Carboxylic Acid Derivatives with Anti-inflammatory Properties

Abstract

The present invention relates to compounds of formula (I) and their use in the treatment or prevention of inflammatory diseases or diseases associated with an undesired immune response, wherein R A1 , R A2 , R C , and R D is as defined herein. TIFF2023508142000465.tif4449

Description

[Technical field]

[0001] The present invention relates to compounds for use in the treatment or prevention of inflammatory diseases or diseases associated with an unwanted immune response, as well as related compositions, methods, uses, and intermediate compounds. [Background technology]

[0002] Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, uveitis, and chronic obstructive pulmonary disease (COPD) pose a significant burden to society due to lifelong debilitating illness, increased mortality, and high costs of treatment and care (Straub RHand Schradin C., 2016). Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widespread drugs used to treat inflammatory diseases, but these drugs do not prevent the progression of inflammation, but only treat the accompanying symptoms. Glucocorticoids are powerful anti-inflammatory agents and can provide emergency treatment of acute inflammatory flares, but when administered long-term, these drugs cause many undesirable side effects and can develop resistance (Straub RHand Cutolo M., 2016). Thus, there remains a significant unmet medical need for the treatment of inflammatory diseases, and extensive efforts are underway to discover new drugs to reduce the burden of these diseases (Hanke T. et al., 2016).

[0003] Dimethyl fumarate (DMF), a diester of the citric acid cycle (CAC) intermediate fumaric acid, has been utilized as an oral therapy to treat psoriasis (Bruck J. et al., 2018) and multiple sclerosis (Mills EA et al., 2018). Importantly, following oral administration, the drug is not detectable in plasma (Dibbert S. et al., 2013), and the only drug-related compounds observed are monomethyl fumarate (MMF), a hydrolysis product of both the parent (DMF) and metabolite (MMF), and glutathione (GSH) conjugates. The mechanism of action of DMF is complex and controversial. The efficacy of this compound is attributed to a variety of phenomena, including the covalent modification of proteins and the conversion of the "prodrug" DMF to MMF.In particular, the following pathways have been highlighted as relevant for the anti-inflammatory effects of DMF: 1) activation of the antioxidant, anti-inflammatory, nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway as a result of the reaction of an electrophilic α,β-unsaturated ester moiety with a nucleophilic cysteine ​​residue on the Kelch-like ECH-associated protein 1 (KEAP1) (Brennan M et al., 2015); 2) induction of activating transcription factor 3 (ATF3) leading to the suppression of the proinflammatory cytokines interleukin (IL)-6 and IL-8 (Muller S. et al., 2017); 3) inactivation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by succinylation of its catalytic cysteine ​​residue by a Michael-accepting unsaturated ester (Kornberg MD et al., 2018; Angiari S. and O'Neill LA, 2018); 4) inhibition of nuclear factor kappa B (NF-κB)-driven cytokine production (Gillard GOet al., 2015); 5) Prevention of the association of PKCθ with the costimulatory receptor CD28, which reduces the production of IL-2 and blocks T cell activation (Blewett MM et al., 2016); 6) Reaction of electrophilic α,β-unsaturated esters with the nucleophilic thiol group of the antioxidant GSH, which affects the cellular response to oxidative stress (Lehmann JCU et al., 2007); 7) Agonism of the hydroxycarboxylic acid receptor 2 (HCA2) by MMF generated in vivo by DMF hydrolysis (von Glehn F. et al., 2018); 8) Allosteric covalent inhibition of p90 ribosomal S6 kinase (Andersen JLet al., 2018); 9) Inhibition of the expression and function of hypoxia-inducible factor-1α (HIF-1α) and its target genes, e.g. IL-8 (Zhao G. et al., 2018). et al., 2014); and 10) inhibition of Toll-like receptor (TLR)-induced M1 and K63 ubiquitin chain formation (McGuire VA et al., 2016). In general, except for HCA2 agonism (Tang H. et al., 2008), the membrane-permeable diester DMF tends to exhibit much more profound biological effects in cells compared to its monoester counterpart MMF.However, the lack of systemic exposure to DMF in vivo has led some researchers to argue that MMF is in fact the primary active component following oral DMF administration (Mrowietz U. et al., 2018). Thus, it is clear that some of the significant biology exerted by DMF in cells is lost due to hydrolysis to MMF in vivo.

[0004] Recently, it has been discovered that during inflammatory macrophage activation, CAC becomes supplemental and is converted to generate the unsaturated diacid itaconic acid "itaconate" (Murphy MP and O'Neill LAJ, 2018; O'Neill LAJ and Artyomov MN, 2019; Yu X.-H. et al., 2019). Instead of being hydrated to isocitrate by aconitate hydratase, the CAC intermediate aconitate is decarboxylated by the protein product of immune responsive gene 1 (IRG1), one of the most highly upregulated genes in macrophages under proinflammatory conditions, to generate itaconic acid, subsequently named aconitate decarboxylase 1 (Michelucci A. et al., 2013). This unsaturated diacid is an inhibitor of the bacterial enzyme isocitrate lyase and exerts antibacterial effects. Furthermore, itaconate has been shown to inhibit the CAC enzyme succinate dehydrogenase (SDH) (Ackermann et al., 1949) and accordingly cause succinate accumulation (Cordes T. et al., 2016). By inhibiting SDH, an enzyme important in inflammatory responses (EL Mills et al., 2016), itaconate ameliorates inflammation in vitro and in vivo during macrophage activation and ischemia-reperfusion injury (Lampropoulou V. et al., 2016).

[0005] Like fumaric acid, itaconic acid is an α,β-unsaturated carboxylic acid. As such, it is a Michael acceptor that induces a global electrophilic stress response. In this regard, the itaconic acid diester dimethyl itaconate (DMI), like DMF, triggers an anti-inflammatory response and reduces the expression levels of the proinflammatory cytokines IL-1β, IL-6, IL-12, and IL-18 in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (WO2017 / 142855A1, incorporated herein by reference). This response appears to be mediated in part by NRF2 activation via alkylation of KEAP1 cysteine ​​residues by the electrophilic α,β-unsaturated ester moiety (Mills et al., 2018), which enhances the expression of downstream genes with antioxidant and anti-inflammatory capabilities. Nevertheless, not all of the remarkable immunomodulatory effects caused by DMI can be attributed to NRF2 activation. Notably, regulation of IκBζ by DMI is independent of NRF2 and is mediated through upregulation of ATF3, a global negative regulator of immune activation that downregulates various cytokines such as IL-6 (Bambouskova M. et al., 2018). Moreover, by inhibiting IκBζ protein production, DMI ameliorates IL-17-mediated pathologies, highlighting the therapeutic potential of this regulatory pathway (WO2019 / 036509A1, incorporated herein by reference). Further highlighting its pharmacological potential, DMI has recently been reported to 1) exhibit protective effects against cerebral ischemia / reperfusion injury, thereby offering a potential treatment for ischemic stroke (Zhang D. et al., 2019), 2) provide protection from the cardiotoxic effects of doxorubicin (Shan Q. et al., 2019), and 3) protect against lipopolysaccharide-induced mastitis in mice by activating MAPK and NRF2 while inhibiting the NF-κB signaling pathway (Zhao C. et al., 2019).In addition, DMI is said to be useful in the prevention and treatment of ulcerative colitis and its cancerization (CN110731955, Sun Yat-sen University Cancer Center), and it has been reported to protect against fungal keratitis by activating the NRF2 / HO-1 signaling pathway (Gu L. et al., 2020). Nevertheless, it should be noted that DMI is not metabolized to itaconic acid in cells (ElAzzouny M. et al., 2017). Other α,β-unsaturated esters and acids have been shown to exhibit IL-1β-lowering effects in macrophages by inhibiting the NLRP3 inflammasome (Cocco M. et al., 2017 and 2014), inhibiting the TLR4 pathway, and ultimately suppressing the stimulation of LPS-induced NF-κB, tumor necrosis factor (TNF)-α, IL-1β, and nitric oxide release (Zhang S. et al., 2012). WO2014 / 152263A1 (Karyopharm Therapeutics, Inc.) describes α,β-unsaturated esters that are said to be chromosomal region maintenance 1 (CRM1) inhibitors. CRM-1 is responsible for exporting several important proteins involved in many inflammatory processes.

[0006] Other itaconic acid derivatives have been shown to induce anti-inflammatory effects (Bagavant G. et al., 1994). A notable example is 4-octyl itaconic acid (4OI), an itaconic acid derivative with improved cellular uptake. Since α,β-unsaturated carboxylic acids are not esterified in 4OI, this electrophile shows a lower reactivity with biological thiols, similar to the situation occurring with itaconic acid itself (Schmidt TJ et al., 2007). As a result of its lower reactivity / electrophilicity, the NRF2-activating effect of 4OI is not attenuated by GSH, in contrast to the results of DMI, which is much more reactive. In this latter case, the α,β-unsaturated carboxylic acid is esterified, so that the IL-6-lowering and NRF2-activating effects of DMI are reversed by the thiols N-acetylcysteine ​​and GSH, respectively. Through its reaction with KEAP1 and the resulting NRF2 activation, as well as GAPDH inhibition (Liao S.-T. et al., 2019), 4OI has been shown to 1) protect neuronal cells from hydrogen peroxide (Liu H. et al., 2018), 2) inhibit inflammatory cytokine production in peripheral blood mononuclear cells from SLE patients (Tang C. et al., 2018), 3) protect human umbilical vein endothelial cells from high glucose (Tang C. et al., 2019), 4) inhibit osteoclastogenesis by suppressing the E3 ubiquitin ligase Hrd1 and activating NRF2 signaling (Sun X. et al., 2019), 5) induce suppression of STING by NRF2 and type I IFN production in cells from patients with STING-dependent interferon disorders (Olagnier D. et al., 2019). al., 2018), 6) protection against renal fibrosis via inhibition of the TGF-beta / Smad pathway, autophagy and reduced generation of reactive oxygen species (Tian F. et al., 2020), 7) reduction of brain viral load in mice intracranially injected with Zika virus (Daniels BP et al. 2019), and 8) protection against hepatic ischemia-reperfusion injury (Yi F. et al. 2020).In addition, itaconate has been reported to regulate tricarboxylic acid and redox metabolism to reduce reperfusion injury (Cordes T. et al., 2020). Moreover, elevated plasma itaconate levels show a clear correlation with reduced rheumatoid arthritis disease activity scores after initiation of treatment with conventional disease-modifying antirheumatic drug (cDMARD) therapy (Daly R. et al., 2019).

[0007] Despite the above findings, there remains a need to identify and develop new α,β-unsaturated carboxyl compounds, such as itaconate and acrylate derivatives, that have enhanced properties compared to currently marketed anti-inflammatory agents, such as DMF. The inventors have surprisingly discovered that certain α,β-unsaturated methacrylic acids with heteroaryl groups are effective in reducing cytokine release, activating NRF2 in cells, and / or improving metabolic stability. These properties are potentially more effective than, in particular, 4-octyl itaconate. Thus, such compounds are expected to have superior anti-inflammatory properties. Summary of the Invention

[0008] In a first aspect, the present invention provides a compound of formula (I) [ka] During the ceremony, [ka] represents a 5-membered heteroaryl ring that contains, in addition to the indicated C=N, one or more additional heteroatoms independently selected from N, O, and S; or [ka] represents a 6-membered heteroaryl ring containing, in addition to the indicated C=N, optionally one or more further N atoms; R A1 But, C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl, -(CH 2 ) 0-6 -C 3-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, -(CH 2 ) 0-6 -aryl, and O-aryl; R A1 But optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 ,SCIENCE FICTION 5 , (CH 2 ) 0-3 C 3-7 cycloalkyl, and 5- to 7-membered heterocyclyl; 3-7 Cycloalkyl and 5- to 7-membered heterocyclyl are optionally selected from halo, C 1-3 Alkyl, and C 1-3 haloalkyl, and two alkyl groups bonded to the same carbon atom are optionally linked to form C 3-7 Forms a cycloalkyl ring, C 3-10 the cycloalkyl group is optionally fused to a phenyl ring, the phenyl ring being optionally substituted with one or more halo atoms; or R A1 But, arbitrarily, C 1-2 Haloalkyl, C 1-2 optionally substituted with haloalkoxy, or one phenyl ring substituted with one or more halo atoms; G 1 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, or (CH 2 ) 0-1 Phenyl, G 1 But optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R A2 But, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, cyano, nitro, NR 1 R 2 , O.G. 2 , and S(O) 0-2 G 2 is selected from the group consisting of G 2 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 haloalkyl, or phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R 1 and R 2 are independently H or C 1-2 alkyl or together, R 1 and R 2 can be combined to form a 5- to 7-membered heterocycle, or R A2 But non-existence, R C and R D are each independently H, C 1-2 Alkyl, hydroxy, fluoro, or C 1-2 Alkoxy or R C and R D Combined, C 3-5 may form a cycloalkyl ring, In the compound of formula (I) [ka] represents the following: [ka] base R A1 and R A2 the total number of carbon atoms, together with any optional substituents thereof, is 6 to 14; [ka] When represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, Or a pharma- ceutically acceptable salt and / or solvate thereof are provided.

[0009] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof.

[0010] In a further aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof for use as a medicament.

[0011] In a further aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prophylaxis of an inflammatory disease or a disease associated with an unwanted immune response.

[0012] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of an inflammatory disease or a disease associated with an immune response.

[0013] In a further aspect, the present invention provides a method for treating or preventing an inflammatory disease or a disease associated with an unwanted immune response comprising administering a compound of formula (I) or a pharma-ceutically acceptable salt and / or solvate thereof. [Brief description of the drawings]

[0014] [Figure 1] 1 shows a combined DSC / TGA thermograph of the crystalline form of Example 1, tromethamine salt. [Diagram 2] 1 shows the XRPD pattern of the crystalline form of Example 1, tromethamine salt (2 g scale). [Diagram 3] 1 shows the 1H NMR spectrum of the crystalline form of Example 1, tromethamine salt (2 g scale). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Compounds of formula (I) The embodiments and preferences described herein with respect to compounds of formula (I) apply equally to the pharmaceutical compositions, compounds used, uses and method aspects of the invention.

[0016] In a first aspect, the present invention provides a compound of formula (I) as defined above.

[0017] Suitably, the present invention relates to a compound of formula (I) [ka] During the ceremony, [ka] represents a 5-membered heteroaryl ring that contains, in addition to the indicated C=N, one or more additional heteroatoms independently selected from N, O, and S; or [ka] represents a 6-membered heteroaryl ring containing, in addition to the indicated C=N, optionally one or more further N atoms; R A1 But, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 0-6 -C 3-10 Cycloalkyl, -(CH 2 )0-6 -C 5-10 Spirocycloalkyl, and -(CH 2 ) 0-6 -aryl; R A1 But optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 ,SCIENCE FICTION 5 , and C 3-7 cycloalkyl, C 3-7 Cycloalkyl is optionally halo, C 1-3 Alkyl, and C 1-3 haloalkyl, and two alkyl groups bonded to the same carbon atom are optionally linked to form C 3-7 Form a cycloalkyl ring or R A1 But, arbitrarily, C 1-2 Haloalkyl, C 1-2 optionally substituted with haloalkoxy, or one phenyl ring substituted with one or more halo atoms; G 1 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, or (CH 2 ) 0-1 phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R A2 But, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, cyano, nitro, NR 1 R 2 , O.G. 2 , and S(O) 0-2 G 2is selected from the group consisting of G 2 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 haloalkyl, or phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R 1 and R 2 are independently H or C 1-2 alkyl or together, R 1 and R 2 can be combined to form a 5- to 7-membered heterocycle, or R A2 But non-existence, R C and R D are each independently H, C 1-2 Alkyl, hydroxy, fluoro, or C 1-2 is an alkoxy; base R A1 and R A2 the total number of carbon atoms, together with any optional substituents thereof, is 6 to 14; [ka] When represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, Or a pharma- ceutically acceptable salt and / or solvate thereof are provided.

[0018] Suitably, the present invention relates to a compound of formula (I) [ka] During the ceremony, [ka] represents a 5-membered heteroaryl ring that contains, in addition to the indicated C=N, one or more additional heteroatoms independently selected from N, O, and S; or [ka] represents a 6-membered heteroaryl ring containing, in addition to the indicated C=N, optionally one or more further N atoms; R A1 But, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 0-6 -C 3-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, and -(CH 2 ) 0-6 -aryl; R A1 But optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , and S(O) 0-2 G 1 and two alkyl groups bonded to the same carbon atom are optionally linked to form C 3-7 Form a cycloalkyl ring or R A1 But, arbitrarily, C 1-2 Haloalkyl, C 1-2 optionally substituted with haloalkoxy, or one phenyl ring substituted with one or more halo atoms; G 1 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 haloalkyl, or phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R A2 But, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, cyano, nitro, NR 1 R 2 , O.G. 2 , and S(O) 0-2 G 2 is selected from the group consisting of G 2 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 haloalkyl, or phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R 1 and R 2 are independently H or C 1-2 alkyl or together, R 1 and R 2 can be combined to form a 5- to 7-membered heterocycle, or R A2 But non-existence, R C and R D are each independently H, C 1-2 alkyl, hydroxy, or fluoro; base R A1 and R A2 the total number of carbon atoms, together with any optional substituents thereof, is 6 to 14; [ka] When represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, Or a pharma- ceutically acceptable salt and / or solvate thereof are provided.

