thiazolyl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l- dimethylethyl)-l-[(5-chloro-3-pyridinyl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-1 -[(5-cyclopropyl-l / f-pyrazol-3-yl)methyl]-5-(l , l-dimethylethyl)-3- piperidinecarboxylic acid, rel-(3R,5R)-l-[(l-cyclobutyl-lH-pyrazol-4-yl)methyl]-5-(1,1 -dimethylethy l)-3 -piperidinecarboxylic acid, or rel-(3R,5R)-l-[(6-cyclobutyl-3- pyridinyl)methyl]-5-(l,l-dimethylethyl)-3-piperidinecarboxylic acid.

[0195] Clause 40. The compound according to clause 1, or a salt thereof, wherein the compound is selected from Examples 1 to 804.

[0196] Clause 41. The compound according to clause 1, or a salt thereof, selected from the following formulae:Clause 42. The compound or salt according to clause 1, selected from the following formulae:Clause 43. A sortilin inhibitor comprising a compound according to any one of clauses 1 to 42, or a salt thereof.

[0199] Clause 44. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 42, or a salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0200] Clause 45. The compound according to any one of clauses 1 to 42, or a salt thereof, for use in treating, preventing, and / or diagnosing a disease or disorder selected from the group consisting of inflammatory diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), psoriasis, type 1 diabetes mellitus (T1DM), and multiple sclerosis (MS); cancers including progranulin-induced metastatic breast cancer, lung metastases, and pancreatic cancer cell invasion; wounds (i.e., wound healing) and traumatic brain injury; CNS diseases such as stroke, schizophrenia-like psychosis, schizophrenia, or bipolar disorder(BPD); atypical parkinsonism, such as corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP); spinocerebellar ataxia 3 (SCA3), limbic-predominant age- related TDP-43 encephalopathy (LATE), and Huntington's diseases (HD); age-related macular degeneration (AMD), retinal degeneration, and other neurodegenerative diseases of the eye; atherosclerosis; neurodegenerative diseases such as frontotemporal dementia(FTD), frontotemporal lobar degeneration (FTLD), neuronal ceroid lipofuscinosis (NCL, a lysosomal storage disease), Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC), amyotrophic lateral sclerosis (ALS),C9ORF72-associated ALS / FTD, sporadic ALS, Alzheimer’s disease (AD), Gaucher disease types 2 and 3, Parkinson’s disease (PD), and major depression; pain; and hearingloss.

[0201] Clause 46. Use of a compound according to any one of clauses 1 to 42, or a salt thereof, in the manufacture of a medicine for the treatment, prophylaxis, and / or diagnosis of a disease or disorder selected from the group consisting of inflammatory diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), psoriasis, type 1 diabetes mellitus (T1DM), and multiple sclerosis (MS); cancers including progranulin-induced metastatic breast cancer, lung metastases, and pancreatic cancer cell invasion; wounds (i.e., wound healing) and traumatic brain injury; CNS diseases such as stroke, schizophrenia-like psychosis, schizophrenia, or bipolar disorder (BPD); atypical parkinsonism, such as corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP); spinocerebellar ataxia 3(SCA3), limbic-predominant age-related TDP-43 encephalopathy (LATE), andHuntington's diseases (HD); age-related macular degeneration (AMD), retinal degeneration, and other neurodegenerative diseases of the eye; atherosclerosis; neurodegenerative diseases such as frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), neuronal ceroid lipofuscinosis (NCL, a lysosomal storage disease),Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC), amyotrophic lateral sclerosis (ALS), C9ORF72-associatedALS / FTD, sporadic ALS, Alzheimer’s disease (AD), Gaucher disease types 2 and 3,Parkinson’s disease (PD), and major depression; pain; and hearing loss.

[0202] Clause 47. The compound according to any one of clauses 1 to 42, or a salt thereof, for use as a sortilin inhibitor.

[0203] Clause 48. The compound according to any one of clauses 1 to 42, or a salt thereof, for use in increasing PGRN levels, inhibiting neurotensin signaling, inhibiting BDNF signaling, inhibiting proNGF signaling, or inhibiting proBDNF signaling.

[0204] Clause 49. The compound according to any one of clauses 1 to 42, or a salt thereof, for use in the treatment, prophylaxis, and / or diagnosis of a disease or disorder associated with sortilin ligands.

[0205] Clause 50. A method of treatment, prophylaxis, and / or diagnosis of a disease or disorder associated with sortilin ligands, such as inflammatory diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), psoriasis, type 1 diabetes mellitus (T1DM), and multiple sclerosis (MS); cancers including progranulin-induced metastatic breast cancer, lung metastases, and pancreatic cancer cell invasion; wounds (i.e., wound healing) and traumatic brain injury; CNS diseases such as stroke, schizophrenia-like psychosis, schizophrenia, or bipolar disorder (BPD); atypical parkinsonism, such as corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP); spinocerebellar ataxia 3(SCA3), limbic-predominant age-related TDP-43 encephalopathy (LATE), andHuntington's diseases (HD); age-related macular degeneration (AMD), retinal degeneration, and other neurodegenerative diseases of the eye; atherosclerosis; neurodegenerative diseases such as frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), neuronal ceroid lipofuscinosis (NCL, a lysosomal storage disease),Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC), amyotrophic lateral sclerosis (ALS), C9ORF72-associatedALS / FTD, sporadic ALS, Alzheimer’s disease (AD), Gaucher disease types 2 and 3,Parkinson’s disease (PD), and major depression; pain; and hearing loss, the method which comprises administering to a subject in need thereof a compound according to any one of clauses 1 to 42, or a salt thereof.

[0206] Clause 51. Use of a compound according to any one of clauses 1 to 42, or a salt thereof, in the manufacture of a medicament for the treatment, prophylaxis, and / or diagnosis of a disease or disorder associated with sortilin ligands.

[0207] Clause 52. A medicament comprising a compound according to any one of clauses 1 to 42, or a salt thereof, for use in the treatment, prophylaxis, and / or diagnosis of a disease or disorder associated with sortilin ligands.

[0208] Clause 53. The compound according to any one of clauses 1 to 42, or a salt thereof, inhibitor, composition, method, use, or medicament according to any one of clauses 43 to 52, for use in the treatment, prophylaxis, or diagnosis of a neurodegenerative disease.

[0209] Clause 54. The compound, or a salt thereof, inhibitor, composition, method, use, or medicament according to clause 53, wherein the disease is selected from frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease or amyotrophic lateral sclerosis.

[0210] Clause 55. The compound according to any one of clauses 1 to 42, or a salt thereof, inhibitor, method, use, or medicament according to any one of clauses 43 and 45 to 54, wherein the compound, or a salt thereof, is provided in the form of a pharmaceutical composition according to clause 44.

[0211] Clause 56. The compound according to any one of clauses 1 to 42, or a salt thereof, inhibitor, composition, method, use, or medicament according to any one of clauses 43 to 55, wherein the compound, or a salt thereof, is administered orally.

[0212] Clause 57. A process for the preparation of a compound according to any one of clauses 1 to 42, or a salt thereof, as described herein.

[0213] ExamplesThe present invention is explained in more detail with reference to Test Examples,Reference Examples, and Examples as below, which are not to be construed as limitative, and the examples may be modified without departing from the scope of the invention.Compounds are named using an automated naming package such as from ChemAxon, using IUPAC rules or are as named by the chemical supplier. The following synthetic procedures are provided for illustration of the methods used; for a given preparation or step the precursor used may not necessarily derive from the individual batch synthesised according to the step in the description given.

[0214] The following abbreviations are used herein.REX: Reference Example number (Intermediates)EX: Example numberSTR: structural formulaPrep: Preparation (The number means that the compound was prepared from corresponding starting materials in a similar manner to the indicated Example)Data: physicochemical data from NMR1: 3 (ppm) in!H-NMR in dimethyl sulfoxide-de;NMR2: 3 (ppm) in 'H-NMR in CDCh; NMR3: 8 (ppm) in!H-NMR in CDaOD and / orMS: Mass spectrumCis (such as in cis racemic) refers to the geometric arrangement of C3 and C5 substituents in the core piperidine ring, where the highest priority groups are situated on the same face of the piperidine ringTrans (such as in trans racemic): refers to the geometric arrangement of C3 and C5 substituents in the core piperidine ring, where the highest priority groups are situated on opposite faces of the piperidine ringAcOEt or EtOAc: ethyl acetateAcOH: acetic acidAcONa: sodium acetate aq.: aqueous solution9-BBN: 9-borabicyclo[3.3.1]nonaneBBra: boron tribromideBFaOEtz: boron trifluoride - diethyl ether complexBn: benzylBoc: tert-butoxycarbonylBpin: boronic acid pinacol esterBPO: benzoyl peroxideBz: benzoylCDI: 1,1* -carbonyldiimidazoleCH3CN / MeCN: acetonitrileCHCI3: chloroformCOMU: ethyl 2-cyano-2-((dimethyliminio)(morpholino)methyloxyimino)acetate hexafluorophosphate cone.: concentratedCS2CO3: cesium carbonateCui: cupper (I) iodideDAST: (diethylamino)sulfur trifluorideDBU : 1 ,8-diazabicyclo[5.4.0]-7-undeceneDCC: dicyclohexylcarbodiimideDCE: 1,2-dichloroethaneDCM: dichloromethaneDEA: diethylamineDEAD: diethyl azodicarboxylateDMP / Dess-Martin periodinane: 1, 1,1 -triacetoxy- 1,1 -dihydro- l,2-benziodoxol-3(lH)- oneDHP: 3,4-dihydro-2H-pyraneDIBAL: diisobutylaluminum hydrideDIBOC: di-f-butyl dicarbonateDIPEA: diisopropylethylamineDMA: N,N-dimethylacetamideDMAP: 4-(dimethylamino)pyridineDME: dimethoxyethaneDMF: N,N-dimethylformamideDMSO: dimethyl sulfoxideDMT-MM: 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chlorideDPPA: diphenylphosphoryl azideEt2O: diethyl etherEtOH: ethanolFmoc: fhiorenylmethyloxycarbonylHC1: hydrochloric acidHexane: n-hexaneh: hour / hoursHATU: l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHBTU: l-[bis(dimethylamino)methylene]-l / / -benzotriazoliuni 3 -oxide hexafluorophosphatelHOAt 3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-olHOBt: 1-hydroxybenzotriazoleIPA: 2-propanolIPE: diisopropyl etherK2CO3: potassium carbonateK3PO4: tripotassium phosphateKHCO3: potassium hydrogen carbonateKHMDS: potassium bis(trimethylsilyl)amideKF: potassium fluorideKOH: potassium hydroxideKOAc: potassium acetateKOtBu: potassium f-butoxideLAH: lithium aluminum hydrideLDA: lithium diisopropylamideL-DTTA: di-p-toluoyl-L-tartaric acidLHMDS: lithium hexamethyldisilazideLiOH: lithium hydroxideMCPBA: m-chloroperoxybenzoic acidMEK: 2-butanoneMeOH: methanolMgS04: magnesium sulfateMhOz: manganese dioxideNz: nitrogen moleculeNaBHt: sodium borohydrideMsCl: methanesulfonyl chlorideNaBH(OAc)a: sodium triacetoxyborohydrideNazCOa: sodium carbonateNaH: sodium hydrideNaHCOa: sodium hydrogen carbonateNaHMDS: sodium hexamethyldisilazideNaOH: sodium hydroxideNaOtBu: sodium t-butoxideNUISOA: sodium sulfateNazSzOa: sodium thiosulfateNBS: N-bromosuccinimide n-BuLi: n-butyllithiumNCS: N-chlorosuccinimideNHa: ammoniaNH4CI: ammonium chlorideNMP: N-methylpyrrolidoneOSO4: osmium (VIII) oxideXPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenylXPhos Pd G3 : (2-dicyclohexylphosphino-2,,4',6'-triisopropyl-l,r-biphenyl)[2-(2,-amino- l,l'-biphenyl)]palladium (II) methanesulfonatePd / C: palladium on carbonPdj(dba)3 : tris(dibenzy lideneacetone)dipalladiumPd(dtbpf)C12: l,l'-bis(di-t-butylphosphino)ferrocene palladium dichloridePd(dppf)Ch: 1 , 1 '-bis(diphenylphosphino)ferrocene]palladiumPd(OAc)2: palladium acetatePd(0H)2-C: palladium hydroxide on carbonPd-PEPPSI IPent: [1,3 -Bis(2,6-Di-3 -pentylphenyl)imidazol-2-ylidene](3 - chloropyridyl)palladium (II) dichloridePd(PPh3)4: tetrakis(triphenylphosphine)palladiumPd(PPha)2C12: bis(triphenylphosphine)palladium (II) dichloridePEG: polyethylene glycolPPTS: pyridinium p-toluenesulfonatePtCh: platinum oxidePyBOP: benzotriazol- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphateRuPhos Pd G3: (2-dicy clohexylphosphino-2',6'-diisopropoxy- 1 , 1 -biphenyl) [2-(2- amino- l,l'-biphenyl)]palladium (II) methanesulfonate sat: saturatedT3P: propylphosphonic anhydrideTBME: tetrabutylmethyl etherZ-BuOH: t-butyl alcoholTEA: triethylamineTEB: triton extraction bufferTEA: trifluoroacetic acidTHE: tetrahydrofuranTMSC1: chlorotrimethylsilaneXphos: 2-dicyclohexylphosphino-2',4,,61-triisopropylbiphenylXhos Pd G3: (2-dicyclohexylphosphino-2,,4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino- l,r-biphenyl)]palladium (II) methanesulfonateWSC: 3-ethyl-l-(3-dimethylaminopropyl)carbodiimide hydrochlorideZC1: benzyl chloroformate

[0215] The "r.t." in the Examples below basically refers to from about 10°C to about 35°C. The ratios in mixed solvents refer to the volume ratio unless otherwise specified. % refers to % by weight unless otherwise specified.

[0216] *H NMR (proton nuclear magnetic resonance spectrum) was determined at room temperature by Fourier transform NMR (any one of Bruker AVANCE III 400 (400 MHz),Bruker AVANCE IDE 500 HD (500 MHz)), and Bruker AVI 400MHz with a QNP probe,Z gradient.

[0217] In silica gel column chromatography, aminopropylsilane-bonded silica gels were used when the term "basic" is described.

[0218] MS (mass spectrum) was measured with LC / MS (Waters Acquity SQD / LC, WatersAcquity UPLC H-Class, or Thermo Fisher scientific ITQ 1100). Data described herein are measured values (found). Molecular ion peaks of a free form (such as [M+H]+and[M-H]"), molecular ion peaks of a free form [M]+or fragment ion peaks thereof, or sodium-adduct ion peaks of a free form [M+Na]+are typically observed.

[0219] When amino silica gel is described for silica gel column chromatography, silica gel modified with amine (e.g., aminopropylsilane bonded silica gel) is used.

[0220] Absolute configurations of compounds were determined by known X-ray crystallography(e.g., Shigeru Ooba and Shigenobu Yano, "Kagakusha no tame no Kiso-Koza 12 X-ray crystallography" (1st ed., 1999)) or estimated from the empirical rules of Shi asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-GuiZhao: Tetrahedron: Asymmetry 1998, 9, 397-401. Yuanming Zhu, Yong Tu, HongwuYu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

[0221] Preparation of intermediatesSynthesis of methyl (3K5SV5-(tert-butvUpiperidine-3-carboxylate:(2R,3R)-2,3-Bis(4-methyIbenzoyIoxy)butanedioic acid methyl (3R,5S)-5-tert- butyIpiperidine-3-carboxylateA suspension of methyl 5-tert-butylpiperidine-3-carboxylate (20 g, 0.1 mol) and di-p- toluoyl-L-tartaric acid (19.4 g, 0.05 mmol) in EtOH (100 mL) was stirred at 85°C for 1 hour and then at 55°C for 1 hour. EtOAc (100 mL) was added to the reaction mixture which was then allowed to cool to room temperature. The precipitate was collected by filtration, washed with EtOH and EtOAc and dried in vacuo to afford the desired product.(7.0 g). *H NMR (400 MHz, DMSO-de): 7.80 (d, J = 7.9 Hz, 4H), 7.29 (d, J = 7.9 Hz,4H), 5.60 (s, 2H), 3.68 (s, 3H), 3.47 (d, J = 14.5 Hz, 2H), 3.13 (d, J = 12.1 Hz, 1H), 3.06(s, 1H), 2.97 (dd, J = 13.0, 4.4 Hz, 1H), 2.35 (s, 6H), 2.12 (d, J = 13.6 Hz, 1H), 1.52-1.40(m, 1H), 1.40-1.17 (m, 1H), 0.83 (s, 9H).Methyl (3R,5S)-5-(tert-butyl)piperidine-3-carboxylate(2R,3R)-2,3-bis(4-methylbenzoyloxy)butanedioic acid methyl (3R,5S)-5 -tertbutylpiperidine-3 -carboxylate (7.50 g, 12.8 mmol) was loaded onto an SCX-2 cartridge(70 g), which was washed with MeOH. The compound was released using IM triethylamine in MeOH (200 mL) to give methyl (3R,5S)-5-(tert-butyl)piperidine-3- carboxylate as a free base. The procedure was repeated with another 7.5 g of 2,3-bis[(4- methylbenzoyl)oxy]butanedioic acid methyl (3R,5S)-5-tert-butylpiperidine-3- carboxylate. The two batches of methyl (3R,5S)-5-(tert-butyl)piperidine-3 -carboxylate were combined to give the desired product (5.0 g).JH NMR (400 MHz, CDCh): 5 3.72(s, 3H), 3.40 (d, 1=12.1 Hz, 1H), 3.10 (d, 1=12.6 Hz, 1H), 2.66 - 2.59 (m, 2H), 2.36 - 2.22(m, 2H), 1.45 - 1.35 (m, 1H), 1.28 - 1.19 (m, 1H), 0.85 (s, 9H).

[0222] Synthesis of dibenzyl (3R.5S)-5-(tert-butvDpiperidine-L 3-dicarboxylate(3R,5S)-5-(tert-Butyl)piperidine-3-carboxylic acid hydrochlorideSodium carbonate (17.60 g, 0.166 mol) was added portion wise over 2 minutes to a stirred mixture of (2R,3R)-2,3-bis(4-methylbenzoyloxy)butanedioic acid methyl (3R,5S)-5-tert- butylpiperidine-3 -carboxylate (40.00 g, 68.3 mmol) in EtOAc (550 mL) and water (550 mL). Over the course of 10 minutes full solution occurred. The layers were separated and the aqueous phase extracted with EtOAc (2 x 300 mL). The pooled organic phases were dried (MgSO4) and the solvent evaporated under reduced pressure to afford free base methyl (3R,5S)-5-(tert-butyl)piperidine-3-carboxylate (13.7 g). 11.5 M Hydrogen chloride (80 mL, 0.920 mol) was added to the free base and the mixture heated at 100°C with stirring for 3 hours then allowed to cool and stir at room temperature overnight. Themixture was evaporated under reduced pressure to afford (3R,5S)-5-(tert- butyl)piperidine-3-carboxylic acid hydrochloride (15.4 g)XH NMR (400 MHz, CDCI3):3 10.22 - 10.17 (m, 1H), 7.88 - 7.83 (m, 1H), 3.45 (d, J=12.6 Hz, 1H), 3.17 (d, 1=11.6 Hz,1H), 3.04 - 2.91 (m, 2H), 2.66 - 2.59 (m, 1H), 2.17 (d, J=13.1 Hz, 1H), 1.60 - 1.37 (m,2H), 0.88 (s, 9H).(3R,5S)-l-((Benzyloxy)carbonyl)-5-(tert-butyI)piperidine-3-carboxy lie acidN-(benzyloxycarbonyloxy)succinimide (18.6 g, 74.9 mmol) was added to a suspension of (3R,5S)-5-(tert-butyl)piperidine-3-carboxylic acid hydrochloride (15.1 g, 68.1 mmol) and NaHCO3 (18.6 g, 221 mmol) in acetonitrile (60 mL) and water (60 mL) and the reaction was stirred at room temperature for 4.5 hours. The reaction was diluted withEtOAc (600 mL) and washed with NH4CI (2x300 mL). The organic phase was concentrated in vacuo to give the desired product (23.5 g) which was used in the next step without further purification.*H NMR (400 MHz, CDCI3): 57.39 (s, 5H), 5.16 - 5.06 (m, 2H), 4.63 (d, 1=13.1 Hz, 1H),4.27 - 4.26 (m, 1H), 2.93 - 2.84 (m, 1H), 2.83 (s, 1H), 2.76 - 2.70 (m, 1H), 2.47 (dd,1=12.0, 12.0 Hz, 1H), 2.32 (d, J=13.1 Hz, 1H), 1.58 - 1.30 (m, 1H), 0.90 (s, 9H).Dibenzyl (3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxylateCS2CO3 (2.47 g, 75.8 mmol) was added portionwise to a stirred solution of (3R,5S)-1-((benzyloxy)carbonyl)-5-(tert-butyl)piperidine-3 -carboxylic acid (22.0 g, 68.9 mmol) in anhydrous DMF (65.0 mL). Benzyl bromide (11.0 mL, 89.5 mmol) was added as a gentle stream with ice cooling. On complete addition the mixture stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (600 mL) and washed with water (2 x500 mL), brine (500 mL), dried (MgSO4) and the solvent evaporated. The residue was purified by silica chromatography (330 g) eluting with 0-50% EtOAc in cyclohexane to afford dibenzyl (3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxylate (22.3 g).THNMR (400 MHz, CDCh): 57.34 - 7.27 (m, 10H), 5.13 (d, 1=12.1 Hz, 3H), 4.98 - 4.97(m, 1H), 4.65 (d, J=13.4 Hz, 1H), 4.28 - 4.27 (m, 1H), 2.89 (dd, J=3.9, 13.5 Hz, 1H), 2.78- 2.70 (m, 1H), 2.46 - 2.46 (m, 1H), 2.28 (d, J=11.6 Hz, 1H), 1.52 - 1.44 (m, 1H), 1.40 -1.30 (m, 1H), 0.87 (s, 9H).MS (ESI) m / z 410.6 [M+H]+.

[0223] .Synthesis of methyl (3R, 5S)-3-butvl-5-tert-butvlpiyeridine-3-carboxvlateGeneral procedure [KHMDS Alkylation]Step 1: Synthesis of 1-benzyl 3-methyl (3S,5S)-3-(but-2-yn-l-yl)-5-tert- butylpiperidine-1 ,3-dicarboxyIateTo a -78 *C solution of 1-benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-l,3- dicarboxylate (1.00 g, 3.00 mmol) in anhydrous tetrahydrofuran (THE) (30.0 mL) underNz atmosphere was added potassium bis(trimethylsilyl)amide (1.19 mL, 5.25 mmol) dropwise. The reaction was stirred for 1 hour then l-bromo-2-butyne (0.656 mL, 7.50 mmol) was added dropwise and continued to stir for another 2 hours then quenched with saturated aqueous solution of NH4CI. The reaction was warmed to room temperature andEtOAc (30 mL) was added. The partitioned organic layer was set aside and the aqueous phase was extracted with EtOAc (3x 30 mL). The combined organics were then dried over anhydrous NazSC>4, filtered, and concentrated under reduced pressure. The residue was purified column chromatography (stationary phase: SiOz eluent: petrol / EtOAc) to afford 1-benzyl 3-methyl (3 S,5 S)-3 -(but-2-yn- 1 -yl)-5-tert-butylpiperidine- 1,3-dicarboxylate (689 mg, 1.79 mmol). MS (ESI) m / z 386 [M+H]+Step 2: synthesis of methyl (3R,5S)-3-butyl-5-tert-butylpiperidine-3-carboxylateGeneral procedure [Hydrog]A mixture of 1-benzyl 3-methyl (3S,5S)-3-(but-2-yn-l-yl)-5-tert-butylpiperidine-l,3- dicarboxylate (689 mg, 1.79 mmol) and 10 % Pd / C (179 mg) in 1:1 MeOH:EtOAc (30 mL) under H2 atmosphere was shaken for 2 hours. The mixture was filtered through celite and concentrated under reduced pressure to afford methyl (3R,5S)-3-butyl-5-tert- butylpiperidine-3-carboxylate (410 mg, 1.61 mmol) as a clear oil. MS (ESI) m / z 256[M+H]+

[0224] Synthesis of dibenzyl (3S, 5S)-5-(tert-butyl)-3-(2-oxoethyl)piperidine-l, 3-dicarboxylateDibenzyl (3R,5S)-3-alIyI-5-(tert-butyl)piperidine-l,3-dicarboxylateThis compound was synthesised from dibenzyl (3R,5S)-5-(tert-butyl)piperidine-l,3- dicarboxylate using a similar procedure as 1 -benzyl 3 -methyl (3R,5S)-3-allyl-5-(tertbutyl)piperidine-l, 3-dicarboxylate. *H NMR (400 MHz, CDCh): 8 7.20 - 7.12 (m, 10H),5.55 - 5.44 (m, 1H), 5.01 - 4.94 (m, 2H), 4.90 - 4.73 (m, 3H), 4.57 - 4.50 (m, 1H), 4.13(bs, 1H), 3.79 - 3.52 (m, 1H), 2.36 - 2.15 (m, 2H), 2.08 (d, J=7.3 Hz, 1H), 1.88 - 1.60 (m,2H), 0.87 - 0.73 (m, 1H), 0.70 (s, 9H), 0.69 - 0.67 (m, 1H).MS (ESI) m / z 450.3 [M+H]+.Dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-oxoethyl)piperidine-l,3-dicarboxylateThis compound was synthesised from dibenzyl (3R,5S)-3-allyl-5-(tert-butyl)piperidine-1,3 -dicarboxylate using a similar procedure as 1 -benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-oxoethyl)piperidine-l,3-dicarboxylate. *HNMR (400 MHz, CDCh): 39.65 (s, 1H),7.33 - 7.26 (m, 10H), 5.16 - 4.95 (m, 3H), 4.73 - 4.64 (m, 2H), 4.33 - 4.20 (m, 1H), 2.62(d, J=11.4 Hz, 1H), 2.45 - 2.31 (m, 2H), 1.93 - 1.65 (m, 1H), 1.52 - 1.35 (m, 1H), 1.09 (t,J=10.9 Hz, 1H), 0.85 - 0.79 (m, 10H).MS (ESI) m / z 452.2 [M+H]+.

[0225] Synthesis of methyl 5-(tert-butyl)-3-hvdroxypiperidine-3-carboxylate, cis racemicBenzyl 5-(tert-butyl)-3-oxo-3,6-dihydropyridine-l(2H)-carboxy lateA stirred mixture of benzyl 3-oxoazetidine-l -carboxylate (3 g, 14.6 mmol), 3,3- dimethylbut-l-yne (5.4 mL, 43.8 mmol), bis(triphenylphosphine)nickel(II) dichloride(1.43 g, 2.19 mmol) and zinc powder (573 mg, 8.76 mmol) in anhydrous MeCN (48 mL) was heated in a glass bomb vessel under a nitrogen atmosphere to 85°C for 7 hours. The cooled reaction mixture was filtered through a pad of eelite, rinsed with MeCN (100 mL) and evaporated. The residue was purified by chromatography on silica gel eluting with cyclohexane / EtOAc 0 to 30% to give benzyl 5-(tert-butyl)-3-oxo-3,6-dihydropyridine- l(2H)-carboxylate (2.24 g)*H NMR (400 MHz, DMSO): 8 7.41 - 7.32 (m, 5H), 5.96 (s, 1H), 5.14 (s, 2H), 4.32 (s,2H), 4.05 (s, 2H), 1.14 (s, 9H).Benzyl 3-(tert-butyl)-5-hydroxypiperidine-l-carboxylateTo a solution of benzyl 5-(tert-butyl)-3-oxo-3,6-dihydropyridine-l(2H)-carboxylate(3.27 g, 11.37 mmol) in EtOAc (50 mL) was added Pt20 (258 mg, 1.14 mmol) and the reaction mixture was hydrogenated at atmospheric pressure at room temperature overnight. The reaction mixture was filtered through a pad of celite, rinsed with EtOAc(100 mL), and the filtrate evaporated to afford benzyl 3-(tert-butyl)-5-hydroxypiperidine-1 -carboxylate (3.33 g). MS (ESI) m / z 292.3 [M+H]+Benzyl 3-(tert-butyl)-5-oxopiperidine-l-carboxylateTo a solution of benzyl 3-(tert-butyl)-5-hydroxypiperidine-l-carboxylate (3.33 g, 11.43 mmol) in anhydrous DCM (100 mL) was added Dess-Matin periodinane (14.54 g, 34.28 mmol) at room temperature and the reaction mixture was stirred at room temperature for20 hours. The reaction mixture was partitioned between 1 N NaOH (50 mL) and DCM(150 mL) and the layers separated. The aqueous phase was extracted with DCM (3 x 50 mL) and the combined organic extracts washed with brine. The organic phase was dried(MgSC>4), filtered and evaporated to afford benzyl 3 -(tert-butyl)-5 -oxopiperidine- 1- carboxylate (3.26 g).:H NMR (400 MHz, DMSO): 5 7.41 - 7.31 (m, 5H), 5.13 (s, 2H),4.06 (d, 1=17.4 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.20 - 3.09 (m, 1H), 2.45 - 2.28 (m, 2H),1.84 - 1.74 (m, 1H), 0.88 (s, 9H).Benzyl 5-(tert-butyI)-3-cyano-3-hydroxypiperidine-l-carboxylate, cis racemicTo a solution of benzyl 3-(tert-butyl)-5-oxopiperidine-l-carboxylate (5.45 g, 18.83 mmol) in THF (180 mL) at 0°C was added a solution of KCN (1.84 g, 28.25 mmol) in water (22 mL) followed by a solution of sodium bisulfite (3.0 g, 28.25 mmol) in water(23 mL) and the mixture was stirred at 0°C for 6 hours. DCM (200 mL) and saturatedNaHCOg (150 mL) were added, and the layers separated. The aqueous layer was extracted with DCM (2 x 50 mL), and the combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel eluting withcyclohexane / EtOAc 0 to 50% to give benzyl 5-(tert-butyl)-3-cyano-3- hydroxypiperidine- 1 -carboxylate (3.4 g). *H NMR (400 MHz, DMSO): 5 7.46 - 7.35 (m,5H), 7.07 (s, 1H), 5.15 - 5.14 (m, 2H), 4.44 - 4.34 (m, 1H), 4.22 - 4.15 (m, 1H), 2.89 -2.85 (m, 1H), 2.78 - 2.63 (m, 1H), 2.23 (d, 1=9.3 Hz, 1H), 1.52 - 1.47 (m, 1H), 0.96 -0.92 (m, 10H).5-(tert-Butyl)-3-hydroxypiperidine-3-carboxylic acid hydrochloride, cis racemicA mixture of cis racemic benzyl 5-(tert-butyl)-3 -cyano-3 -hydroxypiperidine- 1- carboxylate (3.15 g, 9.96 mmol) and cone. HC1 (30 mL, 349 mmol) was heated to 90°C and stirred for 2 hours. The mixture was evaporated and triturated three times with diethyl ether (20 mL) to afford the desired product (1.98 g). *H NMR (400 MHz, DMSO): 57.45- 7.35 (m, 3H), 5.27 - 5.13 (m, 2H), 3.24 - 3.13 (m, 1H), 2.50 - 2.37 (m, 1H), 1.92 - 1.82(m, 1H), 1.31 - 1.21 (m, 2H), 0.96 - 0.88 (m, 9H).Methyl 5-(tert-butyl)-3-hydroxypiperidine-3-carboxylate, cis racemicTo a solution of cis racemic 5-(tert-butyl)-3-hydroxypiperidine-3-carboxylic acid hydrochloride (1.98 g, 8.32 mmol) in dry MeOH (125 mL) was added sulfuric acid (8.5 mL, 159 mmol) and the mixture was heated to 50°C and stirred for 6 hours. After cooling to room temperature, the MeOH was evaporated, and the mixture was partitioned betweenDCM (300 mL) and a saturated NazCOg solution (150 mL). The layers were separated, and the aqueous phase was extracted with DCM (3 x 50 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was loaded in MeOH onto an SCX-2 cartridge, rinsed with MeOH and eluted with 10% EtgN in MeOH to afford the desired product (545 mg). *H NMR (400 MHz, DMSO): 5 5.59 (br s, 1H), 3.68 (s,3H), 3.33 - 3.27 (m, 1H), 3.13 (d, J=17.0 Hz, 1H), 2.92 - 2.89 (m, 1H), 2.32 - 2.26 (m,1H), 2.22 (d, 1=11.6 Hz, 1H), 2.11 (t, J=1L5 Hz, 1H), 1.25 - 1.16 (m, 1H), 1.14 - 1.06 (m,1H), 0.88 (s, 9H).