[0019] Suitably, the compound of formula (I) is [ka] During the ceremony, [ka] represents a 5-membered heteroaryl ring that contains, in addition to the indicated C=N, one or more additional heteroatoms independently selected from N, O, and S; or [ka] represents a 6-membered heteroaryl ring containing, in addition to the indicated C=N, optionally one or more further N atoms; R A1 But, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 1-6 -C 3-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, and -(CH 2 ) 0-6 -aryl; R A1 But optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , and S(O) 0-2 G 1 and two alkyl groups bonded to the same carbon atom are optionally linked to form C 3-7 forming a cycloalkyl ring, G 1 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 haloalkyl, or phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R A2 But, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, cyano, nitro, NR 1 R 2 , O.G. 2 , and S(O) 0-2 G 2 is selected from the group consisting of G 2 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 haloalkyl, or phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R 1 and R 2 are independently H or C 1-2 is alkyl, or R A2 But non-existence, R C and R D are each independently H, C 1-2 alkyl, hydroxy, or fluoro; base R A1 and R A2 the total number of carbon atoms, together with any optional substituents thereof, is 6 to 12; [ka] When represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0020] Preferably, the compound of formula (I) is [ka] During the ceremony, [ka] represents a 5-membered heteroaryl ring that contains, in addition to the indicated C=N, one or more additional heteroatoms independently selected from N, O, and S; or [ka] represents a 6-membered heteroaryl ring containing, in addition to the indicated C=N, optionally one or more further N atoms; R A1 But, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 0-6 -C 3-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, and -(CH 2 ) 0-6 -aryl; R A1 But optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , and S(O) 0-2 G 1 and is substituted with one or more substituents selected from the group consisting of G 1 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 haloalkyl, or phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2Alkoxy, and C 1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R A2 But, Halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, cyano, nitro, NR 1 R 2 , O.G. 2 , and S(O) 0-2 G 2 is selected from the group consisting of G 2 But, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 haloalkyl, or phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 substituted with one or more substituents selected from the group consisting of haloalkoxy; R 1 and R 2 are independently H or C 1-2 is alkyl, or R A2 But non-existence, R C and R D are each independently H, C 1-2 alkyl, hydroxy, or fluoro; base R A1 and R A2 the total number of carbon atoms, together with any optional substituents thereof, is 6 to 12; [ka] When represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, Or a pharma- ceutically acceptable salt and / or solvate thereof are provided.

[0021] "C 1-10 The term "alkyl" refers to a straight or branched chain, fully saturated hydrocarbon group having from 1 to 10 carbon atoms. The term encompasses methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, n-hexyl, and n-octyl. Heptyl-CH(CH 3 )- and hexyl-CH(CH 3 Other branched variants such as - are also included. Other alkyl groups, for example, C 1-9 Alkyl, C 1-8 Alkyl, C 1-7 Alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C 2-10 Alkyl, C 2-9 Alkyl, C 2-8 Alkyl, C 2-7 Alkyl, C 2-6 Alkyl, C 2-5 Alkyl, C 2-4 Alkyl, C 2-3 Alkyl, C 3-10 Alkyl, C 3-9 Alkyl, C 3-8 Alkyl, C 3-7 Alkyl, C 3-6 Alkyl, C 3-5 Alkyl, C 3-4 Alkyl, C 4-10 Alkyl, C 4-9 Alkyl, C 4-8 Alkyl, C 4-7 Alkyl, C 4-6 Alkyl, C 4-5 Alkyl, C 5-10 Alkyl, C 5-9 Alkyl, C 5-8 Alkyl, C 5-7 Alkyl, C 5-6 Alkyl, C 6-10 Alkyl, C 6-9 Alkyl, C 6-8 Alkyl, C 7-10 Alkyl, C 7-9 Alkyl, C7-8 Alkyl, C 8-10 Alkyl, C 8-9 Alkyl, and C 9-10 Alkyl is as defined above, but with a different number of carbon atoms. 1-10 The term "alkyl" also refers to "C alkyl", which is a difunctional, straight-chain or branched, fully saturated hydrocarbon group having the specified number of carbon atoms. 1-10 Exemplary "alkylene" groups include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, n-heptylene, n-octylene, and stereoisomers thereof, such as 2-propylene, 2-butylene, 2-pentylene, 3-pentylene, 2-hexylene, 3-hexylene, 2-heptylene, 3-heptylene, 4-heptylene, 2-octylene, 3-octylene, and 4-octylene.

[0022] "C 2-10 The term "alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms and at least one carbon-carbon double bond. The term is CH=CH 2 , C.H. 2 CH=CH 2 , CH=CHCH 3 , C.H. 2 CH 2 CH=CH 2 , CH=CHCH 2 CH 3 , C.H. 2 CH=CHCH 3 , C.H. 2 CH 2 CH 2 CH=CH 2 , CH=CHCH 2 CH 2 CH 3 , C.H. 2 CH=CHCH 2 CH 3 , C.H. 2 CH 2 CH=CHCH 3 , CH=CHCH=CHCH 3 , and C.H. 2 CH=CHCH=CH 2CH(CH 3 )CH=CH 2 and CH=C(CH 3 )CH 2 Other alkenyl groups, such as C 2-9 Alkenyl, C 2-8 Alkenyl, C 2-7 Alkenyl, C 2-6 Alkenyl, C 2-5 Alkenyl, C 2-4 Alkenyl, C 2-3 Alkenyl, C 3-10 Alkenyl, C 3-9 Alkenyl, C 3-8 Alkenyl, C 3-7 Alkenyl, C 3-6 Alkenyl, C 3-5 Alkenyl, C 3-4 Alkenyl, C 4-10 Alkenyl, C 4-9 Alkenyl, C 4-8 Alkenyl, C 4-7 Alkenyl, C 4-6 Alkenyl, C 4-5 Alkenyl, C 5-10 Alkenyl, C 5-9 Alkenyl, C 5-8 Alkenyl, C 5-7 Alkenyl, C 5-6 Alkenyl, C 6-10 Alkenyl, C 6-9 Alkenyl, C 6-8 Alkenyl, C 7-10 Alkenyl, C 7-9 Alkenyl, C 7-8 Alkenyl, C 8-10 Alkenyl, C 8-9 Alkenyl, and C 9-10 Alkenyl is as defined above but containing a different number of carbon atoms.

[0023] "C 2-10 The term "alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms and at least one carbon-carbon triple bond. The terms include CΞCH, CH 2 CΞCH, CΞC-CH 3 , C.H.2 CH 2 CΞCH, CΞCCH 2 CH 3 , C.H. 2 CΞCCH 3 , C.H. 2 CH 2 CH 2 CΞCH, CΞCCH 2 CH 2 CH 3 , C.H. 2 CΞCCH 2 CH 3 , C.H. 2 CH 2 CΞCCH 3 , CΞCCΞCCH 3 , and C.H. 2 Includes CΞCCΞCH. CH(CH 3 Branched variants such as )CΞCH are also included. Other alkynyl groups, e.g., C 2-9 Alkynyl, C 2-8 Alkynyl, C 2-7 Alkynyl, C 2-6 Alkynyl, C 2-5 Alkynyl, C 2-4 Alkynyl, C 2-3 Alkynyl, C 3-10 Alkynyl, C 3-9 Alkynyl, C 3-8 Alkynyl, C 3-7 Alkynyl, C 3-6 Alkynyl, C 3-5 Alkynyl, C 3-4 Alkynyl, C 4-10 Alkynyl, C 4-9 Alkynyl, C 4-8 Alkynyl, C 4-7 Alkynyl, C 4-6 Alkynyl, C 4-5 Alkynyl, C 5-10 Alkynyl, C 5-9 Alkynyl, C 5-8 Alkynyl, C 5-7 Alkynyl, C 5-6 Alkynyl, C 6-10 Alkynyl, C 6-9 Alkynyl, C 6-8 Alkynyl, C 7-10 Alkynyl, C 7-9 Alkynyl, C7-8 Alkynyl, C 8-10 Alkynyl, C 8-9 Alkynyl, and C 9-10 Alkynyl is as defined above but containing different numbers of carbon atoms.

[0024] "C 3-10 The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group having from 3 to 10 carbon atoms. The term encompasses cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl, as well as bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and adamantyl. Other cycloalkyl groups, such as C 3-9 Cycloalkyl, C 3-8 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl, C 4-10 Cycloalkyl, C 4-9 Cycloalkyl, C 4-8 Cycloalkyl, C 4-7 Cycloalkyl, C 4-6 Cycloalkyl, C 4-5 Cycloalkyl, C 5-10 Cycloalkyl, C 5-9 Cycloalkyl, C 5-8 Cycloalkyl, C 5-7 Cycloalkyl, C 5-6 Cycloalkyl, C 6-10 Cycloalkyl, C 6-9 Cycloalkyl, C 6-8 Cycloalkyl, C 6-7 Cycloalkyl, C 7-10 Cycloalkyl, C 7-9 Cycloalkyl, C 7-8 Cycloalkyl, C 8-10 Cycloalkyl, C 8-9 Cycloalkyl, and C 9-10 Cycloalkyl is as defined above but containing different numbers of carbon atoms.

[0025] "C 5-10 The term "spirocycloalkyl" refers to a bicyclic cycloalkyl group in which the two rings are connected through only one atom. The rings may be different or the same. The term encompasses spiro[3.3]heptyl. Other spirocycloalkyl groups include, for example, C 5-9 Spirocycloalkyl, C 5-8 Spirocycloalkyl, and C 5-7 Spirocycloalkyl is as defined above but contains a different number of carbon atoms.

[0026] The term "5- to 7-membered heterocycle" refers to a non-aromatic cyclic group having 5 to 7 ring atoms, at least one of which is a heteroatom selected from N, O, S, and B. The term "heterocycle" is interchangeable with "heterocyclyl". The term includes pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homomorpholinyl. The 5- to 7-membered heterocyclyl group can typically be substituted with one or more (e.g., one or two) oxo groups. Suitably, the thietanyl is substituted with one or two oxo groups. Bicyclic heterocycles such as the following are also included: [ka]

[0027] The term "aryl" refers to a cyclic group having 6 to 10 ring carbon atoms and having aromatic character containing one or two rings. If the aryl group contains more than one ring, both rings must be aromatic in nature. Preferably, "aryl" encompasses only phenyl and naphthyl. Most preferably, "aryl" is phenyl.

[0028] The term "hydroxy" (which may also be referred to as "hydroxyl") refers to the --OH group.

[0029] The term "halo" as used herein refers to fluorine, chlorine, bromine or iodine. Particular examples of halo are fluorine and chlorine, especially fluorine.

[0030] "C 1-6 The term "haloalkyl" means any of the C groups defined above. 1-6 Alkyl groups (e.g., C 1 "Fluoromethyl" refers to an alkyl group, i.e., methyl, that is substituted with one or more (e.g., 1, 2, or 3) halo atoms. Examples include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and 1,1-difluoroethyl.

[0031] "C 1-2 The term "alkoxy" refers to any of the C groups defined above. 1-2 Alkyl groups (e.g., C 1 It refers to an alkyl group, i.e., methyl, that is specifically linked to oxygen. The term encompasses methoxy and ethoxy.

[0032] "C 1-2 The term "haloalkoxy" refers to any of the C groups defined above. 1-2

[0036] refers to alkoxy, which is substituted with one or more (e.g., 1, 2, or 3) halo atoms. Examples include trifluoromethoxy.

[0033] As referred to herein, the term "leaving group" includes groups such as halo, e.g., chloro, bromo, iodo, alkanesulfonates, e.g., methanesulfonate, or arenesulfonates, e.g., para-toluenesulfonate or benzenesulfonate.

[0034] When a substituent is indicated as being optionally substituted in formula (I) in the embodiments and options described below, the substituent is optionally substituted as specified in the given formula unless otherwise specified, even if possible substitution is not explicitly described in the embodiment.Preferably, any substituent can be bonded to an available carbon atom, meaning a carbon atom bonded to a hydrogen atom, i.e., a CH group.An optional substituent replaces a hydrogen atom bonded to a carbon atom.

[0035] base [ka] teeth, [ka] It can also be expressed as:

[0036] In one embodiment, [ka] represents a 5-membered heteroaryl ring that contains, in addition to the depicted C═N, one or more (eg, 1 or 2) additional heteroatoms independently selected from N, O, and S.

[0037] In one embodiment, [ka] represents a 5-membered heteroaryl ring selected from the group consisting of imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, and tetrazole.

[0038] [ka] When represents imidazole, it is [ka] For the avoidance of doubt, the substituent R A1 and / or R A2 (when present) can be attached to a carbon or nitrogen atom of the imidazole moiety.

[0039] [ka] When represents pyrazole, it is [ka] For the avoidance of doubt, the substituent R A1 and / or R A2 (when present) can be attached to a carbon or nitrogen atom of the pyrazole moiety.

[0040] [ka] When represents oxazole, it is [ka] The purpose is to represent.

[0041] [ka] When represents isoxazole, it is [ka] The purpose is to represent.

[0042] [ka] When represents thiazole, it is [ka] The purpose is to represent.

[0043] [ka] When represents isothiazole, it is [ka] The purpose is to represent.

[0044] [ka] When represents 1,2,3-triazole, it is [ka] For the avoidance of doubt, the substituent R A1 and / or R A2 (when present) may be attached to a carbon or nitrogen atom of the 1,2,3-triazole moiety.

[0045] [ka] When represents 1,2,4-triazole, it is [ka] For the avoidance of doubt, the substituent R A1 and / or R A2 (when present) may be attached to a carbon or nitrogen atom of the 1,2,4-triazole moiety.

[0046] [ka] When represents 1,2,4-oxadiazole, it is [ka] The purpose is to represent.

[0047] [ka] When represents 1,2,5-oxadiazole, it is [ka] The purpose is to represent.

[0048] [ka] When represents 1,3,4-oxadiazole, it is [ka] The purpose is to represent.

[0049] [ka] When represents 1,2,4-thiadiazole, it is [ka] The purpose is to represent.

[0050] [ka] When represents 1,2,5-thiadiazole, it is [ka] The purpose is to represent.

[0051] [ka] When represents 1,3,4-thiadiazole, it is [ka] The purpose is to represent.

[0052] [ka] When represents tetrazole, it is [ka] The purpose is to represent.

[0053] In one embodiment, [ka] represents oxadiazole, in particular 1,2,4-oxadiazole.

[0054] Suitably the 1,2,4-oxadiazole is [ka] It is.

[0055] In one embodiment, [ka] represents 1,3,4-oxadiazole.

[0056] In one embodiment, [ka] represents a 6-membered heteroaryl ring, which, in addition to the depicted C=N, optionally contains one or more (eg, 1 or 2) additional N atoms.

[0057] In one embodiment, [ka] represents a 6-membered heteroaryl ring selected from the group consisting of pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0058] [ka] When represents pyridine, it is [ka] The purpose is to represent.

[0059] [ka] When represents pyridazine, it is [ka] The purpose is to represent.

[0060] [ka] When represents pyrimidine, it is [ka] The purpose is to represent.

[0061] [ka] When represents pyrazine, it is [ka] The purpose is to represent.

[0062] [ka] When represents a triazine, it is [ka] The purpose is to represent.

[0063] In the above representation, the substituent is not shown to be bonded to a carbon atom or nitrogen atom, but instead is shown to cross a double or single bond of the heteroaryl compound, which is an undefined point of attachment and can be any chemically feasible point of attachment. Furthermore, each of the above heteroaryl groups is shown as a single tautomer. Those skilled in the art will recognize that although a single tautomer is shown, the compound can exist as a mixture of tautomeric forms. Thus, the present invention covers all tautomeric forms of the compounds of formula (I).

[0064] In one embodiment, R A1 is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 0-6 -C 3-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, -(CH 2 ) 0-6 -aryl, and O-aryl (eg, O-phenyl).

[0065] In one embodiment, R A1 is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 0-6 -C 3-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, and -(CH 2 ) 0-6 -phenyl.

[0066] Preferably, R A1is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 1-6 -C 3-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, and -(CH 2 ) 0-6 -phenyl.

[0067] Preferably, R A1 is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 1-6 -C 3-10 Cycloalkyl, -(CH 2 ) 1-6 -C 5-10 Spirocycloalkyl, and -(CH 2 ) 1-6 -phenyl.

[0068] In one embodiment, R A1 is C 2-10 Alkyl, especially C 3-10 Alkyl, C 4-10 Alkyl, C 5-10 Alkyl, C 6-10 Alkyl, C 7-10 Alkyl, or C 8-10 Preferably, R A1 is C 7-8 In one embodiment, R A1is selected from the group consisting of ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutan-2-yl, 2,2-dimethylpropyl, 3-methylbutyl, 2-pentyl, 3-pentyl, 3-methylbutan-2-yl, 2-methylbutyl, 1-hexyl, 2-hexyl, 3-hexyl, 1,1-dimethylpentyl, 1,1-dimethylhexyl, 1-heptyl, 1-octyl, 2-octyl, 3-octyl, 4-octyl, 1-nonyl, and 5-nonyl.

[0069] In one embodiment, an alkyl group is linear (i.e., n-alkyl). In another embodiment, an alkyl group is branched.

[0070] Preferably, R A1 is C 7 alkyl, wherein the alkyl group is in a linear configuration, i.e. [ka] has.

[0071] Preferably, R A1 is C 8 alkyl, wherein the alkyl group is in a linear configuration, i.e. [ka] has.

[0072] Preferably, R A1 is C 8 alkyl, where the alkyl group has a branched configuration. For example, branched C 8 The alkyl group is [ka] It could be.

[0073] Or, R A1 But, C 1-10 Alkyl, e.g., C 7-8If alkyl, the alkyl group may be substituted with another alkyl group, resulting in a branched arrangement.

[0074] For example, preferably, R A1 is C 7 The alkyl group is substituted with an alkyl group. For example, C 7 Alkyl is a C group, so that the following group is formed: 1 Can be substituted with alkyl (i.e., methyl): [ka]

[0075] In one embodiment, R A1 is -(CH 2 ) 0-6 -C 3-10 Cycloalkyl, in particular -(CH 2 ) 0-6 -C 4-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Cycloalkyl, or -(CH 2 ) 0-6 -C 5-8 In one embodiment, R A1 is -(CH 2 ) 0-6 -Cyclopropyl, -(CH 2 ) 0-6 -Cyclobutyl, -(CH 2 ) 0-6 -Cyclopentyl, -(CH 2 ) 0-6 -Cyclohexyl, -(CH 2 ) 0-6 -Cycloheptyl, -(CH 2 ) 0-6 -Cyclooctyl, and -(CH 2 ) 0-6 -bicyclo[2.2.1]heptyl, in particular -(CH 2 ) 0-6 -Cyclopentyl, -(CH 2 ) 0-6 -Cyclohexyl, -(CH 2) 0-6 -Cycloheptyl, -(CH 2 ) 0-6 -Cyclooctyl, or -(CH 2 ) 0-6 -bicyclo[2.2.1]heptyl.