[0226] Synthesis of (3S.5S)-5-(tert-butyl)-3-provoxvDiperidine-3-carboxvlic acid hydrochloride1 -Benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxyIateN-(benzyloxycarbonyloxy)succinimide (270.65 g, 1090 mmol) was added in one portion to a stirred solution of (2R,3R)-2,3-bis(4-methylbenzoyloxy)butanedioic acid methyl(3R,5S)-5-tert-butylpiperidine-3-carboxylate (530 g, 905 mmol) and triethylamine (315 mL, 2260 mmol) in DCM (2750 mL). The solution was stirred at room temperature for48 hours. The reaction mixture was diluted with DCM, washed with saturated NaHCOs, water and brine, dried over NazSO4 and concentrated in vacuo. The residue was purified by silica gel pad eluting with 10-15% EtOAc in cyclohexane to afford 1 -benzyl 3 -methyl(3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxylate (288.8 g).’H NMR (400 MHz, CDCb): 5 7.40 - 7.28 (m, 5H), 5.13 (q, J=11.3 Hz, 2H), 4.60 (qd,J=1.8, 13.5 Hz, 1H), 4.34 - 4.24 (m, 1H), 3.69 - 3.53 (m, 1H), 2.90 (dd, 1=4.0, 13.2 Hz,1H), 2.68 (s, 1H), 2.49 - 2.42 (m, 1H), 2.28 (d, 1=12.9 Hz, 1H), 1.35 (dt, J=5.2, 12.6 Hz,1H), 0.91 (s, 9H). MS (ESI) m / z 334.5 [M+H]+.1 -Benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-hydroxypiperidine-l,3-dicarboxyIate1 M potassium bis(trimethylsilyl)amide solution in THE (35 mL, 35.0 mmol) was diluted with THE (220 mL) and cooled to -78°C under an inert atmosphere. To this solution wasadded a solution of 1 -benzyl 3 -methyl (3R,5S)-5-(tert-butyl)piperidine- 1,3 -dicarboxy late(8.17 g, 24.5 mmol) in THE (180 mL) over 35 minutes and the reaction mixture was stirred at -78°C for 75 minutes. A solution of 2-(benzenesulfonyl)-3-phenyl-oxaziridine(9.156 g, 35.0 mmol) in THE (150 mL) was added dropwise at -78°C and the reaction mixture was stirred at -78°C for 70 minutes. The reaction mixture was quenched with a saturated ammonium chloride solution and allowed to warm to room temperature. The reaction was diluted with EtOAc and water and the two phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were filtered through a hydrophobic frit and the solvent was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0 - 40 % EtOAc in cyclohexane, to afford 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-hydroxypiperidine-1,3 -dicarboxylate (7.45 g).*H NMR (400 MHz, DMSO): 5 7.45 - 7.35 (m, 5H), 6.01 (s, 1H), 5.11 (s, 2H), 4.47 (d,1=13.1 Hz, 1H), 4.14 - 4.05 (m, 1H), 3.58 (s, 3H), 2.74 - 2.64 (m, 1H), 2.51 - 2.45 (m,1H), 2.30 (d, 1=11.1 Hz, 1H), 1.28 - 1.21 (m, 2H), 0.92 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-hydroxypiperidine-3-carboxylateTo a solution of 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-hydroxypiperidine-l,3- dicarboxylate (6.62 g, 18.9 mmol) in MeOH (150.00 mL) was added palladium on carbon(10%, 2.016 g, 1.89 mmol) and ammonium formate (4.779 g, 75.8 mmol). The reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through a pad of Celite, which was then washed with MeOH. The solvent was removed in vacuo to give a white solid. The residue was loaded onto an SCX-2 cartridge (70 g), which was washed with MeOH (200 mL).The compound was released using 1 M triethylamine in MeOH (200 mL) to give methyl(3S,5S)-5-(tert-butyl)-3-hydroxypiperidine-3-carboxylate (3.29 g).XHNMR (400 MHz, CDClg): 5 5.57 (s, 1H), 3.64 (s, 3H), 3.28 - 3.21 (m, 1H), 2.88 - 2.84(m, 1H), 2.25 (dq, J=2.3, 5.5 Hz, 1H), 2.17 (d, J=11.9 Hz, 1H), 2.06 (dd, J=11.6, 11.6 Hz,1H), 1.21 - 1.11 (m, 1H), 1.05 (dd, J=12.4, 12.4 Hz, 1H), 0.84 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-hydroxy-l-tritylpiperidine-3-carboxylateTriethylamine (1.3 mL, 9.29 mmol) was added to a stirred solution of methyl (3S,5S)-5- tert-butyl-3-hydroxy-piperidine-3 -carboxylate (1.00 g, 4.64 mmol) and trityl chloride(1.29 g, 4.64 mmol) in anhydrous DCM (15.00 mL) was added at room temperature. The resultant solution was stirred at room temperature for 20 hours. The reaction was quenched by addition of water (20 mL), stirred for 15 minutes and the layers separated.The aqueous phase was extracted with DCM (30 mL), the organics combined, passed through a phase separation cartridge and the solvent evaporated. The residue was purified by chromatography on silica gel (80 g) eluting with 0-20% EtOAc in cyclohexane to afford methyl (3S,5S)-5-(tert-butyl)-3-hydroxy-l-tritylpiperidine-3-carboxylate (1.67 g).TH NMR (400 MHz, CDCI3): 5 7.46- 7.32 (m, 6H), 7.29 - 7.20 (m, 6H), 7.18 - 7.10 (m,3H), 3.98 (s, 3H), 3.37 (d, J=10.9 Hz, 1H), 3.21 - 3.16 (m, 1H), 2.62 (s, 1H), 2.29 - 2.20(m, 2H), 1.53 (d, 1=10.9 Hz, 1H), 1.04 - 0.88 (m, 2H), 0.78 (s, 9H).Methyl (3S,5S)-3-(allyIoxy)-5-(tert-butyI)-l-tritylpiperidine-3-carboxylateSodium hydride (60%, 0.247 g, 6.18 mmol) was added portion-wise to a stirred solution of methyl (3S,5S)-5-(tert-butyl)-3-hydroxy-l-tritylpiperidine-3-carboxylate (1.415 g,3.09 mmol) and allyl bromide (1.1 mL, 12.4 mmol) in anhydrous DMF (25.00 mL) at room temperature under nitrogen. The reaction was stirred at room temperature for 2.5 hours, then diluted with EtOAc (500 mL). The mixture was washed with water (2 x 300 mL), 4%LiCl (100 mL), brine (100 mL) and the organics were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with0-20% EtOAc in cyclohexane to afford methyl (3S,5S)-3-(allyloxy)-5-(tert-butyl)-l-tritylpiperidine-3-carboxylate (1.4 g). 'H NMR (400 MHz, CDCI3): 37.43 - 7.32 (m, 6H),7.28 - 7.08 (m, 9H), 5.86 - 5.75 (m, 1H), 5.20 (d, >16.9 Hz, 1H), 5.11 (d, >10.4 Hz,1H), 3.99 (dd, >5.6, 11.4 Hz, 1H), 3.93 (s, 3H), 3.68 (dd, >5.7, 11.2 Hz, 1H), 3.58 (d,>10.9 Hz, 1H), 3.17 (d, >10.9 Hz, 1H), 2.57 (d, >11.4 Hz, 1H), 2.11 - 2.03 (m, 1H),1.61 (d, >10.9 Hz, 1H), 0.96 - 0.83 (m, 2H), 0.79 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-propoxy-l-tritylpiperidine-3-carboxylateAmmonium formate (1.064 g, 16.9 mmol) was added to a stirred mixture of methyl(3S,5S)-3-(allyloxy)-5-(tert-butyl)-l-tritylpiperidine-3-carboxylate (1.400 g, 2.81 mmol) and palladium (10%, 599 mg, 0.563 mmol) in MeOH (80.00 mL) and the mixture was heated at 65°C for 3.5 hours and then cooled. The mixture was filtered through celite, the filter pad washed with MeOH (50 mL) and the combined filtrate and washings evaporated to afford methyl (3S,5S)-5-(tert-butyl)-3-propoxy-l-tritylpiperidine-3-carboxylate (1.34 g). *H NMR (400 MHz, CDCI3): 8 7.44 - 77.32 (m, 6H), 7.30 - 7.16 (m, 6H), 7.13 - 7.11(m, 3H), 3.92 (s, 3H), 3.79 - 3.71 (m, 1H), 3.59 - 3.35 (m, 3H), 3.30 - 3.13 (m, 2H), 3.08- 3.01 (m, 1H), 2.58 - 2.49 (m, 1H), 2.11 - 1.99 (m, 1H), 1.54 - 1.40 (m, 2H), 0.93 - 0.81(m, 3H), 0.79 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-propoxypiperidine-3-carboxy lateTrifluoroacetic acid (7.7 mL, 0.101 mol) was added dropwise over 2 minutes to a stirred, room temperature solution of methyl (3S,5S)-5-(tert-butyl)-3-propoxy-l-tritylpiperidine-3-carboxylate (1.340 g, 2.68 mmol) and water (0.40 mL) in DCM (60.00 mL) and the resultant bright yellow solution was stirred at room temperature for 30 minutes. The reaction was evaporated and the residue applied onto a SCX-2 cartridge as a solution in1:1 MeOH:DCM (50 mL). The cartridge was washed with 1:1 MeOH:DCM (200 mL) and the product eluted with 10% EtsN in MeOH (250 mL). The basic eluent was evaporated to yield methyl (3S,5S)-5-(tert-butyl)-3-propoxypiperidine-3-carboxylate(660 mg). ‘H NMR (400 MHz, CDCI3): 8 3.78 (s, 3H), 3.61 (d, 1=12.4 Hz, 1H), 3.46 -3.32 (m, 2H), 3.30 - 3.18 (m, 2H), 3.09 - 3.02 (m, 1H), 2.41 (d, J=12.6 Hz, 1H), 2.24 (dd,1=12.0, 12.0 Hz, 2H), 1.60 - 1.50 (m, 1H), 1.29 (dd, 1=12.6, 12.6 Hz, 1H), 1.18 - 0.97 (m,1H), 0.91 - 0.85 (m, 12H).(3S,5S)-5-(tert-Butyl)-3-propoxypiperidine-3-carboxylic acid hydrochlorideMethyl (3S,5S)-5-(tert-butyl)-3-propoxypiperidine-3-carboxylate (280 mg, 1.09 mmol) was dissolved in 12 M HC1 (1.8 mL, 21.8 mmol) and heated to 60°C. After 6 hours the reaction was concentrated to afford (3S,5S)-5-(tert-butyl)-3-propoxypiperidine-3- carboxylic acid hydrochloride (304 mg)1HNMR(400MHz, DMSO): 5 10.16 - 10.13 (m, 1H), 7.85 - 7.81 (m, 1H), 3.74 (d, 3=12.6Hz, 1H), 3.39 - 3.31 (m, 2H), 3.18 (d, 1=11.4 Hz, 1H), 2.81 (t, 1=11.4 Hz, 1H), 2.70 (q,J=11.2 Hz, 1H), 2.33 (d, J=12.6 Hz, 1H), 1.56 - 1.36 (m, 4H), 0,93 - 0.89 (m, 12H).

[0227] Synthesis of methyl (3S,5S)-5-(tert-butvl)-3-f2-methoxyethoxv)piperidme-3-carboxylateMethyl (3S,5S)-5-(tert-butyI)-3-(2-methoxyethoxy)-l-tritylpiperidine-3-carboxylateTo a mixture of methyl (3S,5S)-5-(tert-butyl)-3-hydroxy-l-tritylpiperidine-3-carboxylate(625 mg, 1.37 mmol) in DMF (7.0 mL) were added at room temperature 2-bromoethyl methyl ether (0.64 mL, 6.83 mmol) and sodium hydride (60%, 82 mg, 2.05 mmol). The reaction mixture was stirred at room temperature for 2 hours and additional 2-bromoethyl methyl ether (0.64 mL, 6.83 mmol) and sodium hydride (60%, 82 mg, 2.05 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour then water (50 mL) was carefully added. EtOAc (50 mL) was added, the layers separated, and theaqueous phase extracted with EtOAc (2 x 50 mL). The combined organic phases were dried (MgSO*), filtered and concentrated. The residue was purified by silica gel chromatography eluting with cyclohexane / EtOAc to afford methyl (3S,5S)-5-(tertbutyl)-3-(2-methoxy ethoxy)- l-tritylpiperidine-3 -carboxylate (282 mg). *H NMR (400MHz, CDCh): 3 7.41 - 7.33 (m, 6H), 7.25 - 7.17 (m, 6H), 7.15 - 7.09 (m, 3H), 3.93 (s,3H), 3.66 - 3.57 (m, 2H), 3.43 (t, 1=4.7 Hz, 2H), 3.31 (s, 3H), 3.30 - 3.24 (m, 1H), 3.20 -3.14 (m, 1H), 2.58 - 2.53 (m, 1H), 2.11 - 2.01 (m, 1H), 1.64 (d, J=ll.l Hz, 1H), 0.97 -0.84 (m, 2H), 0.78 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxyethoxy)piperidine-3-carboxy lateTrifluoroacetic acid (1.6 mL, 20.5 mmol) was added to a solution of methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxyethoxy)-l-tritylpiperidine-3-carboxylate (282 mg, 0.547 mmol) in DCM (3.0 mL) / water (0.10 mL). The mixture was stirred at room temperature for 30 minutes and concentrated to dryness. The residue was dissolved in DCM / MeOH 1:1 (20 mL) and loaded onto a 5 g SCX-2 cartridge. The cartridge was rinsed with DCM / MeOH1:1 (50 mL) and then eluted with 20% 7 M NH3 in MeOH (50 mL). The eluted basic fraction was concentrated to dryness and afforded methyl (3S,5S)-5-(tert-butyl)-3-(2- methoxyethoxy)piperidine-3-carboxylate (100 mg). *H NMR (400 MHz, CDCI3): 3 3.79(s, 3H), 3.63 - 3.52 (m, 2H), 3.52 - 3.48 (m, 3H), 3.37 (s, 3H), 3.07 - 3.04 (m, 1H), 2.50 -2.42 (m, 2H), 2.27 (dd, 1=11.8, 11.8 Hz, 1H), 1.33 (dd, 1=12.6, 12.6 Hz, 1H), 1.20 - 1.11(m, 1H), 0.86 (s, 9H).

[0228] 1-Benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-oxoethyl)piperidine-l,3-dicarboxy lateTo a stirred, room temperature solution of 1-benzyl 3-methyl (3R,5S)-3-allyl-5-(tert- butyl)piperidine- 1,3 -dicarboxylate (3.0 g, 8.03 mmol) in THF (44.0 mL) and water (8.0 mL) was added osmium tetroxide 4% in water (4.0%, 5.0 mL, 0.803 mmol) followed by sodium periodate (4.295 g, 20.1 mmol). The resultant mixture was stirred for 4 hours, during which time a flocculent cream precipitate formed. After 4 hours the reaction was quenched with saturated Na2S20a (100 mL) and the mixture extracted with EtOAc (3 x100 mL). The combined organic extracts were dried (MgSCU), filtered and the solvent evaporated to afford 1 -benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-oxoethyl)piperidine-1,3 -dicarboxylate (2.9 g). NMR (400 MHz, CDC13): 5 9.70 (s, 1H), 7.41 - 7.30 (m,5H), 5.17 - 5.12 (m, 2H), 4.66 (d, J=13.4 Hz, 1H), 4.37 - 4.26 (m, 1H), 3.66 - 3.56 (m,3H), 2.60 (d, >13.9 Hz, 3H), 2.41 - 2.31 (m, 2H), 1.76 - 1.62 (m, 1H), 1.09 (t, >12.9 Hz,1H), 0.90 (s, 9H).1-BenzyI 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-hydroxyethyl)piperidine-l,3- dicarboxylateTo a solution 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-oxoethyl)piperidine-l,3- dicarboxylate (1.20 g, 3.20 mmol) in MeOH (20 mL) was added NaBHt (133 mg, 3.52 mmol) at room temperature, and the mixture was stirred for 30 minutes at roomtemperature. The mixture was quenched with saturated NH4CI, diluted with water, and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried (MgS04), filtered and concentrated to give 1-benzyl 3-methyl (3S,5S)-5-(tertbutyl)-3-(2-hydroxyethyl)piperidine- 1,3 -dicarboxylate (1.17 g). ’H NMR (400 MHz,CDCI3): 5 7.42 - 7.27 (m, 5H), 5.17 - 5.11 (m, 2H), 4.73 - 4.69 (m, 1H), 4.33 - 4.25 (m,2H), 3.69 (dd, 1=6.4, 6.4 Hz, 2H), 3.62 - 3.53 (m, 3H), 2.48 - 2.36 (m, 2H), 1.81 - 1.74(m, 2H), 1.38 - 1.30 (m, 1H), 1.00 (t, J=11.5 Hz, 1H), 0.90 (s, 9H).1-BenzyI 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxyethyl)piperidine-13- dicarboxylateTo a solution of 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-hydroxyethyl)piperidine-1,3-dicarboxylate (1.17 g, 3.10 mmol) in DCM (15.0 mL) was added N,N,N',N'- tetramethyl- 1,8-naphthalenediamine (6.64 g, 31.0 mmol) and trimethyloxonium tetrafluoroborate (1.38 g, 9.30 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with IN HC1 and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with 1 N HC1 then brine, dried (MgSC>4), filtered and concentrated to afford 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxyethyl)piperidine- 1,3-dicarboxylate (1.15 g).NMR (400 MHz, CDCh): 5 7.38 - 7.28 (m, 5H), 5.18 - 5.09 (m, 2H), 4.74 - 4.64 (m,1H), 4.32 - 4.23 (m, 2H), 3.61 - 3.55 (m, 3H), 3.42 - 3.29 (m, 2H), 3.28 - 3.22 (m, 3H),2.80 - 2.67 (m, 1H), 2.53 - 2.33 (m, 3H), 1.38 - 1.29 (m, 1H), 0.99 (t, J=12.8 Hz, 1H),0.91 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxyethyl)piperidine-3-carboxylateTo a solution of 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxyethyl)piperidine-1,3-dicarboxylate (1.15 g, 2.94 mmol) in MeOH (15.0 mL) was added ammonium formate (1.11 g, 17.6 mmol) followed by palladium on charcoal (10%, 625 mg, 0.587mmol). The reaction mixture was stirred at 65 °C for 2.5 hours. The reaction mixture was cooled to room temperature, filtered through a bed of celite and rinsed with DCM. The filtrate was concentrated to dryness to afford methyl (3S,5S)-5-(tert-butyl)-3-(2- methoxyethyl)piperidine-3-carboxylate (598 mg). *H NMR (400 MHz, CDCh): 5 4.32 -4.27 (m, 1H), 3.73 (s, 3H), 3.61 - 3.57 (m, 1H), 3.42 - 3.40 (m, 1H), 3.37 - 3.32 (m, 2H),3.26 (s, 3H), 3.23 - 3.17 (m, 1H), 3.15 - 3.10 (m, 1H), 2.41 - 2.24 (m, 3H), 1.32 - 1.25 (m,1H), 1.15 - 1.09 (m, 1H), 0.86 (s, 9H).Lithium (3S,5S)-5-(tert-butyl)-3-(2-methoxyethyl)piperidine-3-carboxylateA mixture of methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxyethyl)piperidine-3-carboxylate(257 mg, 1.0 mmol) and lithium hydroxide monohydrate (63 mg, 1.5 mmol, 1.5 eq) inMeOH (3.0 mL) and water (1.0 mL) was stirred at 60°C for 5 hours. The mixture was concentrated to dryness and dried in a vacuum oven overnight to give lithium (3S,5S)-5-(tert-butyl)-3-(2-methoxyethyl)piperidine-3 -carboxylate (249 mg). MS (ESI) m / z 244.3[M+H]+.

[0229] Synthesis of f3R,5S)-5-(tert-butyl)-3-propvlDiperidine-3-carboxylic acid hydrochloride1-Benzyl 3-methyl (3R,5S)-5-(tert-Jbutyl)piperidine-l,3-dicarboxyIateIn a 3 L round bottom flask, N-(benzyloxycarbonyloxy)succinimide (270.65 g, 1090mmol) was added in one portion to a stirred solution of (2R,3R)-2,3-bis(4- methylbenzoyloxy)butanedioic acid methyl (3R,5S)-5-tert-butylpiperidine-3-carboxylate(530 g, 905 mmol) and triethylamine (315 mL, 2260 mmol) in DCM (2750 mL). The solution was stirred at room temperature for 48 hours. The reaction mixture was diluted with DCM, washed with saturated NaHCOg, water and brine, dried over NazSO4 and concentrated in vacuo. The residue was purified by silica gel pad (1.4 kg silica) eluting with 10-15% EtOAc in cyclohexane to afford 1-benzyl 3-methyl (3R,5S)-5-(tert- butyl)piperidine-l,3-dicarboxylate (288.83 g). MS (ESI) m / z 334.5 [M+H]+.1-Benzyl 3-methyl (3R,5S)-3-allyl-5-(tert-butyl)piperidine-l,3-dicarboxylateThe reaction vessel was charged with 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-1,3 -dicarboxylate (173.0 g, 519 mmol) and 2-methyltetrahydrofuran (2.0 L). This solution was stirred whilst being cooled in a cardice-acetone bath contained in a large washing up bowl. At -73 °C 1 M potassium bis(trimethylsilyl)amide (700 mL, 700 mmol) in THE was added slowly. After completion of addition (~1 hour) the reaction mixture was stirred at -70°C for 1 hour. To this cooled mixture was slowly added a solution of allyl bromide (67 mL, 778 mmol). After completion of addition stirring was continued at-70°C for 2.5 hours and the reaction mixture was allowed to wann to room temperature slowly. Stirring was continued at room temperature overnight. Saturated NH4CI (600 mL) was then added slowly. On complete addition (10 minutes) the mixture was stirred for 20 minutes, diluted with water (300 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2x300 mL) and the pooled organics dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel(EtOAc / cyclohexane) affording 1 -benzyl 3-methyl (3R,5S)-3-allyl-5-(tert- butyl)piperidine- 1,3 -dicarboxy late (159.4 g). 'H NMR (400 MHz, CDCI3): 8 7.42 - 7.28(m, 5H), 5.75 - 5.62 (m, 1H), 5.16 - 5.01 (m, 4H), 4.65 (d, J=11.6 Hz, 1H), 4.29 - 4.28(m, 1H), 3.63 - 3.51 (m, 3H), 2.47 (d, J=12.6 Hz, 1H), 2.37 - 2.19 (m, 4H), 1.40 - 1.29(m, 1H), 0.99 (t, 1=14.5 Hz, 1H), 0.90 (s, 9H).Methyl (3R,5S)-5-(tert-butyl)-3-propylpiperidine-3-carboxylateA stirred solution of 1-benzyl 3-methyl (3R,5S)-3-allyl-5-(tert-butyl)piperidine-l,3- dicarboxylate (80.7 g, 216 mmol) in IMS (Industrial Methylated Spirits) (800 mL) was hydrogenated at room temperature and atmospheric pressure in the presence of palladium on charcoal (10%, 5.00 g, 4.70 mmol) for 108 h. The reaction mixture was filtered, and the filtrate evaporated to afford methyl (3R,5S)-5-(tert-butyl)-3-propylpiperidine-3- carboxylate (51.14 g).*H NMR (400 MHz, CDC13): 5 3.71 (s, 3H), 3.47 (dd, J=2.0, 12.9 Hz, 1H), 3.10 - 3.04(m, 1H), 2.30 - 2.19 (m, 3H), 1.49 - 1.40 (m, 1H), 1.39 - 1.30 (m, 1H), 1.29 - 1.13 (m,2H), 1.11 - 1.05 (m, 1H), 0.99 (t, 1=12.4 Hz, 1H), 0.86 (t, 1=7.1 Hz, 3H), 0.85 (s, 9H).(3R,5S)-5-(tert-Butyl)-3-propylpiperidine-3-carboxylic acid hydrochlorideA mixture of methyl (3R, 5 S)-5-(tert-butyl)-3-propylpiperidine-3 -carboxy late (51.1 g,212 mmol) and 11.5 M hydrogen chloride (800 mL, 9.20 mol) was heated at 100°C for48 h. In a separate vessel a mixture of methyl (3R,5S)-5-(tert-butyl)-3-propylpiperidine-3-carboxylate (45.4 g, 188 mmol) and 11.5 M hydrogen chloride (800 mL, 9.20 mol) was heated at 100°C for 48 h. Both reaction mixtures were combined and evaporated to afford(3R,5S)-5-(tert-butyl)-3-propylpiperidine-3-carboxylic acid hydrochloride (103.7 g).!HNMR (400 MHz, DMSO): 5 13.12 - 13.07 (m, 1H), 10.16 (d, 1=9.7 Hz, 1H), 7.66 (d,1=9.7 Hz, 1H), 3.42 (d, 1=12.4 Hz, 1H), 3.14 (d, J=11.3 Hz, 1H), 2.67 (dd, J=11.9, 11.9Hz, 1H), 2.57 (t, J=10.7 Hz, 1H), 2.12 (d, 1=11.4 Hz, 1H), 1.58 - 1.13 (m, 6H), 0.86 (m,12H).

[0230] Synthesis of (3S.5S)-5-(tert-butvl)-3-ethoxvpiperidine-3-carboxylic acid hydrochlorideMethyl (3S,5S)-5-(tert-butyl)-3-hydroxy-l-tritylpiperidine-3-carboxylateMethyl (3 S,5S)-5-(tert-butyl)-3-hydroxypiperidine-3 -carboxylate (2.50 g, 11.6 mmol) and trityl chloride (3.88 g, 13.9 mmol) were dissolved in DCM (72.6 mL) and triethylamine (3.2 mL, 23.2 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (20 mL) and immediately passed through a phase separator before concentrating on to silica gel and purifying by column chromatography (80 g, 0-20% EtOAc in cyclohexane) to give methyl (3S,5S)-5-(tert-butyl)-3-hydroxy-l-tritylpiperidine-3-carboxylate (4.75 g)!H NMR (400 MHz, CDCb): 5 7.41- 7,34 (m, 6H), 7.29 - 7.20 (m, 6H), 7.18 - 7.11 (m,3H), 3.97 (s, 3H), 3.37 (d, J=ll.l Hz, 1H), 3.17 (d, 1=11.4 Hz, 1H), 2.60 (s, 1H), 2.28 -2.19 (m, 2H), 1.04 - 0.88 (m, 2H), 0.78 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-ethoxy-l-tritylpiperidine-3-carboxylateMethyl (3S,5S)-5-(tert-butyl)-3-hydroxy-l-tritylpiperidine-3-carboxylate (4.20 g, 9.18 mmol) was dissolved in DMF (30.0 mL) and cooled to 0°C. lodoethane (3.0 mL, 36.7 mmol) was then added followed by slow addition of sodium hydride (60%, 1.47 g, 36.7 mmol). The reaction mixture was stirred at 0°C for 30 minutes before allowing to warm to room temperature and stir for further 30 minutes. The reaction mixture was diluted with ether (20 mL) and water (20 ml), and the organic phase separated. The aqueous phasewas further extracted with ether (2 x 20 mL) and the organic phases were combined before washing with water (3 x 15 mL). The organic phase was then dried (MgSC>4), filtered and concentrated under reduced pressure to give methyl (3S,5S)-5-(tert-butyl)-3-ethoxy-l- tritylpiperidine-3 -carboxylate (3.80 g). *H NMR (400 MHz, CDCh): 5 7.48 - 7.30 (m,6H), 7.30 - 7.00 (m, 9H), 3.93 (s, 3H), 3.60 - 3.49 (m, 2R), 3.19 - 3.13 (m, 2H), 2.56 (d,J=11.4 Hz, 1H), 2.12 - 2.02 (m, 1H), 1.54 (d, 1=17.1 Hz, 1H), 1.09 (t, 1=6.9 Hz, 2H), 0.97- 0.81 (m, 3H), 0.78 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-ethoxypiperidine-3-carboxylateMethyl (3S,5S)-5-(tert-butyl)-3-ethoxy-l-tritylpiperidine-3-carboxylate (3.80 g, 4.69 mmol) was dissolved in DCM (40.00 mL) and water (0.25 mL). Trifluoroacetic acid (14 mL, 0.188 mol) was added slowly and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture poured on to an SCX-2 cartridge (2 x20 g) and washed with DCM:MeOH (1:1) (250 mL) before the product was eluted with1.4 M NHs in MeOH (500 mL). The eluent was concentrated under reduced pressure to give methyl (3S,5S)-5-(tert-butyl)-3-ethoxypiperidine-3-carboxylate (1.2 g).lH NMR(400 MHz, CDCh): 5 3.78 (s, 3H), 3.61 (d, J=12.4 Hz, 1H), 3.52 - 3.42 (m, 2H), 3.42 -3.32 (m, 1H), 3.04 (d, J=12.4 Hz, 1H), 2.42 (d, 1=12.6 Hz, 2H), 2.24 (t, 1=12.1 Hz, 1H),1.34 - 1.24 (m, 1H), 1.16 (t, 3=6.9 Hz, 3H), 0.86 (s, 9H).(3 S,5S)-5-(tert-ButyI)-3-ethoxypiperidine-3-carboxylic acid hydrochlorideMethyl (3S,5S)-5-(tert-butyl)-3-ethoxypiperidine-3-carboxylate (526 mg, 2.16 mmol) was dissolved in 12 M hydrogen chloride (9.0 mL, 0.108 mol) and heated to 60°C for 6 hours. The reaction was concentrated to afford (3S,5S)-5-(tert-butyl)-3-ethoxypiperidine-3-carboxylic acid hydrochloride (550 mg). *H NMR (400 MHz, DMSO): 3 13.81 (s, 1H),10.26 (d, 1=9.8 Hz, 1H), 7.83 (d, 1=9.6 Hz, 1H), 3.73 (d, 1=11.8 Hz, 1H), 3.60 - 3.41 (m,2H), 3.18 (d, J=13.0 Hz, 1H), 2.81 (t, 1=11.8 Hz, 1H), 2.69 (q, 1=11.8 Hz, 1H), 2.33 (d,J=10.6 Hz, 1H), 1.51 - 1.33 (m, 2H), 1.14 (t, 1=6.8 Hz, 3H), 0.91 (s, 9H).

[0231] Synthesis of methyl (3R, 5S)-5-(tert-butyl)-3-(methoxymethyl)piperidine-3-carboxylate1-Benzyl 3-methyl (3R,5S)-5-(tert-butyI)-3-(methoxymethyl)piperidine-13- dicarboxylateA solution of 1 M potassium bis(trimethylsilyl)anride (3.0 mL, 3.00 mmol) in Me-THF(10 mL) was cooled to -78°C under Nz, then 1 -benzyl 3-methyl (3R,5S)-5-(tert- butyl)piperidine- 1,3 -dicarboxy late (667 mg, 2.00 mmol) was added in solution in Me-THE (5.0 mL). The mixture was stirred at -78°C for 50 min, then chloromethyl methyl ether (0.30 mL, 4.00 mmol) was added. The mixture was stirred and let warm to room temperature overnight. The mixture was quenched with a saturated aqueous NH4CI solution, extracted with EtOAc twice. The combined organic phases were dried onMgSO4, filtered and concentrated. The crude was purified by silica gel chromatography eluting with 0 to 30% EtOAc in cyclohexane to afford 1 -benzyl 3-methyl (3R,5S)-5-(tert- butyl)-3-(methoxymethyl)piperidine- 1,3 -dicarboxy late (501 mg). MS (ESI) m / z 378.4[M+H]+.Methyl (3R,5S)-5-(tert-butyl)-3-(methoxymethyl)piperidine-3-carboxylateTo a solution of 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)-3-(methoxymethyl)piperidine-1,3 -dicarboxylate (501 mg, 1.33 mmol) in ethanol (8.0 mL) were added ammonium formate (335 mg, 5.31 mmol) and palladium on carbon (10%, 141 mg, 0.133 mmol). The reaction mixture was stirred at 65 °C for 2 hours. The reaction mixture was allowed tocool to room temperature. The reaction mixture was filtered through a pad of celite, which was then washed with DCM. The filtrate was concentrated to dryness to afford methyl(3R,5S)-5-(tert-butyl)-3-(methoxymethyl)piperidine-3-carboxylate (300 mg).'H NMR (400 MHz, CDCI3): 8 3.77 (s, 3H), 3.62 (d, J=11.6 Hz, 1H), 3.45 (d, J=9.1 Hz,1H), 3.29 (s, 3H), 3.25 - 3.19 (m, 1H), 2.48 - 2.42 (m, 1H), 2.38 - 2.23 (m, 2H), 2.18 -2.11 (m, 1H), 1.19 - 1.08 (m, 2H), 0.86 (s, 9H).

[0232] Synthesis of (3S.5S)'-5-(tert-butvl)'-3-(2-fluorovrovvl)viveridine-3-carboxvlic acidDibenzyl (3S,5S)-5-(tert-butyl)-3-(2-fluoroallyl)piperidine-13-dicarboxylateTo a mixture of (dibenzyl (3R,5S)-5-tert-butylpiperidine-l,3-dicarboxylate (2.30 g, 5.62 mmol) in 2-methyltetrahydrofuran (20 mL) at -78°C under nitrogen atmosphere was added 1 M potassium bis(trimethylsilyl)amide (8.4 mL, 8.42 mmol). The mixture was stirred at -78°C for 1.5 hour then 3-bromo-2-fluoro-prop-l-ene (1.00 g, 7.20 mmol, 1.3 eq) was added. The mixture was stirred at -78°C for 1 hour then the cold bath was removed and the mixture stirred and let warm to room temperature. The mixture was quenched with saturated aqueous NH4CI, stirred for 5 min, then the aqueous phase was extracted with EtOAc twice. The combined organic phases were dried on MgSO-i, filtered and concentrated. The crude compound was purified by silica gel chromatography eluting with 0 to 50% EtOAc in cyclohexane to afford dibenzyl (3S,5S)-5-(tert-butyl)-3-(2- fluoroallyl)piperidine-l,3-dicarboxylate (1.83 g). MS (ESI) m / z 468.3 [M+H]+.(3S,5S)-5-(tert-Butyl)-3-(2-fluoropropyl)piperidine-3-carboxylic acidTo a mixture of dibenzyl (3S,5S)-5-tert-butyl-3-(2-fluoroallyl)piperidine-l,3-dicarboxylate (1.83 g, 3.91 mmol) in ethanol (120 mL) was added palladium on carbon(10%, 417 mg, 0.391 mmol). The atmosphere was purged with 3 cycles of vacuum / nitrogen then with 3 cycles of hydrogen / vacuum. The mixture was stirred overnight under hydrogen atmosphere. The mixture was filtered and the filtrate concentrated. The compound was then dried in the vacuum oven to afford (3S,5S)-5-(tert-butyl)-3-(2- fluoropropyl)piperidine-3-carboxylic acid (960 mg). MS (ESI) m / z 246.2 [M+H]+.

[0233] Synthesis of methyl yDmethvUpiperidine-3-carboxvlate(3-Fluorotetrahydrofuran-3-yl)methyl trifluoromethanesulfonateTo a solution of (3-fluorotetrahydrofuran-3-yl)methanol (500 mg, 4.16 mmol) in DCM(10.0 mL) cooled to < -10°C was added trifluoromethanesulfonic anhydride (0.77 mL,4.58 mmol) followed by 2,6-lutidine (0.58 mL, 5.00 mmol) and the reaction stirred overnight allowing to warm to room temperature. The reaction mixture quenched with 2M HC1 and passed through a phase separator. The organic phase was concentrated to afford (3-fluorotetrahydrofman-3-yl)methyl trifluoromethanesulfonate (883 mg).XHNMR (400 MHz, CDC13): 5 4.67 (dq, J=19.5, 12.0 Hz, 2H), 4.08 - 3.83 (m, 4H), 2.38 -2.25 (m, 1H), 2.15 - 1.99 (m, 1H).1-Benzyl 3-methyl (3S,5S)-5-(tert-butyI)-3-((3-fluorotetrahydrofuran-3- yl)methyl)piperidine-13-dicarboxylateThis compound was synthesised from 1-benzyl 3-methyl (3R,5S)-5-(tert- butyl)piperidine- 1 ,3 -dicarboxylate and (3 -fhiorotetrahy drofuran-3 -y l)methy 1 trifluoromethanesulfonate using a similar procedure as dibenzyl (3 S,5 S)-5-(tert-butyl)-3-(2-fluoroallyl)piperidine-l,3-dicarboxylate. MS (ESI) m / z 436.5 [M+H]+.Methyl (3S,5S)-5-(tert-butyl)-3-((3-fluorotetrahydrofuran-3-yl)methyl)piperidine-3-carboxylateThis compound was synthesised from 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-((3- fluorotetrahydrofuran-3 -y l)methyl)piperidine- 1 ,3 -dicarboxylate using a similar procedure as methyl (3R,5S)-5-(tert-butyl)-3-(methoxymethyl)piperidine-3-carboxylate. rH NMR (400 MHz, CDCI3): 8 3.96 - 3.56 (m, 8H), 3.15 (d, J=11.7 Hz, 1H), 2.84 (t,1=13.3 Hz, 1H), 2.53 - 2.47 (m, 2H), 2.30 - 1.80 (m, 4H), 1.38 (dt, 1=4.7, 13.1 Hz, 1H),1.32 - 1.21 (m, 1H), 0.91 (s, 9H).

[0234] Synthesis of methyl (3S,5S)-5-(tert-butyl)-3-((3-fluorooxetan-3-yl}methyl)viperidine-3- carboxylate(3-FIuorooxetan-3-yl)methyl trifluoromethanesulfonateThis compound was synthesised from (3-fluorooxetan-3-yl)methanol using a similar procedure as (3 -fluorotetrahy drofuran-3 -yl)methyl trifluoromethanesulfonate.*H NMR (400 MHz, CDC13): 34.91 - 4.81 (m, 4H), 4,59 (dd, 1=9.1, 15.9 Hz, 2H).(3S,5S)-1- [(Benzyloxy)carbonyl] -5-tert-butyl-3- [(3-fluorooxetan-3- yl)methyl]piperidine-3-carboxylic acidThis compound was synthesised from 1-benzyl 3-methyl (3R,5S)-5-(tert- butyl)piperidine- 1 ,3-dicarboxylate and (3-fluorooxetan-3-yl)methyl trifluoromethanesulfonate using a similar procedure as dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-fluoroallyl)piperidine- 1,3 -dicarboxylate. *H NMR (400 MHz, CDCh): 5 7.41 - 7.27(m, 5H), 520 - 5.09 (m, 2H), 4.76 - 4.70 (m, 3H), 4.53 (td, 1=7.7, 22.4 Hz, 2H), 4.28 (s,1H), 3.53 (s, 3H), 2.53 (d, 1=13.5 Hz, 1H), 2.34 (d, 1=13.5 Hz, 2H), 2.21 (d, 1=24.5 Hz,2H), 1.39 - 1.31 (m, 1H), 1.05 (t, 1=12.8 Hz, 1H), 0.89 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-((3-fluorooxetan-3-yl)methyl)piperidine-3- carboxylateThis compound was synthesised from (3S,5S)-l-[(benzyloxy)carbonyl]-5-tert-butyl-3-[(3 -fluorooxetan-3-yl)methyl]piperidine-3 -carboxylic acid using a similar procedure described in general procedure [Hydrog], *H NMR (400 MHz, CDCI3): 54.78 - 4.68 (m,1H), 4.68 - 4.46 (m, 1H), 3.88 - 3.74 (m, 6H), 2.84 - 2.73 (m, 1H), 2.64 - 2.44 (m, 2H),2.36 - 2.04 (m, 3H), 1.47- 1.18 (m, 2H), 0.94 - 0.82 (m, 9H).MS (ESI) m / z 288.3 [M+H]+.

[0235] Synthesis of 1 -Benzyl 3-methyl 3-aHyl-5-isopronylDiperidine-1.3-dicarboxylateMethyl 5-(prop-l-en-2-yl)pyridine-3-carboxylateA mixture of methyl 5 -bromonicotinate (50.5 g, 224 mmol), isopropenylboronic acid pinacol ester (44.7 g, 258 mmol), XPhos Pd G3 (0.570 g, 0.673 mmol) and K3PO4 (95 g,449 mmol) in THF: water (5:1, 700 ml) under N2 was stirred at 60°C for 3 hours.Isopropenylboronic acid pinacol ester (5.83 g, 33.7 mmol) and XPhos Pd G3 (0.380 g,0.449 mmol) were added and the reaction was stirred at 70°C for 1 hour. The reaction wasquenched with water and extracted with EtOAc. The organic phase was concentrated and the residue was purified by column chromatography (SiOj, EtOAc / hexane) to afford the desired product (47g).lH NMR (400 MHz, CDCI3): 9.12 (d, J = 2.0 Hz, 1H), 8.89 (d, J =2.3 Hz, 1H), 8.34 (t, J = 2.2 Hz, 1H), 5.52 (s, 1H), 5.31-5.24 (m, 1H), 3.98 (s, 3H), 2.22(s, 3H).Methyl 5-isopropylpiperidine-3-carboxy latePlatinum (TV) oxide (1.10 g, 4.84 mmol) was added to a stirred solution of methyl 5-(prop-1 -en-2-yl)nicotinate (12.96 g, 73.1 mmol) in acetic acid (200 mL) under nitrogen.The nitrogen was replaced with hydrogen and the mixture stirred at room temperature and atmospheric pressure for 48 hours. The reaction was filtered through celite and evaporated to afford methyl 5 -isopropylpiperidine-3 -carboxylate acetate (20 g).JH NMR (400 MHz,CDCh): 8 3.76, 3.71 (2s, 3H), 3.55 - 3.45 (m, 1H), 3.33 - 3.20 (m, 1H), 2.97 - 2.70 (m,2H), 2.61 - 2.40 (m, 1H), 2.25 - 2.16 (m, 1H), 1.88 - 1.62 (m, 1H), 1.58 - 1.47 (m, 2H),0.94 - 0.89 (m, 6H). Complex, mixture of cis / trans isomers1 -Benzyl 3-methyl 5-isopropylpiperidine-l,3-dicarboxylateTo a stirred, room temperature solution of methyl 5 -isopropylpiperidine-3 -carboxylate acetate (20.0 g, 81.5 mmol) in DCM (500.0 mL) was added triethylamine (34 mL, 0.245 mol) followed by N-(benzyloxycarbonyloxy)succinimide (25.4 g, 102 mmol). The reaction mixture was stirred at room temperature for 40 hours. Saturated NaHCOa (500 mL) was added, the mixture stirred for 10 minutes and the layers were separated. The aqueous phase was extracted with DCM (2 x 300 mL), the combined organic extracts were dried (MgSC>4), filtered and evaporated. The residue was purified by chromatography on silica gel (330 g) eluting with 0-100% diethyl ether in cyclohexane to afford l-ben2yl 3-methyl 5-isopropylpiperidine-l,3-dicarboxylate (13.85 g).rH NMR(400 MHz, CDCI3): 8 7.38 - 7.32 (m, 5H), 5.20 - 5.06 (m, 2H), 4.16 - 4.10 (m, 1H), 3.87- 3.81 (m, 1H), 3.68 - 3.52 (m, 4H), 3.33 - 3.19 (m, 1H), 2.96 - 2.84 (m, 1H), 2.68 - 2.61(m, 1H), 2.09 - 1.98 (m, 1H), 1.55 - 1.41 (m, 2H), 0.93 (d, 1=6.1 Hz, 6H).1 -Benzyl 3-methyl 3-allyl-5-isopropylpiperidine-l,3-dicarboxylate1 M potassium bis(trimethylsilyl)amide in THE (29 mL, 29.0 mmol) was added slowly over 15 minutes to a stirred solution of 1 -benzyl 3-methyl 5-isopropylpiperidine-l,3- dicarboxylate (6.17 g, 19.3 mmol) in anhydrous 2-methyltetrahydrofuran (98.7 mL) at T<-70°C. On complete addition the reaction mixture was stirred at -78°C for an additional1 hour before allyl bromide (3.3 mL, 38.6 mmol, 2.0 eq) was added dropwise over 10 minutes. On complete addition the reaction mixture was stirred at this temperature for an additional 1 hour, then cooling was removed, and the reaction allowed to warm to ambient and stir for 18 hours. The reaction was quenched with saturated NH4CI (100 mL) and stirred for 10 minutes. Water (30 mL) and EtOAc (50 mL) were added, the layers separated and the aqueous phase extracted with EtOAc (100 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (120 g) eluting with 10-100% EtOAc in cyclohexane to afford 1-benzyl 3-methyl 3-allyl-5-isopropylpiperidine-l,3-dicarboxylate (5.65 g).XHNMR (400 MHz, CDC13): 87.42 - 7.29 (m, 5H), 5.75 - 5.62 (m, 1H), 5.17 - 5.02 (m, 4H),4.70 - 4.60 (m, 1H), 4.25 - 4.25 (m, 1H), 3.51 (br s, 3H), 2.48 -2.46 (m, 1H), 2.37 - 2.15(m, 4H), 1.46 - 1.40 (m, 3H), 0.94 - 0.88 (m, 6H).

[0236] Synthesis of 1 -Benzyl 3-methyl (3R,5S)-5-isopropylpiperidine-l,3-<iicarboxylate(2R3R)-23-Bis(4-methylbenzoyloxy)butanedioic acid methyl (3R,5S)-5-isopropylpiperidine-3-carboxylateTo a solution of methyl 5 -(propan-2-yl)piperidine-3 -carboxylate (52.0 g, 281 mmol) in ethanol (425 ml) was added (-)-Di-l,4-O-toluoyl-L-tartaric acid (108 g, 281 mmol) and the mixture was stirred 1.5 hours at 90QC. The resultant clear solution was cooled to room temperature gradually. After 4 hours, the precipitate was filtered and washed with a small amount of cold ethanol and dried in vacuo to give the desired product (36.3 g).TH NMR(400 MHz, Me-da-OD): 8.03 (d, J = 7.9 Hz, 4H), 7.32 (d, J = 7.9 Hz, 4H), 5.90 (s, 2H),3.78 (s, 3H), 3.67-3.57 (m, 1H), 3.26 (d, J = 12.3 Hz, 1H), 3.11-3.00 (m, 2H), 2.91-2.66(m, 1H), 2.43 (s, 6H), 2.22 (d, J = 13.9 Hz, 1H), 1.67-1.42 (m, 3H), 0.93 (dd, J = 6.6, 4.8Hz, 6H).1-Benzyl 3-methyl (3R,5S)-5-isopropylpiperidine-l,3-dicarboxylateN-(Benzyloxycarbonyloxy)succinimide (3.81 g, 15.3 mmol) was added in one portion to a stirred solution of (2R,3R)-2,3-bis(4-methylbenzoyloxy)butanedioic acid methyl(3R,5S)-5-(propan-2-yl)piperidine-3-carboxylate (7.00 g, 12.2 mmol) and triethylamine(4.3 mL, 30.6 mmol) in DCM (150 mL) at room temperature for 90 hours. The reaction mixture was washed with sat NaHCOa (300 mL) and extracted with DCM (2 x 200 mL).The organic phase was concentrated and the residue was purified by column chromatography on silica gel (EtiO / cyclohexane) to give the desired product.!H NMR(400 MHz, CDC13): 8 7.46-7.30 (m, 5H), 5.28-5.03 (m, 2H), 4.25 (s, 1H), 4.05-3.76 (m,1H), 3.63 (s, 3H), 3.28 (d, 1H), 2.89 (s, 1H), 2.67 (s, 1H), 2.26-1.86 (m, 1H), 1.60-1.38(m, 2H), 1.38-1.06 (m, 1H), 0.95 (d, J = 8.0 Hz, 6H).

[0237] Synthesis of 5-IsoproDyl-3-propvlpiperidine-3-carboxyUc acid hydrochlorideMethyl 5-isopropyl-3-propylpiperidine-3-carboxy lateA stirred solution of 1 -benzyl 3-methyl 3-allyl-5-isopropylpiperidine-l,3-dicarboxylate(2.90 g, 8.07 mmol) in EtOH (75 mL) was hydrogenated at atmospheric pressure and room temperature in the presence of palladium on carbon (10%, 720 mg, 0.68 mmol) for18 hours. The reaction mixture was filtered through celite, the filter pad washed withEtOH (50 mL) and the combined filtrate and washings evaporated to afford methyl 5- isopropyl-3-propylpiperidine-3-carboxylate (1.81 g).JH NMR (400 MHz, CDC13): 3 3.74 (s, 3H), 3.52 (dd, J=1.9, 12.9 Hz, 1H), 3.12 - 3.04(m, 1H), 2.32 - 2.21 (m, 5H), 1.51 - 1.31 (m, 3H), 1.28 - 1.12 (m, 3H), 0.92 - 0.87 (m,9H).5-Isopropyl-3-propylpiperidine-3-carboxylic acid hydrochlorideA stirred solution of methyl 5 -isopropyl-3-propylpiperidine-3 -carboxylate (2.20 g, 9.68 mmol) in 11.5 M hydrochloric acid (48 mL, 557 mmol) was heated at 100°C for 48 hours.After cooling to room temperature, the reaction mixture was evaporated under reduced pressure to afford 5-isopropyl-3-propylpiperidine-3-carboxylic acid hydrochloride (2.01 g).TH NMR (400 MHz, DMSO): 5 13.04 (br s, 1H), 9.74 (d, J=11.2 Hz, 1H), 7.61 (d,1=10.4 Hz, 1H), 3.40 (d, 1=12.1 Hz, 2H), 2.99 (d, J=11.5 Hz, 1H), 2.58 (dd, J=10.4, 12.1Hz, 1H), 2.50 - 2.46 (m, 1H), 1.98 (d, J=12.0 Hz, 1H), 1.49 - 1.23 (m, 3H), 1.21 - 1.01(m, 3H), 0.78 - 0.74 (m, 9H).

[0238] Synthesis of methyl (3S,5S)'-5-(tert-butyl)-3-((4-fluorotetrahydro-2H-vvran-4- yl)methyl)nweridine-3-carboxylate(4-Fluorotetrahydro-2H-pyran-4-yl)methyl trifluoromethanesulfonateThis compound was synthesised from (4-fluorotetrahydropyran-4-yl)methanol using a similar procedure as (3-fluorotetrahydrofuran-3-yl)methyl trifluoromethanesulfonate.XHNMR (400 MHz, CDC13): 54.45 (d, 1=18.9 Hz, 2H), 3.92 - 3.86 (m, 2H), 3.78 - 3.71(m, 2H), 1.92 - 1.80 (m, 3H), 1.80 - 1.68 (m, 1H).1-BenzyI 3-methyl (3S,5S)-5-(tert-butyl)-3-((4-fluorotetrahydro-2H-pyran-4- yl)methyl)piperidine-l,3-dicarboxylateThis compound was synthesised from 1-benzyl 3-methyl (3R,5S)-5-(tert- butyl)piperidine- 1 ,3 -dicarboxylate and (4-fluorotetrahydro-2H-pyran-4-yl)methyl trifluoromethanesulfonate using a similar procedure as dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-fluoroallyl)piperidine- 1 ,3 -dicarboxylate.'H NMR (400 MHz, CDCI3): 57.42 - 728 (m, 5H), 5.21 - 5.11 (m, 2H), 4.80 (d, J=12.5Hz, 1H), 4.35 - 4.25 (m, 1H), 3.82 - 3.46 (m, 8H), 2.57 - 2.38 (m, 3H), 1.86 - 1.55 (m,6H), 1.08 (t, J=12.4 Hz, 1H), 0.90 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-((4-fluorotetrahydro-2H-pyran-4- yl)methyl)piperidine-3-carboxylateThis compound was synthesised from 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-((4- fluorotetrahydro-2H-pyran-4-yl)methyl)piperidine- 1 ,3 -dicarboxylate using a similar procedure as methyl (3R, 5 S)-5-(tert-butyl)-3-(methoxymethyl)piperidine-3 -carboxy late.*H NMR (400 MHz, CDC13): 53.67 - 3.65 (m, 8H), 3.04 - 2.92 (m, 1H), 2.29 (d, J=12.6Hz, 2H), 2.16 (dd, 1=11.5, 11.5 Hz, 1H), 1.91 (d, J=1.8 Hz, 1H), 1.87 - 1.61 (m, 6H), 1.24- 1.06 (m, 1H), 0.87 (s, 9H).

[0239] Cbz HDibenzyl (3R,5S)-5-(tert-butyl)-3-(3-methoxypropyl)piperidine-l,3-dicarboxylateA solution of dibenzyl (3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxylate (3.0 g, 7.33 mmol) in 2-methyltetrahydrofuran (30 mL) was cooled to -70°C, and 1 M potassium bis(trimethylsilyl)amide (11 mL, 11.0 mmol) in THE was added. The mixture was stirred at -70°C for lhour, then l-bromo-3 -methoxy-propane (1.6 mL, 14.7 mmol, 2.0 eq) was added. The mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated NH4CI, extracted with EtOAc (2 x 50 mL), and the combined organic phases dried (MgSCh), filtered and concentrated. The residue was purified by silica gel chromatography eluting with cyclohexane / EtOAc 5 to 80% affording dibenzyl (3R,5 S)-5 -(tert-butyl)-3 -(3-methoxypropyl)piperidine- 1,3- dicarboxylate (2.16 g).LH NMR (400 MHz, CDC13): 5 7.36 - 7.32 (m, 5H), 7.30 - 7.27(m, 5H), 5.17 - 5.10 (m, 3H), 4.98 - 4.88 (m, 2H), 4.75 - 4.67 (m, 1H), 4.34 - 4.19 (m,1H), 3.29 - 3.23 (m, 5H), 2.49 - 2.31 (m, 4H), 1.55 - 1.47 (m, 2H), 1.32 - 1.24 (m, 1H),0.99 - 0.92 (m, 1H), 0.85 (s, 9H).(3R,5S)-5-(tert-Butyl)-3-(3-methoxypropyI)piperidine-3-carboxylic acidTo a mixture dibenzyl (3R,5S)-5-(tert-butyl)-3-(3-methoxypropyl)piperidine-l,3- dicarboxylate (2.16 g, 4.48 mmol) in EtOH (150 mL) was added palladium on carbon(10%, 477 mg, 0.448 mmol), and the reaction mixture was stirred under a Hi atmosphere for 24 hours. The reaction mixture was filtered, rinsed with MeOH (100 mL), and the filtrate was concentrated to dryness to give (3R,5S)-5-(tert-butyl)-3-(3- methoxypropyl)piperidine-3-carboxylic acid (1.08 g). 'H NMR (400 MHz, CDCI3): 53.42 - 3.31 (m, 3H), 3.30 (s, 3H), 2.56 (t, 1=12.6 Hz, 1H), 2.43 (d, 1=12.1 Hz, 1H), 2.11(d, J=11.9 Hz, 1H), 1.90 - 1.80 (m, 1H), 1.64 - 1.48 (m, 5H), 1.44 - 1.29 (m, 1H), 1.09 (t,1=12.9 Hz, 1H), 0.88 (s, 9H).

[0240] Synthesis of f3S,5S)-5-(tert-butyl)-3-(2-ethoxvethyl)piperidine-3-carboxvlic acidDibenzyl (3S,5S)-5-(tert-butyl)-3-(2-hydroxyethyl)piperidine-l,3-dicarboxylateTo a mixture of dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-oxoethyl)piperidine-l,3- dicarboxylate (1.00 g, 2.21 mmol) in MeOH (12.0 mL) was added sodium borohydride(251 mg, 6.64 mmol). The mixture was stirred at room temperature for 1 hour. Water was added and the aqueous phase extracted with EtO Ac twice. The combined organic phases were dried on MgSO4, filtered and concentrated to afford dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-hydroxyethyl)piperidine-l,3-dicarboxylate (911 mg). MS (ESI) m / z 454.3 [M+H]+.Dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-ethoxyethyl)piperidine-l,3-dicarboxyIateTo a solution of dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-hydroxyethyl)piperidine-l,3- dicarboxylate (685 mg, 1.51 mmol) in DCM (8.0 mL) was added triethyloxonium tetrafluoroborate (861 mg, 4.53 mmol) and N,N,N',N'-tetramethyl- 1,8- naphthalenediamine (1.62 g, 7.55 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with HC1 IN and extracted with EtO Actwice. The combined organic phases were dried over MgSO4, filtered and concentrated.The crude was purified by silica gel chromatography eluting with 0 to 100% EtOAc in cyclohexane to afford dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-ethoxyethyl)piperidine-l,3- dicarboxylate (127 mg). MS (ESI) m / z 482.3 [M+H]+.(3S,5S)-5-(tert-ButyI)-3-(2-ethoxyethyl)piperidine-3-carboxylic acidTo a mixture of dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-ethoxyethyl)piperidine-l,3- dicarboxylate (127 mg, 0.264 mmol) in MeOH (20 mL) was added palladium on carbon(10%, 28 mg, 0.0264 mmol). The mixture was stirred under Ha atmosphere for 24 hours.The mixture was filtered and concentrated to dryness to afford (3S,5S)-5-(tert-butyl)-3-(2-ethoxyethyl)piperidine-3-carboxylic acid (54 mg). *HNMR (400 MHz, CDCI3): 54.30- 4.06 (m, 1H), 3.72 - 3.56 (m, 1H), 3.50 - 3.39 (m, 4H), 2.53 (dd, 1=9.6, 12.1 Hz, 2H),2.30 - 2.25 (m , 1H), 2.16 - 2.03 (m, 2H), 1.67 - 1.54 (m, 1H), 1.27 - 1.13 (m, 4H), 0.89(s, 9H).

[0241] Synthesis of (3R,5S)-5-(tert-butyl)-3-(3.3-difluoropropvl)piperidine-3-carboxylic acid hydrochloride1-Benzyl 3-methyl (3R,5S)-5-(tert-butyl)-3-(3,3-dimethoxypropyl)piperidine-l,3-dicarboxylatePotassium bis(trimethylsilyl)amide (45 mL, 45.0 mmol) (IM solution in THE) was added dropwise over 15 minutes to a stirred solution of 1-benzyl 3-methyl (3R,5S)-5-(tertbutyl)piperidine- 1,3 -dicarboxylate (10.0 g, 30.0 mmol) in 2-methyltetrahydrofuran (150 mL) at -75°C. On complete addition the reaction was stirred at -75°C for 1 hour. 3- bromopropionaldehyde dimethyl acetal (8.3 mL, 60.6 mmol) was added dropwise over 5 minutes at -75°C. The resultant mixture was allowed to warm to room temperature whilst stirring overnight. Saturated aqueous NH4CI was added, the mixture stirred for 10 minutes and then diluted with water. The aqueous phase was extracted with EtOAc (2 x 100 mL), and the combined organic phases were dried (MgSCh), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0 to 50% EtOAc in cyclohexane to afford 1 -benzyl 3 -methyl (3R,5S)-5-(tert-butyl)-3-(3,3- dimethoxypropyl)piperidine-l,3-dicarboxylate (9.4 g). *H NMR (400 MHz, CDCh): 87.41 - 7.28 (m, 5H), 5.16 - 5.12 (m, 2H), 4.70 - 4,64 (m, 1H), 4.31 - 4.27 (m, 2H), 3.63 -3,51 (m, 3H), 3.29 (s, 3H), 3.29 (s, 3H), 2.50 - 2.33 (m, 3H), 1.64 - 1.47 (m, 5H), 1.39 -1.24 (m, 1H), 0.90 (s, 9H).1-Benzyl 3-methyl (3R,5S)-5-(tert-butyl)-3-(3-oxopropyl)piperidine-13- dicarboxylateA mixture of (3R,5 S)-5-(tert-butyl)-3 -(3 ,3-dimethoxypropyl)piperidine- 1,3- dicarboxylate (9.40 g, 21.6 mmol) in 1 M hydrogen chloride (132 mL, 0.132 mol, 6.1 eq) and THE (125 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc (2 x 150 mL). The combined organic phases were dried (MgSC>4), filtered and concentrated to afford 1-benzyl 3-methyl(3R,5S)-5-(tert-butyl)-3-(3-oxopropyl)piperidine-l,3-dicarboxylate (7.5 g).JH NMR(400 MHz, CDCh): 8 9.74 (s, 1H), 7.41 - 7.27 (m, 5H), 5.14 - 5.13 (m, 2H), 4.69 - 4.60(m, 1H), 4.31 - 4.24 (m, 1H), 3.64 - 3.49 (m, 3H), 2.50 - 2.29 (m, 5H), 1.90 - 1.79 (m,2H), 1.38 - 1.28 (m, 1H), 0.98- 0.95 (d, 1=12.6 Hz, 1H), 0.90 (s, 9H).1-Benzyl 3-methyl (3R,5S)-5-(tert-butyl)-3-(3,3-difluoropropyl)piperidine-l,3- dicarboxylateTo a stirred solution of 1 -benzyl 3 -methyl (3R,5S)-5-(tert-butyl)-3-(3- oxopropyl)piperidine-l,3-dicarboxylate (7.50 g, 19.3 mmol) in anhydrous DCM (150 mL) at -10°C under nitrogen was added (diethylamino)sulfur trifluoride (20 mL, 0.154 mol) slowly over 5 minutes. The reaction was stirred at - 10°C for 1 hour, cooling removed and the reaction allowed to warm to room temperature overnight. The reaction mixture was cooled in an ice-bath and saturated NaHCOa (400 mL) was added slowly (care fizzing) and the mixture stirred for 30 minutes. The layers were separated, and the aqueous layer was extracted with DCM (2 x 200 mL). The combined organic extracts were washed with water and brine, dried (NaaSO^, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography eluting with 0-40% EtOAc in cyclohexane to afford 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)-3-(3,3- difluoropropyl)piperidine- 1,3 -dicarboxylate (3.63 g)lH NMR (400 MHz, CDC13): 6 7.41 - 7.27 (m, 5H), 5.77 (tt, 1=4.4, 56.5 Hz, 1H), 5.17 -5.12 (m, 2H), 4.67 - 4.57 (m, 1H), 4.29 - 4.26 (m, 1H), 3.66 - 3.50 (m, 4H), 2.48 - 2.31(m, 3H), 1.88 - 1.60 (m, 3H), 1.35 (tt, 1=3.4, 12.2 Hz, 1H), 0.99 - 0.92 (m, 1H), 0.91 (s,9H).(3R,5S)-5-(tert-Butyl)-3-(3,3-difluoropropyl)piperidine-3-carboxylic acid hydrochlorideA solution of 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)-3-(3,3-difluoropropyl)piperidine-1,3 -dicarboxylate (3.63 g, 8.82 mmol) in 12 M hydrochloric acid (75 mL, 0.90 mol) was stirred at 100°C for 72 hours. The reaction was cooled and evaporated to afford (3R,5S)-5-(tert-butyl)-3-(3,3-difluoropropyl)piperidine-3-carboxylic acid hydrochloride (2.68 g).*H NMR (400 MHz, DMSO): 8 10.09 (d, 1=9.9 Hz, 1H), 7.76 (d, J=9.9 Hz, 1H), 6.13 (tt,J=3.9, 56.9 Hz, 1H), 3.52 (d, 1=12.6 Hz, 1H), 3.19 (d, J=11.6 Hz, 1H), 2.82 - 2.73 (m,1H), 2.63 (dd, J=11.2, 11.2 Hz, 1H), 2.17 (d, 1=10.1 Hz, 1H), 1.96 - 1.59 (m, 4H), 1.40 -1.29 (m, 2H), 0.91 (s, 9H).