[0076] Preferably, R A1 is -(CH 2 ) 0 -C 3-10 Cycloalkyl, for example, -(CH 2 ) 0 -C 6 Cycloalkyl, -(CH 2 ) 0 -C 7 Cycloalkyl, or -(CH 2 ) 0 -C 8 It is cycloalkyl.

[0077] In one embodiment, R A1 is -(CH 2 ) 1-6 -C 3-10 Cycloalkyl, in particular -(CH 2 ) 1-6 -C 4-10 Cycloalkyl, -(CH 2 ) 1-6 -C 5-10 Cycloalkyl, or -(CH 2 ) 1-6 -C 5-8 In one embodiment, R A1 is -(CH 2 ) 1-6 -Cyclopropyl, -(CH 2 ) 1-6 -Cyclobutyl, -(CH 2 ) 0-6 -Cyclopentyl, -(CH 2 ) 1-6 -Cyclohexyl, -(CH 2 ) 1-6 -Cycloheptyl, -(CH 2 ) 1-6 -Cyclooctyl, and -(CH 2 ) 1-6-bicyclo[2.2.1]heptyl, in particular -(CH 2 ) 1-6 -Cyclopentyl, -(CH 2 ) 1-6 -Cyclohexyl, -(CH 2 ) 1-6 -Cycloheptyl, -(CH 2 ) 1-6 -Cyclooctyl, or -(CH 2 ) 1-6 -bicyclo[2.2.1]heptyl.

[0078] In one embodiment, C 3-10 The cycloalkyl group is fused to a phenyl ring, which is optionally substituted with one or more (e.g., one, two, or three, e.g., two) halo atoms. 3-10 Cycloalkyl is C 5 Preferably, the phenyl group is substituted with one or more (e.g., one, two or three, e.g., two) halo atoms, and most preferably, one or more, e.g., two, halo atoms are chloro.

[0079] In one embodiment, R A1 is -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, in particular -(CH 2 ) 0-6 -spiro[3.3]heptyl. Preferably, R A1 is -(CH 2 ) 1-6 -C 5-10 It is a spirocycloalkyl.

[0080] In one embodiment, R A1 is -(CH 2 ) 0-6 -aryl, for example -(CH 2 ) 0-6 -phenyl or -(CH 2 ) 0-6 -naphthyl. A1 is -(CH 2 ) 1-6-aryl. Preferably, R A1 is -(CH 2 ) 0-6 -phenyl. Preferably, R A1 is -(CH 2 ) 1-6 -phenyl.

[0081] Preferably, R A1 is -(CH 2 ) 0-2 -phenyl, for example, -(CH 2 ) 1-2 -phenyl. In one embodiment, R A1 is phenyl. In another embodiment, R A1 is CH 2 In another embodiment, R A1 is (CH 2 ) 2 -phenyl. Most preferably, R A1 is phenyl or -CH 2 -phenyl.

[0082] In one embodiment, R A1 is O-aryl, for example O-phenyl.

[0083] In one embodiment, R A1 is C 7-8 Alkyl or -(CH 2 ) 0-2 -phenyl, e.g., C 7-8 Alkyl or -(CH 2 ) 1-2 -phenyl.

[0084] In another embodiment, R A1 is C 7-8 Alkyl or -(CH 2 ) 0-2 -phenyl, e.g., C 7-8 Alkyl or -(CH 2 ) 0-1 -phenyl.

[0085] In one embodiment, R A1 is not replaced.

[0086] In one embodiment, R A1 But, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 ,SCIENCE FICTION 5 , (CH 2 ) 0-3 C 3-7 cycloalkyl, and 5- to 7-membered heterocyclyl, and the C 3-7 Cycloalkyl and the 5- to 7-membered heterocyclyl are optionally selected from halo, C 1-3 Alkyl, and C 1-3 haloalkyl, and two alkyl groups bonded to the same carbon atom are optionally linked to form C 3-7 Form a cycloalkyl ring or R A1 But, arbitrarily, C 1-2 Haloalkyl, C 1-2 Optionally substituted with haloalkoxy, or one phenyl ring substituted with one or more halo atoms.

[0087] In one embodiment, R A1 But, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 ,SCIENCE FICTION 5 , and (CH 2 ) 0-3 C 3-7 cycloalkyl, wherein the C is substituted with one or more, e.g., one, two, three, or four, e.g., one, substituent selected from the group consisting of 3-7 Cycloalkyl is optionally halo, C 1-3 Alkyl, and C 1-3 haloalkyl, and two alkyl groups bonded to the same carbon atom are optionally linked to form C 3-7Form a cycloalkyl ring or R A1 But, arbitrarily, C 1-2 Haloalkyl, C 1-2 Optionally substituted with haloalkoxy, or one phenyl ring substituted with one or more halo atoms.

[0088] In one embodiment, R A1 But, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , and S(O) 0-2 G 1 Two alkyl groups substituted with one or more, e.g., one, two, three, or four, e.g., one, substituents, and attached to the same carbon atom, optionally linked together, are selected from the group consisting of: 3-7 Form a cycloalkyl or R A1 But, arbitrarily, C 1-2 Haloalkyl, C 1-2 Haloalkoxy, or substituted with one phenyl ring substituted with one or more halo atoms.

[0089] In one embodiment, R A1 is substituted with one substituent. A1 is substituted with two substituents. A1 is substituted with three substituents. A1 is substituted with four substituents. A1 is substituted with five substituents, particularly when the substituents are halo. A1 is substituted with one substituent or with three substituents.

[0090] In one embodiment, R A1 In a second embodiment, R is substituted with halo, e.g., fluoro, chloro, or bromo. A1 is C 1-6 In a third embodiment, R A1 is C 1-6 Haloalkyl, e.g., CF 3In a fourth embodiment, R A1 In a fifth embodiment, R A1 In a sixth embodiment, R A1 O.G. 1 In a seventh embodiment, R A1 is S(O) 0-2 G 1 In an eighth embodiment, R A1 SF 5 In a ninth embodiment, R A1 is (CH 2 ) 0-3 C 3-7 substituted with cycloalkyl, 3-7 Cycloalkyl is optionally selected from halo, C 1-3 Alkyl and C 1-3 In a tenth embodiment, R A1 is substituted with 5-7 membered heterocyclyl, for example pyrrolidinyl, the 5-7 membered heterocyclyl optionally being selected from halo, C 1-3 Alkyl and C 1-3 haloalkyl.

[0091] Preferably, R A1 is one SF 5 Alternatively, R A1 is one SG 1 is replaced by G 1 But CF 3 It is.

[0092] In one embodiment, one or more of the substituents is selected from the group consisting of SG 1 In a second embodiment, one or more of the substituents is S(O)G 1 In a third embodiment, one or more of the substituents is S(O) 2 G 1 Suitably, one or more (e.g. one) of the substituents is SG 1 It is.

[0093] In one embodiment, R A1 is (CH2 ) 0-3 C 3-7 Cycloalkyl (e.g., one (CH 2 ) 0-3 C 3-7 cycloalkyl), and the C 3-7 Cycloalkyl is optionally selected from halo, C 1-3 Alkyl and C 1-3 haloalkyl.

[0094] In one embodiment, R A1 is C 3-7 In a second embodiment, R A1 is CH 2 C 3-7 In a third embodiment, R A1 is (CH 2 ) 2 C 3-7 Cycloalkyl, e.g., CH 2 CH 2 In a fourth embodiment, R A1 is (CH 2 ) 3 C 3-7 It is substituted with cycloalkyl.

[0095] In one embodiment, R A1 is (CH 2 ) 0-3 C 3-7 substituted with cycloalkyl, 3-7 The cycloalkyl is unsubstituted.

[0096] In one embodiment, R A1 is (CH 2 ) 0-3 C 3-7 substituted with cycloalkyl, 3-7 Cycloalkyl is halo, C 1-3 Alkyl and C 1-3 Substituted with one or more (eg, 1, 2 or 3, eg, 1) groups selected from haloalkyl.

[0097] Suitably, the substituent is halo, for example fluoro. Alternatively, the substituent is C 1-3 alkyl, e.g., methyl, ethyl, or n-propyl, e.g., n-propyl. Alternatively, the substituent is 1-3 Haloalkyl, e.g., CF 3 It is.

[0098] In one embodiment, R A1 is C 3 substituted with cycloalkyl, 3 Cycloalkyl is C 1-3 Haloalkyl, e.g., CF 3 is replaced by.

[0099] In another embodiment, R A1 is C 3 substituted with cycloalkyl, 3 The cycloalkyl is substituted with n-propyl.

[0100] In another embodiment, R A1 is (CH 2 ) 2 C 3 It is substituted with cycloalkyl.

[0101] Preferably, one of the following moieties is formed: [ka]

[0102] Other variations having different arrangements and numbers of carbon atoms will be readily envisioned by those skilled in the art.

[0103] R A1 is substituted with 5- to 7-membered heterocyclyl, preferably R A1 In this embodiment, the 5- to 7-membered heterocyclyl is connected to R via a heteroatom (e.g., N) present in the 5- to 7-membered heterocyclyl. A1 Preferably, the 5- to 7-membered heterocyclyl is pyrrolidinyl, which is connected to R via a nitrogen atom.A1 (e.g., phenyl).

[0104] In one embodiment, the 5- to 7-membered heterocyclyl is unsubstituted. In another embodiment, the 5- to 7-membered heterocyclyl is halo, C 1-3 Alkyl, and C 1-3 haloalkyl.

[0105] In another embodiment, R A1 is optionally C 1-2 Haloalkyl, e.g., CF 3 , C 1-2 Haloalkoxy, e.g., OCF 3 , or one or more, e.g., one, two, three, or four, e.g., one phenyl ring substituted with halo atoms (e.g., bromo, chloro and / or fluoro).

[0106] Preferably, R A1 is one C 1-6 Alternatively, R A1 is one OG 1 group, preferably G 1 is C 1-6 alkyl, for example n-butyl. A1 is a group consisting of two alkyl groups, e.g., C 1-6 Alkyl, e.g., C 1-2 Alkyl, e.g., substituted with two methyl groups, attached to the same carbon atom, optionally linked, C 3-7 Cycloalkyl, for example, forms a cyclopropyl ring, R A1 is further substituted with one halo atom, e.g., bromo. Suitably, in these embodiments, R A1 is -(CH 2 ) 0-1 -phenyl. Most preferably, the phenyl ring is substituted at the para position.

[0107] In one embodiment, R A1 is optionally halo (e.g., fluoro or chloro), C 1-2Alkyl, C 1-2 Haloalkyl (e.g., CF 3 ), hydroxy, cyano, O(C 1-2 alkyl), and S(O) 2 C 1-2 alkyl. A1 is C 1 Substituted with alkyl (ie, methyl), fluoro or chloro.

[0108] In another embodiment, R A1 may optionally contain two alkyl groups, e.g., C 1-6 Alkyl, e.g., C 1-2 The alkyl group is R A1 It bonds to the same carbon atom in the 3-7 Form a cycloalkyl group. Preferably, the two alkyl groups are R A1 Substituent C present in 1-6 Alkyl, C 1-6 Haloalkyl or OG 1 The alkyl group (i.e., C 1-6 Alkyl or C 1-6 Haloalkyl, G 1 (base).

[0109] R A1 But, arbitrarily, C 1-6 When substituted with an alkyl and two alkyl groups, they are attached to the same carbon atom and are optionally linked to form C 3-7 A cycloalkyl ring is formed, forming a group of the structure: [ka] wherein n is an integer selected from 1, 2, 3, 4, and 5. Preferably, n is 3.

[0110] Preferably, C 3-7 Cycloalkyl groups are C 3 Cycloalkyl groups: [ka] It is.

[0111] Preferably, C 3-7 Cycloalkyl groups are C 4 Cycloalkyl groups: [ka] It is.

[0112] Preferably, C 3-7 Cycloalkyl groups are C 5 Cycloalkyl groups: [ka] It is.

[0113] Preferably, C 3-7 Cycloalkyl groups are C 6 Cycloalkyl groups: [ka] It is.

[0114] Preferably, C 3-7 Cycloalkyl groups are C 7 Cycloalkyl groups: [ka] It is.

[0115] Most preferably, C 3-7 Cycloalkyl groups are C 3-4 It is a cycloalkyl group.

[0116] In this embodiment, preferably, R A1 is -(CH 2 ) 1-6 -phenyl, for example, -CH 2 -phenyl. The phenyl ring may be optionally substituted, for example, with halo, for example, chloro and / or fluoro, for example, chloro. Alternatively, the phenyl ring may be optionally substituted with bromo.

[0117] Preferably, R A1 But -(CH 2 ) 0-2 -phenyl, for example, -(CH 2 ) 1-2 -phenyl, the phenyl group is substituted with chloro, for example, the phenyl group is substituted with chloro at the para position. The phenyl group may be substituted with additional fluoro. Most preferably, R A1 But -(CH 2 ) 0-2 -phenyl, for example, -CH 2 -phenyl, the phenyl group is substituted, for example, at the para position with bromo.

[0118] Appropriately, R A1 But -(CH 2 ) 0-2 -phenyl, for example, -(CH 2 ) 1-2 -phenyl, the phenyl group may be substituted with an additional phenyl ring, optionally substituted with one or more (e.g., one) halo atoms. Suitably, the additional phenyl ring is substituted with one or more (e.g., one) halo atoms, for example, one or more (e.g., one) chloro atoms. Alternatively, the additional phenyl ring is unsubstituted.

[0119] Preferably, R A1 But, C 1-10 If it is alkyl, R A1 But optionally halo, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 ,SCIENCE FICTION 5 , (CH 2 ) 0-3 C 3-7 cycloalkyl, and 5- to 7-membered heterocyclyl; and 3-7 Cycloalkyl and the 5- to 7-membered heterocyclyl are optionally selected from halo, C 1-3 Alkyl, and C 1-3haloalkyl, and two alkyl groups bonded to the same carbon atom are optionally linked to form C 3-7 It forms a cycloalkyl ring.

[0120] Preferably, R A1 But, C 1-10 If it is alkyl, R A1 But optionally halo, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , and S(O) 0-2 G 1 and two alkyl groups attached to the same carbon atom are optionally linked to form C 3-7 forming a cycloalkyl ring, or R A1 But, arbitrarily, C 1-2 Haloalkyl, C 1-2 Haloalkoxy, or substituted with one phenyl ring that is substituted with one or more (eg, 1, 2, 3, or 4, eg, 1) halo atoms.

[0121] Preferably, R A1 But, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 0-6 -C 3-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, and -(CH 2 ) 0-6 -aryl, R A1 But optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 ,SCIENCE FICTION 5 , (CH 2 ) 0-3 C 3-7cycloalkyl, and 5- to 7-membered heterocyclyl; and 3-7 Cycloalkyl and the 5- to 7-membered heterocyclyl are optionally selected from halo, C 1-3 Alkyl, and C 1-3 haloalkyl, and two alkyl groups bonded to the same carbon atom are optionally linked to form C 3-7 Forms a cycloalkyl ring, C 3-10 The cycloalkyl group is optionally fused to a phenyl ring, and the phenyl ring is optionally substituted with one or more halo atoms.

[0122] Preferably, R A1 But, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH 2 ) 0-6 -C 3-10 Cycloalkyl, -(CH 2 ) 0-6 -C 5-10 Spirocycloalkyl, and -(CH 2 ) 0-6 -aryl, R A1 But optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , and S(O) 0-2 G 1 and two alkyl groups attached to the same carbon atom are optionally linked to form C 3-7 Form a cycloalkyl ring or R A1 But, arbitrarily, C 1-2 Haloalkyl, C 1-2 Haloalkoxy, or substituted with one phenyl ring substituted with one or more (eg, 1, 2, 3, or 4, eg, 1) halo atoms.

[0123] In one embodiment, G 1 is C 1-6 Alkyl, C3-7 Cycloalkyl, C 1-6 Haloalkyl, or (CH 2 ) 0-1 phenyl (e.g., phenyl), and G 1 But optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 and substituted with one or more substituents selected from the group consisting of haloalkoxy.

[0124] In one embodiment, G 1 is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 haloalkyl, or phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 Substituted with one or more (eg, 1, 2, 3, or 4, eg, 1) substituents selected from the group consisting of haloalkoxy.

[0125] In one embodiment, G 1 is C 1-6 In a second embodiment, G 1 is C 3-7 In a third embodiment, G is C 1-6 Haloalkyl, e.g., CF 3 In the fourth embodiment, G 1 is (CH 2 ) 0-1 phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 In another embodiment, G is substituted with one or more (e.g., one, two, three, or four, e.g., one) substituents selected from the group consisting of haloalkoxy. 1is phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 In another embodiment, G is substituted with one or more substituents selected from the group consisting of haloalkoxy. 1 is CH 2 -phenyl, which is optionally halo, C 1-2 Alkyl, C 1-2 Haloalkyl, hydroxy, cyano, nitro, C 1-2 Alkoxy, and C 1-2 Preferably, G is substituted with one or more substituents selected from the group consisting of haloalkoxy. 1 is not further substituted. Alternatively, G 1 is C 1-2 Most preferably, G is substituted with alkoxy. 1 is C 1-6 Alkyl, for example, n-butyl.

[0126] In one embodiment, R A2 But it is not replaced.

[0127] In one embodiment, R A2 is non-existent.

[0128] In one embodiment, R A2 is C 1-6 Alkyl, e.g., C 1-4 Alkyl, for example, n-butyl.

[0129] R C and R D are each independently H, C 1-2 Alkyl, hydroxy, fluoro, or C 1-2 Alkoxy or R C and R D Combined, C 3-5 A cycloalkyl ring may be formed.

[0130] In one embodiment, R C and RD are each independently H, C 1-2 It is alkyl, hydroxy, or fluoro.

[0131] In one embodiment, R C is H. In a second embodiment, R C is C 1-2 In a third embodiment, R C In a fourth embodiment, R C In a fifth embodiment, R C is C 1-2 Alkoxy, for example, OMe.