[0242] Synthesis of acid hydrochloride1-Benzyl 3-methyl 3-(3,3-dimethoxypropyl)-5-isopropylpiperidine-l,3- dicarboxylate1 M potassium bis(trimethylsilyl)amide in THF (12 mL, 11.7 mmol) was added slowly over 10 minutes to a stirred solution of 1 -benzyl 3-methyl 5-isopropylpiperidine-l,3- dicarboxylate (2.50 g, 7.83 mmol) in anhydrous 2-methyltetrahydrofuran (40.0 mL) at -70°C under nitrogen. On complete addition the mixture was stirred at -70°C for 1 hour.3 -Bromopropionaldehyde dimethyl acetal (2.1 mL, 15.7 mmol) was then added dropwise at such a rate that the temperature remained below -70°C. On complete addition the mixture was stirred at -70°C for 1 hour and then allowed to warm to room temperatureand to stir overnight. The reaction was quenched with saturated NH4CI (30 mL) and stirred for 10 minutes. Water (30 mL) and EtOAc (50 mL) were added, the layers separated, and the aqueous phase extracted with EtOAc (100 mL). The combined organic extracts were dried, filtered (MgSCU) and evaporated. The residue was purified by column chromatography on silica gel eluting with 10-80% diethyl ether in cyclohexane to afford1 -benzyl 3 -methyl 3 -(3,3 -dimethoxypropyl)-5 -isopropylpiperidine- 1 ,3 -dicarboxylate(1.28 g).XH NMR (400 MHz, CDCh): 5 7.45 - 7.32 (m, 5H), 5.24 - 5.10 (m, 2H), 4.76 -4.63 (m, 1H), 4.32 - 4.25 (m, 2H), 3.63 - 3.52 (m, 3H), 3.32 (d, J=2.1 Hz, 6H), 2.54 - 2.28(m, 4H), 1.71 - 1.34 (m, 6H), 0.97 - 0.89 (m, 6H).1-Benzyl 3-methyl 5-isopropyl-3-(3-oxopropyl)piperidine-l,3-dicarboxylateA mixture of 1-benzyl 3-methyl 3-(3,3-dimethoxypropyl)-5-isopropylpiperidine-l,3- dicarboxylate (1.28 g, 3.04 mmol) in THE (20 mL) and 1 M hydrochloric acid (20 mL,20.0 mmol) was stirred at room temperature overnight. The mixture was diluted with water (20 mL) and EtOAc (40 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 25 mL), and the combined organic extracts were dried(MgSCM), filtered and evaporated to afford 1-benzyl 3-methyl 5-isopropyl-3-(3- oxopropyl)piperidine- 1,3 -dicarboxylate (1.2 g). *H NMR (400 MHz, CDCI3): 8 9.77 (s,1H), 7.45 - 7.33 (m, 5H), 5.20 - 5.11 (m, 2H), 4.70 - 4.67 (m, 1H), 4.28 - 4.28 (m, 1H),3.67 - 3.56 (m, 3H), 2.52 - 2.44 (m, 3H), 2.41 - 2.29 (m, 2H), 1.93 - 1.84 (m, 1H), 1.82 -1.78 (m, 1H), 1.52 - 1.38 (m, 3H), 0.95 (dd, 1=2.0, 6.5 Hz, 6H).1-Benzyl 3-methyl 3-(3,3-difluoropropyl)-5-isopropylpiperidine-l,3-dicarboxylate(Diethylamino)sulfur trifluoride (3.4 mL, 25.6 mmol) was added dropwise over 5 minutes to a stirred solution of 1-benzyl 3-methyl 5-isopropyl-3-(3-oxopropyl)piperidine-l,3- dicarboxylate (1.20 g, 3.20 mmol) in anhydrous DCM (25 mL) at -10 to 0°C under N2.On complete addition the mixture was stirred at this temperature for 1 hour before thecooling bath was removed allowing the reaction to warm to room temperature and to stir for 40 hours. The reaction was carefully quenched to basic pH with saturated aqueousNaHCOa, DCM (30 mL) was added, the layers separated, and the aqueous phase extracted with DCM (2 x 30 mL). The combined organic extracts were dried (MgSCh), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 0-60% diethyl ether in cyclohexane to give 1 -benzyl 3 -methyl 3-(3,3-difluoropropyl)-5- isopropylpiperidine-l,3-dicarboxylate (890 mg). ‘H NMR (400 MHz, CDCI3): 5 7.35 -7.22 (m, 5H), 5.70 (tt, J=4.0, 56.6 Hz, 1H), 5.08 (dd, J=13.0, 27.0 Hz, 2H), 4.60 - 4.57(m, 1H), 4.22 - 4.19 (m, 1H), 3.55 - 3.47 (m, 3H), 2.42 - 2.36 (m, 1H), 2.28 (d, J=12.7Hz, 2H), 1.81 - 1.57 (m, 4H), 1.43 - 1.28 (m, 3H), 0.87 - 0.80 (m, 6H).3-(3,3-Difluoropropyl)-5-isopropyIpiperidine-3-carboxylic acid hydrochlorideA solution of 1-benzyl 3-methyl 3-(3.,3-difluoropropyl)-5-isopropylpiperidine-l,3- dicarboxylate (890 mg, 2.24 mmol) in 11.5 M hydrochloric acid (15 mL, 173 mmol) was stirred at 100°C for 120 hours. The reaction was cooled and evaporated under reduced pressure to afford 3-(3,3-difluoropropyl)-5-isopropylpiperidine-3-carboxylic acid hydrochloride (550 mg). *HNMR (400 MHz, DMSO): 5 13.37 (br s, 1H), 9.75 (d, J=10.8Hz, 1H), 7.77 (d, J=10.6 Hz, 1H), 6.09 (tt, 1=3.9, 56.7 Hz, 1H), 3.51 (d, 1=12.4 Hz, 1H),3.10 (d, 1=11.4 Hz, 1H), 2.74 (dd, J=11.6, 11.6 Hz, 1H), 2.61 - 2.54 (m, 1H), 2.09 (d,1=12.2 Hz, 1H), 1.95 - 1.79 (m, 1H), 1.77 - 1.47 (m, 4H), 1.45 - 1.34 (m, 1H), 1.28 (t,1=12.6 Hz, 1H), 0.87 (dd, 1=3.4, 6.8 Hz, 6H).

[0243] Synthesis of 3 -isobutyl-5-isopropylpiperidme-3 -carboxylic acidl-BenzyI 3-methyl 5-isopropyI-3-(2-methylallyl)piperidine-l>3-dicarboxylateThis compound was synthesised from 1 -benzyl 3 -methyl 5-isopropylpiperidine-l,3- dicarboxylate and 3-bromo-2-methylpropene using a similar procedure as dibenzyl(3 S, 5 S)-5-(tert-butyl)-3-(2-fluoroallyl)piperidine- 1,3 -dicarboxylate.XHNMR (400 MHz,CDCh): 5 7.37 - 7.29 (m, 5H), 5.18 - 5.08 (m, 2H), 4.84 (d, J=1.5 Hz, 1H), 4.73 - 4.67(m, 2H), 4.25 - 4.23 (m, 1H), 3.59 (m, 1H), 3.52 (s, 2H), 2.46 (d, 1=12.0 Hz, 1H), 2.38 -2.16 (m, 4H), 1.62 (s, 1H), 1.59 (s, 1H), 1.46 - 1.38 (m, 4H), 0.94 - 0.88 (m, 6H)Methyl 3-isobutyl-5-isopropyIpiperidine-3-carboxylateThis compound was synthesised from 1-benzyl 3-methyl 5-isopropyl-3-(2- methyl ally l)piperi dine- 1,3 -dicarboxy late using a similar procedure as (3S,5S)-5-(tert- butyl)-3-(2-fluoropropyl)piperidine-3 -carboxylic acid. *H NMR (400 MHz, CDCh): 53.61 (s, 3H), 3.44 (dd, 1=2.0, 12.9 Hz, 1H), 3.01 - 2.89 (m, 1H), 2.60 (d, 1=12.8 Hz, 1H),2.20 - 2.09 (m, 3H), 1.71 - 1.48 (m, 1H), 1.38 (dd, J=6.8, 14.1 Hz, 1H), 1.31 - 1.22 (m,3H), 1.16 - 1.01 (m, 1H), 0.82 - 0.72 (m, 12H).3-Isobutyl-5-isopropylpiperidine-3-carboxylic acidA solution of methyl 3-isobutyl-5-isopropylpiperidine-3-carboxylate (1.65 g, 6.84 mmol) in 12M HC1 (24 mL, 0.276 mol) was heated at 100°C for 3 days. The reaction was cooled and evaporated to afford 3 -isobutyl-5-isopropylpiperidine-3 -carboxylic acid (1.7 g). *HNMR (400 MHz, ds-DMSO): 63.70 (s, 2H), 3.50 (d, J=15.5 Hz, 1H), 3.07 (d, 1=15.5 Hz,1H), 2.70 (t, J=13.3 Hz, 1H), 2.08 (d, 1=15.5 Hz, 1H), 1.69 - 1.33 (m, 6H), 1.23 (t, 1=14.4Hz, 1H), 0.89 - 0.83 (m, 12H).

[0244] Synthesis of methyl carboxylate1-Benzyl 3-methyl (3R,5S)-5-(tert-butyl)-3-(2-cyclopropyIethyl)piperidine-l,3- dicarboxylateA solution of 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxylate (1.30 g, 3.90 mmol) in 2-methyltetrahydrofuran (20.0 mL) at -78°C under a nitrogen atmosphere was treated dropwise with 1 M potassium bis(trimethylsilyl)amide (IM inTHF) (5.8 mL, 5.85 mmol). The reaction mixture was stirred at -78°C for 1.25 hours. 2-Cyclopropylethyl trifluoromethanesulfonate (1.70 g, 7.80 mmol) was added slowly and after a further 30 minutes at -78°C the mixture was allowed to warm to ambient temperature. The reaction was stirred for a further 3 hours at room temperature. The reaction mixture was quenched with a saturated NHtCl solution and extracted into EtOAc(2 x 50 mL). The combined organic extracts were washed with brine, dried over Na2SC>4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-30% EtOAc in cyclohexane to afford 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)-3-(2-cyclopropylethyl)piperidine-l,3-dicarboxylate (1.57 g). MS (ESI) m / z 402.5 [M+H]+Methyl (3R,5S)-5-(tert-butyl)-3-(2-cyclopropylethyI)piperidine-3-carboxy lateA mixture of 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)-3-(2-cyclopropylethyl)piperidine-1,3-dicarboxylate (1.56 g, 3.89 mmol), ammonium formate (2.45 g, 38.9 mmol) and palladium (10% on carbon) (207 mg, 0.194 mmol) in MeOH (25.0 mL) was heated at reflux for 1 hour. The cooled reaction mixture was filtered through celite, washed withMeOH and the filtrate concentrated in vacuo. The residue was loaded onto an SCX-2 cartridge rinsing with MeOH and eluting with 2N NHa / MeOH to afford methyl (3R,5S)-5-(tert-butyl)-3-(2-cyclopropylethyl)piperidine-3-carboxylate (945 mg). MS (ESI) m / z268.4 [M+H]+

[0245] Synthesis of methyl (3S, 5S)-5-ftert-butvl)-3-(2-(3, 3 -difluor oazetidin-1 - yl)ethyl)piperidine-3-carbaxylate1-Benzyl 3-methyI (3S,5S)-5-(tert-butyl)-3-(2-(3r3-difluoroazetidin-l- yl)ethyl)piperidine-l,3-dicarboxylateA mixture of 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-oxoethyl)piperidine-l,3- dicarboxylate (725 mg, 1.93 mmol), 3,3-difluoroazetidine hydrochloride (250 mg, 1.93 mmol) and triethylamine (0.27 mL, 1.93 mmol) in anhydrous DCM (20.0 mL) was stirred at room temperature for 1.25 hours. Sodium triacetoxyborohydride (1023 mg, 4.83 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 20 h. Saturated NaHCCh (20 mL) was added, and the mixture stirred for 10 minutes. The layers were separated, and the aqueous phase extracted with DCM (2 x 20 mL). The combined organic extracts were passed through a phase separation cartridge and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in cyclohexane affording 1 -benzyl 3-methyl (3S,5S)-5-(tert- butyl)-3-(2-(3,3-difluoroazetidin-l-yl)ethyl)piperidine-l,3-dicarboxylate (830 mg),NMR (400 MHz, CDCla): 87.42 - 7.29 (m, 5H), 5.17 - 5.12 (m, 2H), 4.70 - 4.63 (m, 1H),4.34 - 4.29 (m, 1H), 3.64 - 3.55 (m, 3H), 3.48 (t, 1=12.0 Hz, 4H), 2.58 - 2.30 (m, 5H),1.59 - 1.49 (m, 2H), 1.44 - 1.21 (m, 2H), 0.90 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-(2-(3,3-difluoroazetidin-l-yl)ethyl)piperidine-3- carboxylateA mixture of 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-(3,3-difluoroazetidin-l- yl)ethyl)piperidine- 1,3 -dicarboxy late (830 mg, 1.83 mmol), ammonium formate (1.16 g,18.3 mmol) and palladium on carbon (10%, 293 mg, 0.275 mmol) in MeOH (20 mL) was heated at 65°C for 1.5 hours. The cooled reaction mixture was filtered through celite, the filter pad was washed with MeOH (100 mL) and the combined filtrate and washings were evaporated to afford a pale grey paste. The material was triturated with DCM (3 x 10 mL), the combined solvents filtered and the filtrate evaporated to afford methyl (3S^S)-5-(tert- butyl)-3 -(2-(3 ,3 -difluoroazetidin- 1 -yl)ethyl)piperidine-3 -carboxylate (600 mg).*HNMR (400 MHz, CDCb): 5 8.41 (s, 1H), 3.78 (s, 3H), 3.73 - 3.65 (m, 2H), 3.51 - 3.46(m, 4H), 3.39 - 3.30 (m, 1H), 2.60 - 2.47 (m, 2H), 2.27 - 2.22 (m, 2H), 1.88 - 1.79 (m,1H), 1.51 - 1.41 (m, 1H), 1.31 - 124 (m, 1H), 1.16 (t, 1=12.9 Hz, 1H), 0.88 (s, 9H).

[0246] Synthesis of (3S.5S)-5-(tert-butyl)-3-(2-methoxvpropyl)piperidine-3-carboxylic acidO'O .0.TfO'Bn OBnNCbz NCbz2-Methoxypropyl trifluoromethanesulfonateA solution of 2-methoxypropan-l-ol (850 mg, 9.43 mmol) and 2,6-lutidine (1.8 mL, 15.1 mmol) in DCM (11.0 mL) at -78°C under a nitrogen atmosphere was treated dropwise with trifluoromethanesulfonic anhydride (2.4 mL, 14.1 mmol) and stirred cold for 3 hours.The reaction mixture was passed through a silica plug without any work-up eluting withDCM to afford 2-methoxypropyl trifluoromethanesulfonate (1.28 g). *H NMR (400 MHz,CDCh): 54.45 - 4.37 (m, 2H), 3.69 - 3.63 (m, 1H), 3.41 (s, 3H), 1.22 (d, 1=6.3 Hz, 3H).Dibenzyl (3S,5S)-5-(tert-butyl)-3-(2-methoxypropyl)piperidine-l,3-dicarboxylateA solution of dibenzyl (3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxylate (1.50 g, 3.66 mmol) in 2-methyltetrahydrofuran (20 mL) was cooled to -78°C and a solution of 1 M potassium bis(trimethylsilyl)amide in THE (5.5 mL, 5.49 mmol) was added dropwise.The mixture was then stirred at -78°C for 30 minutes prior to addition of a crude solution of 2-methoxypropyl trifluoromethanesulfonate (1.63 g, 7.33 mmol) in 2- methyltetrahydrofuran (15 mL) and the solution maintained below -60°C. The solution was allowed to warm slowly to room temperature overnight. The reaction mixture was quenched with saturated aqueous NH4CI and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 x 20 mL) and the combined organic extracts washed with water (3 x 20 mL). The organic phase was dried (MgSC>4), filtered and concentrated. The residue was purified by column chromatography on silica gel (0-50% diethyl ether in cyclohexane) to afford dibenzyl (3S,5S)-5-(tert-butyl)-3-(2- methoxypropyl)piperidine-l,3-dicarboxylate (310 mg). *H NMR (400 MHz, CDCI3): 57.38 - 7.28 (m, 10H), 5.18 - 5.04 (m, 3H), 5.03 - 4.88 (m, 2H), 4.35 - 4.12 (m, 2H), 3.42- 3.27 (m, 3H), 3.16 (s, 3H), 2.54 - 2.30 (m, 2H), 1.27 - 1.10 (m, 2H), 1.05 - 0.99 (m, 3H),0.93 - 0.80 (m, 9H). Mixture of diastereomers.(3S,5S)-5-(tert-Butyl)-3-(2-methoxypropyl)piperidine-3-carboxylic acidDibenzyl (3S,5S)-5-(tert-butyl)-3-(2-methoxypropyl)piperidine-l,3-dicarboxylate (1.65 g, 3.43 mmol) and ammonium formate (864 mg, 13.7 mmol) were dissolved in EtOH(50.0 mL). Palladium on charcoal (10%, 365 mg, 0.343 mmol) was then added and the reaction heated to reflux for 1 hour. The reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure to afford (3S,5S)-5-(tert-butyl)-3-(2- methoxypropyl)piperidine-3-carboxylic acid (980 mg).XH NMR (400 MHz, CDCh): 5 3.54 - 3.30 (m, 4H), 3.25 (d, J=12.1 Hz, 3H), 2.59 - 2.44(m, 2H), 2.18 - 1.91 (m, 2H), 1.65 - 1.53 (m, 2H), 1.44 - 1.27 (m, 1H), 1.16 - 1.09 (m,3H), 0.8g (d, J=5.6 Hz, 9H).

[0247] Synthesis of methyl (3S, 5S)-5-ftert-butvl)-3-(2-methoxvpropyl)piperidine-3-carboxvlate1-Benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxypropyl)piperidine-l,3- dicarboxylateA solution of 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxylate (1.15 g, 3.4 mmol) in THF (20.0 mL) at -78°C under a nitrogen atmosphere was treated dropwise with 1 M lithium bis(trimethylsilyl)amide (IM in THF) (5.2 mL, 5.17 mmol) and stirred cold for 1.25 hours. 2-methoxypropyl trifluoromethanesulfonate (1.51 mg, 6.8 mmol) was added dropwise and the mixture was allowed to warm to ambient temperature and stirred for an additional 3 hours. The reaction was quenched with saturated. NH4CI and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried (Na2SO<), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc in cyclohexane to afford 1 -benzyl3-methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxypropyl)piperidine-l,3-dicarboxylate (1.31 g)-XH NMR (400 MHz, CDCI3): 5 7.39 - 7.27 (m, 5H), 5.20 - 5.09 (m, 2H), 4.79 - 4.69 (m,1H), 4.36 - 4.22 (m, 1H), 3.55 - 3.50 (m, 3H), 3.40 - 3.28 (m, 2H), 3.20 (d, J=8.3 Hz, 3H),2.49 - 2.30 (m, 3H), 1.89 - 1.73 (m, 1H), 1.29 - 1.20 (m, 1H), 1.11 - 0.97 (m, 4H), 0.90(d, J=8.1 Hz, 9H).MS (ESI) m / z 406.4 [M+H]+Methyl (3S,5S)-5-(tert-butyI)-3-(2-methoxypropyl)piperidine-3-carboxylateA mixture of 1 -benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(2-methoxypropyl)piperidine-1,3 -dicarboxylate (1.31 g, 3.23 mmol), ammonium formate (2.037 g, 32.3 mmol) and palladium (10% on carbon) (10%, 172 mg, 0.162 mmol) in MeOH (20.0 mL) was heated at reflux for 1 hour. The cooled reaction mixture was filtered through Celite, washed withMeOH (50 mL) and concentrated in vacuo to afford methyl (3S,5S)-5-(tert-butyl)-3-(2- methoxypropyl)piperidine-3-carboxylate (887 mg).MS (ESI) m / z 272.2 [M+H]+.

[0248] Synthesis of acid hydrochloride 'Step 1: (3R,5S)-l-[(tert-butoxy)carbonyI]-5-tert-butylpiperidine-3-carboxyIic acidTo a solution of (3 R,5S)-5-tert-butylpiperidine-3 -carboxy lie acid hydrochloride (3.8 g,17.1 mmol) in DCM (50 mL) were added triethylamine (7.2 mL, 51.4 mmol) and di-tert- butyl decarbonate (4.3 mL, 18.9 mmol). The reaction was stirred at room temperature for3 hours. The reaction was quenched with water and 2N HC1 and extracted with DCM.The organic phase was concentrated in vacuo. The crude material was used in the next step without further purifications (6.0 g). MS (ESI) m / z 285.0 [M+H]+.Step 2: 1-tert-butyl 3-(4-methoxyphenyl)methyl (3R,5S)-5-tert-butylpiperidine-l,3- dicarboxylateA mixture of (3R,5S)-l-[(tert-butoxy)carbonyl]-5-tert-butylpiperidine-3-carboxylic acid(2.8 g, 10.0 mmol), CS2CO3 (3.6 g, 11.0 mmol) and 4-methoxybenzyl chloride (1.8 mL,13.0 mmol) in DMF (40 mLO was stirred at room temperature for 4 hours. The reaction was diluted with water and extracted with EtOAc. The organic phase was concentrated and the residue was purified by column chromatography (SiOz, EtOAc / hexane) to give the desired product (1.6 g).XH NMR (400 MHz, CDC13) 5 7.34 - 7.27 (m, 2H), 6.89 - 6.86 (m, 2H), 5.16 - 5.05 (m,1H), 4.97 (d, J=11.9 Hz, 1H), 4.57 - 4.49 (m, 1H), 4.28 - 4.10 (m, 1H), 3.80 (s, 3H), 3.69(s, 1H), 2.86 - 2.80 (m, 1H), 2.71 - 2.64 (m, 1H), 2.50 - 2.34 (m, 1H), 2.27 (d, 1=11.7 Hz,1H), 1.43 (s, 9H), 1.37 - 1.26 (m, 1H), 0.87 (s, 9H).Step 3: 1-tert-butyl 3-(4-methoxyphenyl)methyl (3R,5R)-5-(but-2-yn-l-yl)-5-tert- butylpiperidine-13-dicarboxylateA solution of 1 -tert-butyl 3-(4-methoxyphenyl)methyl (3R,5S)-5-tert-butylpiperidine-1,3 -dicarboxylate (1.6 g, 3.9 mmol) in 2-methyltetrahydrofuran (20 mL) was cooled to -70°C and then IM KHMDS (5.9 mL, 5.9 mmol) was added. After 1 hour, l-bromo-2- butyne (0.4 mL, 4.73 mmol) was added. The reaction was stirred at room temperature for72 hours and then quenched with NH4CI and extracted with EtOAc. The organic phase was concentrated and the residue was purified by column chromatography (SiOz,EtOAc / hexane) to give the desired product (540 mg). MS (ESI) m / z 358.0 [M- tBu]+.Step 4: (3S,5S)-3-(but-2-yn-l-yl)-5-tert-butylpiperidine-3-carboxylic acid hydrochlorideA mixture of 1 -tert-butyl 3-(4-methoxyphenyl)methyl (3R,5R)-5-(but-2-yn-l-yl)-5-tert- butylpiperidine- 1,3 -dicarboxy late (270 mg, 0.59 mmol) in 4N HC1 in dioxane (2.2 mL,8.8 mmol) was stirred at room temperature for 16 hours. The reaction was concentrated and then dilute with water and extracted with EtOAc. Aqueous phase was concentrated in vacuo to give the desired product (145 mg). MS (ESI) m / z 238.3 [M- tBu]+.

[0249] 1-Benzyl 3-methyl (3R,5S)-5-tert-butyl-3-[(oxan-4-yl)methyl]piperidine-l,3- dicarboxylateThe title compound was made following similar methods described in general procedure[KHMDS alkylation] starting from 1-benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-1,3-dicarboxylate and 4-(bromomethyl)oxane. MS (ESI) m / z 432.2 [M+H]+.Methyl (3R,5S)-5-tert-butyl-3-[(oxan-4-yl)methyl]piperidine-3-carboxylateThe title compound was made following similar methods described in general procedure[Hydrog] starting from 1 -benzyl 3-methyl (3R,5 S)-5 -tert-butyl-3 -[(oxaneyl)methyl]piperi dine- 1,3 -dicarboxylate. MS (ESI) m / z 298.4 [M+H]+.Potassium (3R,5S)-5-tert-butyl-3-[(oxan-4-yl)methyl]piperidine-3-carboxylateTo a solution of methyl (3R,5S)-5-tert-butyl-3-[(oxan-4-yl)methyl]piperidine-3- carboxylate (500 mg, 1.68 mmol) in anhydrous THE (20.0 mL) was added potassium trimethylsilanolate (1.08 g, 8.41 mmol). The reaction mixture was stirred vigorously at reflux (70 °C) for 20 hours. At this stage, the reaction mixture was cooled to room temperature and the desired product was collected by filtration, washed with THE (3 x 10 mL) and EtzO (50 mL), before being dried in vacuo to give potassium (3R,5S)-5-tert- butyl-3-[(oxan-4-yl)methyl]piperidine-3-carboxylate (948 mg). MS (ESI) m / z 284.2[M+H]+.

[0250] Synthesis of (3R,5S)-5-tert-butvl-3-(4.4-difluorobutvl)viveridine-3-carbox\>lic acidhydrochlorideOl-benzyl O3-methyl (3R,5S)-5-tert-butyl-3-[3-(13-dioxolan-2- yl)propyl]piperidine-l,3-dicarboxylateThe title compound was made following similar methods described in general method[KHMDS alkylation] starting from 1-benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-1,3-dicarboxylate and 2-(3-bromopropyl)-l,3-dioxolane. MS (ESI) m / z 448 [M+H]+.1-benzyl O3-methyl (3R,5S)-5-tert-butyl-3-(4-oxobutyl)piperidine-13- dicarboxylateTo a stirred solution of IM aqueous HCI (25.0 mL, 25.0 mmol) in THE (25.0 mL) was added Ol-benzyl O3-methyl (3 R,5 S)-5 -tert-buty 1-3 - [3 -( 1 ,3 -dioxo lan-2- yl)propyl]piperidine- 1,3 -dicarboxylate (6.20 g, 10.7 mmol). The mixture was heated to40°C overnight. Further IM aqueous HCI (25.0 mL) was added and heating continued for4 days. The solution was allowed to cool to room temperature and extracted with EtOAc.The separated organic layer was washed with IM aqueous HCI and brine, then dried(Na2SO<), filtered and evaporated in vacuo, azeotroping with DCM to afford 01 -benzyl03-methyl (3R,5S)-5-tert-butyl-3-(4-oxobutyl)piperidine-l,3-dicarboxylate (5.13 g). MS(ESI) m / z 404 [M+H]+.Ol-benzyl O3-methyl (3R,5S)-5-tert-butyl-3-(4,4-difluorobutyI)piperidine-l,3- dicarboxylateTo a stirred solution of Ol-benzyl 03-methyl (3R,5S)-5-tert-butyl-3-(4- oxobutyl)piperidine-l,3-dicarboxylate (4.40 g, 10.9 mmol) in DCM (90 mL) cooled in an ice bath under a nitrogen atmosphere was added diethylaminosulfur trifluoride (6.10 ml.,46.5 mmol). After stirring at low temperature for 15 mins, the pale yellow solution was stirred at room temperature for 3 hrs. Saturated aqueous NaHCOa (100 ml) was added slowly, followed by solid NaHCOa. The separated aqueous layer was extracted with DCM(2 x 100 mL), then activated charcoal was added and the mixture was stirred for 15 mins.NazSO4 was added and the mixture was filtered and evaporated in vacuo to leave a yellow oil. The crude material was purified by column chromatography over silica eluting with a gradient of EtOAc (0% to 50%; v / v) in iso-hexane to afford Ol-benzyl 03-methyl(3R,5S)-5-tert-butyl-3-(4,4-difhiorobutyl)piperidine-l,3-dicarboxylate (2.88 g). MS(ESI) m / z 426 [M+H]+.Methyl (3R,5S)-5-tert-butyl-3-(4,4-difluorobutyl)piperidine-3-carboxylateThe title compound was made following similar methods described in general method[Hydrog] starting from Ol-benzyl 03-methyl (3R,5S)-5-tert-butyl-3-(4,4- difluorobutyl)piperidine-l,3-dicarboxylate. MS (ESI) m / z 292 [M+H]+.(3R,5S)-5-tert-Butyl-3-(4,4-difluorobutyl)piperidine-3-carboxylic acid hydrochlorideThe title compound was made following similar methods described in general method[HC1 hydrol] starting from methyl (3R,5S)-5-tert-butyl-3-(4,4-difluorobutyl)piperidine-3 -carboxylate. MS (ESI) m / z 278 [M+H]+.

[0251] Synthesis of (3S.5S)-5-(tert-btityl)-3-(methylthio)piperidine-3-carboxylic acid hydrochloride1-Benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(methylthio)piperidine-l,3-dicarboxy lateThe title compound was made following similar methods described in general method[KHMDS alkylation] starting from 1-benzyl 3-methyl (3R,5S)-5-(tert-butyI)piperidine-1,3 -dicarboxylate and dimethyl disulfide. MS (ESI) m / z 380 [M+H]+.(3S,5S)-5-(tert-Butyl)-3-(methyIthio)piperidine-3-carboxyIic acid hydrochlorideThe title compound was made following similar methods described in general method[HCI hydrol] starting from 1-benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(methylthio)piperidine-l,3-dicarboxylate. MS (ESI) m / z 232 [M+H]+.

[0252] Synthesis of (3 R, 5S)-3-(Cvclopropylmethvl)-5-isopropyl-piperidine-3-carboxylic acidOl-benzyl O3-methyl (3R,5S)-3-(cyclopropyhnethyl)-5-isopropyl-piperidine-l,3- dicarboxylateThe title compound was made following similar methods described in general method[KHMDS alkylation] starting from (3R,5S)-l-[(benzyloxy)carbonyl]-5-(propan-2- yl)piperidine-3-carboxylic acid and cyclopropylmethyl bromide. MS (ESI) m / z 374[M+H]+.Methyl (31?,55)-3-(cyclopropylmethyl)-5-isopropyI-piperidine-3-carboxylateThe title compound was made following similar methods described in general method[Hydrog] starting from 01 -benzyl 03-methyl (3J?,5S)-3-(cyclopropylmethyl)-5- isopropyl-piperidine-l,3-dicarboxylate. MS (ESI) m / z 240 [M+H]+.(3R,5S)-3-(cyclopropylmethyl)-5-isopropyl-piperidine-3-carboxylic acidThe title compound was made following similar methods described in general method[NaOH Hydrol] starting from methyl (3R,5S)-3-(cyclopropylmethyl)-5-isopropyl- piperidine-3-carboxylate. MS (ESI) m / z 226 [M+H]+.

[0253] Synthesis of (3R.5S)'-3-(2-Cyclopropyleth.yB-5-isopropyl-piperidine-3-carboxvUc acid hydrochloride oOl-benzyl O3-methyl (3R,5S)-3-(2-cyclopropylethyl)-5-isopropyl-piperidine-l,3- dicarboxylateThe title compound was made following similar methods described in general method[KHMDS alkylation] starting from (3R,5S)-l-[(benzyloxy)carbonyl]-5-(propan-2- yl)piperidine-3 -carboxylic acid and (2-bromoethyl)cyclopropane. MS (ESI) m / z 388[M+H]+.Methyl (3R,5S)-3-(2-cyclopropylethyl)-5-isopropylpiperidine-3-carboxylateThe title compound was made following similar methods described in general method[Hydrog] starting from Ol-benzyl 03-methyl (3R,5S)-3-(2-cyclopropylethyl)-5- isopropyl-piperidine- 1,3 -dicarboxy late. MS (ESI) m / z 254 [M+H]+.(3R,5S)-3-(2-Cyclopropylethyl)-5-isopropylpiperidine-3-carboxylic acid hydrochlorideThe title compound was made following similar methods described in general method[LiOH hydrol / HCl salt] starting from methyl (3R,5S)-3-(2-cyclopropylethyl)-5- isopropylpiperidine-3-carboxylate. MS (ESI) m / z 240 [M+H]+.