[0132] In one embodiment, R D is H. In a second embodiment, R D is C 1-2 In a third embodiment, R D In a fourth embodiment, R D In a fifth embodiment, R D is C 1-2 Alkoxy, for example, OMe.

[0133] In one embodiment, R C and R D Both are H.

[0134] In another embodiment, R C and R D are connected, C 3-5 A cycloalkyl ring, for example a cyclopropyl ring, may be formed.

[0135] In one embodiment, the compound of formula (I) is: [ka] or a pharma- ceutically acceptable salt and / or solvate thereof; In the formula, A, R A1 , R A2 , R C, and R D is as defined elsewhere herein. The carbon-carbon double bond in this structure is designated "exo."

[0136] In another embodiment, the compound of formula (I) is: [ka] or a pharma- ceutically acceptable salt and / or solvate thereof; In the formula, A, R A1 , R A2 , and R C is as defined elsewhere herein. The carbon-carbon double bond in this structure is referred to as "endo."

[0137] In endo embodiments, the double bond may be cis or trans, such that both of the following moieties are encompassed: [ka]

[0138] Similarly, as used herein, the following structures: [ka] Both cis and trans isomers are included [ka]

[0139] Suitably, the endo double bond in the compound of formula (I) is trans.

[0140] Typically, for example, as shown in the Biological Examples section, compounds of formula (I) in which the carbon-carbon double bond is exo are more potent (e.g., have a lower IC in the assays described herein) than comparable compounds of formula (I) in which the carbon-carbon double bond is endo. 50 , lower EC 50, and / or a higher E max (Having).

[0141] Compounds of formula (I) in which the carbon-carbon double bond is endo can generally be obtained by isomerization from compounds of formula (I) in which the carbon-carbon double bond is exo, and such isomerization can occur in an in vitro assay or in vivo after administration of an exo compound. In some cases, isomerization in an in vitro assay, such as an in vitro hepatocyte stability assay, or in vivo after administration of an exo compound can be partial, thus resulting in a mixture of endo and exo compounds. In some cases, a mixture of endo and exo isomers can contribute to the activity observed in a particular assay. Suitably, compounds of formula (I), such as those in which the carbon-carbon double bond is exo, are stable to isomerization.

[0142] The group R taken together with any of their optional substituents A1 and R A2 The total number of carbon atoms is 6 to 14, for example, 6 to 12, preferably 7 to 12 or 8 to 12, for example, 6 to 10, 7 to 10, or 8 to 10.

[0143] In one embodiment, R A2 is absent and the group R A1 The total number of carbon atoms is 7 to 12 or 8 to 12, or 6 to 10, 7 to 10, or 8 to 10.

[0144] [ka] When represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl. [ka] When represents isoxazole, R A1 is phenyl, phenyl substituted with halo, or C 1-10In one embodiment, it does not represent phenyl substituted with alkyl. [ka] When represents isoxazole, R A1 does not represent phenyl or substituted phenyl.

[0145] In one embodiment, the compound of formula (I) is 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-octyl-1,3,4-oxadiazol-2-yl)methyl)acrylic acid, and 2-((5-octyl-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0146] In one embodiment, the compound of formula (I) is 2-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-heptyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0147] In one embodiment, the compound of formula (I) is 2-((3-(2-methylheptan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((1-octyl-1H-1,2,4-triazol-3-yl)methyl)acrylic acid, 2-((3-(3,4-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(tert-butyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3,5-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-pentylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(2-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-chlorophenyl)cyclobutyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(2-methyloctan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-pentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(2-(4-chlorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(cyclohexylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-(4-chlorophenyl)propyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(octyl-d17)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(oct-7-yn-1-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-propylphenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-octyl-1,3,4-thiadiazol-2-yl)methyl)acrylic acid, 2-((4-octylthiazol-2-yl)methyl)acrylic acid, 2-((4-octyloxazol-2-yl)methyl)acrylic acid, (R)-2-((3-(octan-2-yl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-ethylphenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, (S)-2-((3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-methoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(trifluoromethoxy)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(7,7,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1-(trifluoromethyl)cyclopropyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-bromophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxybenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-chloro-3-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-nonyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(8,8,8-trifluorooctan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-octylthiazol-2-yl)methyl)acrylic acid, 2-((3-undecyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(oct-3-yn-1-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(8,8-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-octyloxazol-2-yl)methyl)acrylic acid, 2-((3-(9,9,9-trifluorononyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(dispiro[3.1.3 6 .1 4 ]decan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-cyclooctyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-cyclohexyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-cycloheptyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, and 2-((3-(adamantan-1-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0148] In one embodiment, the compound is 2-((3-(1-(3,5-dichlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(6-methylheptyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-neopentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-propylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1,1-difluoropropyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1-propylcyclopropyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(3,3,3-trifluoropropyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4-chlorophenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(5,5,5-trifluoropentyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(2-cyclopropylethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(pentafluoro-λ 6 -sulfanayl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(difluoromethoxy)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1,1-difluoropentyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-butoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-(1,1-difluorooctyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((5-((4-chlorophenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((5-((4-bromophenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((3-(1-(4-((trifluoromethyl)thio)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(6,6,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1,1-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-((4-chlorophenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((3-((4-bromophenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4-butylphenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(difluoro(4-(trifluoromethyl)phenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1,1-difluoropentyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(difluoro(4-(trifluoromethoxy)phenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-(4-butylbenzyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((5-(4-butoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((5-(difluoro(4-(trifluoromethyl)phenyl)methyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((3-(4-(1,1-difluorobutyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((3-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((4-(4-butylphenyl)oxazol-2-yl)methyl)acrylic acid, 2-((5-octylisoxazol-3-yl)methyl)acrylic acid, 2-((4-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)oxazol-2-yl)methyl)acrylic acid, 2-((4-octylpyridin-2-yl)methyl)acrylic acid trifluoroacetate, 2-((5-octylpyridin-2-yl)methyl)acrylic acid trifluoroacetate, 2-((5-octylpyrimidin-2-yl)methyl)acrylic acid, 2-((5-octylpyrazin-2-yl)methyl)acrylic acid, 2-((6-octylpyridazin-3-yl)methyl)acrylic acid, 2-((5-methyl-4-octyloxazol-2-yl)methyl)acrylic acid, 2-(hydroxy(3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-butyl-4-(4-chlorophenyl)oxazol-2-yl)methyl)acrylic acid, 2-(methoxy(3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-cyclobutoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-cyclopentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-cyclopropoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, and 2-((3-(1-(4-cyclopentylphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0149] In one embodiment, the compound is 2-((3-(1-(4-iodophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-iodophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(difluoro(4-iodophenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(pentafluoro-λ 6 -sulfanayl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(pentafluoro-λ 6 -sulfanayl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((4,5-dibutyloxazol-2-yl)methyl)acrylic acid, 2,2-((3-(difluoro(4-(pentafluoro-λ 6-sulfanayl)phenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2,2-((3-(difluoro(4-fluorophenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butylphenoxy)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((4-(4-butylbenzyl)oxazol-2-yl)methyl)acrylic acid, 2-((3-(4-cyclobutylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxy-3-fluorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-cyclobutylphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(pyrrolidin-1-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3,5-dichloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3,5-dichloro-4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-chloro-3,5-difluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3-chloro-4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-chloro-4-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-bromo-3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-bromo-3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3-chloro-4-methoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3-chloro-4-methylphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-cyclobutoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-cyclopentyloxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, (R)-2-((3-(4-(sec-butoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, (S)-2-((3-(4-(sec-butoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(4,4,4-trifluorobutoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1-propylcyclopropyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-propoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((3-chloro-4-methoxyphenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((3-chloro-4-methylphenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4-chlorophenyl)fluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((3,5-dichloro-4-fluorophenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4-bromo-3-chlorophenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(difluoro(4-((trifluoromethyl)thio)phenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-(1-(3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)acrylic acid, 3-methyl-2-methylene-3-(3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)butanoic acid, 2-((3-(1-(4-((trifluoromethyl)sulfinyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-((trifluoromethyl)thio)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(3-methoxypropoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxy-3-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxy-3,5-difluorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-chloro-4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-chloro-3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-chloro-4-methylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, (E)-2-methyl-3-(3-octyl-1,2,4-oxadiazol-5-yl)acrylic acid, (E)-3-(3-(4-butoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-methylacrylic acid, (E)-3-(3-(1-(4-bromophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-2-methylacrylic acid, (E)-2-Methyl-3-(3-(1-(4-(pentafluoro-lambda 6 -sulfanayl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)acrylic acid, (E)-2-methyl-3-(3-(1-(4-((trifluoromethyl)thio)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)acrylic acid, 2-((6-(4-chlorobenzyl)pyridin-2-yl)methyl)acrylic acid trifluoroacetate, 2-(1-(3-(difluoro(4-(trifluoromethyl)phenyl)methyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)acrylic acid, 2-methylene-3-(3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)butanoic acid, 2-((6-(1-(4-chlorophenyl)cyclopropyl)pyridin-2-yl)methyl)acrylic acid, and 2-((3-(1-(4-bromo-3,5-dichlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0150] In one embodiment, the compound of formula (I) is 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0151] In one embodiment, the compound is 2-((3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-bromophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, and 2-((3-(4-butoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0152] In one embodiment, the compound is 2-((3-(1-(4-((trifluoromethyl)thio)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, and 2-((3-(1-(4-(pentafluoro-λ 6 -sulfanayl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0153] In one embodiment, there is provided a tromethamine salt of the compound of formula (I). In one particular embodiment, there is provided a tromethamine salt of Example 1.

[0154] The tromethamine salt of Example 1 may exist as a crystalline solid. The tromethamine salt was prepared as described in the Examples and characterization data is shown in Figures 1-3.

[0155] Thus, in one embodiment, there is provided the tromethamine salt of Example 1 in a crystalline form, in particular in a crystalline form having an X-ray powder diffraction pattern with at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) peak selected from peaks at 12.9, 13.5, 17.0, 18.0, 19.9, 20.1, 20.6, 21.0, 23.0, 23.4, 23.6, or 29.3 (±0.2 degrees, 2 theta value). Particularly characteristic peaks of the crystalline form of the tromethamine salt of Example 1 are selected from the peaks at 12.9, 17.0, 19.9, 20.1, 23.0, and 23.4 (±0.2 degrees, 2 theta values), and thus preferably there is at least one (e.g. 1, 2, 3, 4, 5, or 6) peaks selected from the peaks at 12.9, 17.0, 19.9, 20.1, 23.0, and 23.4 (±0.2 degrees, 2 theta values).

[0156] The crystalline form of the tromethamine salt of Example 1 was found to have good physical stability, as shown by TGA and DSC analysis.

[0157] The compounds of the present invention can be prepared by the general methods described herein.In particular, the compounds of formula (I) can be prepared as described in the Examples, for example with reference to general procedures A and B, or by methods analogous thereto, or by other methods known to those skilled in the art.

[0158] Compounds of formula (I) may be prepared using the routes set out in the following schemes.

[0159] Scheme 1: Synthesis of certain compounds of formula (I) [ka] A, R A1 , R A2 , R C , and R D is defined elsewhere herein.

[0160] Step (i): reacting a compound of formula (V) - where X represents a leaving group, such as chloro, bromo, iodo, an alkanesulfonate, such as methanesulfonate or an arenesulfonate, such as para-toluenesulfonate or benzenesulfonate - with a trialkylphosphonoacetate of formula (IV) - where R 11 , R 12 , and R 3 are independently optionally substituted with halo, 1-4 represents alkyl - to provide a compound of formula (III).

[0161] Step (ii): The compound of formula (III) undergoes a condensation reaction with formaldehyde or a formaldehyde equivalent thereof, such as paraformaldehyde, to give the α,β-unsaturated ester of formula (II).

[0162] Step (iii): Compounds of formula (II) can be prepared under standard acid or base hydrolysis conditions, e.g., by hydrolysis of R 3 When is tert-butyl, it is hydrolyzed with TFA in DCM to give the compound of formula (I).

[0163] Scheme 2: Synthesis of certain compounds of formula (III) [ka] R 11 , R 12 , and R 3 is defined in Scheme 1 above, and R A1 , R C , and R D is defined elsewhere in this document and R A2 is absent. Compounds of formula (III) can be prepared by reacting amidoxime (VI) with acid (VII) in the presence of a coupling agent such as HATU and a base such as DIPEA. Compounds of formula (I) can be obtained from compounds of formula (III) as described in Scheme 1.

[0164] Scheme 3: Synthesis of certain compounds of formula (III) [ka] R 11 , R 12 , and R 3 is defined in Scheme 1 above, and R A1 , R C , and R D is defined elsewhere in this document and R A2 is absent. Certain compounds of formula (III) can be prepared in six steps from commercially available phosphonoacetates of formula (XII) and nitriles of formula (XIV).

[0165] Step (i): The amidoxime of formula (XIII) is reacted with NaHCO in a solvent such as isopropanol. 3 The nitrile (XIV) can be reacted with hydroxylamine hydrochloride in the presence of a base such as

[0166] Step (ii): Compounds of formula (XI) can be obtained by reacting phosphonate (XII) with an appropriate ester bearing a leaving group under basic conditions, such as in the presence of NaH in tetrahydrofuran.

[0167] Step (iii): Carboxylic acids of formula (X) can be obtained by hydrolysis of the ester in compounds of formula (XI) under basic conditions such as, for example, 1M aqueous sodium hydroxide in tetrahydrofuran.

[0168] Steps (iv) and (v): Compounds of formula (VIII) can be obtained by reacting compounds of formula (X) with chloroformate in the presence of a base such as 4-methylmorpholine to form intermediates of formula (IX), followed by addition of amidoxime of formula (XIII) to compound of formula (IX) under basic conditions such as in the presence of triethylamine to obtain compounds of formula (VIII).

[0169] Step (vi): The compound of formula (III) is reacted with a compound of formula (VIII) in the presence of tetrahydrofuran to form a compound of formula (VIII) represented by Cs 2 CO 3 to give compounds of formula (III).

[0170] Scheme 4: Synthesis of certain compounds of formula (III) [ka] Compounds of formula (III) can be obtained in one step by reacting together compounds of formula (IV-a) and (XV) in the presence of an activating agent such as silver trifluoromethanesulfonate or silver tetrafluoroborate, where R A1 , R C , R D , R 3 , R 11 , R 12 and X is as defined elsewhere herein.

[0171] Scheme 5: Synthesis of certain compounds of formula (I) [ka] R A1 and R A2 is as defined elsewhere herein and P is a carboxylic acid protecting group such as para-methoxybenzyl or tert-butyl. A2 It is particularly useful for compounds of formula (I) where is other than absent.

[0172] Step (i): Oxidation of the double bond in commercially available compounds of formula (XXIII) under conditions known to one skilled in the art (such as mCPBA in DCM at low temperature) provides epoxides of formula (XXII).

[0173] Step (ii): Epoxides of formula (XXII) undergo nucleophilic ring opening, for example using HBr in THF, to give haloalcohols of formula (XXI).

[0174] Step (iii): Oxidation of the alcohol in a compound of formula (XXI) under conditions known to one skilled in the art (such as DMP in DCM) provides a ketone of formula (XX).

[0175] Step (iv): Reaction of a ketone of formula (XX) with an amide of formula (XIX) followed by in situ hydrolysis provides an acid of formula (XVIII). Upon heating, the tert-butyl ester is hydrolyzed and step (v) is required. If step (iv) is carried out at room temperature, the tert-butyl ester remains intact, step (v) is not required and P is tert-butyl.

[0176] Step (v): The acid of formula (XVIII) is protected using a standard carboxylic acid protecting group (eg, para-methoxybenzyl) to give a compound of formula (XVII).

[0177] Step (vi): Olefination with elimination of diethyl phosphate gave compounds of formula (XVI) using conditions described elsewhere herein.

[0178] Step (vii): Removal of the protecting group P under conditions known to one skilled in the art provides compounds of formula (I).

[0179] Scheme 6: Synthesis of certain compounds of formula (I) [ka] R A1 is as defined elsewhere herein. This synthesis is C and R D are connected, C 3-5 When forming a cycloalkyl ring, or R C and R D is particularly useful when both are other than H.

[0180] Step (i): Hydrolysis of ester (XXVII) under alkaline conditions, such as aqueous NaOH, provides the acid of formula (XXVI).

[0181] Step (ii): Coupling of a compound of formula (VI) with an acid (XXVI) provides a compound of formula (XXV).

[0182] Step (iii): Under standard conditions (a strong base, e.g., LDA, and a triflutting agent, e.g., Tf 2 Trifractionation of the ketone in the compound of formula (XXV) with NPh provides the vinyl triflate of formula (XXIV).

[0183] Step (iv): The vinyl triflate of formula (XXIV) can be converted to the unsaturated carboxylic acid of formula (I) under metal catalyzed carbonylation conditions, such as palladium phosphine catalyst in the presence of CO, followed by hydrolysis (basic hydrolysis, e.g., aqueous K 2 CO 3 , followed by acidification, etc.) to give compounds of formula (I).

[0184] Scheme 7: Synthesis of certain compounds of formula (I) [ka] In the formula, R A1 , R A2 , A, and R C is defined elsewhere herein.

[0185] Step (i): Certain compounds of formula (I) can be obtained by isomerizing compounds of formula (I) under basic conditions, for example using an organic base such as diethylamine. Other organic bases suitable for the reaction will be readily known to those skilled in the art.

[0186] Those skilled in the art will understand that protecting groups can be used throughout the above synthetic schemes to obtain protected derivatives of any of the above compounds or general formulas. Protecting groups and the means for their removal are described in "Protective Groups in Organic Synthesis" by Theodora W. Greene and Peter GMWuts, published by John Wiley & Sons Inc; 4th Rev Ed., 2006, ISBN-10:0471697540. Examples of nitrogen protecting groups include tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzyl (Bn) and para-methoxybenzyl (PMB). Examples of oxygen protecting groups include acetyl (Ac), methoxymethyl (MOM), para-methoxybenzyl (PMB), benzyl, tert-butyl, methyl, ethyl, tetrahydropyranyl (THP), and silyl ethers and esters (e.g., trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers and esters).