[0254] Synthesis of methyl yUmethyUpiperidine-3-carboxylate(S)-(T etrahy dr ofuran-2-yl)m ethyl trifluoromethanesulfonate(S)-(Tetrahydrofuran-2-yl)methanol (395 mg, 3.87 mmol) was dissolved in DCM (10.0 mL). 2,6-dimethylpyridine (1.3 mL, 11.2 mmol) was added and the resulting mixture was cooled to -78 °C under N2. Trifluoromethanesulfonic anhydride (0.66 mL, 3.92 mmol,1.01 eq) was added, and the mixture was allowed to stir at -78 °C under N2 for 1 hour.The mixture was then poured on to rapidly stirred, cold (0 °C) mixture of isohexane (100 mL) and sat. NaHCCh (100 mL). The organic phase was washed with IM HC1 (100 mL) before being concentrated in vacuo. The resulting hexane solution of (S)-(tetrahydrofuran-2-yl)methyl trifluoromethanesulfonate was used directly in the next step.1-Benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(((R)-tetrahydrofuran-2- yl)methyl)piperidine-l,3-dicarboxylate1-Benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxylate (700 mg, 2.10mmol) was dissolved in THE (25.0 mL) and cooled to -78 °C. Potassium bis(trimethylsilyl)azanide (3.5 mL, 3.15 mmol) was added and the resulting mixture stirred for 1 hour at -78 °C under N2. The hexane solution of (S)-(tetrahydrofuran-2- yl)methyl trifluoromethanesulfonate (885 mg, 3.78 mmol) was added to mixture at -78 °C, under N2. The mixture was then allowed to warm to and stir at room temperature for 19 hours. The mixture was concentrated to dryness and the resulting brown oil was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with additional EtOAc (50 mL), the organics were combined and concentrated and the crude material was purified by column chromatography over silica eluting with a gradient of EtOAc (0% to 35%; v / v) in isohexane to afford the desired product (545 mg). MS (ESI) m / z 418 [M+H]+.Methyl (3S,5S)-5-(tert-butyl)-3-(((R)-tetrahydrofuran-2-yl)methyl)piperidine-3- carboxylateThe title compound was made following similar methods described in general procedure[Hydrog] starting from 1 -benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-(((R)-tetrahydrofuran-2-yl)methyl)piperidine- 1,3 -dicarboxylate. MS (ESI) m / z 284 [M+H]+.

[0255] Synthesis of methyl yllmethvUpiperidine-3-carboxylate1-Benzyl 3-methyl (3R,5S)-5-tert-butyl-3-({[tris(propan-2- yl)silyl]oxy}methyl)piperidine-l,3-dicarboxylateThe title compound was made following similar methods described in general method[KHMDS alkylation] starting from 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-1,3 -dicarboxylate and chloromethoxy(triisopropyl)silane. MS (ESI) m / z = 520 [M+H]+.1-Benzyl 3-methyl (3R,5S)-5-tert-butyI-3-(hydroxymethyl)piperidine-l,3- dicarboxylateTo a solution of 1-benzyl 3-methyl (3R,5S)-5-tert-butyl-3-({[tris(propan-2- yl)silyl]oxy}methyl)piperidine-l,3-dicarboxylate (4.97 g, 6.31 mmol) in THE (86.5 mL) was added tetrabutylammonium fluoride (14.9 mL, 14.9 mmol) dropwise and the mixture was stirred at room temperature for 1 h. The reaction was concentrated in vacuo before being redissolved in DCM (200 mL). Water (200 mL) was added and the layers were separated. The aqueous was extracted with further DCM (100 mL). The combined organics were then dried (NaiSO^ and concentrated in vacuo. The crude material was purified by column chromatography over silica eluting with a gradient of EtOAc (0% to50%; v / v) in isohexane to afford 1-benzyl 3-methyl (3R,5S)-5-tert-butyl-3-(hydroxymethyl)piperidine-l,3-dicarboxylate (2.46 g). MS (ESI) m / z = 364 [M+H]+.1 -Benzyl 3-methyl (3R,5S)-5-tert-butyl-3-formylpiperidine-l,3-dicarboxy lateThe title compound was made following similar methods described in general method[Oxidation 1] starting from 1 -benzyl 3 -methyl (3R,5S)-5-tert-butyl-3-(hydroxymethyl)piperidine-l,3-dicarboxylate.!H NMR (400 MHz, Chloroform-d) 3 9.53 (s, 1H), 7,41 - 7.29 (m, 5H), 5.21 - 5.06 (m,2H), 4.76 (d, J = 13.7 Hz, 1H), 4.31 (s, 1H), 3.65 (d, J = 31.1 Hz, 3H), 2.94 (d, J = 13.7Hz, 1H), 2.42 (d, J = 27.3 Hz, 2H), 1.51 (q, J = 13.4, 12.4 Hz, 1H), 1.31 (t, J = 12.7 Hz,1H), 0.93 (s, 9H).1-Benzyl 3-methyl (3S,5S)-5-tert-butyl-3-{[(3R)-3-flnoropyrrolidin-l- yl]methyl}piperidine-13-dicarboxylateThe title compound was made following similar methods described in general method[Red Ami] starting from 1-benzyl 3-methyl (3R,5S)-5-tert-butyl-3-formylpiperidine-l,3- dicarboxylate and (3 R)-3 -fluoropyrrolidine hydrochloride in the presence of triethylamine. MS (ESI) m / z = 435 [M+H]+.Methyl (3R,5S)-5-tert-butyl-3-[[(3R)-3-fluoropyrrolidin-l-yl]methyl}piperidine-3- carboxylateA solution of 1-benzyl 3-methyl (3S,5S)-5-tert-butyl-3-{[(3R)-3-fluoropyrrolidin-l- yl]methyl}piperidine-l,3-dicarboxylate (636 mg, 1.46 mmol) in EtOAc (12.0 mL) and methanol (12.0 mL) was purged with Na before the addition of Palladium on activated charcoal (64.0 mg, 10%wt) as a slurry in EtOAc. The resulting mixture was purged withNa before being purged with Ha. The mixture was then rapidly stirred under 1 atm of Ha for 24 h.The reaction was purged with Na, diluted with EtOAc (100 mL), filtered through Celite, and the solids were washed with copious of EtOAc. The filtrate was then concentrated invacuo to afford the desired product (504 mg).TH NMR (400 MHz, Methanol-cU) 8 5.16- 4.97 (m, 1H), 3.73 (s, 3H), 3.56 - 3.49 (m, 1H), 3.08 - 3.01 (m, 1H), 2.84 - 2.69 (m,4H), 2.59 (d, J = 13.2 Hz, 1H), 2.53 - 2.46 (m, 1H), 2.31 - 2.18 (m, 3H), 2.14 - 2.04 (m,1H), 1.97 - 1.83 (m, 1H), 1,15 - 1.09 (m, 2H), 0.87 (s, 9H).

[0256] Synthesis of methyl (3R,5S)-5-tert-butvl-3-[(3,3-difluoroazetidin-l-yl)methvllDweridine-3-carboxylateCbz H1-Benzyl 3-methyl (3R,5S)-5-tert-butyl-3-{[2-(trimethylsilyl)ethoxy]methyl]piperidine-l,3-dicarboxylateThe title compound was made following similar methods described in General method[KHMDS alkylation] starting from 1 -benzyl 3-methyl (3R,5S)-5-(tert-butyl)piperidine-1,3 -dicarboxylate and [2-(chloromethoxy)ethyl]trimethylsilane. MS (ESI) m / z 464.2[M+H]+.1-Benzyl 3-methyl (3R,5S)-5-tert-butyl-3-(hydroxymethyl)piperidine-l,3- dicarboxylateTo a solution of 1 -benzyl 3-methyl (3R,5S)-5-tert-butyl-3-{ [2-(trimethylsilyl)ethoxy]methyl}piperidine-l,3-dicarboxylate (4.59 g, 9.90 mmol.) inDCM (153 mL) was added trifluoroacetic acid (19.1 mL, 250 mmol). The resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then poured onto saturated NaHCOa solution (200 mL) and the pH was then adjusted to pH 8.The mixture was then extracted with DCM (2 x 150 mL), washed with H2O (1 x 150 mL), brine (1 x 150 mL), then dried over NazSO4, filtered and evaporated to give 1 -benzyl 3- methyl (3R,5S)-5-tert-butyl-3-(hydroxymethyl)piperidine-l,3-dicarboxylate (3.37 g).MS (ESI) m / z 364.0 [M+H]+.1-Benzyl 3-methyl (3R,5S)-5-tert-butyl-3-formylpiperidine-l,3-dicarboxylateTo a solution of 1 -benzyl 3-methyl (3R,5S)-5-tert-butyl-3-(hydroxymethyl)piperidine-1,3 -dicarboxylate (1.10 g, 3.03 mmol) in DCM (54.0 mL) was added solid Dess-Martin periodinane (2.57 g, 6.05 mmol, 2.00 eq.) and the suspension was stirred at room temperature for 3 hours. The reaction was quenched with a 1:1 mixture of saturatedNazSzOa and saturated NaHCOs solution (100 mL). Additional DCM was added (50 mL) and the aqueous layer was extracted twice more with DCM (2 x 50 mL). The organics were combined, washed with saturated NaHCOs solution (2 x 100 mL), brine (100 mL), dried over NaaSO4 and concentrated to afford 1 -benzyl 3-methyl (3R,5S)-5-tert-butyl-3- formylpiperidine-l,3-dicarb oxy late (1.15 g). MS (ESI) m / z 362.2 [M+H]+.1-Benzyl 3-methyl (3S,5S)-5-tert-butyl-3-[(3,3-difluoroazetidin-l- yl)methyl]piperidine-l,3-dicarboxylateA mixture of 3,3-difluoroazetidine hydrochloride (488 mg, 3.77 mmol) and triethylamine(0.600 mL, 4.31 mmol) in DCE (36.1 mL) was stirred to full dissolution. To this mixture was added 1 -benzyl 3-methyl (3R, 5 S)-5-tert-buty 1-3 -formylpiperidine- 1,3 -dicarboxy late(1.15 g, 3.18 mmol) and the resultant mixture was stirred at room temperature for 2 hours.After this time, NaBH(OAc)s (1.35 g, 6.35 mmol) was added and the reaction mixturewas stirred at room temperature for 20 hours. The reaction mixture was then concentrated in vacuo (to ca. 20 mL) and poured onto saturated NaHCOa solution (100 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organics were washed with NaHCOa solution (2 x 50 mL) and brine (1 x 50 mL), dried over Na2SO4, filtered and evaporated. This crude material was purified by column chromatography on silica gel eluting with 0-60% EtOAc in iso-hexane to give the desired product (482 mg).MS (ESI) m / z 439.0 [M+H]+.Methyl (3R,5S)-5-tert-butyl-3- [(3,3-difluoroazetidin-l-yl)methyl] piperidine-3- carboxylateThe title compound was made following similar methods described in general method[Hydrog] starting from 1 -benzyl 3-methyl (3S,5S)-5-tert-butyl-3-[(3,3-difluoroazetidin- l-yl)methyl]piperidine- 1,3 -dicarboxylate. MS (ESI) m / z 305.2 [M+H]+.

[0257] Synthesis of methyl (3S, 5S)-5-(tert-butyl)-3-isobutoxypiperidine-3-carboxylate1-Benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-((2-methylallyl)oxy)piperidine-l,3- dicarboxylateThe title compound was prepared starting from 1 -benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3 -hydroxypiperidine- 1,3 -dicarboxylate and 3-bromo-2-methylpropene following similar methods to those described in general procedure [NaH Alkylation].lH NMR (400 MHz,CDC13): 5 7.41 - 7.27 (m, 5H), 5.15 - 5.12 (m, 2H), 4.96 (s, 1H), 4.87 (s, 1H), 4.76 -4.72 (m, 1H), 4.30 - 4.27 (m, 1H), 3.88 (d, J=11.6 Hz, 1H), 3.80 - 3.76 (m, 1H), 3.70 -3.55 (m, 3H), 2.74-2.70 (m, 1H), 2.59- 2.52 (m, 1H), 2.48 - 2.44 (m, 1H), 1.73 (s, 3H),1.47 - 1.38 (m, 2H), 0.92 (s, 9H).Methyl (3S,5S)-5-(tert-butyl)-3-isobutoxypiperidine-3-carboxylateThe title compound was prepared stating from 1 -benzyl 3-methyl (3S,5S)-5-(tert-butyl)-3-((2-methylallyl)oxy)piperidine-l,3-dicarboxylate following similar methods to those described in general procedure [Hydrog]. *H NMR (400 MHz, DMSO): 3 3.71 (s, 3H),3.24 - 3.15 (m, 2H), 3.06 - 3.01 (m, 1H), 2.95 - 2.89 (m, 1H), 2.46 - 2.39 (m, 1H), 2.27(d, 1=11.9 Hz, 1H), 2.21 - 2.09 (m, 1H), 1.73 - 1.65 (m, 1H), 1.26 - 1.16 (m, 1H), 1.13 -1.06 (m, 1H), 0.89 - 0.85 (m, 15H).

[0258] (3S, 5S)-5-Tert-butyl-3-fluoroviperidine-3-carboxylic acid hydrochlorideMethyl (3R,5S)-5-tert-butyl-l-(triphenylmethyl)piperidine-3-carboxylateTriethylamine (3.0 mL, 21.5 mmol) was added to a suspension of (2R,3R)-2,3-bis(4- methylbenzoyloxy)butanedioic acid methyl (3R,5S)-5-tert-butylpiperidine-3-carboxylate(2.2 g, 3.7 mmol) inDCM (30.0 mL) followed by (chlorodiphenylmethyl)benzene (1.3 g,4.6 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted with EtOAc and washed with NaHCOg and brine. The organic phase was concentrated and the residue was purified by column chromatography(EtOAc / heptane) to give the desired product (1.37 g). *H NMR (400 MHz, Chloroform- d) 8 7.55 - 7.02 (m, 15H), 3.87 (s, 3H), 3.52 (d, J = 11.5 Hz, 1H), 3.22 (d, J = 11.2 Hz,1H), 2.65 (s, 1H), 2.18 (d, J = 12.9 Hz, 2H), 1.69 (s, 1H), 1.56 (s, 1H), 0.96 (td, J = 16.3,15.5, 9.8 Hz, 1H), 0.79 (s, 9H).Methyl (3S,5S)-5-tert-butyl-3-fluoro-l-(triphenyhnethyl)piperidine-3-carboxylateLiHMDS IM in THE (1.5 mL, 3.0 mmol) was added to a solution of methyl (3R,5S)-5- tert-butyl- l-(triphenylmethyl)piperidine-3 -carboxylate (0.82 g, 1.85 mmol) in THF (30.0 mL) at -78C, under N2. After 30 minutes, a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (1.0 g, 3.17 mmol) in THF (lOmL) was added and the reaction was stirred at room temperature overnight. The reaction was diluted withEtOAc and washed with NaHCOg and brine. The organic phase was concentrated to give the desired product (1.1 g) which was used in the next step without further purification.(3S,5S)-5-tert-Butyl-3-fluoropiperidine-3-carboxylic acid hydrochlorideHC1 4M in dioxane (5.0 mL, 20.0 mmol) was added to methyl (3S,5S)-5-tert-butyl-3- fluoro- l-(triphenylmethyl)piperidine-3 -carboxylate (180.0 mg, 0.39 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, the residue was diluted in TBME and the product was extracted with water. The aqueous phase was freeze dried to give the desired product (400 mg). MS(ESI) m / z 218 [M+H]+.’H NMR (400 MHz, DMSO-de) 5 10.48 (s, 1H), 8.64 (s, 1H), 3.81 (s, 3H), 3.20 (d, J =12.2 Hz, 2H), 2.73 (t, J = 12.8 Hz, 2H), 2.35 (d, J = 12,3 Hz, 1H), 1.76 (dt, J = 15.3, 12.7Hz, 1H), 1.57 (t, J = 12.7 Hz, 1H), 0.89 (s, 9H).

[0259] Synthesis of (3S.5S)-5-tert-butyl-3-(2-methoxvethyl)niperidine-3-carboxvlic acid1,3-Dibenzyl (3S,5S)-5-tert-butyl-3-(2-methoxyethyl)piperidine-l,3-dicarboxylateTo a -78 °C solution of dibenzyl (3R,5S)-5-(tert-butyl)piperidine-l,3-dicarboxylate (2.85g, 6.96 mmol) in THE (30.0 mL) was added KHMDS (10.4 mL, 10.5 mmol) over 10 minutes. The reaction was stirred for 1 hour and then 1 -bromo-2-methoxyethane (1.3 mL,13.9 mmol) and stirred at -78 °C for 35 minutes before warming to room temperature overnight. The reaction mixture was diluted with EtOAc (200mL) and washed with satNH4CI, brine and dried over sodium sulfate. The crude material was purified by column chromatography over silica eluting with a gradient 0-100% EtOAc in isohexane to afford the desired product (2.0 g). MS (ESI) m / z 468.4 [M+H]+.(3S,5S)-5-tert-ButyI-3-(2-methoxyethyl)piperidine-3-carboxylic acidTo solution of 1,3-dibenzyl (3S,5S)-5-tert-butyl-3-(2-methoxyethyl)piperidine-l,3- dicarboxylate (2.0 g, 4.277mmol) in EtOAc (30.0 mL). The reaction mixture was degassed and a slurry of 10% Pd / C in EtOAc (0.210 g, in 4 mL) added under nitrogen.The reaction was subjected to 1 atm of H2 gas overnight. The reaction mixture was filtered through a celite pad, washed with EtOAc, MeCN / water 1:1 (2x20mL). The solvent was removed in vacuo to afford the desired product (815 mg). MS (ESI) m / z 244.2 [M+H]+.

[0260] (3R,5S)-5-tert-Butyl-3- [(oxan-4-yl)methyl] piperidine-3-carboxylic acid hydrochlorideA solution of methyl (3R,5S)-5-tert-butyl-3-[(oxan-4-yl)methyl]piperidine-3 -carboxy late(600.0 mg, 2.017 mmol) in cone. HC1 (10.0 mL) was stirred at 100 °C for 8 days.The reaction mixture was cooled and concentrated in vacuo. The residue was then redissolved in acetonitrile / water and concentrated and dried in a vacuum oven. This afforded (3R,5S)-5-tert-butyl-3-[(oxan-4-yl)methyl]piperidine-3-carboxylic acid hydrochloride (726.0 mg).‘HNMR (400 MHz, DMSO) 5 13.19 (s, 1H), 9.94 (d, J = 12.2 Hz, 1H), 7.57 (d, J = 12.0Hz, 1H), 3.77 (dd, J = 10.4, 5.2 Hz, 2H), 3.52 (d, J = 12.5 Hz, 1H), 3.25 (dt, J = 12.5, 9.8Hz, 2H), 3.13 (d, J= 11.8 Hz, 1H), 2.71 (t, J = 11.9 Hz, 1H), 2.53 (s, 1H), 2.10 (d, J = 8.8Hz, 1H), 1.66 - 1.38 (m, 5H), 1.27 (d, J = 9.3 Hz, 2H), 1.16 (q, J = 12.1 Hz, 2H), 0.84 (s,9H).

[0261] Synthesis of methyl (2R.6S)-6-tert-butylmorvholine-2-carbox\>lateStepl: !-[({[!, l'-biphenyl]-4-yl}methyl)amino]-3,3-dimethylbutan-2-olA solution of 4-phenylbenzylamine (11g, 60 mmol) and 2-tert-butyloxirane (6 g, 60 mmol) in EtOH (300 mL) was stirred at 80°C under Nz for 48 h. The reaction was concentrated in vacuo and the residue was purified by column chromatography (SiOi,EtOAcZEtOH / NHa) to give the desired product (6.7 g).‘HNMR (400 MHz, CDC13): 57.60-7.55 (m, 4 H), 7.46-7.33 (m, 5 H), 3.85 (dd, J = 13.3,33.8 Hz, 2 H), 3.32 (dd, J = 2.8, 10.7 Hz, 1 H), 2.85 (dd, J = 2.9, 11.8 Hz, 1 H), 2.54-2.47(m, 1 H), 0.92 (s, 9 H).Step 2: 4-({[l,l'-biphenyl]-4-yl}methyl)-2-tert-butyl-6-ethenylmorpholinePPha (2.6 g, 10.1 mmol) and Pd(PPh3)4(1.9 g, 1.7 mmol) were added to a solution of 1-[({[l,r-biphenyl]-4-yl}methyl)amino]-3,3-dimethylbutan-2-ol (9.6 g, 34.0 mmol), but-2-en-l,4-diyl diacetated (5.9 g, 34.2 mmol) and DBU (10.0 mL, 68.3 mmol) in dioxane(450 mL) under Na. The reaction was stirred at 100°C for 18 h. The solvent was removed in vacuo and the crude material was purified by column chromatography (SiOi, cyclohexane / EtOH) to give the desired product as the trans isomer (2.2 g). (6.6 g of the cis isomer were also obtained)Trans isomer. MS (ESI) m / z 336 [M+H]+Step 3: l-[4-({[l,l'-biphenyl]-4-yI}methyl)-6-tert-butyhnorpholin-2-yl]ethane-l,2- diolOsO4(4% solution in water, 0.47 mL, 0.07 mmol) was added to a solution of 4-({[l,l'- biphenyl]-4-yl}methyl)-2-tert-butyl-6-ethenyhnorpholine (2.1g, 6.4 mmol) and 4- methylmorpholine N-oxide (837 mg, 7.1 mmol) in acetone (30 mL) and water (3 mL).The reaction was stirred at room temperature overnight.The reaction as quenched with NaaSaCb and extracted with EtOAc. The organic phase was washed with NaHCOa and then concentrated n vacuo. The residue was filtered through AI2O3 with DCM / MeOH to give the desired product (2.2g)MS (ESI) m / z 370.4 [M+H]+Step 4: 4-({[l,r-biphenyl]-4-yl}methyl)-6-tert-butylmorphoIine-2-carbaldehydeNaIO4 (3.3g, 15.4 mmol) was added to as solution of l-[4-({[l,l'-biphenyl]-4-yl}methyl)-6-tert-butylmorpholin-2-yl]ethane-l,2-diol (2.2 g, 6.1 mmol) in THF (75 mL) and water(25 mL). The reaction was stirred at room temperature for 3h. The reaction was filteredto remove the residual solid and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and brine. The organic phase was concentrated in vacuo to give the desired product (2.3 g).XH NMR (400 MHz, CDCh): 8 9.84 (s, 1 H), 7.59 (d, J = 7.8 Hz, 2 H), 7.54 (d, J = 8.1Hz, 2 H), 7.43 (dd, J = 7.6, 7.6 Hz, 2 H), 7.37-7.30 (m, 3 H), 4.15-4.08 (m, 1 H), 3.61-3.52 (m, 2 H), 3.44 (d, J = 13.4 Hz, 1 H), 3.21 (d, J = 11.6 Hz, 1 H), 2.78 (d, J = 11.1 Hz,1 H), 2.28-2.18 (m, 1 H), 2.00 (d, J = 10.6 Hz, 1 H), 0.96 (s, 9 H).Step 5: methyl (2R,6S)-4-({[l,l,-biphenyl]-4-yl}methyl)-6-tert-butylmorpholine-2- carboxylateNaClCh (1.8g, 20.4 mmol) and NaH2?O4 (2.2 g, 18.5 mmol) were added to a solution of4-({ [1 , 1 '-biphenyl]-4-yl}methyl)-6-tert-butylmorpholine-2-carbaldehyde (2.1 g, 6.1 mmol) in tBuOH / water (1:1 64 mL) at 0°C. The reaction was stirred for 30 min. The reaction was extracted with EtOAc and the organic phase was concentrated in vacuo. The residue was dissolved in toluene (10 mL) and water (10 mL) and then(trimethylsilyl)diazomethane (0.6M in hexane, 10.3 mL, 6.1 mmol) was slowly added drop wise. The resulting mixture was stirred at room temperature for 5min. AcOH (4 drops) was added to the mixture and the solvent was removed in vacuo. The residue was purified by column chromatography (SiCh, EtOAc / cyclohexane) to give the desired product (1.6 g) as a trans racemic mixture.The material was purified by chiral SFC (LUX-Cellulose-3, 21.2 x 250 mm, 5 uM.15 / 85% MeOH (0.1% DEA))Isomer 1 (745 mg) was used in the following stepMS (ESI) m / z 368 [M+H]+Step 6: methyl (2R,6S)-6-tert-butylmorpholine-2-carboxylateA suspension of Pd / C (10%, 400 mg, 3.7 mmoL), methyl (2R,6S)-4-({[l,l'-biphenyl]-4-yl}methyl)-6-tert-butylmorpholine-2-carboxylate (700 mg, 1.9 mmol) and ammonium formate (780 mg, 12.4 mmol) in EtOH (25 mL) was stirred at 65°C for 1 h. The reaction was filtered through Celite and the filtrate was concentrated in vacuo to give the desired product (560 mg) (1 : 1 mixture of morpholine head and 4-phenyltpluene).*H NMR (400 MHz, CDCb): 5 4.34 (d, J = 4.3 Hz, 1 H), 3.79 (s, 3 H), 3.50-3.44 (m, 1H), 3.35 (d, J = 12.6 Hz, 1 H), 3.00-2.87 (m, 2 H), 2.61 (dd, J = 11.7, 11.7 Hz, 1 H), 0.92(s, 9 H).

[0262] The following intermediates were also prepared as described:Table 1 - Additional intermediates, methods of preparation and characterisation.

[0263] Synthesis of 5-(vvridin-2-vl)-l,2-oxazole-3-carbaldehvdeStepl. Synthesis of 5-(pyridin-2-yl)-l,2-oxazol-3-yl]methanol.General procedure [DIBAL Red]To a solution of methyl 5 -(pyridin-2-yl)-l,2-oxazole-3 -carboxylate (500 mg, 2.45 mmol) in THE (12 mL) at -78°C under N2, DIBAL (1.0M in hexane, 7.35 mL, 7.35 mmol) was added and the reaction was allowed to warm up to room temperature over 2 hours. The reaction mixture was quenched with Rochelle’s salt and extracted with AcOEt. The organic phase was concentrated in vacuo, the crude material was purified by column chromatography (KP-sil, AcOEt / petrol) to give the desired product 5-(pyridin-2-yl)-l,2- oxazol-3-yl]methanol (437 mg). MS (ESI) m / z 177.0 [M+H]+Step 2. Synthesis of 5-(pyridin-2-yI)-l,2-oxazole-3-carbaldehyde.General procedure [Oxidation 1]To a suspension of 5-(pyridin-2-yl)-l,2-oxazol-3-yl]methanol (437 mg, 2.48 mmol) inDCM (12 mL) at 0°C, Dess Martin periodinane (1.37 g, 3.23 mmol) was added and the reaction was allowed to warm up to room temperature over 3 hours. The reaction was quenched with NaiSOs, extracted with DCM and concentrated in vacuo. The crude material was purified by column chromatography (KP-sil, AcOEt / petrol) to give the desired product (267 mg). *H NMR (400 MHz, CDCI3): 8 10.25 (s, 1H), 8.79-8.75 (m,1H), 8.02-7.96 (m, 1H), 7.93-7.87 (m, 1H), 7.45-7.41 (m, 1H), 7.30 (s, 1H).

[0264] Synthesis of 4-chloro-N-hydroxypyridine-2-carhonimidovl chlorideGeneral procedure [Oxime formation]As suspension of 4-chloropyridine-2-carbaldehyde (500 mg, 3.53 mmol), hydroxylamine hydrochloride (319 mg, 4.59 mmol) and NaiCOa (243 mg, 2.30 mmol) in water (12 mL) was heated at 100°C in a microwave oven for 5 hours. The reaction mixture was washed with brine, extracted with DCM and concentrated in vacuo. The residue was dissolved inCHCI3 (12 mL) and N-chlorosuccinimide (472 mg, 3.53 mmol) was added. The reaction mixture was stirred at room temperature overnight, washed with brine, extracted withDCM and concentrated in vacuo. The crude material was used in the next step without further purification.

[0265] S'yn / Aesi? o / '2-r5-(bromomethvl')-L2-oxazol-3-vll-4-chloropvridineGeneral procedure [Isoxazole acetylene]A solution of 4-chloro-N-hydroxypyridine-2-carbonimidoyl chloride (598 mg, 3.53 mmol), propargyl bromide (393 pL, 3.53 mmol), CuSO4 (11 mg, 0.02 mmol), NaHCOa(1.2 g, 14.1 mmol), sodium ascorbate (70 mg, 0.35 mmol) in water / tBuOH (12 mL, 1:1) was stirred at room temperature for 16 hours. The reaction was washed with brine, extracted with AcOEt and concentrated in vacuo. The crude material was purified by column chromatography (KP-sil, acetone / petrol) to give 2-[5-(bromomethyl)-l,2-oxazol-3-yl]-4-chloropyridine (247 mg). *HNMR (400 MHz, CDCh): 58.59 (d, J = 5.3 Hz, 1H),8.15-8.07 (m, 1H), 7.39 (dd, J = 5.3, 2.1 Hz, 1H), 6.98 (s, 1H), 4.55 (d, J = 0.6 Hz, 2H).

[0266] Synthesis of 5-(bromomethvl)-3-[3-(cvclobutvlmethyl)vhenyllisoxazole.The title compound was prepared starting from 3-(cyclobutylmethyl)benzaldehyde following similar methods to those described in general procedures [Oxime formation] and [Isoxazole acetylene].MS (ESI) m / z 344.0 [M+H]+

[0267] Synthesis of 5-(4-Chloropyridin-2-yl)-l,2-oxazole-3-carbaldehydeStep 1. Synthesis of Ethyl 5-(4-chloropyridin-2-yl)-l,2-oxazole-3-carboxylateThe title compound was prepared starting from 4-chloro-2-ethynylpyridine and ethyl(2Z)-2-chloro-2-(hydroxyimino)acetate following similar methods to those described in general procedure [Isoxazole acetylene]. MS (ESI) m / z 253.0 [M+H]+Step 2. Synthesis of [5-(4-ChIoropyridin-2-yl)-l,2-oxazol-3-yl]methanoIGeneral procedure [NaBH4 red]NaBEU (75 mg, 2 mmol) was added to a solution of ethyl 5-(4-chloropyridin-2-yl)-l,2- oxazole-3 -carboxylate (250 mg, 1 mmol) in ethanol (4 mL) at room temperature. The reaction was stirred for 1.5 hours and was then concentrated under reduced pressure. The residue was partitioned between EtOAc and IN HC1 (aq.). The organic phase was dried and concentrated under reduced pressure. Column chromatography (SiCh) gave the title compound (140 mg) which was used in the next step without further purification.Step 3. Synthesis of 5-(4-Chloropyridin-2-yI)-l,2-oxazoIe-3-carbaldehydeThe title compound was prepared starting from [5-(4-Chloropyridin-2-yl)-l,2-oxazol-3- yl]methanol following similar methods to those described in general procedure[Oxidation 1]. MS (ESI) m / z 241.0 [M+Na]+

[0268] Synthesis of 5-(5-chloro-4-methylpyri<Bn-2-yl)thiophene-2-carbaldehydeGeneral procedure [Suzuki 1]A suspension of 2-bromo-5-ehloro-4-methylpyridine (477 mg, 2.3 mmol), (5- formylthiophen-2-yl)boronic acid (300 mg, 1.92 mmol), K2CO3 (1.3 g, 9.6 mmol),Pd(dtbpf)Cb (125 mg, 0.19 mmol) in toluene / MeOH (2.5 mL, 1:1) was heated in a microwave oven at 90°C for 20 minutes. The reaction mixture was diluted with water and extracted with DCM. The organic phase was dried and concentrated in vacuo. The residue was purified by column chromatography (KP-sil, EtOAc / petrol) to give the desired product (117 mg).!HNMR (400 MHz, CDCh): 8 9.95 (s, 1H), 8.53 (s, 1H), 7.78 (d, J =4.0 Hz, 1H), 7.66 (d, J = 4.0 Hz, 1H), 7.61 (s, 1H), 2.48 (s, 3H).