[0187] Thus, in one embodiment, a compound of formula (I): [ka] or a salt thereof, which is, for example, a pharma- ceutically acceptable salt thereof, comprising a compound of formula (II): [ka] or a salt thereof, During the ceremony, [ka] R A1 , R A2 , R C , R D , and R 3is defined elsewhere herein.

[0188] In one embodiment, a compound of formula (II): [ka] or a salt thereof, comprising a compound of formula (III): [ka] or a salt thereof, reacting with formaldehyde or an equivalent thereof; During the ceremony, [ka] R A1 , R A2 , R C , R D , R 3 , R 11 , and R 12 is defined elsewhere herein.

[0189] In one embodiment, a compound of formula (III): [ka] or a salt thereof, comprising a compound of formula (V): [ka] or a salt thereof, A compound of formula (IV), [ka] or a salt thereof, During the ceremony, [ka] R A1 , R A2 , R C , RD , R 3 , R 11 , R 12 and X is defined elsewhere herein.

[0190] In one embodiment, a compound of formula (III): [ka] or a salt thereof, comprising a compound of formula (VI): [ka] or a salt thereof, A compound of formula (VII), [ka] or a salt thereof, In the formula, R A1 , R C , R D , R 3 , R 11 , and R 12 is defined elsewhere herein.

[0191] In one embodiment, a compound of formula (III): [ka] or a salt thereof, comprising a compound of formula (VIII): [ka] or a salt thereof, Cs 2 CO 3 and reacting with a base such as In the formula, R A1 , R C , R D , R 3 , R 11 , and R 12is defined elsewhere herein.

[0192] In one embodiment, a compound of formula (III): [ka] or a salt thereof, comprising a compound of formula (IV-a): [ka] or a salt thereof, [ka] or a salt thereof, In the formula, X, R A1 , R C , R D , R 3 , R 11 , and R 12 is defined elsewhere herein.

[0193] In one embodiment, there is provided a process for preparing a compound of formula (I), or a salt thereof, for example a pharma- ceutically acceptable salt thereof, comprising the step of: [ka] or a salt thereof, In the formula, R A1 and R A2 is defined elsewhere herein and P is a carboxylic acid protecting group, such as para-methoxybenzyl.

[0194] In one embodiment, there is provided a process for preparing a compound of formula (I), or a salt thereof, for example a pharma- ceutically acceptable salt thereof, comprising the step of: [ka] or a salt thereof, Reaction with carbon monoxide in the presence of a metal catalyst, e.g., a palladium catalyst, followed by hydrolysis (e.g., basic hydrolysis, e.g., aqueous K 2 CO 3 followed by acidification) to obtain a compound of formula (I), In the formula, R A1 is defined elsewhere herein.

[0195] In one embodiment, a compound of formula (II): [ka] or a salt thereof, wherein [ka] R A1 , R A2 , R C , R D , and R 3 is defined elsewhere herein, or a salt thereof.

[0196] In one embodiment, a compound of formula (III): [ka] or a salt thereof, wherein [ka] R A1 , R A2 , R C , R D , R 11 , R 12 , and R 3 is defined elsewhere herein, or a salt thereof.

[0197] In one embodiment, a compound of formula (V): [ka] or a salt thereof, wherein [ka] R A1 , R A2 , R C , R D and X is defined elsewhere herein, or a salt thereof.

[0198] In one embodiment, a compound of formula (VIII): [ka] or a salt thereof, wherein R A1 , R C , R D , R 3 , R 11 , and R 12 is as defined elsewhere herein, or a salt thereof.

[0199] In one embodiment, a compound of formula (XVI): [ka] or a salt thereof, In the formula, R A1 and R A2 is defined elsewhere herein and P is a carboxylic acid protecting group, such as para-methoxybenzyl, or a salt thereof.

[0200] In one embodiment, a compound of formula (XXIV): [ka] or a salt thereof, In the formula, R A1 is defined elsewhere herein, or a salt thereof.

[0201] Certain novel compounds can be used in the synthesis of compounds of formula (I). Thus, in one embodiment, 5-(chloromethyl)-3-octyl-1,2,4-oxadiazole, 5-(chloromethyl)-3-heptyl-1,2,4-oxadiazole, 5-(chloromethyl)-3-(octan-2-yl)-1,2,4-oxadiazole, 5-(chloromethyl)-3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazole, 5-(chloromethyl)-3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazole, and A compound selected from the group consisting of 9,9,9-trifluorononanenitrile, Alternatively, salts thereof, for example pharma- ceutically acceptable salts and / or solvates thereof, are provided.

[0202] In one embodiment, a compound selected from the group consisting of intermediates 13-85: Alternatively, salts thereof, for example pharma- ceutically acceptable salts and / or solvates thereof, are provided.

[0203] In another embodiment, a compound selected from the group consisting of intermediates 86-151: Alternatively, salts thereof, for example pharma- ceutically acceptable salts and / or solvates thereof, are provided.

[0204] In another embodiment, a compound selected from the group consisting of intermediates 152-223: Alternatively, salts thereof, for example pharma- ceutically acceptable salts and / or solvates thereof, are provided.

[0205] In one embodiment, the molecular weight of the compound of formula (I) is between 150 Da and 500 Da, in particular between 200 Da and 350 Da.

[0206] It will be understood that the salt of the compound of formula (I) should be pharma- ceutically acceptable for use in therapy. Suitable pharma- ceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include basic addition salts such as sodium, potassium, calcium, aluminum, zinc, magnesium, and other metal salts. Pharmaceutically acceptable salts can also be formed with organic bases, including, for example, ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine. Other pharma- ceutically acceptable salts include trifluoroacetate salts. Suitably, the pharma- ceutically acceptable salt is a tromethamine salt. Thus, in one embodiment, a compound of formula (I) is provided in the form of a pharma- ceutical acceptable salt. Alternatively, a compound of formula (I) is provided in the form of a free acid. When the compound contains a basic group as in the free acid, it can be zwitterionic.

[0207] The compound of formula (I) can be prepared in crystalline or non-crystalline form, and if crystalline, can be optionally solvated, for example as a hydrate.The present invention includes within its scope stoichiometric solvates (e.g., hydrates), as well as compounds that contain variable amounts of solvent (e.g., water).Preferably, the compound of formula (I) is not a solvate.

[0208] It should be understood that the present invention encompasses all isomers of the compounds of formula (I), including all geometric, tautomeric, and optical forms, as well as mixtures thereof (e.g., racemic mixtures). As far as described herein, for example in claim 1, certain structural isomers are provided as part of the present invention. In particular, the present invention extends to all tautomeric forms of the compounds of formula (I). When additional chiral centers are present in the compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms can be separated or resolved from one another by conventional methods, or any given isomer can be obtained by conventional synthetic methods, or by stereospecific or asymmetric synthesis.

[0209] The present invention also includes all isotopic forms of the compounds provided herein, whether in the form (i) all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is essentially predominant (referred to herein as "natural isotopic forms"), or (ii) one or more atoms are replaced with an atom having the same atomic number but a mass number different from the mass number of the essentially predominant atom (referred to herein as "non-natural variant isotopic forms"). It is understood that atoms may naturally exist as a mixture of mass numbers. The term "non-natural variant isotopic forms" further includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers that are less commonly found in nature (referred to herein as "rare isotopes") is increased compared to that occurring in nature, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (referred to in the latter embodiment as "isotopically enriched variant forms"). The term "non-naturally occurring variant isotopic form" further includes embodiments in which the proportion of a rare isotope is reduced compared to that occurring in nature. Isotopic forms can include radioactive forms (i.e., incorporating a radioactive isotope) and non-radioactive forms. Radioactive forms will usually be isotopically enriched variant forms.

[0210] Therefore, non-natural variant isotopic forms of a compound may contain deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-15( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Fluorine-18( 18 F), iodine-123( 123 I), iodine-125( 125I), or may include an increased proportion of said isotopes compared to the proportion that predominates in nature for one or more atoms.

[0211] Non-natural variant isotopic forms containing radioactive isotopes can be used, for example, in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. 2 Non-natural variant isotopes incorporating H or D may provide certain therapeutic benefits due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Furthermore, non-natural variant isotope forms may be 11 C. 18 F, 15 O, and 13 They can be prepared by incorporating positron emitting isotopes, such as N, making them useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0212] In one embodiment, the compound of formula (I) is provided in a natural isotopic form. In one embodiment, the compound of formula (I) is provided in a non-natural variant isotopic form. In certain embodiments, the non-natural variant isotopic form is a form in which hydrogen is substituted for one or more atoms of the compound of formula (I) with deuterium (i.e. 2 In one embodiment, the atoms of the compound of formula (I) are in isotopic form that is not radioactive. In one embodiment, one or more atoms of the compound of formula (I) are in isotopic form that is radioactive. The preferred radioisotopes are stable isotopes. Preferably, the non-natural variant isotopic form is a pharma- ceutically acceptable form.

[0213] In one embodiment, a compound of formula (I) is provided whereby a single atom of the compound exists in a non-natural variant isotopic form. In another embodiment, a compound of formula (I) is provided whereby two or more atoms exist in a non-natural variant isotopic form.

[0214] Non-natural isotopic variant forms can generally be prepared by conventional techniques readily known to those skilled in the art or by processes described herein, such as processes similar to those described in the accompanying examples for preparing natural isotopic forms. Thus, non-natural isotopic variant forms can be prepared by substituting appropriate isotopic variant (or labeled) reagents in place of the conventional reagents used in the examples. As the compounds of formula (I) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more preferably at least 75% pure, preferably at least 85%, particularly at least 98% pure (% being weight on a weight basis). Impure preparations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0215] Treatment indications The compound of formula (I) is used in therapy, particularly for the treatment or prevention of inflammatory diseases or diseases associated with an undesirable immune response. As shown in Biological Example 1 below, the compound of formula (I) of Example 1 has a lower IC 50 As shown by IC values, this compound reduced cytokine release more effectively than 4-octyl itaconate and 2-(2-chlorobenzyl)acrylic acid. This compound also activates NRF2 more potently and with greater efficacy than 4-octyl itaconate and 2-(2-chlorobenzyl)acrylic acid while also demonstrating improved stability in both mouse and human cryopreserved hepatocytes. Other exemplary compounds of formula (I) have lower IC values. 50As shown by the values, it reduces cytokine release more effectively than 4-octyl itaconate and 2-(2-chlorobenzyl)acrylic acid and / or activates NRF2 with greater potency and greater potency than 4-octyl itaconate and 2-(2-chlorobenzyl)acrylic acid, while exhibiting improved stability in both mouse and human cryopreserved hepatocytes. Cytokines are important mediators of inflammatory and immune-mediated diseases, as evidenced by the therapeutic benefits afforded by antibodies targeting them.

[0216] Thus, in a first aspect, the present invention provides a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt and / or solvate thereof, for use as a medicament. Additionally, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt and / or solvate thereof. Such a pharmaceutical composition comprises a compound of formula (I) and a pharma- ceutically acceptable carrier or excipient.

[0217] In a further aspect, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of an inflammatory disease or a disease associated with an undesired immune response. In a further aspect, the present invention provides the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of an inflammatory disease or a disease associated with an undesired immune response. In a further aspect, the present invention provides a method for the treatment or prevention of an inflammatory disease or a disease associated with an undesired immune response comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0218] In all aspects of the invention, preferably the compound is administered to a subject in need thereof, which is preferably a human subject.

[0219] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment of an inflammatory disease or a disease associated with an undesired immune response. In one embodiment, the present invention provides the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment of an inflammatory disease or a disease associated with an undesired immune response. In one embodiment, the present invention provides a method of treating an inflammatory disease or a disease associated with an undesired immune response comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0220] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the prophylaxis of inflammatory diseases or diseases associated with an undesired immune response. In one embodiment, the present invention provides the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the prophylaxis of inflammatory diseases or diseases associated with an undesired immune response. In one embodiment, the present invention provides a method for the prophylaxis of inflammatory diseases or diseases associated with an undesired immune response comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0221] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prophylaxis of an inflammatory disease. In one embodiment, the present invention provides the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of an inflammatory disease. In one embodiment, the present invention provides a method for treating or prophylaxis of an inflammatory disease comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0222] In one embodiment, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a disease associated with an undesired immune response. In one embodiment, the present invention provides the use of a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment or prevention of a disease associated with an undesired immune response. In one embodiment, the present invention provides a method for the treatment or prevention of a disease associated with an undesired immune response comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0223] An unwanted immune response is typically one that causes a pathology, ie, a pathological immune response or reaction.

[0224] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is an autoimmune disease.

[0225] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is selected from the group consisting of psoriasis (including chronic plaque, erythroderma, pustular, guttural, inverse and nail variants), asthma, chronic obstructive pulmonary disease (including COPD, chronic bronchitis and emphysema), heart failure (including left ventricular failure), myocardial infarction, angina pectoris, other atherosclerosis and / or atherothrombosis related disorders (including peripheral vascular disease and ischemic stroke), mitochondrial and neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, or ...). doria encephalomyopathy), autoimmune paraneoplastic retinopathy, transplant rejection (including antibody-mediated and T cell-mediated), multiple sclerosis, transverse myelitis, ischemia-reperfusion injury (e.g., during elective surgery such as cardiopulmonary bypass for coronary artery bypass grafting or other cardiac surgery, after percutaneous coronary intervention, after acute ST-segment elevation myocardial infarction or ischemic stroke, organ transplantation, or after treatment of acute compartment syndrome), AGE-induced genomic damage, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), primary sclerosing cholangitis (PSC), PSC-autoimmune hepatitis overlap syndrome, nonalcoholic fatty liver disease Nonalcoholic fatty liver disease (nonalcoholic steatohepatitis), rheumatic, granuloma annulare, cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, drug-induced lupus, autoimmune myocarditis or myopericarditis, Dressler syndrome, giant cell myocarditis, postpericardiotomy syndrome, drug-induced hypersensitivity syndrome (including hypersensitivity myocarditis), eczema, sarcoidosis, erythema nodosum, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (including MOG-EM), optic neuritis, CLIPPERS (schizophrenia), and rheumatoid arthritis (rheumatoid arthritis). chronic lymphocytic inflammation with pontine perivascular enhancement in response to steroids), diffuse spinal crushing sclerosis, Addison's disease, alopecia areata, ankylosing spondylitis, other spondyloarthritis (including peripheral spondyloarthritis associated with psoriasis, inflammatory bowel disease, reactive arthritis or juvenile-onset forms), antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid (including bullous pemphigoid, mucous membrane pemphigoid, cicatricial pemphigoid, gestational pemphigoid or pemphigoid, ocular cicatricial pemphigoid), linear IgA disease, Behçet's disease, celiac disease, Chagas disease, dermatomyositis, type I diabetes mellitus,Endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome and its subtypes (including acute inflammatory demyelinating polyneuropathy, AIDP, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), pharyngeal-cervical-brachial plexus variant, Miller Fisher variant and Bickerstaff brainstem encephalitis), progressive inflammatory neuropathies, Hashimoto's disease, hidradenitis suppurativa, inclusion body myositis, necrotizing myopathy, Kawasaki disease, IgA nephropathy, Henoch-Schönlein purpura, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura (T thrombocytopenic purpura), and idiopathic thrombocytopenic purpura (T thrombocytopenic purpura). TP), Evans syndrome, interstitial cystitis, mixed connective tissue disease, undifferentiated connective tissue disease, morphea, myasthenia gravis (including MuSK antibody positive and seronegative variants), narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriatic arthritis, polymyositis, primary biliary cholangitis (also known as primary biliary cirrhosis), rheumatoid arthritis, palindromic rheumatism, schizophrenia, autoimmune (meningo)encephalitis syndrome, scleroderma, Sjögren's syndrome, stiff-body syndrome, polymyalgia rheumatica, giant cell arteritis (temporal arteritis), Takayasu's arteritis, polyarteritis nodosa, Kawasaki disease, Granulomatosis with polyangiitis (GPA; formerly known as Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome), microscopic polyarteritis / polyangiitis, hypocomplementemic urticarial vasculitis, hypersensitivity vasculitis, cryoglobulinemia, thromboangiitis obliterans (Buerger's disease), vasculitis, leukocytoclastic vasculitis, vitiligo, acute disseminated encephalomyelitis, adrenoleukodystrophy, Alexander disease, Alper's disease, Baroconcentric sclerosis or Marburg disease, idiopathic organizing pneumonia (formerly known as obstructive bronchial organizing pneumonia) vascular inflammation), Canavan disease, central nervous system vasculitis syndrome, Charcot-Marie-Tooth disease, childhood ataxia with central nervous system hypomyelination, chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic retinopathy, globoid cell leukodystrophy (Krabbe disease), graft-versus-host disease (GVHD) (including acute and chronic forms, and intestinal GVHD), hepatitis C (HCV) infection or complications, herpes simplex virus infection or complications, human immunodeficiency virus (HIV) infection or complications, lichen planus, Hirayama disease, cystic fibrosis, pulmonary arterial hypertension (PAH,idiopathic PAH), pulmonary sarcoidosis, idiopathic pulmonary fibrosis, childhood asthma, atopic dermatitis, allergic dermatitis, contact dermatitis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca, dry eye, xerophthalmia, glaucoma, macular edema, diabetic macular edema, central retinal vein occlusion (CRVO), macular degeneration (including dry and / or wet age-related macular degeneration, AMD), postoperative cataract inflammation, uveitis (including posterior, anterior, intermediate and panuveitis), iridocyclitis, scleritis, corneal graft and keratocyte graft rejection, glomerulonephritis ... Celiac disease, dermatitis herpetiformis, eosinophilic esophagitis, achalasia, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune esophagitis, autoimmune orchitis, autoimmune pancreatitis, aortitis and perivascular inflammation, autoimmune retinopathy, autoimmune urticaria, Behçet's disease, (idiopathic) Castleman's disease, Cogan's syndrome, IgG4-related disease, retroperitoneal fibrosis, juvenile idiopathic arthritis including systemic juvenile idiopathic arthritis (Still's disease), adult-onset Still's disease, lignified conjunctivitis, Mooren's ulcer, acute pityriasis lichenoides (PLEVA, Mucha-Habermann's disease) also known as), multifocal motor neuropathy (MMN), childhood acute-onset neuropsychiatric syndromes (PANS) (including pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)), paraneoplastic syndromes (including paraneoplastic cerebellar degeneration, Lambert-Eaton myoneuropathy syndrome, limbic encephalitis, brainstem encephalitis, opsoclonus-myoclonus ataxia, anti-NMDA receptor encephalitis, thymoma-associated multisystem autoimmunity), perivenous encephalomyelitis, reflex sympathetic dystrophy, relapsing polychondritis, sperm and testicular autoimmunity, Susac syndrome, Tolosa-Hunt syndrome, Follicular hyperplasia, and pulmonary hypertension). Collins-Koyanagi-Harada syndrome, antisynthetase syndrome, autoimmune enteropathy, immunodysregulatory polyendocrinopathy enteropathy X-linked (IPEX), microscopic colitis, autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APEX), gout, pseudogout, amyloid (including AA or secondary amyloidosis), eosinophilic fasciitis (Schulman syndrome), progesterone hypersensitivity (including progesterone dermatitis), familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS),Hypergammopathy D with periodic fever syndromes (HIDS), PAPA (septic arthritis, pyoderma gangrenosum, severe prurigo cystica) syndrome, interleukin-1 receptor antagonist (DIRA) deficiency, interleukin-36 receptor antagonist (DITRA) deficiency, cryopyrin-associated periodic syndromes (CAPS) (including familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease [NOMID]), NLRP12-associated autoinflammatory disease (NLRP12AD), periodic fever aphthous stomatitis (PFAPA), chronic atypical neutrophilic dermatosis with lipodystrophy and hypertension (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold autoinflammatory syndrome, and mutant adenosine deaminase 2 and being or associated with a disease selected from the group consisting of monogenic interferonopathies (including Aicardi-Goutières syndrome, retinal vasculopathy with cerebral leukodystrophy, spondylochondrodysplasia, STING [stimulator of interferon genes]-associated vasculopathy of infancy, proteasome-associated autoinflammatory syndrome, familial chilblains, hereditary symmetrical dyschromia), Schnitzler syndrome; familial cylindromatosis, congenital B-cell lymphocytosis, OTULIN-associated autoinflammatory syndrome, type 2 diabetes, insulin resistance and metabolic syndrome (including obesity-associated inflammation), atherosclerosis (e.g., myocardial infarction, angina pectoris, ischemic heart failure, ischemic nephropathy, ischemic stroke, peripheral vascular disease, aortic aneurysm), renal inflammatory disease (e.g., diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, kidney transplantation),