[0269] Synthesis of l-(3-chlorophenyl)~lH-imidazole-4-carbdldehydeStep 1. Synthesis of [l-(3-chlorophenyl)-lH-imidazol-4-yl]methanoLGeneral procedure [Borane red]A solution of 1 -(3 -chlorophenyl)- lH-imidazole-4-carboxy lie acid (500 mg, 2.25 mmol) and BH3 (THF complex, IM, 4.5 mL, 4.5 mmol) in THF (5 mL) were refluxed for 2 hours.Three more aliquots of BH3-THF (4.5 mL) were added every 24 hours. The reaction was quenched with MeOH (15 mL) and partitioned between water and AcOEt. The organic phase was dried and concentrated in vacuo. The residues was purified by column chromatography (KP-sil, AcOet / petrol) to give the desired product (165 mg). MS (ESI) m / z209 [M+H]+Step 2. Synthesis of l-(3-chlorophenyl)-lH-imidazole-4-carbaldehydeThe title compound was prepared starting from [1 -(3 -chlorophenyl)- lH-imidazol-4- yljmethanol following similar methods to those described in general procedure[Oxidation 1]. MS (ESI) m / z 207 [M+H]+.

[0270] Synthesis of l-fimidazori,2-a]pyridin-8-vl}-lH-imidazole-4-carbaldehydeStep 1. Synthesis of (l-{hnidazo[l^-a]pyridin-8-yl}-lH-hnidazol-4-yl)methanolA suspension of 8-bromoimidazo[l,2-a]pyridine (350 mg, 1.8 mmol), (lH-imidazol-4- yl)methanol (209 mg, 2.1 mmol), 4,7-dimethoxy-l,10-phenanthroline (64 mg, 0.27mmol), CS2CO3 (810 mg, 2.5 mmol), CuaO (13 mg, 0.09 mmol), PEG Mn 3.400 (700 pL) and NMP (900 pL) was stirred at 110°C for 16 hours. The reaction was filtered throughCelite and concentrated in vacuo. The residue was purified by column chromatography(KP-sil, AcOEt / petrol) to give the desired product (301 mg).'H NMR (400 MHz, CDCI3): 5 8.54 (s, 1H), 8.16 (dd, J = 6.9, 1.2 Hz, 1H), 7.75 (d, J =5.8 Hz, 3H), 7.26-7.18 (m, 1H), 6.90 (t, J = 7.2 Hz, 1H), 4,74 (s, 2H).Step 2. Synthesis of l-{imidazo[l,2-a]pyridin-8-yl}-lH-imidazole-4-carbaldehyde.General procedure [Oxidation 2]MnCh (1.22 g, 14.1 mmol) was added to a solution of (l-{imidazo[l,2-a]pyridin-8-yl}- lH-imidazol-4-yl)methanol (301 mg, 1.4 mmol) in DCM (7 ml) at 0°C. The reaction was the stirred at room temperature for 7 hours. The reaction was filtered through Celite and the filtrate was purified by column chromatography (KP-sil, AcOEt / petrol) to give the desired product (45 mg). MS (ESI) m / z 213 [M+H]+

[0271] Synthesis of 5-chloro-2-methoxvbenzamideGeneral procedure [benzamide formation]To a solution of 5-chloro-2-methoxybenzoic acid (700 mg, 3.75 mmol) in anhydrousDMF (10 mL) and DIPEA (0.98 mL, 5.63 mmol) was added HATU (1.57 g, 4.13 mmol), and the resulting mixture was stirred at room temperature for 25 minutes. This solution was then added to a suspension of NH4CI (602 mg, 11.25 mmol) in anhydrous DMF (10 mL) and DIPEA (2.6 mL, 15.01 mmol), and the reaction was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc (150 mL) and a dilutedNaCOa solution (10%, 200 mL). The layers were separated, and the organic phase was washed with a diluted NaCOa solution (2 x 10%, 200 mL) and brine (30 mL), dried overMgSO4, filtered, and evaporated to afford 5-chloro-2-methoxybenzamide (596 mg). MS(ESI) m / z 186 [M+H]+.

[0272] Synthesis of 2-(2-ethoxypvridin-3-yl)thiazole-5-carbaldehydeGeneral procedure [thiazole cyclisation]Step 1: Synthesis of 2-ethoxypyridine-3-carbothioamideTo a solution of 2-ethoxynicotinamide (615 mg, 3.70 mmol) in CHCla (37 mL) was addedLawesson’s reagent (748 mg, 1.85 mmol), and the reaction was heated at 65°C for 3 hours.After cooling to room temperature, the reaction mixture was evaporated to dryness and purified by column chromatography on silica gel, eluting with 0-60% EtOAc in cyclohexane to afford 2-ethoxypyridine-3 -carbothioamide (488 mg). MS (ESI) m / z 183[M+H]+.Step 2. Synthesis of 2-(2-ethoxypyridin-3-yl)thiazoIe-5-carbaldehydeTo a solution of 2-ethoxypyridine-3-carbothioamide (488 mg, 2.68 mmol, 1.0 eq) in anhydrous THF (27 mL) and pyridine (0.87 mL, 10.71 mmol, 4.0 eq) was added at room temperature bromomalonaldehyde (647 mg, 4.28 mmol, 1.6 eq). The reaction mixture was heated at reflux for 16 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (200 mL) and a diluted NaiCOa solution (10%, 200 mL). The layers were separated, and the organic phase was washed with a diluted NazCOa solution(2 x 10%, 200 mL) and brine (30 mL), dried over MgSO4, filtered and evaporated invacuo. The residue was purified by column chromatography on silica gel, eluting with 5-80% EtOAc in cyclohexane to afford 2-(2-ethoxypyridin-3-yl)thiazole-5-carbaldehyde(387 mg, 1.66 mmol, 62%) as a pale yellow solid. MS (ESI) m / z 235.0 [M+H]+.

[0273] Synthesis of 5-(3-(2.2-difluoroethoxv)pyridin-2-yl)thioohene-2-carbaldehydeStep 1: synthesis of 2-bromo-3-(2,2-difluoroethoxy)pyridineTo a solution of 2-bromopyridin-3-ol (150 mg, 0.86 mmol, 1.0 eq) and l,l-difluoro-2- iodoethane (83 |1L, 0.95 mmol, 1.1 eq) in DMF (3 mL) was added CS2CO3 (421 mg, 1.29 mmol, 1.5 eq) and the mixture was heated to 60°C and stirred for 2 hours. The mixture was then partitioned between EtzO (30 mL) and brine (30 mL). The organic layer was washed again with brine, dried over Na2SC>4, filtered and concentrated to afford 2-bromo-3-(2,2-difluoroethoxy)pyridine (145 mg).JH NMR (400 MHz, CDCb) 3 8.10 - 8.07 (m,1H), 7.27 - 7.18 (m, 2H), 6.17 (tt, 1=54.8, 4.2 Hz, 1H), 4.27 (dt, J=3.9, 12.7 Hz, 2H).Step 2: synthesis of 5-(3-(2,2-difluoroethoxy)pyridin-2-yl)thiophene-2-carbaldehydeThe title compound was prepared from 2-bromo-3-(2,2-difluoroethoxy)pyridine and 5-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yI)thiophene-2-carbaldehyde following a similar procedure to that described in general procedure [Suzuki 1]. *H NMR (400 MHz,CDCh) 39.96 (s, 1H), 8.35 (dd, 1=1.7, 4.0 Hz, 1H), 8.04 (d, 1=4.0 Hz, 1H), 7.78 (d, 1=4.1Hz, 1H), 7.33 - 7.27 (m, 2H), 6.27 (tt, J=3.9, 54.6 Hz, 1H), 4.38 (dt, 1=3.9, 12,9 Hz, 2H).

[0274] Synthesis of 2-(4-ethoxvpyridin-3-yl)thiazole-5-carba.ldehydeStep 1: synthesis of 4-ethoxynicotinamideGeneral procedure [benzamide formation 2]Ethyl 4-ethoxynicotinate (950 mg, 4.87 mmol) was dissolved in 7 N NHa in MeOH (5 mL, 35 mmol) and 35% aqueous ammonia (10 mL, 181 mmol) was added. The reaction mixture was stirred in a sealed tube at 45°C for 18 hours. The cooled mixture was evaporated to dryness and the solid residue collected by filtration. The filter cake was washed with ice-cooled water (5 mL) and dried to afford 4-ethoxynicotinamide (400 mg).MS (ESI) m / z 167.2 [M+H]+.Step 2: Synthesis of 2-(4-ethoxypyridin-3-yl)thiazole-5-carbaldehydeThe title compound was prepared starting from 4-ethoxynicotinamide following similar methods to those described in general procedures [benzamide formation] and [thiazole cyclisation] to give 2-(4-ethoxypyridin-3-yl)thiazole-5-carbaldehyde. MS (ESI) m / z235.0 [M+H]+.

[0275] Synthesis of 2-(2-(2-( (tert-butyldimethvlsilvl)oxy)ethoxv)-5-chlorovhenyl)thiazole-5- carbaldekvdeStepl: synthesis of methyl 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-chlorobenzoateTo a solution of methyl 5-chloro-2-hydroxybenzoate (1.0 g, 5.36 mmol) in anhydrousDMF (11 mL) was added K2CO3 (1.11 g, 8.04 mmol) followed by (2-bromoethoxy)(tertbutyl)dimethylsilane (1.4 mL, 6.70 mmol). The resulting suspension was stirred at 60°C for 18 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (100 mL) and a diluted NazCCh solution (10%, 100 mL). The layers were separated, and the organic phase was washed with a diluted NazCCh solution (2 x10%, 100 mL) and brine (30 mL), dried over MgSCh, filtered and evaporated to afford methyl 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-chlorobenzoate (1.88 g).MS (ESI) m / z 345 [M+H]+.Step 2: Synthesis of 2-(2-(2-((tert-butyMimethylsilyI)oxy)ethoxy)-5- chlorophenyI)thiazoIe-5-carbaldehydeThe title compound was prepared starting from methyl 2-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-5-chlorobenzoate following similar methods to those described in [benzamide formation 2] and [thiazole cyclisation]. MS (ESI) m / z 398[M+H]+.

[0276] Synthesis of 5-(4-ethoxwvridazin-3-vl)thiovhene-2-carbaldehvdeStep 1: synthesis of 3-chloro-4-ethoxypyridazineTo a solution of 3,4-dichloropyridazine (737 mg, 4.95 mmol) in EtOH (25 mL) was addedCS2CO3 (1.77 g, 5.44 mmol), and the mixture was stirred at room temperature for 16 hours.The reaction mixture was then filtered, the filter cake washed with DCM (30 mL) and thefiltrate evaporated. The residue was purified by column chromatography on silica gel (0-100% EtOAc in cyclohexane) to afford 3-chloro-4-ethoxypyridazine (628 mg). *H NMR(400 MHz, CDCh): 8 8.89 (d, J=5.8 Hz, 1H), 6.86 (d, J=5.6 Hz, 1H), 4.20 (q, J=7.0 Hz,2H), 1.55 (t, J=7.0 Hz, 3H).Step 2: synthesis of 5-(4-ethoxypyridazin-3-yl)thiophene-2-carbaldehydeThe title compound was prepared starting from 3 - chlor o -4 - ethoxy py ridazine and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde following similar methods to those described in general procedure [Suzuki 1] using Pd(dppf)C12DCM complex. *H NMR (400 MHz, CDCI3): 3 10.01 (s, 1H), 9.06 (d, J=6.0 Hz, 1H),8.18 (d, J=4.0 Hz, 1H), 8.11 (d, J=4.0 Hz, 1H), 7.51 (d, J=6.1 Hz, 1H), 4.40 (q, J=7.0 Hz,2H), 1.52 (t, J=7.0, 3H). MS (ESI) m / z 235.0 [M+H]+.

[0277] Synthesis of 5-(3-ethoxypyridin-2-yl)-4-fluorothiophene-2-carbaldehyde0Step 1: synthesis of 3-ethoxy-2-(tributylstannyl)pyridineTo a solution of 2-bromo-3-ethoxypyridine (150 mg, 0.7 mmol) in THF (5 mL) at -78°C was added n-BuLi (2.5 M in THF, 0.3 mL, 0.7 mmol) dropwise and the mixture was stirred at -78°C for 30 min. Then, tributyltin chloride (0.22 mL, 0.8 mmol) was added dropwise and the mixture was allowed to warm to rt and stirred overnight. The mixture was quenched with sat. NH4CI (30 mL) and extracted with EtOAc (3x 30 mL), the combined organics were washed with H2O (30 mL), brine (30 mL), dried over NztiSO^ filtered and concentrated to afford 3-ethoxy-2-(tributylstannyl)pyridine (306 mg). Crude material used in the next step without further purification. MS (ESI) m / z 414 [M+H]+.Step 2: synthesis of methyl 5-(3-ethoxypyridin-2-yl)-4-fluorothiophene-2- carboxylateGeneral procedure [Stille coupling]A degassed solution of 3-ethoxy-2-(tributylstannyl)pyridine (306 mg, 0.7 mol), methyl 5- bromo-4-fluorothiophene-2-carboxylate (118 mg, 0.5 mmol), Pd(PPh3)4 (86 mg, 0.07 mmol) and CsF (188 mg, 1.2 mmol) in dioxane (5 mL) was heated to 110°C and stirred for 20 hours. After cooling to room temperature, the mixture was quenched with sat.NH4CI (30 mL) and extracted with EtOAc (3x 30 mL), the combined organics were washed with H2O (30 mL), brine (30 mL), dried over Na2SC>4, filtered and concentrated.The residue was purified by column chromatography on silica gel, eluting with 0-50%EtOAc in cyclohexane to afford methyl 5-(3-ethoxypyridin-2-yl)-4-fluorothiophene-2- carboxylate (34 mg). MS (ESI) m / z 282 [M+H]+.Step 3: synthesis of (5-(3-ethoxypyridin-2-yl)-4-fluorothiophen-2-yl)methanolGeneral procedure [LAH Red]To a solution of methyl 5-(3-ethoxypyridin-2-yl)-4-fluorothiophene-2-carboxylate (55 mg, 0.2 mmol) in THF (0.8 mL) at 0°C was added LiAlHU (1 M in THF, 0.22 mL, 0.2 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for2 hours. The mixture was quenched with H2O (40 mL), 2M NaOH (40 mL), extracted with EtOAc (40 mL), dried over Na2SO4, filtered and concentrated to afford (5-(3- ethoxypyridin-2-yl)-4-fluorothiophen-2-yl)methanol (44 mg). MS (ESI) m / z 254 [M+H]+.Step 4: Synthesis of 5-(3-ethoxypyridin-2-yl)-4-fluorothiophene-2-carbaldehydeThe title compound was prepared from (5-(3-ethoxypyridin-2-yl)-4-fluorothiophen-2- yl)methanol following a similar procedure to that described in general procedure[Oxidation 2]. MS (ESI) m / z 252 [M+H]+.

[0278] Synthesis of 3 '-(difluoromethoxy)-[2, 2 '-bithiapheneJ-S-carbaldehydeFStep 1: synthesis of 2-bromo-3-methoxy thiopheneTo a solution of 3 -methoxythiophene (571 mg, 5.1 mmol) in DMF (4.0 mL) was addedNBS (891 mg, 5.1 mmol) and the mixture was stirred at room temperature for 2 hours.The mixture was then partitioned between EtOAc and HzO and the two phases were separated. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with 0-20% EtOAc in cyclohexane to afford 2-bromo-3 -methoxythiophene (740 mg). ’H NMR (400 MHz,CDCh) 3 7.21 (d, 1=5.9 Hz, 1H), 6.77 (d, 1=5.9 Hz, 1H), 3.90 (s, 3H).Step 2: synthesis of 3’-methoxy-[2,2’-bithiophene]-5-carbaldehydeThe title compound was prepared from 2-bromo-3 -methoxythiophene and 5-(4, 4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde following a similar procedure to that described in general procedure [Suzuki 1]. *H NMR (400 MHz, CDCh)6 9.86 (s, 1H), 7.65 (d, 1=4.0 Hz, 1H), 7.27 - 7.22 (m, 2H), 6.90 (d, 1=5.6 Hz, 1H), 4.02(s, 3H).Step 3: synthesis of 3'-hydroxy-[2,2'-bithiophene]-5-carbaldehydeTo a solution of 3'-methoxy-[2,2'-bithiophene]-5-carbaldehyde (157 mg, 0.7 mmol) inDMF (4.0 mL) was added NaSMe (123 mg, 1.75 mmol) and the mixture was heated to100°C in a microwave reactor and stirred for 20 minutes. After cooling to room temperature, the mixture was partitioned between EtzO and sat. aq. NH4CI. The aqueous phase was acidified with 2M aq. HC1 and extracted with EtOAc. The combined organics were dried over NazSO4, filtered and concentrated. The residue was purified by columnchromatography on silica gel, eluting with 0-10% EtOAc in cyclohexane to afford 3'- hydroxy-[2,2'-bithiophene]-5-carbaldehyde (82 mg). ‘H NMR (400 MHz, CDCb) 8 9.74(s, 1H), 7.97 - 7.93 (m, 1H), 7.65 - 7.61 (m, 1H), 7.18 - 7.09 (m, 2H), 6.77 (d, 1=5.6 Hz,1H).Step 4: synthesis of 3'-(difluoromethoxy)-[2,2'-bithiophene]-5-carbaldehydeTo a solution of 3'-hydroxy-[2,2'-bithiophene]-5-carbaldehyde (82 mg, 0.39 mmol) andCS2CO3 (254 mg, 0.78 mmol) in DMF (4.0 mL) was added sodium chlorodifluoroacetate(119 mg, 0.78 mmol) and the mixture was stirred for 2 hours. The mixture was then partitioned between EtzO and H2O and the two phases were separated. The organic phase was dried over NazSO^ filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with 0-40% EtOAc in cyclohexane to afford 3'-(difluoromethoxy)-[2,2'-bithiophene]-5-carbaldehyde (67 mg).'H NMR (400 MHz, CDCb) 69.90 (s, 1H), 7.70 - 7.67 (m, 1H), 7.38 - 7.32 (m, 1H), 7.32- 7.27 (m, 1H), 7.02 - 6.98 (m, 1H), 6.66 (t, J= 73.1 Hz, 1H).

[0279] Synthesis of 5-(2-(difluoromethoxy)vhenvl)'isoxazole-3-carbaldehvdeStep 1: synthesis of ((2-(difluoromethoxy)phenyl)ethynyl)trimethylsilanel-bromo-2-(difluoromethoxy)benzene (2.00 g, 8.97 mmol), ethynyltrimethylsilane (1.4 mL, 9.87 mmol), PPha (470 mg, 1.79 mmol) and diethylamine (9.3 mL, 89.7 mmol) were combined and split between two microwave vials and degassed for 5 minutes before addition of bis(triphenylphosphine)palladium (II) dichloride (378 mg, 0.538 mmol) and copper (I) iodide (102 mg, 0.538 mmol). The vials were heated to 100°C for 50 mins in the microwave. The mixtures were combined to work up, diluted with diethyl ether / water(20 mL each), the organics extracted with ether (2 x 20 mL) and combined, washed with water (3 x 20 mL). The organic phases were passed through a phase separator and concentrated. The crude material was purified by silica column chromatography eluting with 0-10% diethyl ether in cyclohexane to give ((2-(difluoromethoxy)phenyl)ethynyl)trimethylsilane (1.90 g).lHNMR (400 MHz, CDCb):5 7.49 (dd, J=1.6, 7.6 Hz, 1H), 7.34- 7.29 (m, 1H), 7.19 - 7.14 (m, 2H), 6.60 (t, 1=74.4Hz, 1H), 0.26 (s, 9H).Step 2: synthesis of l-(difhioromethoxy)-2-ethynylbenzene((2-(difluoromethoxy)phenyl)ethynyl)trimethylsilane (75%, 1.90 g, 5.93 mmol) was dissolved in 2-methyltetrahydrofuran (20.0 mL) and 1 M tetrabutylammonium fluoride solution (5.9 mL, 5.93 mmol) added at room temperature, the mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by silica column chromatography eluting with 0-20%, EtOAc in cyclohexane) to give 1-(difluoromethoxy)-2-ethynylbenzene (500 mg).JH NMR (400 MHz, CDCb): 5 7.54 (dd,1=1.7, 7.7 Hz, 1H), 7.36 (dt, J=1.8, 7.9 Hz, 1H), 7.22 - 7.17 (m, 2H), 6.60 (t, 1=73.8 Hz, lH), 3.31 (s, 1H).Step 3: synthesis of ethyl 5-(2-(difluoromethoxy)phenyl)isoxazoIe-3-carboxylate l-(difluoromethoxy)-2-ethynylbenzene (450 mg, 2.68 mmol) and ethyl 2-chloro-2-(hydroxyimino)acetate (608 mg, 4.01 mmol) were dissolved in a mixture of DCM (4.0mL) and 2-methyltetrahydrofuran (12.0 mL) and heated to 60°C before triethylamine(0.56 mL, 4.01 mmol) was added and the reaction stirred for 1 hour at 60°C.The reaction mixture was allowed to cool to room temperature, diluted with EtOAc and water, the organic phase was separated and concentrated. The crude was purified by silica column chromatography eluting with 0-100% EtOAc in cyclohexane to give ethyl 5-(2-(difhioromethoxy)phenyl)isoxazole-3 -carboxylate (310 mg). MS (ESI) m / z 284.2[M+H]+.Step 4: synthesis of (5-(2-(difluoromethoxy)phenyI)isoxazol-3-yl)methanolEthyl 5-(2-(difluoromethoxy)phenyl)isoxazole-3-carboxylate (300 mg, 1.06 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and cooled to 0°C, 1 M lithium aluminium hydride (1.1 mL, 1.06 mmol) was then added and the reaction stirred for 30 mins. The mixture was quenched by addition of H2O (0.05 mL), 2N NaOH (0.1 mL) andH2O (0.1 mL) dropwise in sequential fashion. The mixture was stirred for 15 mins,MgSO4 added (~ 5g), and the mixture diluted with EtOAc (15 mL), stirred and allowed to warm to room temperature. The solids were filtered off, washed with EtOAc (50 mL) and the combined filtrate and washings evaporated to (5-(2-(difluoromethoxy)phenyl)isoxazol-3-yl)methanol (126 mg). *H NMR (400 MHz,CDCb): 3 8.03 (dd, >1.8, 7.9 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.35 (dt, >1.1, 7.7 Hz, 1H),7.23 (dd, >0.9, 82 Hz, 1H), 6.85 (s, 1H), 6.61 (s, 1H), 4.86 - 4.83 (m, 2H), 2.05 (s, 1H).Step 5: synthesis of 5-(2-(difluoromethoxy)phenyl)isoxazole-3-carbaldehyde(5-(2-(difluoromethoxy)phenyl)isoxazol-3-yl)methanol (100 mg, 0.415 mmol) was dissolved in tetrahydrofuran (20.0 mL) and manganese(IV) oxide (360 mg, 4.15 mmol) added before heating to 60°C for 2 hours. The reaction mixture was filtered through celite and concentrated to give 5-(2-(difluoromethoxy)phenyl)isoxazole-3-carbaldehyde (85 mg). 'HNMR (400 MHz, CDCh): 8 10.22 (s, 1H), 8.07 (d, >7.8 Hz, 1H), 7.51 (dd, >7.8,7.8 Hz, IH), 7.38 (dd, 1=7.7, 7.7 Hz, 1H), 7.27 (d, J=9.6 Hz, IH), 7.14 (s, IH), 6.64 (t,1=72.7 Hz, IH).

[0280] Synthesis of 5 -(3 -(Difluoromethoxy) -6-isopropylpvridin-2-yl)thiophene-2-carbaldehvdeStep 1: synthesis of 2-chloro-6-iodo-3-(methoxymethoxy)pyridineDIPEA (4.1 mL, 23.54 mmol) was added dropwise over 2 minutes to a stirred solution of2-chloro-6-iodopyridin-3-ol (3.0 g, 11.74 mmol) and chloromethyl methyl ether (1.0 mL,13.17 mmol) in anhydrous DCM (15 mL) at ambient temperature. After 2 hours the reaction was quenched with a saturated NH4CI solution (30 mL), diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined extracts were dried overMgSO4 and the solvent evaporated to afford 2-chloro-6-iodo-3 -(methoxymethoxy )pyri dine (3.7 g).1HNMR(400MHz, CDCla): 37.56 (d, J=8.6Hz, 1H),7.18 (d, 1=8.2 Hz, IH), 5.25 (s, 2H), 3.52 (s, 3H).Step 2: synthesis of 5-(3-(Meth0xymethoxy)-6-(prop-l-en-2-yl)pyridin-2- yl)thiophene-2-carbaldehydeThe title compound was prepared starting from 2-chloro-6-iodo-3 -(methoxymethoxy )pyridine and iospropenylboronic acid pinacol ester following similar methods to those described in general procedure [Suzuki 1] using XPhos Pd G2. *H NMR(400 MHz, CDCI3): 8 9.95 (s, IH), 8.10 (d, 1=4.0 Hz, IH), 7.77 (d, J=4.0 Hz, 1H), 7.54-7.44 (m, 2H), 5.85 (s, 1H), 5.39 (s, 2H), 5.30-5.28 (m, 1H), 3.53 (s, 3H), 2.25 (s, 3H).Step 3: synthesis of 5-(6-Isopropyl-3-(methoxymethoxy)pyridin-2-yl)thiophene-2- carbaldehydeThe title compound was prepared starting from 5-(3-(methoxymethoxy)-6-(prop-l-en-2- yl)pyridin-2-yl)thiophene-2-carbaldehyde following similar methods to those described in general procedure [Hydrog]. MS (ESI) m / z 292.0 [M+H]+.Step 4: synthesis of 5-(3-Hydroxy-6-isopropylpyridin-2-yI)thiophene-2- carbaldehyde4N HC1 in 1,4-dioxane (5.6 mL, 22.31 mmol) was added to 5-(6-isopropyl-3-(methoxymethoxy)pyridin-2-yl)thiophene-2-carbaldehyde (650 mg, 2.23 mmol) and the mixture stirred at ambient temperature. After 5 minutes an additional portion of 4N HC1 in 1,4-dioxane (5.6 mL, 22.31 mmol) was added and stirring continued for 30 minutes.MeOH (30 mL) was added and the resultant solution stirred for 18 hours. The solvent was removed in vacuo to afford 5 -(3 -hydroxy-6-isopropylpyridin-2-yl)thiophene-2- carbaldehyde (600 mg). MS (ESI) m / z 248.0 [M+H]+.Step 5: synthesis of 5-(3-(Difluoromethoxy)-6-isopropylpyridin-2-yl)thiophene-2- carbaldehydeGeneral procedure [OCF2H alkylation]A mixture of 5-(3-hydroxy-6-isopropylpyridin-2-yI)thiophene-2-carbaldehyde (650 mg,2.23 mmol), sodium chlorodifluoroacetate (680 mg, 4.46 mmol) and CS2CO3 (2.18 g, 6.69 mmol) in DMF (12 mL) was heated at 60°C for 2.5 hours. The cooled mixture was concentrated in vacuo and the residue purified by silica gel chromatography (elution with30% EtOAc in cyclohexane) to afford 5-(3-(difluoromethoxy)-6-isopropylpyridin-2- yl)thiophene-2-carbaldehyde (310 mg). ‘H NMR (400 MHz, CDC13): 39.95-9.95 (m, 1H),7.99-7.98 (m, 1H), 7.78-7.76 (m, 1H), 7.50-7.47 (m, 1H), 7.17-7.14 (m, 1H), 6.61 (t,Hz, 1H), 3.13-3.05 (m, 1H), 1.34 (d, 1=6.8 Hz, 6H).

[0281] Synthesis of 5-(7-(difluoromethoxy)imidazofl,2-alpvridin-8-vl)thiophene-2- carbaldehydeStep 1: synthesis of 5-(7-methoxyimidazo[l,2-a]pyridin-8-yl)thiophene-2- carbaldehydeThe title compound ewas prepared starting from 8-iodo-7-methoxyimidazo[ly2- a]pyridine and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde following similar methods to those described in general procedure [Suzuki 1].lH NMR(400 MHz, CDCh) 5 9.99 (s, 1H), 9.00 (d, J=4.3 Hz, 1H), 8.13 (d, J=7.4 Hz, 1H), 7.84(d, 1=4.1 Hz, 1H), 7.66 (d, 1=1.3 Hz, 1H), 7.54 (d, 1=1.4 Hz, 1H), 6.84 (d, 1=7.4 Hz, 1H),4.12 (s, 3H).Step 2: synthesis of 5-(7-hydroxyimidazo[l,2-a]pyridin-8-yl)thiophene-2- carbaldehydeIn a microwave vial, 5-(7-methoxyimidazo[l,2-a]pyridin-8-yl)thiophene-2-carbaldehyde(182 mg, 0.71 mmol) was dissolved in DMF (3.0 mL). NaSMe (198 mg, 2.82 mmol) was added and the reaction mixture was heated in the microwave at 100°C for 30 minutes.The solution was concentrated and the residue was purified by column chromatography on silica gel, eluting with 0-100% EtOAc / EtOH 3:1 in cyclohexane to give 5-(7- hydroxyimidazo[l,2-a]pyridin-8-yl)thiophene-2-carbaldehyde (82 mg).rH NMR (400MHz, DMSO) 5 11.90 (s, 1H), 9.95 (s, 1H), 9.07 - 8.52 (m, 1H), 8.39 (br. s, 1H), 8.02 (d,J=4.3 Hz, 1H), 7.83 (s, 1H), 7.52 (d, 1=1.5 Hz, 1H), 6.73 (s, 1H).Step 3: synthesis of 5-(7-(difluoromethoxy)imidazo[l,2-a]pyridin-8-yl)thiophene-2- carbaldehydeThe title compound was prepared starting from 5-(7-hydroxyimidazo[l,2-a]pyridin-8- yl)thiophene-2-carbaldehyde following similar methods to those described in general procedure [OCF2H alkylation].:H NMR (400 MHz, CDC13) 3 10.00 (s, 1H), 8.61 (d, 1=4.1 Hz, 1H), 8.14 (d, J=7.4 Hz,1H), 7.85 (d, 1=4.1 Hz, 1H), 7.73 (d, 1=1.3 Hz, 1H), 7.65 (d, J=1.3 Hz, 1H), 6.95 (d, 1=7.4Hz, 1H), 6.65 (t, 1=71.3 Hz, 1H).MS (ESI) m / z 295 [M+H]+.

[0282] Synthesis of l-(2-(5-Chloro-2-(difluoromethoxy)phenyl)thiazol-5-vl)ethyl methanesulfonateGeneral procedure [Mesylate formation]Step 1: synthesis of l-(2-(5-Chloro-2-(difluoromethoxy)phenyl)thiazol-5-yl)ethan-l- olA solution of 2-(5-chloro-2-(difluoromethoxy)phenyl)thiazole-5-carbaldehyde (105 mg,0.36 mmol) in THF (2 mL) at 0°C under a nitrogen atmosphere was treated dropwise with methyl magnesium chloride (3M in THF, 0.18 mL, 0.54 mmol) and the mixture stirred cold before the cooling bath was removed and the mixture stirred at ambient temperature for 1 hour. An additional portion of methyl magnesium chloride (3M in THF, 0.04 mL,0.12 mmol) and the mixture stirred for a further 1 hour. The reaction was quenched with water and extracted into EtOAc (2 x 10 mL). The combined extracts were dried overMgS04 and concentrated in vacuo. Purification by silica gel chromatography (elution with 0-100% DCM in cyclohexane followed by 0-10% MeOH in DCM) to afford l-(2-(5-chloro-2-(difluoromethoxy)phenyl)thiazol-5-yl)ethan-l-ol (65 mg). *H NMR (400MHz, d6-DMSO): 5 8.28 (d, J=2.6 Hz, 1H), 7.84 (s, 1H), 7.62 (dd, J=2.8, 8.9 Hz, 1H),7.50 (t, J=73.1 Hz, 1H), 7.44 (d, 1=8.8 Hz, 1H), 5.82 (d, 1=4.9 Hz, 1H), 5.13-5.07 (m,1H), 1.50 (d, J=6.4 Hz, 3H).Step 2: synthesis of l-(2-(5-ChIoro-2-(difluoromethoxy)phenyl)thiazol-5-yl)ethyl methanesulfonateA solution of l-(2-(5-chloro-2-(difluoromethoxy)phenyl)thiazol-5-yl)ethan-l-ol (290 mg,0.95 mmol) and EtaN (0.26 mL, 1.90 mmol) in DCM (10 mL) at 0 under a nitrogen atmosphere was treated with methanesulfonyl chloride (0.088 mL, 1.14 mmol) and the mixture stirred cold for 1 hour. An additional portion of EtaN (0.06 mL, 0.44 mmol) and methanesulfonyl chloride (0.03 mL, 0.39 mmol) were added and stirring continued for a further 30 minutes at ambient temperature. The reaction was quenched with water (5 mL), extracted into DCM (10 mL), dried over MgSCU and concentrated in vacuo to afford 1-(2-(5-chloro-2-(difluoromethoxy)phenyl)thiazol-5-yl)ethyl methanesulfonate (370 mg).!H NMR (400MHz, CDCb): 5 8.37-8.36 (m, 1H), 7.83 (s, 1H), 7.38 (dd, 1=2.7, 8.7 Hz,1H), 7.23-7.20 (m, 1H), 6.65 (t, J=72.7 Hz, 1H), 5.46-5.40 (m, 1H), 3.67 (s, 3H), 2.00 (d,J=6.8 Hz, 3H).

[0283] Synthesis 5-(3-(Difluoromethoxv)-6-(dimethvlgmino)pvridin-2-vDthioT)hene-2- carbaldehydeStep 1: synthesis of 6-Chloro-5-(methoxymethoxy)-N,N-dimethylpyridin-2-amineA degassed suspension of 2-chloro-6-iodo-3-(methoxymethoxy)pyridine (2.9 g, 9.68 mmol), dimethylamine (2M in THE, 9.7 mL, 19.37 mmol), L-proline (446 mg, 3.87 mmol), Cui (369 mg, 1.94 mmol) and K2CO3 (2.68 g, 19.37 mmol) in DMSO (10 mL) was heated at 70°C for 4 hours before quenching with HC1 (IM). The mixture was extracted with EtjO twice, the combined organic extracts filtered through a hydrophobic paper and concentrated in vacuo. Purification by silica gel chromatography (elution with0-50 % EtOAc in cyclohexane) to afford 6-chloro-5-(methoxymethoxy)-N,N- dimethylpyridin-2-amine (1.49 g). ‘HNMR (400 MHz, CDC13): 37.32 (d, 1=8.8 Hz, 1H),6.35 (d, J=8.9 Hz, 1H), 5.08 (s, 2H), 3.54 (s, 3H), 3.03 (s, 6H).Step 2: synthesis of 5-(6-(DimethyIamino)-3-(methoxymethoxy)pyridin-2- yl)thiophene-2-carbaldehydeThe title compound was prepared starting from 6-chloro-5-(methoxymethoxy)-N,N- dimethylpyridin-2-amine and 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde following similar methods to those described in general procedure[Suzuki 1]. *H NMR (400 MHz, CDCI3) 5 9.92 (s, 1H), 8.01 (d, 1=4.0 Hz, 1H), 7.74 (d,1=4.0 Hz, 1H), 7.45 (d, 1=9.1 Hz, 1H), 6.53 (d, J=9.1 Hz, 1H), 5.23 (s, 2H), 3.51 (s, 3H),3.10 (s, 6H).Step 3: synthesis of 5-(6-(Dimethylamino)-3-hydroxypyridin-2-yI)thiophene-2- carbaldehyde hydrochlorideTo a solution of 5-(6-(dimethylamino)-3-(methoxymethoxy)pyridin-2-yl)thiophene-2- carbaldehyde (122 mg, 0.42 mmol) in MeOH (5 mL) was added HC1 in 1,4-dioxane (1 mL, 4.17 mmol) and the mixture was stirred at ambient for 5 hours. An additional portion of HC1 in 1,4-dioxane (2 mL, 8.34 mmol) was added and the mixture stirred for a further16 hours before being concentrated in vacuo to afford 5-(6-(dimethylamino)-3-hydroxypyridin-2-yl)thiophene-2-carbaldehyde (100 mg).XH NMR (400 MHz, DMSO) 8 10.30 (br s, 1H), 9.95 (br s, 1H), 8.70 (s, 1H), 8.05 (d,J=4.1 Hz, 1H), 8.02 (d, J=4.0 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 6.83 (d, J=9.1 Hz, 1H),3.06 (s, 6H).Step 4: synthesis of 5-(3-(Difluoromethoxy)-6-(dimethylamino)pyridin-2- yl)thiophene-2-carbaldehydeThe title compound was prepared starting from 5-(6-(dimethylamino)-3-hydroxypyridin-2-yl)thiophene-2-carbaldehyde following a similar procedure described in genral procedure [OCF2H alkylation], *H NMR (400 MHz, CDCla): 5 9.93 (s, 1H), 7.90 (d,1=4.2 Hz, 1H), 7.74 (d, J=4.3 Hz, 1H), 7.38 (d, 3=9.2 Hz, 1H), 6.49 (d, 1=9.6 Hz, 1H),6.44 (t, 1=73.5 Hz, 1H), 3.13 (s, 6H).

[0284] Synthesis of carbaldehydeStep 1: synthesis of Methyl 6-bromo-5-methoxypyrazolo[l,5-a]pyridine-3- carboxylateTo a solution of 3-bromo-4-methoxypyridine (1.85 g, 9.85 mmol) in DMF (30 mL) at ambient temperature was added O-(2,4-dinitrophenyl)hydroxylamine (2.16 g, 10.84mmol) and the resulting mixture was stirred at ambient temperature for 16 hours. K2CO3(1.85 g, 13.38 mmol) was then added, followed by methyl propiolate (830 mg, 9.81 mmol) dropwise. The mixture was stirred for 3 hours, concentrated in vacuo, dry loaded onto MgSO4 and purified by silica gel chromatography (elution with 0-60% EtOAc / EtOH(3:1) in cyclohexane). Fractions containing the product were combined, concentrated in vacuo, dissolved in EtOAc and washed with water. The organic phase was filtered through a hydrophobic paper, concentrated in vacuo and re-purified by silica gel chromatography (elution with 0-50% EtOAc in cyclohexane) to afford methyl 6-bromo-5-methoxypyrazolo[l,5-a]pyridine-3-carboxylate (843 mg).rH NMR (400 MHz, CDCI3):8 8.63 (s, 1H), 8.27 (s, 1H), 7.47 (s, 1H), 4.03 (s, 3H), 3.90 (s, 3H).Step 2: synthesis of 6-bromo-5-methoxypyrazolo[l,5-a]pyridineMethyl 6-bromo-5-methoxypyrazolo[l,5-a]pyridine-3-carboxylate (340 mg, 1.19 mmol) was suspended in hydrobromic acid (47-49% in H2O, 5 mL) at ambient. The mixture was brought to reflux and stirred for 3 hours. The pH of the cooled mixture was adjusted to-pH 12 using a solution of NaOH (5M) and extracted into EtzO twice. The phases were separated, the organic phase filtered through a hydrophobic paper and concentrated in vacuo to afford 6-bromo-5-methoxypyrazolo[l,5-a]pyridine (226 mg). 'H NMR (400MHz, CDCh): 5 8.58 (s, 1H), 7.85 (s, 1H), 6.77 (s, 1H), 6.34 (s, 1H), 3.91 (s, 3H).Step 3: synthesis of 5-(5-Methoxypyrazolo[l,5-a]pyridin-6-yl)thiophene-2- carbaldehydeCompound 5-(5-methoxypyrazolo[l,5-a]pyridin-6-yl)thiophene-2-carbaldehyde was prepared starting from 6-bromo-5-methoxypyrazolo[l,5-a]pyridine and 5-(4, 4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde following a similar procedure described in general procedure [Suzuki 1].rH NMR (400 MHz, CDCI3): 69.93(s, 1H), 8.74 (s, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.75 (d, J=4.0 Hz, 1H), 7.49 (d, 1=4.0 Hz,1H), 6.87 (s, 1H), 6.38 (d, J=2.1 Hz, 1H), 3.98 (s, 3H).Step 4: synthesis of 5-(5-Hydroxypyrazolo[l,5-a]pyridin-6-yl)thiophene-2- carbaldehydeA solution of 5-(5-methoxypyrazolo[l,5-a]pyridin-6-yl)thiophene-2-carbaldehyde (120 mg, 0.47 mmol) in DMF (2 mL) was treated with sodium thiomethoxide (81 mg, 1.16 mmol) and heated at 100°C for 30 minutes in a microwave oven. The cooled mixture was purified direction by silica gel chromatography(elution with 0-100% EtOAc / EtOH (3:1) in cyclohexane) to afford 5-(5-hydroxypyrazolo[l,5-a]pyridin-6-yl)thiophene-2- carbaldehyde (86 mg). *H NMR (400 MHz, d6-DMSO): 5 11.39 (s, 1H), 9.98 (s, 1H),9.30 (s, 1H), 8.06 (d, 1=4.0 Hi, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.97 (d, 1=4.1 Hz, 1H), 7.03(s, 1H), 6.40 (d, J=2.3 Hz, 1H).Step 5: synthesis of 5-(5-(Difhioromethoxy)pyrazoIo[l,5-a]pyridin-6-yl)thiophene-2- carbaldehydeCompound 5-(5 -(difluoromethoxy)pyrazolo [1,5 -a]pyridin-6-yl)thiophene-2- carbaldehyde was prepared starting from 5-(5-hydroxypyrazolo[l,5-a]pyridin-6- yl)thiophene-2-carbaldehyde following a similar procedure described in general procedure [OCF2H alkylation].IHNMR(400 MHz, CDCh): 89.94 (s, 1H), 8.78 (s, 1H),8.03 (d, 1=2.3 Hz, 1H), 7.78 (d, J=3.9 Hz, 1H), 7.47 (d, 1=3.9 Hz, 1H), 7.33 (s, 1H), 6.63(t, 1=72.2 Hz, 1H), 6.55 (d, 1=1.9 Hz, 1H).

[0285] Synthesis of 2-(2-(Difluoromethoxv)-5-fluorophenyl)thiazole-5-carbaldehydeStep 1: synthesis of Methyl 2-(2-(difluoromethoxy)-5-fluorophenyI)thiazole-5-carboxylateMethyl 2-(2-(difluoromethoxy)-5-fluorophenyl)thiazole-5-carboxylate was prepared starting from 2-bromo-l-(difluoromethoxy)-4-fluorobenzene following a similar procedure described to prepare compound methyl 2-(2-(difluoromethoxy)pyridin-3- yl)thiazole-5-carboxylate. *H NMR (400MHz, CDCI3): 5 8.17 (dd, J=3.2, 9.2 Hz, 1H),7.46-7.41 (m, 1H), 7.30-7.25 (m, 1H), 7.26 (s, 1H), 6.67 (t, 1=72.4 Hz, 1H), 3.95 (s, 3H).Step 2: synthesis of 2-(2-(Difluoromethoxy)-5-fIuorophenyl)thiazol-5-yl)methanoIThe title compound was prepared starting from methyl 2-[2-(difluoromethoxy)-5-fluoro- phenyl]thiazole-5 -carboxylate following similar methods to those described in general procedure [LAH red].lH NMR (400MHz, CDCI3): 5 8.07 (dd, J=3.0, 9.3 Hz, 1H), 7.81(s, 1H), 7.26 (s, 1H), 7.11 (ddd, 1=3.1, 7.1, 9.0 Hz, 1H), 6.61 (t, 1=73.1 Hz, 1H), 4.95 (d,J=5.8 Hz, 2H), 1.97 (dd, 1=5.9, 5.9 Hz, 1H).Step 3: synthesis of 2-(2-(Difluoromethoxy)-5-fluorophenyl)thiazole-5-carbaldehyde2-(2-(Difluoromethoxy)-5-fluorophenyl)thiazole-5-carbaldehyde was prepared starting from 2-(2-(difluoromethoxy)-5-fluorophenyl)thiazol-5-yl)methanol following a similar procedure described in general procedure [Oxidation 2].XH NMR (400MHz, CDCI3): 510.12 (s, 1H), 8.50 (s, 1H), 8.20 (dd, J=3.0, 9.1 Hz, 1H), 7.32 (dd, J=4.4, 9.0 Hz, 1H),7.25-7.18 (m, 1H), 6.70 (t, J=72.0 Hz, 1H).

[0286] Synthesis of carbaldehvdeStep 1: synthesis of l-amino-3-methoxypyridin-l-ium 2,4-dinitrophenolateTo a solution of O-(2,4-dinitrophenyl)hydroxylamine (9.5 g, 47.9 mmol) in DMF (250 mL) at room temperature was added 3 -methoxypyridine (4.6 mL, 45.7 mmol), and the mixture was stirred at room temperature for 16 hours. EtaO was then added to the mixture until precipitation was observed. The mixture was filtered and the solid was collected and dried to give l-amino-3-methoxypyridin-l-ium 2,4-dinitrophenolate of an orange solid(7.5 g). Following this, the filtrate was concentrated to dryness, and the resulting oil was triturated with EtaO. The precipitate was collected by filtration, washed once with EtaO and dried to give another clean batch (5.5 g) of the title compound. The solid materials were combined to give l-amino-3-methoxypyridin-l-ium 2,4-dinitrophenolate (13 g). *HNMR (400 MHz, DMSO) 5 8.61 - 8.58 (m, 2H), 8.46 (s, 2H), 8.41 (d, J=2.6 Hz, 1H),7.94 (d, 1=3.5 Hz, 1H), 7.79 (dd, 1=3.1, 9.8 Hz, 1H), 6.32 (d, 1=9.8 Hz, 1H), 3.98 (s, 3H).Step 2: synthesis of methyl 6-methoxypyrazolo[l,5-a]pyridine-3-carboxylateTo a solution of l-amino-3-methoxypyridin-l-ium 2,4-dinitrophenolate (13 g, 42.2 mmol) in DMF (100 mL) at room temperature were successively added K2CO3 (8.74 g,63.3 mmol) and methyl propiolate (4.1 mL, 46.4 mmol), and the resulting mixture was stirred for 16 hours, before concentrating under vacuum. The residue was then partitioned between EtOAc (250 mL) and a saturated solution of NaHCOa (300 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (3 x 250 mL). Thecombined organic extracts were washed with a IM HC1 solution (500 mL), dried(MgSO-i), filtered and concentrated. Purification by column chromatography on silica gel(10-30 % EtOAc in cyclohexane) gave methyl 6-methoxypyrazolo[l,5-a]pyridine-3- carboxylate (0.93 g). *HNMR (400 MHz, CDCI3) 5 8.31 (s, 1H), 8.10 (d, J=1.9 Hz, 1H),8.04 (d, J=9.7 Hz, 1H), 7.20 (dd, J=2.2, 9.6 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H).Step 3: synthesis of methyl 7-bromo-6-methoxypyrazolo[l,5-a]pyridine-3- carboxylateTo a solution of methyl 6-methoxypyrazolo[l,5-a]pyridine-3-carboxylate (960 mg, 4.66 mmol) in DCM (40 mL) was added NBS (911 mg, 5.12 mmol) at room temperature, and the mixture was stirred at this temperature for 16 hours, before concentrating under vacuum. The residue was purified by column chromatography on silica gel (0-50%EtOAc in cyclohexane) to give methyl 7-bromo-6-methoxypyrazolo[l,5-a]pyridine-3- carboxylate (1.05 g).1HNMR (400 MHz, CDC13) 5 8.45 (s, 1H), 8.17 (d, 1=9.7 Hz, 1H),7.36 (d, J=9.7 Hz, 1H), 4.01 (s, 3H), 3.92 (s, 3H).Step 4: synthesis of 7-bromo-6-methoxypyrazolo[l,5-a]pyridineA suspension of methyl 7-bromo-6-methoxypyrazolo[l,5-a]pyridine-3-carboxylate (1.05 g, 3.68 mmol) in aqueous sulfuric acid (45%, 40 mL) was stirred under reflux for 2 hours.Aqueous NaOH (6 M) was added until pH 11-12, and the aqueous layer was extracted three times with EtOAc (50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (EtOAc / cyclohexane) to give 7-bromo-6- methoxypyrazolo[l,5-a]pyridine (640 mg).!HNMR (400 MHz, CDCI3) 8 8.02 (d, J=2.4Hz, 1H), 7.53 (d, J=9.5 Hz, 1H), 7.11 (d, J=9.5 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 3.97 (s,3H).Step 5: synthesis of 5-(6-methoxypyrazolo [1 ,5-a] pyridin-7-yl)thiophene-2-carbaldehydeTo a degassed solution of 7-bromo-6-methoxypyrazolo[l,5-a]pyridine (220 mg, 0.969 mmol), 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde (277 mg, 1.16 mmol), and potassium phosphate tribasic (617 mg, 2.91 mmol) in dioxane (4.0 mL) and water (0.8 mL) was added XPhos Pd G2 (76 mg, 0.097 mmol) and the mixture was heated to 90°C and stirred for 2 hours. The reaction mixture was partitioned betweenEtOAc (20 mL) and water (10 mL), and the layers separated. The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were dried (MgSCM), filtered and evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate / cyclohexane) to afford 5-(6-methoxypyrazolo[l,5-a]pyridin-7- yl)thiophene-2-carbaldehyde (104 mg).XHNMR (400 MHz, CDCla) 8 10.03 (s, 1H), 8.79(d, J=4.3 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.85 (d, J=4.1 Hz, 1H), 7.62 (d, J=9.5 Hz, 1H),7.26 (d, 1=3.5 Hz, 1H), 6.66 (d, 1=2.3 Hz, 1H), 4.05 (s, 3H).Step 6: synthesis of 5-(6-hydroxypyrazolo[l,5-a]pyridin-7-yl)thiophene-2- carbaldehydeIn a microwave reaction vial, 5-(6-methoxypyrazolo[l,5-a]pyridin-7-yl)thiophene-2- carbaldehyde (104 mg, 0.403 mmol) was dissolved in DMF (2 mL) at room temperature.NaSMe (113 mg, 1.61 mmol) was added, and the suspension was stirred for 20 minutes at 140°C under micro wave irradiation. After cooling, the reaction mixture was transferred to a round bottom flask, HM-N resin was added, and the resulting suspension was concentrated under vacuum. The residue was purified by column chromatography on silica gel (EtOAc / cyclohexane) to give 5-(6-hydroxypyrazolo[l,5-a]pyridin-7- yl)thiophene-2-carbaldehyde (45 mg). MS (ESI) m / z 245.0 [M+H]+Step 7: synthesis of 5-(6-(difhioromethoxy)pyrazolo[l,5-a]pyridin-7-yl)thiophene-2- carbaldehydeTo a solution of 5-(6-hydroxypyrazolo[l,5-a]pyridin-7-yl)thiophene-2-carbaldehyde (45 mg, 0.184 mmol) and caesium carbonate (120 mg, 0.368 mmol) in DMF (2 mL) was added sodium chlorodifluoroacetate (56 mg, 0.368 mmol) and the mixture was stirred for2 hours at 60°C. The reaction mixture was then partitioned between ether and water and the layers separated. The organic phase was dried (MgSCU), filtered and evaporated to afford 5-(6-(difluoromethoxy)pyrazolo[l,5-a]pyridin-7-yl)thiophene-2-carbaldehyde (34 mg). *H NMR (400 MHz, CDC13) 6 10.05 (s, 1H), 8.31 - 8.27 (m, 1H), 8.11 - 8.08 (m,1H), 7.89 - 7.87 (m, 1H), 7.66 - 7.61 (m, 1H), 7.44 - 7.37 (m, 1H), 6.77 - 6.73 (m, 1H),6.51 (t, J=73.3 Hz, 1H).

[0287] Synthesis of2-(thienoT3.2-clpyridin-4-vUthiazole-5-carbdldehydeStep 1: synthesis of Methyl 2-(thieno[3,2-c]pyridin-4-yl)thiazoIe-5-carboxylateMethyl thiazole-5-carboxylate (300 mg, 2.10 mmol), 4-chlorothieno[3,2-c]-pyridine (533 mg, 3.14 mmol), Pd(OAc)i (24 mg, 0.11 mmol, 0.05 eq), tri-tert-butylphosphonium tetrafluoroborate (61 mg, 0.21 mmol), 1 -adamantanecarboxylic acid (113 mg, 0.63 mmol) and K2CO3 (579 mg, 4.19 mmol) were purged with nitrogen for 10 minutes. Toluene (10 mL) was added and the reaction mixture was heated at 110°C for 20 hours. Additional portions of Pd(OAc)z (24 mg, 0.11 mmol), tri-tert-butylphosphonium tetrafluoroborate(61 mg, 0.21 mmol) and 1 -adamantanecarboxylic acid (113 mg, 0.63 mmol) were added and the reaction mixture heated at 110°C for a further 24 hours. The cooled reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The solvents were removed in vacuo and the residue purified by silica gel chromatography(EtOAc / cyclohexane) to afford methyl 2-(thieno[3,2-c]pyridin-4-yl)thiazole-5-carboxylate (238 mg). *H NMR (400 MHz, CDC13): 8 8.73 (dd, J=0.8, 5.6 Hz, 1H), 8.57(s, 1H), 8.51 (d, 1=5.5 Hz, 1H), 7.91 (dd, 1=0.9, 5.4 Hz, 1H), 7.69 - 7.67 (m, 1H), 3.96 (s,3H).Step 2: synthesis of (2-(thieno[3,2-c]pyridin-4-yl)thiazol-5-yl)methanolTo a stirred suspension of methyl 2-(thieno[3,2-c]pyridin-4-yl)thiazole-5-carboxylate(285 mg, 1.03 mmol) in EtOH (5 mL) and water (0.6 mL) was added NaBH* (117 mg,3.09 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. An additional portion of NaBHt (117 mg, 3.09 mmol) was added and the reaction mixture was stirred at ambient temperature for 20 hours. An additional portion of NaBHt (585 mg,15.5 mmol) were added and the reaction mixture was stirred at room temperature for a further 72 hours. The reaction was quenched with water and partitioned between a saturated NH4CI solution and DCM. The two phases were separated and the aqueous phase was extracted with DCM twice. The combined organic extracts were passed through a phase separator and concentrated in vacuo. Purification by silica gel chromatography (EtOAc / cyclohexane) to afford (2-(thieno[3,2-c]pyridin-4-yl)thiazol-5- yl)methanol (206 mg). *H NMR (400 MHz, CDCI3): 3 8.72 (d, 1=5.6 Hz, 1H), 8.47 (d,J=5.6 Hz, 1H), 7.88 (s, 1H), 7.85 (d, 1=5.3 Hz, 1H), 7.62 (d, J=5.3 Hz, 1H), 4.96 (s, 2H),1.91 - 1.87 (m, 1H).Step 3: synthesis of 2-(thieno[3,2-c]pyridin-4-yl)thiazoIe-5-carbaldehydeTo a stirred suspension of (2-(thieno[3,2-c]pyridin-4-yl)thiazol-5-yl)methanol (206 mg,0.83 mmol) in CHCI3 (10.0 ml) was added MnCh (721 mg, 8.30 mmol). The reaction mixture was stirred at ambient temperature for 3.5 hours then filtered through a pad ofCelite washing with DCM. The filtrate was concentrated in vacuo to afford 2-(thieno[3,2- c]pyridin-4-yl)thiazole-5-carbaldehyde (126 mg).JH NMR (400 MHz, CDCI3): 8 10.12(s, 1H), 8.74 (d, J=5.6 Hz, 1H), 8.57 (s, 1H), 8.53 (d, J=5.3 Hz, 1H), 7.94 (d, J=5.3 Hz,1H), 7.70 (d, J=5.6 Hz, 1H).

[0288] Synthesis of2-(2-(difluoromethoxv)phenyl)-4-propylthiazole-5-carbaldehvdeStep 1: synthesis of (2-bromo-4-propylthiazol-5-yl)methanol(2-Bromo-4-propylthiazol-5-yl)methanol was prepared starting from ethyl 2-bromo-4- propylthiazole-5 -carboxylate following a similar procedure described in general procedure [DIBAL red]. *H NMR (400 MHz, d6-DMSO): 5 5.71 (dd, 1=5.4, 5.4 Hz, 1H),4.63 (d, J=5.6 Hz, 2H), 2.62 (dd, J=7.5, 7.5 Hz, 2H), 1.67-1.58 (m, 2H), 0.92 (dd, 1=7.3,7.3 Hz, 3H).Step 2: synthesis of (2-(2-(difluoromethoxy)phenyl)-4-propylthiazol-5-yl)methanol(2-(2-(difluoromethoxy)phenyl)-4-propylthiazol-5-yl)methanol was prepared starting from (2-bromo-4-propylthiazol-5-yl)methanol and 2-(2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane following a similar procedure described in general procedure [Suzuki 1] using XPhos Pd G2. *H NMR (400 MHz, d6-DMSO): 58.33 (dd, 1=1.6, 8.0 Hz, 1H), 7.59-7.54 (m, 1H), 7.50 (t, 1=73.8 Hz, 1H), 7.42 (dd, 1=7.7,7.7 Hz, 2H), 5.61 (dd, J=5.6, 5.6 Hz, 1H), 4.73 (d, J=5.6 Hz, 2H), 2.73 (dd, J=7.5, 7.5 Hz,2H), 1.73 (dd, J=7.5, 14.8 Hz, 2H), 0.97 (dd, J=7.3, 7.3 Hz, 3H).Step 3: synthesis of 2-(2-(difluoromethoxy)phenyI)-4-propyIthiazole-5-carbaldehyde2-(2-(Difluoromethoxy)phenyl)-4-propylthiazole-5-carbaldehyde was prepared starting from (2-(2-(difluoromethoxy)phenyl)-4-propylthiazol-5-yl)methanol following a similar procedure described in general procedure [Oxidation 2]. 'H NMR (400 MHz, d6-DMSO):8 1024 (s, 1H), 8.46 (dd, J=1.8, 8.3 Hz, 1H), 7.74-7.69 (m, 1H), 7.59 (t, J=73.0 Hz, 1H),7.50 (dd, J=7.3, 7.3 Hz, 2H), 3.19 (dd, J=7.3, 7.3 Hz, 2H), 1.86 (dd, J=7.3, 14.9 Hz, 2H),1.02 (dd, 1=7.3, 7.3 Hz, 3H).

[0289] Synthesis of 5-(thienof2, 3-clvvridin-7-vl) isoxazole-3-carbdldehydeStep 1: methyl 5-(thieno [2,3 -c]pyridin-7-yl) is oxazole-3- carb oxy lateA 25 mL microwave vial was charged with a solution of methyl 5-(tributylstannyl)isoxazole-3-carboxylate 7-chlorothieno[2,3-c]pyridine (200 mg, 0.48 mmol) and 7-chlorothieno[2,3-c]pyridine (98 mg, 0.58 mmol) in 1,4-dioxane (4 mL) was degassed, purged with nitrogen, treated with PdCh(PPh3)2 (34 mg, 0.048 mmol) and heated at 150°C for 1 hour in a microwave oven. The cooled mixture was concentrated in vacuo and the residue purified by silica gel chromatography (EtOAc / cyclohexane) to afford methyl 5-(thieno[2,3-c]pyridin-7-yl)isoxazole-3-carboxylate (50 mg). ’H NMR(400MHz, CDCh): 3 8.66 (d, 1=5.3 Hz, 1H), 7.91 (d, 1=5.5 Hz, 1H), 7.85 (d, J=5.4 Hz,1H), 7.60 (s, 1H), 7.51 (d, J=5.4 Hz, 1H), 4.05 (s, 3H).Step 2: 5-(thieno[2,3-c]pyridin-7-yl)isoxazole-3-carbaldehydeA solution of methyl 5-(thieno[2,3-c]pyridin-7-yl)isoxazole-3-carboxylate (64 mg, 0.25 mmol) in toluene (6 mL) at -78°C under a nitrogen atmosphere was treated dropwise withDIBAL (IM in toluene, 0.8 mL, 0.8 mmol) and the mixture stirred cold for 2 hours. The reaction was quenched by the additional of MeOH, dry-loaded on MgSC>4 and purified by silica gel chromatography (ethyl acetate / cyclohexane then MeOH / ethyl acetate) to afford 5-(thieno[2,3-c]pyridin-7-yl)isoxazole-3-carbaldehyde (13 mg). ’H NMR(400MHz, CDC13): δ 10.20 (s, 1H), 8.59-8.56 (m, 1H), 7.80-7.73 (m, 2H), 7.43-7.37 (m,2H).

[0290] Synthesis of3-(2-(difluoromethoxy)-5-fluorovhenvl)isoxazole-5-carbaldehydeThis compound was synthesised from 2-bromo-l-(difluoromethoxy)-4-fluorobenzene using a similar procedure as 3-(2-(difluoromethoxy)phenyl)isoxazole-5-carbaldehyde. *HNMR (400 MHz, CDC13): δ 10.05 (s, 1H), 7.75 (dd, J=3.0, 8.6 Hz, 1H), 7.46 (s, 1H),7.31 - 7.27 (m, 1H), 7.25 - 7.19 (m, 1H), 6.53 (t, 1=72.7 Hz, 1H).

[0291] Synthesis of3-(5-chloro-2-(difluorornethoxy)vhenyl)isoxazole-5-carbaldehydeThis compound was synthesised from 2-bromo-4-chloro-l-(difluoromethoxy)benzene using a similar procedure as 3-(2-(difluoromethoxy)phenyl)isoxazole-5-carbaldehyde. *HNMR (400 MHz, CDCI3): 8 10.05 (s, 1H), 8.03 (d, 1=2.5 Hz, 1H), 7.48 (dd, J=2.5, 8.8Hz, 1H), 7.44 (s, 1H), 7.22 (dd, 1=8.6, 14.6 Hz, 1H), 6.57 (t, J=73.0 Hz, 1H).