[0226] In one embodiment, the inflammatory disease or disease associated with an undesired immune response is selected from the group consisting of familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), hypergammopathy D with periodic fever syndrome (HIDS), PAPA (septic arthritis, pyoderma gangrenosum, severe prurigo cystica) syndrome, interleukin-1 receptor antagonist (DIRA) deficiency, interleukin-36 receptor antagonist (DITRA) deficiency, cryopyrin-associated periodic syndromes (CAPS) (including familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome, neonatal-onset multisystem inflammatory disease [NOMID]), NLRP12-associated autoinflammatory disease (NLRP12AD), periodic fever aphthous stomatitis (PFA or associated with a disease selected from the group consisting of: chronic atypical neutrophilic dermatosis with lipodystrophy and hyperthermia (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold autoinflammatory syndrome, mutant adenosine deaminase 2 and monogenic interferonopathies (including Aicardi-Goutières syndrome, retinal vasculopathy with cerebral leukodystrophy, spondylochrondrodysplasia, STING [stimulator of interferon genes]-associated vasculopathy of infantile onset, proteasome-associated autoinflammatory syndrome, familial chilblains, hereditary contralateral dyschromia), and Schnitzler syndrome.

[0227] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is a disease selected from the following diseases mediated by excess NF-κB or gain of function of the NF-κB signaling pathway (including non-canonical NF-κB signaling), or contributes significantly to or is associated with an aberrant pathogenesis therefrom: familial cylindromatosis, congenital B-cell lymphocytosis, OTULIN-associated autoinflammatory syndrome, type 2 diabetes, insulin resistance and metabolic syndrome (including obesity-associated inflammation), atherosclerosis (e.g., myocardial infarction, angina pectoris, ischemic heart failure, ischemic nephropathy, ischemic stroke, peripheral vascular disease, aortic aneurysm), renal inflammatory disease (e.g., diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, kidney transplant), asthma, COPD, type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), and SLE.

[0228] In one embodiment, the disease is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, uveitis, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, juvenile idiopathic arthritis, and chronic obstructive pulmonary disease.

[0229] In one embodiment, the disease is multiple sclerosis.

[0230] In one embodiment, the disease is psoriasis.

[0231] In one embodiment, the compound of formula (I) has a lower IC50 value compared to 4-octyl itaconate when tested in a cytokine assay, e.g., as described in Biological Example 1. 50 In one embodiment, the compound of formula (I) exhibits a lower EC50 value compared to 4-octyl itaconate when tested in the NRF2 assay, e.g., as described in Biological Example 2. 50 In one embodiment, the compound of formula (I) exhibits a higher E compared to 4-octyl itaconate when tested in the NRF2 assay, e.g., as described in Biological Example 2.max In one embodiment, the compound of formula (I) exhibits a lower EC50 value compared to 4-octyl itaconate when tested in the NRF2 assay, e.g., as described in Biological Example 2. 50 and / or higher E max In one embodiment, the compound of formula (I) exhibits a lower EC50 value compared to 4-octyl itaconate when tested in the NRF2 assay, e.g., as described in Biological Example 2. 50 and higher E max In one embodiment, the compound of formula (I) exhibits a lower Cl content compared to 4-octyl itaconate when tested in a hepatocyte stability assay, e.g., as described in Biological Example 3. int In one embodiment, the compound of formula (I) exhibits a longer half-life compared to 4-octyl itaconate when tested in a hepatocyte stability assay, e.g., as described in Biological Example 3. In one embodiment, the compound of formula (I) exhibits a lower Cl-I activity compared to 4-octyl itaconate when tested in a hepatocyte assay, e.g., as described in Biological Example 3. int and exhibits a longer half-life. In any one of the above embodiments, suitably the hepatocytes are human cryopreserved hepatocytes.

[0232] Administration Compound of formula (I) is usually administered as a pharmaceutical composition.Therefore, in one embodiment, a pharmaceutical composition is provided that comprises a compound of formula (I) and one or more pharma- ceutically acceptable diluents or carriers.

[0233] The compounds of formula (I) may be administered by any convenient way, for example by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and by pharmaceutical compositions adapted accordingly.

[0234] The compounds of formula (I) can be administered locally to a target organ, for example, to the eye, lung, nose, or skin. Thus, the present invention provides pharmaceutical compositions comprising a compound of formula (I), optionally in combination with one or more topically acceptable diluents or carriers.

[0235] Compounds of formula (I) that are active when given orally can be formulated as liquids or solids, for example, as syrups, suspensions, emulsions, tablets, capsules, or lozenges.

[0236] Liquid formulations generally consist of a suspension or solution of the compound of formula (I) in a suitable liquid carrier.Preferably, the carrier is non-aqueous, for example, polyethylene glycol or oil.The formulation may also contain a suspending agent, a preservative, a flavoring agent and / or a coloring agent.

[0237] A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose, and cellulose.

[0238] A composition in the form of a capsule can be prepared using normal encapsulation procedures, for example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example aqueous gums, celluloses, silicates, or oils, and then the dispersion or suspension can be filled into a soft gelatin capsule.

[0239] A typical parenteral composition will consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.

[0240] Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations usually contain a solution or fine suspension of the compound of formula (I) in a pharma-ceutically acceptable aqueous or non-aqueous solvent, and are usually presented in single or multiple doses in a sterile form in a sealed container that can take the form of a cartridge or refill for use in a nebulizer. Alternatively, the sealed container can be a disposable dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser with a metering valve. When the dosage form comprises an aerosol dispenser, it will contain a propellant that can be a compressed gas, eg air, or an organic propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). The aerosol dosage form can also take the form of a pump atomizer.

[0241] Topical administration to the lung can be achieved by using an aerosol formulation, which typically contains the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC).

[0242] Local administration to the lungs can also be achieved by using non-pressurized formulations, such as aqueous solutions or suspensions. These can be administered, for example, by hand-held, portable, or home or hospital (i.e., non-portable) nebulizers. The formulations can include excipients such as water, buffers, tonicity adjusters, pH adjusters, surfactants, and cosolvents.

[0243] Topical administration to the lung can also be achieved by use of a dry powder formulation, which will typically contain a locally acceptable diluent such as lactose, glucose, or mannitol, preferably lactose.

[0244] The compound of the present invention can also be administered rectally in the form of suppository or enema, including, for example, aqueous or oily solution, as well as suspension and emulsion and foam.Such compositions are prepared according to standard procedures well known to those skilled in the art.For example, suppository can be prepared by mixing active ingredient with conventional suppository base such as cocoa butter or other glycerides.In this case, drug is mixed with suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, and therefore melts in rectum to release drug.Such materials are cocoa butter and polyethylene glycol.

[0245] Generally, for compositions intended for topical administration to the eye in the form of eye drops or eye ointment, the total amount of the compounds of the invention will be from about 0.0001 to less than 4.0% (w / w).

[0246] Preferably, for topical ocular administration, compositions administered in accordance with the present invention will be formulated as solutions, suspensions, emulsions, and other dosage forms.

[0247] The composition administered according to the present invention may also contain various other components, including but not limited to tonicity agent, buffer, surfactant, stabilizing polymer, preservative, cosolvent, and viscosity building agent.The suitable pharmaceutical composition of the present invention includes the compound of the present invention formulated with tonicity agent and buffer.The pharmaceutical composition of the present invention may optionally further contain surfactant and / or emollient and / or stabilizing polymer.

[0248] Various tonicity agents can be used to adjust the tonicity of the composition, preferably the ophthalmic composition to that of natural tears. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and / or simple polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates can be added to the composition to approximate physiological tonicity. The amount of such tonicity agents will vary depending on the particular agent added. However, in general, the composition will have a sufficient amount of tonicity agent to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm, most preferably about 290 mOsm). Generally, the tonicity agents of the present invention will be present in the range of 2-4% w / w. Preferred tonicity agents of the present invention include simple sugars or sugar alcohols such as D-mannitol.

[0249] An appropriate buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate, or boric acid) can be added to the composition to prevent pH drift under storage conditions. The specific concentrations will vary depending on the agent used. However, preferably, the buffer will be selected to maintain the target pH within the range of pH 5-8, more preferably at a target pH of pH 5-7.

[0250] Surfactants can optionally be used to deliver higher concentrations of the compounds of the invention. Surfactants function to solubilize the compounds and stabilize colloidal dispersions such as micellar solutions, microemulsions, emulsions, and suspensions. Examples of surfactants that can be optionally used include polysorbates, poloxamers, polyoxyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants used in the present invention have a hydrophilic / lipophilic / balance "HLB" in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as Triton X114 and tyloxapol.

[0251] An additional agent that can be added to the ophthalmic composition of the compounds of the present invention is a mucilage, which acts as a stabilizing polymer. The stabilizing polymer must be an example of ionic / charged nature preferred for topical ocular use, more specifically the polymer must carry a negative charge on the surface, exhibit a zeta potential of (-)10-50 mV for physical stability, and be dispersible in water (i.e. water-soluble). The preferred stabilizing polymer of the present invention is, at 0.1-0.5% w / w, a polyelectrolyte, or, if more than one, a polyelectrolyte from the family of crosslinked polyacrylates, such as Carbomer and Pemulen®, in particular Carbomer 974p (polyacrylic acid).

[0252] Other compounds can also be added to the ophthalmic composition of the present invention to increase the viscosity of the carrier.Examples of viscosity enhancers include, but are not limited to, polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family, vinyl polymers, and acrylic acid polymers.

[0253] Topical ophthalmic products are usually packaged in multi-dose form. Thus, preservatives are necessary to prevent microbial contamination during use. Suitable preservatives include benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, disodium edentate, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically used at levels of 0.001-1.0% w / v. The unit dose compositions of the present invention are sterile, but will typically be non-preserved. Thus, such compositions will generally not contain preservatives.

[0254] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles wherein the compound of formula (I) is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0255] Compositions suitable for transdermal administration include ointments, gels, and patches.

[0256] The composition may contain 0.1% to 100% by weight, for example 10 to 60% by weight, of the compound of formula (I), depending on the method of administration. The composition may contain 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain 0.05 mg to 1000 mg, for example 1.0 mg to 500 mg, for example 1.0 mg to 50 mg, for example about 10 mg, of the compound of formula (I), depending on the method of administration. The composition may contain 50 mg to 1000 mg, for example 100 mg to 400 mg, of the carrier, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way depending on the severity of the disorder, the weight of the patient, and other similar factors. However, as a general guide, suitable unit doses may be from 0.05 to 1000 mg, more preferably from 1.0 to 500 mg, for example from 1.0 mg to 50 mg, for example about 10 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for several weeks or months.

[0257] In one embodiment of the present invention, the compound of formula (I) is used in combination with additional therapeutic agent or agents.When the compound of formula (I) is used in combination with other therapeutic agents, the compounds can be administered sequentially or simultaneously by any convenient route.Alternatively, the compounds can be administered separately.

[0258] Therapeutic agents that can be used in combination with the present invention include corticosteroids (glucocorticoids), retinoids (e.g., acitretin, isotretinoin, tazarotene), anthralin, vitamin D analogs (e.g., calcitriol, calcipotriol), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus), phototherapy or photochemotherapy (e.g., psoralen ultraviolet radiation, PUVA) or other forms of ultraviolet radiation therapy, cyclosporine, thiopurines (e.g., azathioprine, 6-mercaptopurine), methotrexate, anti-TNFα agents (e.g., infliximab, etanercept, , adalimumab, certolizumab, golimumab, and biosimilars), phosphodiesterase-4 (PDE4) inhibitors (e.g., apremilast, crisaborole), anti-IL-17 agents (e.g., brodalumab, ixekizumab, secukinumab), anti-IL12 / IL-23 agents (e.g., ustekinumab, briakinumab), anti-IL-23 agents (e.g., guselkumab, tildrakizumab), JAK (Janus kinase) inhibitors (e.g., tofacitinib, ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immunoglobulin (IVIG), cyclophosphamide, anti-CD20 B cell depleting agents (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab), anthracycline analogues (e.g., mitoxantrone), cladribine, sphingosine 1-phosphate receptor modulators or sphingosine analogues (e.g., fingolimod, siponimod, ozanimod, etrasimod), interferon beta preparations (including interferon beta 1b / 1a), glatiramer, anti-CD3 therapy (e.g., OKT3), anti-CD52 targeted agents (e.g., alemtuzumab), leflunomide, amide, teriflunomide, gold compounds, laquinimod, potassium channel blockers (e.g., dalfampridine / 4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogues (e.g., pentostatin), mTOR (mechanistic target of rapamycin) pathway inhibitors (e.g., sirolimus, everolimus), anti-thymocyte globulin (ATG), IL-2 receptor (CD25) inhibitors (e.g., basiliximab, daclizumab), anti-IL-6 receptor or anti-IL-6 agents (e.g., tocilizumab,Other B-cell targeted therapies including siltuximab), Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), tyrosine kinase inhibitors (e.g., imatinib), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B-cell activating factor (BAFF, also known as BLyS, B-lymphocyte stimulatory agent) inhibitors (e.g., belimumab, blisibimod), fusion proteins targeting both APRIL (proliferation-inducing ligand) and BLyS (e.g., atacicept), PI3K inhibitors including pan-inhibitors, or p110 including isoforms Inhibitors targeting delta and / or p110gamma (e.g., idelalisib, copanlisib, duvelisib), interferon alpha receptor inhibitors (e.g., anifrolumab, sifalimumab), T cell costimulation blockers (e.g., abatacept, belatacept), thalidomide and its derivatives (e.g., lenalidomide), dapsone, clofazimine, leukotriene antagonists (e.g., montelukast), theophylline, anti-IgE therapy (e.g., omalizumab), anti-IL-5 agents (e.g., mepolizumab, reslizumab), long-acting muscarinics (e.g., tiotropium, aclidinium, umeclidinium), PDE4 inhibitors (e.g., roflumilast), riluzole, free radical scavengers (e.g., edaravone), proteasome inhibitors (e.g., bortezomib), complement cascade inhibitors including those directed against C5 (e.g., eculizumab), immunoadsorbents, antithymocyte globulin, 5-aminosalicylic acid and its derivatives (e.g., sulfasalazine, balsalazide, mesalamine), antiintegrin agents including those targeting α4β1 and / or α4β7 integrins (e.g., , natalizumab, vedolizumab), anti-CD11-α agents (e.g., efalizumab), nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates (e.g., aspirin), propionic acids (e.g., ibuprofen, naproxen), acetates (e.g., indomethacin, diclofenac, etodolac), oxicams (e.g., meloxicam), fenamates (e.g., mefenamic acid), selective or comparatively selective COX-2 inhibitors (e.g., celecoxib, etroxicoxib, valdecoxib and etodolac, meloxicam, nabumetone), colchicine,These include IL-4 receptor inhibitors (e.g., dupilumab), local / contact immunotherapy (e.g., diphenylcyclopropenone, squaric acid dibutyl ester), anti-IL-1 receptor therapy (e.g., anakinra), IL-1β inhibitors (e.g., canakinumab), IL-1 neutralization therapy (e.g., rilonacept), chlorambucil, certain antibiotics with immunomodulatory properties and / or the ability to modulate NRF2 (e.g., minocycline, clindamycin, tetracyclines, including macrolide antibiotics), antiandrogen therapy (e.g., cyproterone, spironolactone, finasteride), pentoxifylline, ursodeoxycholic acid, obeticholic acid, fibrates, cystic fibrosis transmembrane conductance (CFTR) regulator, VEGF (vascular endothelial growth factor) inhibitors (e.g., bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone, and mizoribine. ,

[0259] Compounds of formula (I) may exhibit one or more of the following desirable properties: Low IC for inhibiting release of cytokines, e.g., IL-1β and / or IL-6, from cells 50 value, Low EC for activating the enzyme NQO1 or NRF2 pathway 50 and / or high E max value, - improved metabolic stability and / or enhanced maximal response; - Improved pharmacokinetics, particularly reduced dose and dosing frequency as a result of enhanced hepatocyte stability; Improved oral systemic bioavailability, - Decreased plasma clearance after intravenous administration, - improved metabolic stability, as demonstrated, for example, by improved stability in plasma and / or hepatocytes; Increased cell permeability, Enhanced water solubility, - well tolerated, for example by limiting flushing and / or gastrointestinal side effects caused by oral DMF (Hunt T. et al., 2015; WO2014 / 152494A1, incorporated herein by reference) or by reducing or eliminating HCA2 activity; - low toxicity at relevant therapeutic doses; Distinct anti-inflammatory profiles resulting from different electrophilicities leading to differential targeting of the cysteine ​​proteome (van der Reest J. et al., 2018) and therefore altering effects on gene activation; ●Glutathione-saving effect, ● Avoidance of oncometabolite fumarate (Kulkarni RA et al., 2019), • Improved physical form (solid) or higher melting point. [Table 1-1] [Table 1-2] [Table 1-3] EXAMPLES

[0260] Analyzer NMR spectra were recorded using a Bruker 400MHz Avance III spectrometer equipped with a BBFO 5mm probe or a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbeTM. Spectra were measured at 298K and referenced to the solvent resonance unless otherwise stated. Chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software.

[0261] UPLC / MS analysis was performed on a Waters Acquity UPLC system using either a Waters Acquity CSH C18 or BEH C18 column (2.1x30mm) maintained at a temperature of 40 °C and eluted with a linear acetonitrile gradient appropriate to the lipophilicity of the compounds over 3 or 10 min at a constant flow rate of 0.77 mL / min. The aqueous portion of the mobile phase was either 0.1% formic acid (CSH C18 column), 10 mM ammonium bicarbonate, or 10 mM ammonia (BEH C18 column). LC-UV chromatograms were recorded from 210-400 nm using a Waters Acquity PDA detector. Mass spectra were recorded using a Waters Acquity Qda detector with electrospray ionization switched between positive and negative ion modes. Sample concentrations were adjusted to obtain an appropriate UV response.

[0262] LCMS analysis was performed on an Agilent LCMS system using either a Waters Acquity CSH C18 or BEH C18 column (4.6x30mm) maintained at a temperature of 40°C and eluted with a linear acetonitrile gradient appropriate to the lipophilicity of the compounds over 4 or 15 min at a constant flow rate of 2.5mL / min. The aqueous portion of the mobile phase was either 0.1% formic acid (CSH C18 column), 10mM ammonium bicarbonate, or 10mM ammonia (BEH C18 column). LC-UV chromatograms were recorded at 254nm using an Agilent VWD or DAD detector. Mass spectra were recorded using an Agilent MSD detector with electrospray ionization switched between positive and negative ion modes. Sample concentrations were adjusted to obtain an appropriate UV response.

[0263] Alternatively, the following analytical LCMS equipment and methods were also used: [Table 2]

[0264] DSC DSC data were collected on a PerkinElmer Pyris 6000 DSC equipped with a 45 position sample holder. The instrument was verified for energy and temperature calibration using certified indium. A predefined amount of sample, 0.5-3.0 mg, was placed in a pinhole aluminum pan and incubated at 20 °C for min. -1 Heat to 30-350℃ with a 20 ml bottle or change according to the experimental instructions. -1 A purge of dry nitrogen at 37 °C was maintained over the sample. Instrument control, data acquisition, and analysis were performed using Pyris software v11.1.1 revision H.

[0265] TGA TGA data were collected on a PerkinElmer Pyris 1 TGA equipped with a 20 position autosampler. The instrument was calibrated for temperature using certified weights and certified Alumel and Perkalloy. A predefined amount of 1-5 mg sample was loaded into a pre-tared aluminum crucible and heated from ambient to 400 °C at 20 °C.min. -1 The sample was heated at 20°C for 2 min. -1 A nitrogen purge of 1000 s was maintained. Instrument control, data acquisition, and analysis were performed using Pyris software v11.1.1 revision H.

[0266] XRPD X-ray powder diffraction patterns were collected on a PANalytical diffractometer using CuKα radiation (45 kV, 40 mA), a θ-θ goniometer, a focusing mirror, a divergence slit (1 / 2''), Soller slits (4 mm) in both the incident and diverging beams, and a PIXcel detector. The software used for data collection was X'Pert Data Collector version 2.2f, and data were presented using X'Pert Data Viewer version 1.2d. XRPD patterns were acquired under ambient conditions through a transmission foil sample stage (polyimide-Kapton, 12.7 μm thick film) using a PANalytical X'Pert PRO. The data collection range was 2.994-35° 2θ, with a continuous scan speed of 0.202004° s -1 It was.

[0267] Common methods All reactions were stirred unless otherwise noted.

[0268] General Procedure A [ka]

[0269] Step 1, Method A Tert-Butyl diethylphosphonoacetate (1 equiv.) was added dropwise to a solution of sodium hydride (60 wt% dispersion in mineral oil, 1.1 equiv.) in NMP (0.6 M) at 0° C. The reaction was allowed to warm to room temperature and stirred for 2 h. A solution of chloromethyl-heteroarene (1.1 equiv.) in NMP (1.3 M) was added dropwise and the mixture was heated to 60° C. for 2 h. The mixture was cooled to room temperature, poured into water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated. The crude product was purified by chromatography on silica gel to give the required compound.

[0270] Step 1, Method B Sodium hydride (60% dispersion in mineral oil, 1.5 equiv.) was added portionwise to a solution of tert-butyl diethyl phosphonoacetate (1.4 equiv.) in THF (0.6 M) at 0 °C. The mixture was warmed to room temperature and stirred for 1 h. Separately, sodium iodide (1.1 equiv.) was added to chloromethylheteroarene (1 equiv.) in THF (1.8 M) at room temperature. The mixture was stirred for 1 h and then added to the mixture of phosphonoacetate and sodium hydride. The reaction was heated to 70 °C, stirred for 3 h, then cooled to room temperature before partitioning between EtOAc and water. The phases were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic phase was washed with brine, dried (MgSO 4 ), and concentrated. The crude product was purified by chromatography on silica gel to give the required compound.

[0271] Step 1, Method C Sodium hydride (1.3 equiv.) was added portionwise to a solution of tert-butyl diethylphosphonoacetate (1.3 equiv.) in THF (0.67 M) at 0 °C. The mixture was warmed to room temperature and stirred for 1 h. The solution was added dropwise to a mixture of chloromethyl-heteroarene (1 equiv.) and sodium iodide (1.1 equiv.) in THF (0.7 M) at room temperature. The reaction was stirred at room temperature for 2 h, then water was added and the mixture was concentrated to remove THF. The mixture was diluted with water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc, then the combined organic phases were washed with brine and dried (MgSO 4 ), and concentrated. The crude product was purified by chromatography on silica gel to give the required compound.

[0272] Step 1, Method D A suspension of sodium hydride in mineral oil (60 wt%, 1.2 equiv.) was added to a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (1.1 equiv.) in THF (0.36 M) at 0° C. and the mixture was stirred at 0° C. for 0.5 h. Then, chloromethylheteroarene (1 equiv.) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NH 4The mixture was quenched with Cl solution and extracted with EtOAc (3x). The combined organic phase was washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure The residue was purified by flash column chromatography to give the required product.

[0273] Step 2, Method A Sodium hydride (60% weight dispersion in mineral oil, 1 equiv.) was added to a solution of phosphonate (1 equiv.) in THF (0.2 M) at 0° C. After 10 min, paraformaldehyde (3 equiv.) was added and the reaction was then allowed to warm to room temperature and stirred for 45 min. The reaction was then washed with saturated aqueous NaHCO 3 The mixture was quenched with EtOAc (x3) and the mixture was extracted with EtOAc (x3). The combined organic extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated. The crude product was purified by chromatography on silica gel to give the required compound.

[0274] Step 2, Method B Paraformaldehyde (1.1-2.5 equiv.) was added to a mixture of phosphonate (1 equiv.) and potassium carbonate (1.2-2 equiv.) in THF (0.15 M). The mixture was heated to 65 °C and stirred for 4 h, then cooled to room temperature and poured into water (150 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic phase was washed with brine, dried (MgSO 4 ), concentrated and the crude product was then purified by chromatography on silica gel to give the required compound.

[0275] Step 2, Method C A solution of formaldehyde in water (37 wt%, 2-30 equiv.) was added to a mixture of phosphonate (1 equiv.) and potassium carbonate (2-3 equiv.) in THF (0.1-0.5 M). The mixture was stirred at room temperature for 2-5 h and then extracted with EtOAc (3 times) or MTBE (3 times). The combined organic phase was washed with brine, dried (Na 2 SO 4), concentrated and the crude product was then purified by chromatography on silica gel to give the required compound.

[0276] Step 3 TFA (10-350 equiv.) was added to a solution of the tert-butyl ester (1 equiv.) in DCM (to give a final concentration of 30-50% v / v TFA). The mixture was stirred at room temperature for 1-16 h, then concentrated and coevaporated with toluene (2 times). The crude product was purified by chromatography on silica gel or preparative HPLC to give the required compound.

[0277] General Procedure B [ka]

[0278] Method A HATU (1.2-1.5 equiv.) and amidoxime (1-1.5 equiv.) were added to a solution of 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutanoic acid (1 equiv.) and DIPEA (5 equiv.) in dimethylformamide (0.2 M). The mixture was stirred at room temperature for 1 h and then heated to 90 °C for 2 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3 times). The combined organic phase was washed with 1 M HCl (200 mL), brine (200 mL), dried (MgSO 4 ), and concentrated. The crude product was purified by chromatography on silica gel to give the required compound.

[0279] Method B Triethylamine (2.0-4.0 equiv.) was added to a suspension of amidoxime (1.0-1.3 equiv.) and 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutanoic acid (1 equiv.) in EtOAc or dimethylformamide (0.4-0.8 M) at room temperature. A solution of T3P (50 wt. % in EtOAc or dimethylformamide, 2.0-2.5 equiv.) was added dropwise over 20 min at 0 °C or room temperature. The mixture was heated to 80 °C and stirred for 17 h. The mixture was cooled to room temperature, diluted with brine and 1 M HCl, and extracted with EtOAc (3 times). The combined organic phase was washed with 1 M HCl (aq.) (3 times), dried (MgSO 4 ), and concentrated. The crude product was purified by chromatography on silica gel to give the required compound.

[0280] Method C Triethylamine (2-3 equiv.) was added to a suspension of amidoxime (1 equiv.) and 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutanoic acid (1 equiv.) in EtOAc or dimethylformamide (0.4 M) at room temperature. A solution of T3P (50 wt. % in EtOAc or dimethylformamide, 2.0-2.5 equiv.) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 h, diluted with water and extracted with EtOAc (3 times). The combined organic phase was dried (MgSO 4 ) and concentrated. The residue was taken up in THF (0.2 M) and cesium carbonate (2 equiv.) was added. The mixture was heated to 70 °C and stirred for 1-5 h, cooled to room temperature, diluted with water and extracted with EtOAc (3x). The combined organic phase was dried (MgSO 4 ), and concentrated. The crude product was purified by chromatography on silica gel to give the required compound.

[0281] Intermediate 1-5-(chloromethyl)-3-octyl-1,2,4-oxadiazole [ka]

[0282] Step 1 Sodium bicarbonate (11.8 g, 141 mmol) was added to a suspension of hydroxylamine hydrochloride (5.88 g, 85 mmol) in isopropanol (100 mL). The mixture was stirred at room temperature for 10 min, then nonanenitrile (10 mL, 57 mmol) was added and the mixture was heated to reflux for 12 h, then cooled to room temperature. The mixture was filtered and concentrated in vacuo to give N-hydroxynonaniimidamide (9.74 g, 52.0 mmol, 92% purity) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.67(s,1H), 5.31(s,2H), 2.03-1.87(m,2H), 1.58-1.43(m,2H), 1.39-1.17(m,10H), 0.90-0.83(m,3H). (Major tautomer assignment)LCMS m / z 173.2(M+H) + (ES + ).

[0283] Step 2 Chloroacetyl chloride (3.8 mL, 48 mmol) was added dropwise over 10 min to a solution of N-hydroxynonanimidamide (7.5 g, 44 mmol) and triethylamine (6.9 mL, 50 mmol) in DCM (100 mL). The mixture was warmed to room temperature and stirred for 2 h, then diluted with EtOAc (100 mL) and washed with water (150 mL). The organic phase was washed with brine (150 mL) and dried (MgSO 4 ) and concentrated. The residue was taken up in toluene (100 mL) and heated to 120 °C for 3 h, then cooled to room temperature and stirred for 15 h. The reaction mixture was concentrated. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give the title compound (6.79 g, 44 mmol) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 5.07(s,2H), 2.72(t,J=7.4Hz,2H), 1.73-1.50(m,2H), 1.41-1.21(m,10H), 0.90-0.82(m,3H). LCMS m / z 231.0 / 233.0(M+H) + (ES + ).

[0284] Intermediate 2-2(chloromethyl)-5-octyl-1,3,4-oxadiazole [ka]

[0285] Step 1 A mixture of ethyl nonanoate (10 mL, 46 mmol) and hydrazine hydrate (50%, 5.8 mL, 92 mmol) in ethanol (50 mL) was heated to reflux overnight. The mixture was cooled to room temperature and concentrated. The residue was coevaporated with toluene (20 mL) and then suspended in MTBE (50 mL). The solid was isolated by filtration and washed with MTBE (2×20 mL) to give nonane hydrazide (4.9 g, 28 mmol) as a colorless solid. 1 H NMR(400MHz,DMSO-d6)δ 8.89(s,1H), 4.09(br.s,2H), 1.99(t,J=7.4Hz,2H), 1.63-1.41(m,2H), 1.24(s,10H), 0.94-0.75(m,3H). LCMS m / z 173.6(M+H) + (ES + ).

[0286] Step 2 A suspension of nonanhydrazide (1.00 g, 5.8 mmol), 2-chloroacetic acid (0.55 g, 5.8 mmol), and phosphorus oxychloride (4 mL, 43 mmol) was heated to 80° C. for 2 h. The mixture was cooled to room temperature and concentrated. The residue was evaporated with toluene (2×15 mL), then taken up in hot water (45° C.) and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give the title compound (0.861 g, 3.54 mmol) as a pale pink oil. 1H NMR(400MHz,DMSO-d6)δ 5.02(s,2H), 2.88(t,J=7.4Hz,2H), 1.75-1.61(m,2H), 1.34-1.22(m,10H), 0.90-0.82(m,3H). LCMS m / z 231.0 / 233.0(M+H) + (ES + ).

[0287] Intermediate 3-3(chloromethyl)-5-octyl-1,2,4-oxadiazole [ka]

[0288] Step 1 Sodium carbonate (7.02 g, 66.2 mmol) was added portionwise to a mixture of 2-chloroacetonitrile (8.4 mL, 132 mmol) and hydroxylamine hydrochloride (9.20 g, 132 mmol) in water (30 mL) such that the internal temperature did not exceed 30 °C. The reaction mixture was stirred at 30 °C for 15 min and then extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried (Na 2 SO 4 ), and concentrated to give 2-chloro-N-hydroxyacetimidamide (8.0 g, 67 mmol) as an orange solid. 1 H NMR (400MHz, DMSO-d6) δ 9.43(s,1H), 5.62(s,2H), 4.01(s,2H).

[0289] Step 2 HATU (17.5 g, 46.1 mmol) was added to a solution of 2-chloro-N-hydroxyacetimidamide (5.0 g, 46 mmol), nonanoic acid (8.0 mL, 46 mmol), and DIPEA (16 mL, 92 mmol) in dimethylformamide (50 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 5 h before being poured into water (250 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (2×40 mL), dried (Na 2 SO 4The residue was redissolved in dimethylformamide (50 mL) and heated to 120° C. with stirring for 16 h. The mixture was cooled to room temperature and poured into water (250 mL) and then extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine (2×100 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give the title compound (3.18 g, 11.0 mmol, 80% purity) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 4.85(s,2H), 2.95(t,J=7.5Hz,2H), 1.78-1.68(m,2H), 1.35-1.21(m,10H), 0.88-0.84(m,3H). LCMS m / z 231.0 / 233.0(M+H) + (ES + ).

[0290] The following compounds were synthesized using the same procedure used to synthesize Intermediate 1. [Table 3-1] [Table 3-2] [Table 3-3]

[0291] Intermediate 12-9,9,9-trifluorononanenitrile [ka] 8-Bromo-1,1,1-trifluorooctane (5.00 g, 20.2 mmol) was added dropwise to a suspension of sodium cyanide (1.09 g, 22.3 mmol) and potassium iodide (40.0 mg, 0.24 mmol) in DMSO (11 mL) at 40° C. The mixture was stirred at 80° C. for 1 h and then at 120° C. for 5 h. The reaction was cooled to room temperature and poured into water (30 mL). The solution was extracted with MTBE (3×15 mL). The combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ), and concentrated to give 9,9,9-trifluorononanenitrile (3.91 g, 20 mmol) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ 2.50-2.46(m,2H), 2.31-2.16(m,2H), 1.60-1.42(m,4H), 1.41-1.26(m,6H). 19 F NMR(376MHz,DMSO-d6)δ-64.79.

[0292] Intermediate 12 was converted to intermediate 11 using a similar method as described above.