[0292] Synthesis of 2-(4-methyli}yridin-2-yl) thiazole- 5 -carb aldehydeMethyl 2-(4-methylpyridin-2-yl)thiazole-5-carboxy late2-Bromo-4-methylpyridine (0.35 mL, 3.14 mmol), methyl thiazole-5 -carboxylate (300 mg, 2.10 mmol), 1 -adamantanecarboxylic acid (113 mg, 0.63 mmol), palladium(II) acetate (47 mg, 0.21 mmol), tri-tert-butylphosphonium tetrafluoroborate (122 mg, 0.42 mmol) and K2CO3 (579 mg, 4.19 mmol) were sparged with nitrogen for 5 minutes.Toluene (10 mL) was added, and the reaction mixture was heated at 110°C overnight.The cooled reaction mixture was diluted with EtOAc and filtered through a pad of celite.The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc in cyclohexane) to afford methyl 2-(4- methylpyridin-2-yl)thiazole-5-carboxylate(301 mg). *HNMR(400 MHz, CDCh): 58.50- 8.45 (m, 2H), 8.06 (s, 1H), 7.22 - 7.18 (m, 1H), 3.93 (s, 3H), 2.44 (s, 3H).(2-(4-Methylpyridin-2-yl)thiazol-5-yl)methanolTo a solution of methyl 2-(4-methylpyridin-2-yl)thiazole-5-carboxylate (100 mg, 0.427 mmol) in THE (3.0 mL) at 0°C was added 1 M lithium aluminium hydride in THE (0.85 mL, 0.85 mmol). The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched with 1 M NaOH solution (2 mL) and diluted with dichloromethane(20 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane (2 x 20 mL). The combined organic extracts were filtered through a hydrophobic frit and the filtrate was evaporated to afford (2-(4-methylpyridin-2- yl)thiazol-5-yl)methanol (57 mg). 'HNMR (400 MHz, CDCI3): 5 8.46 (d, 1=5.1 Hz, 1H),8.00 (s, 1H), 7.78 (s, 1H), 7.15 (d, J=4.2 Hz, 1H), 4.93 (s, 2H), 3.75 (t, J=6.4 Hz, 1H),2.43 (s, 3H).2-(4-Methylpyridin-2-yl)thiazoIe-5-carbaldehydeTo a solution of (2-(4-methylpyridin-2-yl)thiazol-5-yl)methanol (145 mg, 0.703 mmol) in DCM (7.0 mL) was added manganese(IV) oxide (306 mg, 3.51 mmol) and the reaction was stirred at room temperature for 2 hours. Additional manganese(IV) oxide (306 mg,3.51 mmol) was added and the reaction was stirred overnight at room temperature. The reaction mixture was filtered through a cartridge frit followed by syringe filtration (orange syringe filter). The filtrate was evaporated to give 2-(4-methylpyridin-2-yl)thiazole-5- carbaldehyde (140 mg). *H NMR (400 MHz, CDC13): 5 10.08 (s, 1 H), 8.52 (d, J = 5.1Hz, 1 H), 8.47 (s, 1 H), 8.09 (s, 1 H), 7.24 (d, J = 4.2 Hz, 1 H), 2.46 (s, 3 H).MS (ESI) m / z 205.1 [M+H]+.

[0293] Synthesis of 2-(2-(difluoromethoxy)pyridin-2-yl)thiazole-5-carbaldelTyde3-Bromo-2-(difluoromethoxy)pyridineNajSO4 (8.98 g, 63.2 mmol) was added to a stirred mixture of 3-bromo-2- hydroxypyridine (10.00 g, 57.5 mmol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.9 mL, 66.7 mmol) in anhydrous MeCN (200 mL) at room temperature under nitrogen. On complete addition the mixture was stirred for a further 18 hours. The reaction was concentrated in vacuo and the residue partitioned between EtOAc (200 mL) and water(200 mL). The phases were separated, the aqueous phase extracted with EtOAc (200 mL), the combined organic phases dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (elution with 0-50% EtOAc in cyclohexane) to afford 3- bromo-2-(difluoromethoxy)pyridine (9.50 g). *H NMR (400MHz, CDCI3): 5 8.14-8.12(m, 1H), 7.95-7.92 (m, 1H), 7.47 (t, 1=72,2 Hz, 1H), 7.01 (dd, 1=4.8, 7.8 Hz, 1H).Methyl 2-(2-(difluoromethoxy)pyridin-3-yI)thiazoIe-5-carboxyIateA stirred mixture of 3-bromo-2-(difluoromethoxy)pyridine (4.28 g, 19.1 mmol), methyl thiazole-5-carboxylate (3.42 g, 23.9 mmol, 1.25 eq) and RuPhos Pd G2 (0.742 g, 0.955 mmol) in anhydrous 2 -methyltetrahydrofuran (150 mL) was degassed, purged with nitrogen and treated with 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex solution (17% in THF, 35 mL, 23.9 mmol) in a steady stream. On complete addition the reaction was heated at 70°C for 1.25 hours. The reaction was cooled and allowed to stand at room temperature for 18 hours. The reaction was quenched with a saturated NH4CI solution and extracted into EtOAc (2 x 100 mL). The combined organic extracts were washed with brine, dried over NaeSO4 and concentrated in vacuo.Purification by silica gel chromatography (elution with 0-50% diethyl ether in cyclohexane) to afford methyl 2-(2-(difluoromethoxy)pyridin-3-yl)thiazole-5- carboxylate (3.77 g). ^NMR (400MHz, CDCb): 3 8.80 (dd, J=1.9, 7.8 Hz, 1H), 8.51 (s,1H), 8.31 - 8.28 (m, 1H), 7.68 (t, J=72.1 Hz, 1H), 7.29 (dd, 1=4.9, 7.8 Hz, 1H), 3.96-3.95(m, 3H). MS (ESI) m / z 287.2 [M+H]+.(2-(2-(Difluoromethoxy)pyridin-3-yl)thiazol-5-yl)methanolA stirred solution of methyl 2-(2-(difluoromethoxy)pyridin-3-yl)thiazole-5-carboxylate(3.70 g, 12.9 mmol) in anhydrous DCM (100 mL) at -5°C was treated with a steady stream of DIBAL-H (IM in cyclohexane, 32.3 mL, 32.3 mmol) over 5 minutes. The reaction was stirred at 0°C for 1 hour, quenched with a saturated solution of Rochelle’s salt (100 mL) and the mixture stirred at ambient temperature for 20 minutes. DCM (100 mL) was added and the mixture filtered through Celite®. The phases were separated and the aqueous extracted with DCM (4 x 100 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo to afford (2-(2-(difluoromethoxy)pyridin-3-yl)thiazol-5- yl)methanol (3.3 g). TINMR (400MHz, CDCI3): 88.71 (dd, J=1.9, 7.8 Hz, 1H), 8.23 (dd,J=1.9, 4.8 Hz, IH), 7.83-7.46 (m, 2H), 7.26 (dd, J=4.8, 7.8 Hz, 1H), 4.96 (d, J=0.9 Hz,2H), 2.06 (br s, IH). MS (ESI) m / z 259.2 [M+H]+.2-(2-(Difluoromethoxy)pyridin-3-yl)thiazole-5-carbaldehydeA mixture of (2-(2-(difluoromethoxy)pyridin-3-yl)thiazol-5-yl)methanol (3.30 g, 12.8 mmol) and MnOa (11.11 g, 128 mmol) in anhydrous 2-methyltetrahydrofuran (200 ml.) was heated at 68°C for 1.5 hours. The cooled mixture was filtered through Celite®, the filter pad washed with DCM (250 mL) and the combined filtrate and washings concentrated in vacuo to afford 2-(2-(difluoromethoxy)pyridin-3-yl)thiazole-5- carbaldehyde (2.83 g). *H NMR (400 MHz, CDC13): 5 10.13 (s, IH), 8.83 (dd, 1=1.9, 7.8Hz, IH), 8.51-8.51 (m, IH), 8.34-8.32 (m, IH), 7.68 (t, J=71.5 Hz, IH), 7.32 (dd, J=4.8,7.8 Hz, 1H). MS (ESI) m / z 257.2 (M+H]+.

[0294] Synthesis of3-(2-(difluoromethoxv)phenvl)isoxazole-5-carbaldehydeF(E)-N-{[2-(Difluoromethoxy)phenyl]methylidene}hydroxyIamineTo a solution of2-(difluoromethoxy)benzaldehyde (0.769 mL, 5.810 mmol) in water(25.0 mL) was added sodium carbonate (0.753 g, 7.101 mmol) followed by hydroxylamine hydrochloride (0.753 g, 10.831 mmol) and the resulting solution was heated to 120QC for 2 hours. The reaction mixture was cooled to room temperature and extracted with a DCM (3 x30 mL), dried (NaiSCh) and concentrated to afford (E)-N-{ [2-(difhioromethoxy)phenyl]methylidene}hydroxylamine (l.l g). 1H NMR (400 MHz,Chloroform-d) 5 8.45 (s, IH), 7.85 (dd, J = 7.9, 1.7 Hz, IH), 7.40 (ddd, J = 8.1, 7.4, 1.7Hz, IH), 7.23 (dt, J = 7.8, 0.9 Hz, IH), 7.17 (dd, J= 8.3, 1.1 Hz, IH), 6.54 (t, J = 73.3 Hz,1H).(3-(2-(Difluoromethoxy)phenyl)isoxazol-5-yl)methanoITo a solution of(E)-N-{[2-(difluoromethoxy)phenyl]methylidene}hydroxylamine(1.01 g, 5.408 mmol) in DMF (15.0 mL) was added N-chlorosuccinimide (0.81 g, 6.056 mmol) in one portion. The resulting solution was stirred at rt for 1 hour. The solution was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The organics were combined and washed with brine (10 mL). The solution was taken through to the next step without further purifications. To a solution of (Z)-2-(difluoromethoxy)-N- hydroxybenzene- 1 -carbonimidoyl chloride in DCM (30.0 mL) was added propargyl alcohol (0.48 mL, 8.111 mmol) followed by triethylamine (1.1 mL, 8.111 mmol). The resulting solution was stirred at room temperature overnight. The solution was concentrated and the residue was purified by column chromatography (SiOz EtOAc / iso. hexanes) to afford {3-[2-(difluoromethoxy)phenyl]-l,2-oxazol-5-yl}methanol (1.33 g).1H NMR (400 MHz, Chloroform-d) 67.97 (dd, J = 7.7, 1.8 Hz, 1H), 7.49 (td, J = 7.9, 1.8Hz, 1H), 7.34 (td, J = 7.6, 12 Hz, 1H), 7.28 - 7.23 (m, 1H), 6.76 - 6.34 (m, 2H), 4.87 (s,2H). OH not observed.3-(2-(Difluoromethoxy)phenyl)isoxazole-5-carbaldehydeA mixture of (3-(2-(difluoromethoxy)phenyl)isoxazol-5-yl)methanol (259 mg, 1.1. mmo) and MnOz (467 mg, 5.37 mmol) in DCM (5.0 mL) was stirred at room temperature for90 minutes. MnOz (467 mg, 5.37 mmol) was added and the reaction was stirred overnight.The reaction was filtered through Celite and then purified by column chromatography(SiOz, EtOAc / cyclohexane) to give the desired product 3-(2-(difluoromethoxy)phenyl)isoxazole-5-carbaldehyde (98 mg) *H NMR (400 MHz,CDCb): 3 10.03 (s, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.46 (s, 1H), 7.39 -7.35 (m, 1H), 6.71 (s, 1H), 6.54 (t, >74.3 Hz, 1H).

[0295] Synthesis of5-(2-(difluoromethoxv)phenyl)thiazole-2-carbaldehyde(5-(2-(Difluoromethoxy)phenyl)thiazol-2-yI)methanolReaction was performed in 3 x 50 mL capped reaction tubes with 1 / 3 aliquot of each reagent and solvent in each tube.A stirred mixture of l-bromo-2-(difluoromethoxy)benzene (1.43 g, 6.41 mmol), bis(pinacolato)diboron (1.79 g, 7.05 mmol) and KOAc (1.89 g, 19.2 mmol) in anhydrous1,4-dioxane (27 mL) was flushed with nitrogen for 5 minutes prior to the addition ofPd(dppf)Ch (238 mg, 0.321 mmol). The tubes were capped and heated at 80°C for 20 hours. The reaction mixture was cooled, (5-bromothiazol-2-yl)methanol (1.24 g, 6.41 mmol), CS2CO3 (6.27 g, 19.2 mmol) and water (5.3 mL) were added and the tube flushed with nitrogen for 2 minutes prior to addition of Pd(dppf)Ch (238 mg, 0.321 mmol). The tubes were capped and heated at 100°C for 3 hours. The cooled reaction mixtures were pooled, diluted with EtOAc (100 mL) and the phases separated. The aqueous layer was extracted further with EtOAc (3 x 20 mL). The combined organic extracts were dried overMgSO4 and concentrated in vacuo. Purification by silica gel chromatography (elution with 0-100% EtOAc in cyclohexane) to afford (5-(2-(difluoromethoxy)phenyl)thiazol-2- yl)methanol (1.70 g). Reaction repeated as above and an additional L62 g of (5-(2-(difluoromethoxy)phenyl)thiazol-2-yl) was isolated. The combined batches were triturated with cyclohexane, collected by filtration, washed with cyclohexane and air- dried to afford 5-(2-(difhioromethoxy)phenyl)thiazol-2-yl) (1.80 g). NMR (400MHz,CDCh): 8 8.03 (s, 1H), 7.63 (dd, 1=1.6, 7.7 Hz, 1H), 7.39-7.34 (m, 1H), 7.30-7.23 (m,2H), 6.54 (t, J=73.3 Hz, 1H), 4.99 (d, J=6.1 Hz, 2H), 2.79 (dd, J=6.2, 6.2 Hz, 1H).5-(2-(Difluoromethoxy)phenyl)thiazole-2-carbaldehyde5-(2-(Difluoromethoxy)phenyl)t...

Claims

1. CLAIMS

1. A compound of formula (I):9 or a salt thereof, wherein:R1is:1) H,2) halo,3) OH,4) R11optionally substituted with the same or different one or more R12, or5) -L1R11optionally substituted with the same or different one or more R12;L1is O or S;R11is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl;R12is each independently halo, -OH, -N(Ra)(Rb), -O-C1-6alkyl, -O- C1-6alkyl-N(Ra)(Rb), C3-8 cycloalkyl, or saturated 3- to 8-membered monocyclic heterocyclyl comprising at least one heteroatom independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein R12is optionally substituted with the same or different one or more halo, C1-6alkyl, or CN;Rais H or C1-6alkyl;Rbis H, C1-6alkyl, or C(=0)0C1-6alkyl;R2is:1) C1-6alkyl optionally substituted with the same or different one or more halo orCN,2) C3-8 cycloalkyl optionally substituted with the same or different one or more C1-6alkyl, halo or CN, or3) Si(C1-6alkyl)3;R3is CH2 or O;R4is H or C1-6alkyl;Ring A is 5- or 6-membered heteroaryl or 6-membered aryl;Ring A may be optionally substituted with the same or different one or more A1selected from the group consisting of halo, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkyl-0 C1-6haloalkyl-O-, C1-6alkylene(C3-6 cycloalkyl), C1-6alkylene(3- to 10-membered heterocyclyl), C1-6alkylene(C6-10aryl), C1-6alkylene-0-(C6-10aryl), C1-6alkylene(5- to 12- membered heteroaryl), C0-6alkyleneOH, C0-3 alkyleneOC2-3 alkylene(OH), C0-6alkylene(N(Rc)(Rd)), -OC0-6 alkylene(OC1-6alkyl), -OC0-6 alkylene(N(Rc)(Rd)), and C0-3 alkyleneOCi.3 alkylene(N(R°)(Rd));Rcis H or C1-6alkyl;Rdis H or C1-6alkyl, C1-6haloalkyl, or C(=O)OC1-6alkyl;Ring A may be optionally substituted with the same or different one or two RingG;Ring G is a monocyclic or bicyclic 6- to 10-membered aryl, a monocyclic or bicyclic 5- to 12-membered heteroaryl, C3-8 cycloalkyl, or a saturated or partially unsaturated monocyclic or bicyclic 3- to 16-membered heterocyclyl; wherein the bicyclic aryl comprises a 6-membered aryl attached to Ring A, and the bicyclic heteroarylcomprises a 5- or 6-membered heteroaryl attached to Ring A;Ring G may be independently optionally substituted with the same or different one or more G1A;G1Ais halo, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6haloalkenyl, C2-6alkynyl, -(CRxRy)v-CN, -(CH2)v-NRxRy, -(CH2)v-C3-8cycloalkyl, -(CH2)v-C3-8 cycloalkenyl, -(CH2)v-(3- to 10-membered heterocyclyl), -(CH2)v-C6-10aryl, -(CH2)v-(5- to 12- membered heteroaryl), -(CRxRy)v-O-Rz, -0-(CRxRy)n-0Rz, nitro, Si(Rx)4, -S(O)q-Rx, -C(=O)RX, -(CRxRy)v-C(=O)ORz, -(CRXR3>O-C(=O)-RZ, -(CRxRy)v-C(=O)NRxRy, -(CH2)v-NRxC(=O)Ry, -(CH2)v-OC(=O)NRxRy, -(CH2)v-NRxC(-O)ORy, -NRX-(CH2)V-RZ,-(CH2)V-O-C(=O)-C1-4alkyl-NRxRy, -(CH2)y-NRx-(CH2)n-O-C(=O)-Rz, -(CH2)v-NRx-(CH2)v-SO2-Ry, -(CH2)v-NH-SO2-NRxRy, -(CH2)v-SO2NRxRygroups, and -P(=O)(RX)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C6-10aryl, 3- to 10-membered heterocyclyl, and 5- to 12-membered heteroaryl groups may be optionally substituted with the same or different one or more Rxgroups and the two Rxmay join to form a 3- to 7-membered ring optionally containing one or two additional heteroatoms selected from O, N, S, and oxidized forms of N or S;Rx, Ryand Rzeach independently represent halo, H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -(CH2)v-C3-8 cycloalkyl, -(CH2)v-C3-8cycloalkenyl, -(CH2)v-C6-10aryl, -(CH2)V-5- to 12-membered heteroaryl, -(CH2)v-(3- to 10-membered heterocyclyl), -(CH2)vOH optionally substituted with the same or different one or more halo, -C(=O)OC1-6alkyl,OH, =0, C1-6alkyl-O-, C1-6haloalkyl, -(CH2)n-O-C1-6alkyl, -C(=0)-(CH2)n- C1-6alkyl-0-C(=0)-C1-6alkyl, -(CH2)VC(=O)(OG2A), -(CH2)v-CN, C1-6alkyl-N(H)2-q(Rh)q, -N(H)2. q(Rh)q, -C(=0)-N(H)2-q(C1-6alkyl)q, -(CH2)v-NH-SO2-N(H)2-q(C1-6alkyl)q, -(CH2)v-N(CI.4 alkyl)-SO2-N(H)2_q(C1-6alkyl)q, and -(CH2)v-0-C(=0)-C1-6alkyl-N(H)2^( C1-6alkyl),; and when attached to nitrogen, carbon, silicon, or phosphorus atom, Rxand Rymay jointo form a 3- to 7-membered ring optionally containing one or two additional heteroatoms selected from O, N, S, and oxidized forms of N or S;G24is H, C1-6alkyl, C0-3 alkylene(C6-10aryl) or C0-3 alkylene(5- to 12-membered heteroaryl), wherein said aryl or heteroaryl may be optionally substituted with the same or different one or more groups selected from the group consisting of halo, CN, OH, Ci-6 alkyl, C1-6haloalky 1, C1-6alkyl-O-, C1-6haloalkyl-O-, and C3-6 cycloalkyl;Rhis C1-6alkyl, C1-6haloalkyl, or C(=O)OC1-6alkyl; v independently represents an integer from 0-4; n independently represents an integer from 1-4; p independently represents an integer from 0-4; and q represents an integer from 0-2; provided that the compound is not l-(2-fluorobenzyl)-5-methylpiperidine-3- carboxylic acid.

2. The compound according to claim 1, or a salt thereof^ wherein R2is:1) C2-6alkyl optionally substituted with the same or different one or more halo orCN,2) C3-8 cycloalkyl optionally substituted with the same or different one or more C1-6alkyl, halo or ON, or3) Si(C1-6alkyl)3, provided that the compound is not rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[[2-(l / f-1 ,2,4-triazol-l-yl)phenyl]methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 - dimethylethyl)-l-[(6-oxo-l,6-dihydropyridin-3-yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)- 1 - [3 -acetamidobenzyl)-5-(l , 1 -dimethylethyl]-3 -piperidinecarboxylic acid,rel-(3R,5R)-5-(l , 1 -dimethylethyl)- 1 - [(3 ,5 -dimethyl- 1 -( 1 -methylethyl)- 1 H-pyrazol-4- yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[4- cbloropyridin-3-yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l ,1 - dimethylethyl)- 1 -[(3 ,5-dimethyl-4-pyridinyl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[((4-cyanothiophen-2-yl)methyl]-3- piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[3-chloro-5- hydroxybenzyl)-3-piperidinecarboxy lie acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[(3- methoxy-l-methyl-lH-pyrazol-4-yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(1,1 -dimethylethyl)- 1 - [[3 -( 1 -methylethyl)-4-isoxazolyl]methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)-! -[(3-fluoro-2-pyridinyl)methyl]-3- piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)- 1 -[(2-cyclopropyl- 1H- imidazol-5-yl)methy]-3 -piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)- 1 -[(4-fluoro-2-hydroxyphenyl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l- dimethy lethy 1)- 1 - [(4,5 -dimethy 1- 1 H-pyrazol-3 -y l)methy 1] -3 -piperidinecarboxylic acid,5-(l , 1 -dimethylethyl)- 1 - [ 1 -[(5-chloro-2-thiazolyl)methyl]-3-piperidinecarboxylic acid,5-(l,l-dimethylethyl)-l-[(5-ethyl-l-methyl-lH-pyrazol-4-yl)methyl]-3- piperidinecarboxylic acid, 5-(l ,1 -dimethylethyl)-! -[(1 -cyclobutyl- lH-pyrazol-4- yl)methyl]-3 -piperidinecarboxylic acid, 5 -( 1 , 1 -dimethylethyl)- 1 - [(6-cy clobuty 1-3 - pyridinyl)methyl]-3 -piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)-! -[(3 - ethoxy-2-hydroxyphenyl)methyl]-3-piperidineearboxylic acid, rel-(3R,5R)-5-(l ,1- dimethylethy 1)- 1 - [[3 -(dimethy lamino)-5 -fluoro -4-pyridiny l]methy 1] -3 - piperidinecarboxylic acid, rel-(3R,5R)-5-( 1 , 1 -dimethylethyl)- 1 - [(4-chloro- 1 -methyl- 1 H- pyrazol-3 -yl)methy l]-3 -piperidinecarboxylic acid, rel-(3 R,5R)-5-(l , 1 -dimethylethyl)- 1 -[[5-(trifluoromethyl)-2-furanyl]methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l- dimethylethyl)-! - [3 -(1 , 1 -dimethylethyl)- 1 -ethyl- 1 H-pyrazol-4-y IJmethy 1] - 3 -piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[[l-(2,2-difluoroethyl)-3-methyl-!H-pyrazol-4-yl]methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 - dimethylethy 1)- 1 - [(5 -ethyl- 1 -methyl- 1 H-pyrazol-4-y l)methy 1] -3 -piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)-! -[[1 -(cyclopropylmethyl)-!H-pyrazol-5- yljmethyl] -3 -piperidinecarboxylic acid, rel-(3R,5R)-5-(l , 1 -dimethylethyl)- 1 -[[1 -(2,2,2- trifluoroethyl)-lH-pyrazol-4-yl]methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[(2-amino-3-fluorophenyl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-( 1 , 1 -dimethylethyl)- 1 -[[1 -(2-propen- 1 -yl)- 1 H-pyrazol-4-yl] -3 - piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[(5-ethyl-!H-imidazol-2-yl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l-dimethylethyl)-l-[(2- methoxy-5-thiazolyl)methyl]-3-piperidinecarboxylic acid, rel-(3R,5R)-5-(l,l- dimethylethyl)-! -[(5-chloro-3-pyridinyl)methyl]-3 -piperidinecarboxylic acid, rel-(3R,5R)-l-[(5-cyclopropyl-177-pyrazol-3-yl)methyl]-5-(l,l-dimethylethyl)-3- piperidinecarboxylic acid, rel-(3R,5R)-l-[(l-cyclobuiyl-lH-pyrazol-4-yl)methyl]-5-(l,l-dimethylethyl)-3-piperidinecarboxylic acid, or rel-(3R,5R)-l-[(6-cyclobutyl-3- pyridinyl)methyl]-5-(l,l-dimethylethyl)-3-piperidinecarboxylic acid.

3. The compound according to claim 1 or 2, or a salt thereof, wherein Ring A is substituted with the same or different one or two Ring G.

4. The compound according to any one of claims 1 to 3, or a salt thereof, whereinRing A is pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, or phenyl.

5. The compound according to any one of claims 1 to 4, or a salt thereof, whereinRing A is pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

6. The compound according to any one of claims 1 to 5, or a salt thereof, whereinRing G is selected from the following groups:HN > aN O NH NH k / NH NH H

7. The compound according to any one of claims 1 to 6, or a salt thereof, wherein R1is halo, OH, R11optionally substituted with the same or different one or more R12, or -L1- R11optionally substituted with the same or different one or more R12.

8. The compound according to any one of claims 1 to 6, or a salt thereof, whereinR1is H, R11optionally substituted with the same or different one or more R12, or -L*-Rnoptionally substituted with the same or different one or more R12;L1is O;R11is C1-6alkyl;R12is each independently halo or C3-8 cycloalkyl;R2is C2-6alkyl;R3is CH2 or 0;R4is H;Ring A is isoxazolyl, thiazolyl, pyridinyl, or phenyl;Ring A may be optionally substituted with the same or different one or more A1selected from the group consisting of C1-6alkyl and -OC1-6alkylene(N(Rc)(Rd));Rcis C1-6alkyl;Rdis C1-6alkyl;Ring A may be optionally substituted with Ring G;Ring G is phenyl, pyrazolyl, or pyridyl;Ring G may be independently optionally substituted with the same or different one or more G1A; andG1Ais each independently halo, CN, -O-C1-6haloalkyl, pyridyl, azetidinyl optionally substituted with one or more groups independently selected from the group consisting of halo and C1-6alkyl, or piperazinyl optionally substituted with C1-6alkyl.

9. The compound according to any one of claims 1 to 8, or a salt thereof, whereinR1is R11optionally substituted with the same or different one or more R12, or-O-R11optionally substituted with the same or different one or more R12;Ruis C1-6alkyl;R12is each independently halo or C3-8 cycloalkyl;R2is C2-6alkyl;R3is CH2 or O;R4is H;Ring A is isoxazolyl, thiazolyl, pyridinyl, or phenyl;Ring A may be optionally substituted with the same or different one or more A1selected from the group consisting of C1-6alkyl and -OC1-6alkylene(N(Rc)(Rd));Rcis C1-6alkyl;Rdis C1-6alkyl;Ring A may be optionally substituted with Ring G;Ring G is phenyl, pyrazolyl, or pyridyl;Ring G may be independently optionally substituted with the same or different one or more G1A; andG1Ais each independently halo, CN, -O-C1-6haloalkyl, pyridyl, azetidinyl optionally substituted with one or more groups independently selected from the group consisting of halo and C1-6alkyl, or piperazinyl optionally substituted with C1-6alkyl.

10. The compound according to claim 1, or a salt thereof, wherein the compound is selected from Examples 1 to 804.

11. The compound according to claim 1, or a salt thereof, selected from the following formulae:

12. The compound or salt according to claim 1, selected from the following formulae:

13. A sortilin inhibitor comprising a compound according to any one of claims 1 to12, or a salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a salt thereof, and a pharmaceutically acceptable carrier or excipient

15. The compound according to any one of claims 1 to 12, or a salt thereof, for use in treating, preventing, and / or diagnosing a disease or disorder selected from the group consisting of inflammatory diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), psoriasis, type 1 diabetes mellitus (T1DM), and multiple sclerosis (MS); cancers including progranulin-induced metastatic breast cancer, lung metastases, and pancreatic cancer cell invasion; wounds (i.e., wound healing) and traumatic brain injury; CNS diseases such as stroke, schizophrenia-like psychosis, schizophrenia, or bipolar disorder(BPD); atypical parkinsonism, such as corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP); spinocerebellar ataxia 3 (SCA3), limbic-predominant age- related TDP-43 encephalopathy (LATE), and Huntington's diseases (HD); age-related macular degeneration (AMD), retinal degeneration, and other neurodegenerative diseases of the eye; atherosclerosis; neurodegenerative diseases such as frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), neuronal ceroid lipofuscinosis (NCL, a lysosomal storage disease), Niemann-Pick disease type A(NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC), amyotrophic lateral sclerosis (ALS), C90RF72-associated ALS / FTD, sporadic ALS,Alzheimer’s disease (AD), Gaucher disease types 2 and 3, Parkinson’s disease (PD), and major depression; pain; and hearing loss.

16. Use of a compound according to any one of claims 1 to 12, or a salt thereof, in the manufacture of a medicine for the treatment, prophylaxis, and / or diagnosis of a disease or disorder selected from the group consisting of inflammatory diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), psoriasis, type 1 diabetes mellitus(T1DM), and multiple sclerosis (MS); cancers including progranulin-induced metastatic breast cancer, lung metastases, and pancreatic cancer cell invasion; wounds (i.e., wound healing) and traumatic brain injury; CNS diseases such as stroke, schizophrenia-like psychosis, schizophrenia, or bipolar disorder (BPD); atypical parkinsonism, such as corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP); spinocerebellar ataxia 3 (SC A3), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Huntington's diseases (HD); age-related macular degeneration (AMD), retinal degeneration, and other neurodegenerative diseases of the eye; atherosclerosis; neurodegenerative diseases such as frontotemporal dementia(FTD), frontotemporal lobar degeneration (FTLD), neuronal ceroid lipofuscinosis(NCL, a lysosomal storage disease), Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB), Niemann-Pick disease type C (NPC), amyotrophic lateral sclerosis (ALS), C9ORF72-associated ALS / FTD, sporadic ALS, Alzheimer’s disease(AD), Gaucher disease types 2 and 3, Parkinson’s disease (PD), and major depression;pain; and hearing loss.

17. A method of treatment, prophylaxis, and / or diagnosis of a disease or disorder selected from the group consisting of inflammatory diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), psoriasis, type 1 diabetes mellitus (T1DM), and multiple sclerosis (MS); cancers including progranulin-induced metastatic breast cancer, lung metastases, and pancreatic cancer cell invasion; wounds (i.e., wound healing) and traumatic brain injury; CNS diseases such as stroke, schizophrenia-like psychosis, schizophrenia, or bipolar disorder (BPD); atypical parkinsonism, such as corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP); spinocerebellar ataxia 3(SCA3), limbic-predominant age-related TDP-43 encephalopathy (LATE), andHuntington's diseases (HD); age-related macular degeneration (AMD), retinal degeneration, and other neurodegenerative diseases of the eye; atherosclerosis; neurodegenerative diseases such as frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), neuronal ceroid lipofuscinosis (NCL, a lysosomal storage disease), Niemann-Pick disease type A (NPA), Niemann-Pick disease type B (NPB),Niemann-Pick disease type C (NPC), amyotrophic lateral sclerosis (ALS), C9ORF72- associated ALS / FTD, sporadic ALS, Alzheimer’s disease (AD), Gaucher disease types2 and 3, Parkinson’s disease (PD), and major depression; pain; and hearing loss, the method which comprises administering to a subject in need thereof a compound according to any one of claims 1 to 12, or a salt thereof.

18. The compound according to any one of claims 1 to 12, or a salt thereof, for use as a sortilin inhibitor.

19. The compound according to any one of claims 1 to 12, or a salt thereof, for use in increasing PGRN levels, inhibiting neurotensin signaling, inhibiting BDNF signaling, inhibiting proNGF signaling, or inhibiting proBDNF signaling.

20. The compound according to any one of claims 1 to 12, or a salt thereof, for use in the treatment, prophylaxis, and / or diagnosis of a disease or disorder associated with sortilin ligands.

21. A method of treatment, prophylaxis, and / or diagnosis of a disease or disorder associated with sortilin ligands, the method which comprises administering to a subject in need thereof a compound according to any one of claims 1 to 12, or a salt thereof.

22. Use of a compound according to any one of claims 1 to 12, or a salt thereof, in the manufacture of a medicament for the treatment, prophylaxis, and / or diagnosis of a disease or disorder associated with sortilin ligands.

23. A medicament comprising a compound according to any one of claims 1 to 12,or a salt thereof, for use in the treatment, prophylaxis, and / or diagnosis of a disease or disorder associated with sortilin ligands.

24. The compound according to any one of claims 1 to 12, or a salt thereof, or the inhibitor, composition, method, use, or medicament according to any one of claims 13 to 23, for use in the treatment, prophylaxis, and / or diagnosis of a neurodegenerative disease.

25. The compound, or a salt thereof, inhibitor, composition, method, use, or medicament according to claim 24, wherein the disease is selected from frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease or amyotrophic lateral sclerosis.

26. The compound according to any one of claims 1 to 12, or a salt thereof, or the inhibitor, method, use, or medicament according to any one of claims 13 and 15 to 25, wherein the compound, or a salt thereof, is provided in the form of a pharmaceutical composition according to claim 14.

Images