[0293] Intermediate 22-3-(chloromethyl)-1-octyl-1H-1,2,4-triazole [ka]

[0294] Step 1 Sodium hydride (60 wt% dispersion in mineral oil, 2.05 g, 51.1 mmol) was added portionwise to a solution of methyl 1H-1,2,4-triazole-3-carboxylate (5.00 g, 39.3 mmol) in dimethylformamide (25 mL) at 0° C. The mixture was stirred for 30 min, after which 1-iodooctane (9.92 g, 7.46 mL, 41.3 mmol) was added dropwise over 10 min at 0° C. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give methyl 1-octyl-1H-1,2,4-triazole-3-carboxylate (3.83 g, 16 mmol) as a white solid. LCMS m / z 240.2 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 8.70(s,1H), 4.24(t,J=7.0Hz,2H), 3.84(s,3H), 1.87-1.73(m,2H), 1.35-1.13(m,10H), 0.91-0.80(m,3H).

[0295] Step 2 Sodium borohydride (3.03 g, 80.0 mmol) was added to a suspension of methyl 1-octyl-1H-1,2,4-triazole-3-carboxylate (3.83 g, 16.0 mmol) and lithium chloride (3.39 g, 80.0 mmol) in ethanol (60 mL) and THF (60 mL) at room temperature. The mixture was stirred for 18 h and then washed with saturated aqueous NH 4 The mixture was stirred for 30 min, then the phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (50 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-10% MeOH / DCM) to give (1-octyl-1H-1,2,4-triazol-3-yl)methanol (2.22 g, 10 mmol) as a white solid. LCMS m / z 212.2 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 8.39(s,1H), 5.18(s,1H), 4.40(s,2H), 4.10(t,J=7.0Hz,2H), 1.80-1.68(m,2H), 1.33-1.16(m,10H), 0.92-0.78(m,3H).

[0296] Step 3 Thionyl chloride (20 mL, 273 mmol) was carefully added to (1-octyl-1H-1,2,4-triazol-3-yl)methanol (2.22 g, 10 mmol). The resulting solution was heated to 80° C. for 1.5 h. The mixture was concentrated and the residue was dissolved in DCM (50 mL) and saturated NaHCO 3 (2×25 mL), water (25 mL), and brine (25 mL). The organic layer was then dried (Na 2 SO 4 ) and concentrated to give 3-(chloromethyl)-1-octyl-1H-1,2,4-triazole (2.40 g, 10 mmol), which was used without purification. LCMS m / z 230.2 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 8.51(s,1H), 4.70(s,2H), 4.14(t,J=7.0Hz,2H), 1.80-1.71(m,2H), 1.29-1.19(m,10H), 0.89-0.81(m,3H).

[0297] Intermediate 23-8,8-difluoro-N-hydroxynonanimidamide [ka] A suspension of hydroxylamine hydrochloride (1.19 g, 17.1 mmol) and sodium bicarbonate (2.40 g, 28.5 mmol) in IPA (14 mL) was stirred at room temperature for 15 min. 8,8-Difluorononanenitrile (2.00 g, 11.4 mmol) was added and the mixture was heated to 85° C. and stirred for 16 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated and coevaporated with toluene (2×10 mL). The resulting white solid was triturated with iso-hexane (20 mL) and filtered to give 8,8-difluoro-N-hydroxynonanimidamide (2.08 g, 9.9 mmol) as a white solid. LCMS m / z 209.2 (M+H) + (ES + ). 11H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 5.34 (s, 2H), 1.94 (t, J = 7.6 Hz, 2H), 1.90 - 1.76 (m, 2H), 1.58 (t, J = 18.9 Hz, 3H), 1.52 - 1.43 (m, 2H), 1.42 - 1.34 (m, 2H), 1.32 - 1.23 (m, 4H).

[0298] The following compounds were synthesized using the same procedure.

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

[0299] Intermediate 57-2,2-Dimethylheptanitrile [ka] Isobutyronitrile (1.4 mL, 16 mmol) was dissolved in THF (20 mL). LDA (2 M, 8 mL, 16 mmol) was added dropwise at -78 °C and the solution was stirred for 30 min. 1-Bromopentane (1.6 mL, 13 mmol) was added and the mixture was stirred at room temperature for 18 h. Saturated aqueous NH 4 Cl (50 mL) was added and the resulting mixture was extracted with DCM (3x50 mL). The combined organic layers were dried (phase separator) and concentrated. The crude product was used directly in the next step.

[0300] The following compounds were synthesized using the same procedure: [Table 5]

[0301] Intermediate 59-8,8,9,9,9-Pentafluorononanenitrile [ka] Methanesulfonyl chloride (2.6 mL, 34 mmol) and triethylamine (6.3 mL, 45 mmol) were added dropwise to a cooled solution of 7,7,8,8,8-pentafluorooctan-1-ol (5.00 g, 22.7 mmol) in THF (32 mL). The mixture was stirred at room temperature for 2 h and then cooled with saturated aqueous NaHCO 3 (50 mL). The mixture was extracted with MTBE (3×50 mL) and the combined organic phase was dried (MgSO 4The residue was dissolved in DMSO (32 mL), sodium cyanide (3.34 g, 68 mmol) was added and the mixture was heated to 120 °C for 24 h. The mixture was cooled to room temperature, diluted with MTBE (200 mL) and washed with water (3 x 40 mL). The combined organic phase was dried (MgSO 4 ) and concentrated to give 8,8,9,9,9-pentafluorononanenitrile (4.58 g, 18 mmol, 91% purity) as a yellowish solid which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ 2.49(t,J=7.1Hz,2H), 2.18(tt,J=18.8,7.9Hz,2H), 1.63-1.46(m,4H), 1.39(dq,J=7.4,3.4Hz,4H).

[0302] The following compounds were synthesized using the same procedure: [Table 6]

[0303] Intermediate 61-2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetonitrile [ka] Pd(dppf)Cl 2The -DCM adduct (1.31 g, 1.60 mmol) was added to a degassed mixture of 2-(4-bromophenyl)acetonitrile (3.13 g, 16.0 mmol), (4-chlorophenyl)boronic acid (2.50 g, 16.0 mmol), and potassium carbonate (6.63 g, 48 mmol) in a mixture of water (11 mL) and 1,4-dioxane (75 ml). The resulting mixture was stirred at 80 °C for 5 h. The reaction was cooled to room temperature and filtered using a Whatmans GF / F filter washing with EtOAc (10 ml). The mixture was concentrated and the crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give 2-(4'-chloro-[1,1'-biphenyl]-4-yl)acetonitrile (4.32 g, 13 mmol, 71% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 7.75-7.66 (m, 4H), 7.55-7.49 (m, 2H), 7.48-7.41 (m, 2H), 4.09 (s, 2H).

[0304] Intermediate 6 2-2-(4-butylphenyl)acetonitrile [ka]

[0305] Step 1 Thionyl chloride (9.1 mL, 125 mmol) was added to a solution of 2-(4-butylphenyl)acetic acid (2.00 g, 10.4 mmol) in DCM (33 mL) at 0° C. The reaction mixture was heated to reflux for 2 h and then cooled to room temperature. The mixture was concentrated and the residue was coevaporated with toluene (2×10 mL). The residue was dissolved in THF (14 mL), cooled to 0° C. and a solution of ammonium hydroxide (19.2 mL, 28 wt%, 135 mmol) was added dropwise over 10 min. The mixture was allowed to warm to room temperature and stirred for a further 2 h. The mixture was then extracted with DCM (3×25 mL) and the combined organic layers were dried (phase separator) and concentrated to give 2-(4-butylphenyl)acetamide (1.90 g, 8.9 mmol, 90% purity) as an off-white solid. LCMS m / z 192.3 (M+H)+ (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.41(s,1H), 7.16(d,J=8.1Hz,2H), 7.10(d,J=8.1Hz,2H), 6.83(s,1H), 3.31(s,2H) ), 2.57-2.51(m,2H), 1.59-1.47(m,2H), 1.37-1.21(m,2H), 0.89(t,J=7.3Hz,3H).

[0306] Step 2 TFAA (5.5 mL, 40 mmol) was added dropwise to a solution of 2-(4-butylphenyl)acetamide (1.90 g, 9.93 mmol) and triethylamine (5.5 mL, 40 mmol) in 1,4-dioxane (20 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated and poured into water (30 mL) and then extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (30 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give 2-(4-butylphenyl)acetonitrile (1.75 g, 9.85 mmol) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 7.28-7.18(m,4H), 3.98(s,2H), 2.61-2.53(m,2H), 1.59-1.49(m,2H), 1.36-1.22(m,2H), 0.89(t,J=7.4Hz,3H).

[0307] The following compounds were synthesized using the same procedure: [Table 7]

[0308] Intermediate 67-4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutanoic acid [ka]

[0309] Step 1 Sodium hydride (60 wt% dispersion in mineral oil, 9.00 g, 225 mmol) was added portionwise to a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (50 mL, 213 mmol) in THF (500 mL) at 0° C. The mixture was stirred for 15 min, after which ethyl bromoacetate (23 mL, 210 mmol) was added dropwise. The mixture was stirred for 1 h and then washed with saturated aqueous NH 4 It was quenched with Cl (100 mL) and extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine (300 mL) and dried (MgSO 4 ) and concentrated to give 1-(tert-butyl) 4-ethyl 2-(diethoxyphosphoryl)succinate (77.1 g, 182 mmol, 80% purity) as a colorless oil. LCMS m / z 361.2 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 4.13-4.01(m,6H), 3.28(ddd,J=23.8,11.3,3.9Hz,1H), 2.78(ddd,J=17.2,11.3,8.2Hz,1H) , 2.64(ddd,J=17.1,8.5,4.0Hz,1H), 1.40(s,9H), 1.28-1.21(m,6H), 1.18(t,J=7.1Hz,3H).

[0310] Step 2 Aqueous sodium hydroxide (1 M, 250 mL, 250 mmol) was added to a solution of 1-(tert-butyl) 4-ethyl 2-(diethoxyphosphoryl)succinate (77.1 g, 182 mmol, 80% purity) in THF (250 mL). The mixture was stirred at room temperature for 16 h. The mixture was partially concentrated to about 250 mL and then extracted with EtOAc (3 x 100 mL). The aqueous phase was acidified to pH 1 with concentrated HCl and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (250 mL), dried (MgSO 4) and concentrated. The residue was triturated with hexanes (300 mL) and the resulting solid was collected by filtration to give 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutanoic acid (53.00 g, 0.15 mmol, 90% purity) as a white solid. LCMS m / z 333.2 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.44(s,1H), 4.11-3.99(m,4H), 3.22(ddd,J=23.7,11.5,3.7Hz,1H), 2.73(ddd,J=17.3,11 .5,7.6Hz,1H), 2.56(ddd,J=17.3,8.6,3.7Hz,1H), 1.40(s,9H), 1.25(dt,J=8.3,7.0Hz,6H). 31 P NMR (162MHz, DMSO-d6) δ 21.88.

[0311] Intermediate 68-2-(3-butylphenyl)acetonitrile [ka] Butylboronic acid (2.73 g, 26.8 mmol). Pd(PPh 3 ) 4 (206 mg, 0.18 mmol) and potassium carbonate (2.47 g, 17.9 mmol) were added to a solution of 2-(3-bromophenyl)acetonitrile (3.50 g, 17.9 mmol) in toluene (50 mL). The reaction mixture was heated to 110 °C and stirred for 10 h, then at room temperature for 18 h. The solution was diluted with EtOAc (100 mL) and washed with water (100 mL) and brine (100 mL). The organic phase was dried (MgSO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-(3-butylphenyl)acetonitrile (2.50 g, 13 mmol, 90% purity) as a clear, colorless oil. 1H NMR(400MHz,DMSO-d6)δ 7.33-7.26(m,1H), 7.19-7.11(m,3H), 4.00(s,2H), 2.58(t,J=7.7Hz,2H), 1.63-1.46(m,2H), 1.31(h,J=7.3Hz,2H), 0.90(t,J=7.3Hz,3H).

[0312] The following compounds were synthesized using the same procedure: [Table 8]

[0313] Intermediate 71-N-hydroxynonanimidamide-d17 [ka]

[0314] Step 1 A stirred solution of nonanamide-d17 acid (1.00 g, 5.70 mmol) in DCM (20 mL) at 0° C. was treated dropwise with thionyl chloride (2.1 mL, 29 mmol). The mixture was stirred at 0° C. for 15 min and then at 40° C. for 3 h. The reaction mixture was concentrated and then coevaporated with toluene (2×10 mL). The residue was taken up in THF (10 mL), cooled to 0° C. and treated dropwise with ammonium hydroxide (28% aqueous, 8.0 mL 57 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was partially concentrated and extracted with DCM (3×10 mL). The combined organic extracts were dried (phase separator) and concentrated to give nonanamide-d17 (844 mg, 4.84 mmol) as a white solid, which was used in the next step without further purification. LCMS m / z 175.3 (M+H) + (ES + ).

[0315] Step 2 A stirred suspension of nonanamide-d17 (844 mg, 4.84 mmol) and triethylamine (2.7 mL, 19 mmol) in 1,4-dioxane (10 mL) at 0° C. was treated dropwise with TFAA (2.0 mL, 14 mmol). The resulting solution was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated and the residue was poured into water (20 mL) and extracted with EtOAc (20 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried (phase separator) and concentrated to afford nonanamide-d17 (1.2 g) as a yellow oil which was used in the next step without further purification or analysis assuming quantitative yield.

[0316] Step 3 A suspension of hydroxylamine hydrochloride (685 mg, 9.76 mmol) in IPA (10 mL) was treated with sodium bicarbonate (1.24 g, 14.8 mmol) and stirred for 15 min. A solution of nonanenitrile-d17 (approximately 1.2 g, 4.84 mmol [assumed]) in IPA (5 mL) was added dropwise and the reaction mixture was then stirred at 85° C. for 18 h. The reaction mixture was cooled to room temperature, filtered, and washed with EtOAc (50 mL). The filtrate was concentrated in vacuo to give N-hydroxynonaniimidamide-d17 (1.37 g, 4.84 mmol [assumed]) as a yellow oil, which was used in the next step without further purification, assuming quantitative yield. LCMS m / z 190.3 (M+H) + (ES + ).

[0317] Intermediate 7 2-1-Bromo-2-one [ka] Bromine (1.65 mL, 32 mmol) was added dropwise to a solution of decan-2-one (6.1 mL, 32 mmol) in MeOH (23 mL) at 0° C. The reaction was stirred at 0° C. for 1.5 h, then aqueous potassium carbonate (1 M, 100 mL) was added. The mixture was concentrated under reduced pressure and extracted with EtOAc (3×25 mL). The combined organic layers were washed with potassium carbonate (1 M, 2×20 mL), dried (Na 2 SO 4 ) and concentrated. The residue was dissolved in THF (150 mL) and sulfuric acid (1 M, 100 mL). The mixture was vigorously stirred at 70° C. for 1.5 h. The mixture was concentrated and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with saturated aqueous NaHCO 3 (2x20mL), washed with brine (20mL) and dried (Na 2 SO 4 ), and concentrated to give 1-bromodecan-2-one (7.50 g, 31.5 mmol) as a colorless oil which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.33(s,2H), 2.57(t,J=7.3Hz,2H), 1.53-1.44(m,2H), 1.28-1.21(m,10H), 0.89-0.83(m,3H).

[0318] Intermediate 7 3-(R)-2-Methyloctanitrile [ka]

[0319] Step 1 p-TsCl (8.1 g, 42 mmol) was added portionwise to a mixture of (S)-octan-2-ol (5.0 g, 38 mmol) in pyridine (11 mL) at -5 °C. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was quenched with ice, then water (100 mL) was added. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% citric acid (3 x 100 mL), water (100 mL) and dried (MgSO 4) and concentrated to give (S)-octan-2-yl 4-methylbenzenesulfonate (9.86 g, 33 mmol) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.84-7.73(m,2H), 7.48(d,J=8.0Hz,2H), 4.63-4.46(m,1H), 2.42(s,3H), 1.56-1.37(m,2H), 1.25-0.95(m,11H), 0.83(t,J=7.1Hz,3H).

[0320] Step 2 Sodium cyanide (1.78 g, 36.2 mmol) was added to a solution of (S)-octan-2-yl 4-methylbenzenesulfonate (9.86 g, 33 mmol) in DMSO (50 mL) at 50 °C. The mixture was stirred at 50 °C for 18 h and cooled to room temperature. Water (500 mL) was added, the phases were separated and the aqueous phase was extracted with DCM (3 x 100 mL). The combined organic phases were washed with brine (3 x 100 mL) and dried (MgSO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give (R)-2-methyloctanitrile (3.47 g, 22 mmol) as a clear, colorless oil. 1 H NMR (400 MHz, CDCl 3 )δ 2.67-2.53(m,1H), 1.70-1.12(m,13H), 0.97-0.81(m,3H). 1 H NMR(400MHz,DMSO-d6)δ 7.84-7.73(m,2H), 7.48(d,J=8.0Hz,2H), 4.63-4.46(m,1H), 2.42(s,3H), 1.56-1.37(m,2H), 1.25-0.95(m,11H), 0.83(t,J=7.1Hz,3H).

[0321] The following compounds were synthesized using the same procedure: [Table 9]

[0322] Intermediate 76-1-(4-(trifluoromethoxy)phenyl)cyclopropane-1-carbonitrile [ka] A solution of NaOH (5.97 g, 149 mmol) in water (8 mL) was added dropwise to a mixture of 2-(4-(trifluoromethoxy)phenyl)acetonitrile (5.00 g, 25 mmol), 1-bromo-2-chloroethane (3.1 mL, 37.3 mmol), and benzyl(triethyl)ammonium chloride (113 mg, 0.5 mmol) at 50 °C. The mixture was stirred at 50 °C for 16 h and then at room temperature for 3 days. The mixture was diluted with water (200 mL) and extracted with DCM (3x75 mL). The combined organic phase was washed with 1 M HCl (2x100 mL), water (100 mL), dried (MgSO 4 ), and concentrated to give 1-(4-(trifluoromethoxy)phenyl)cyclopropane-1-carbonitrile (5.42 g, 21 mmol, 86% purity) as an orange oil. 1 H NMR (400 MHz, CDCl 3 )δ 7.38-7.33(m,2H), 7.25-7.18(m,2H), 1.84-1.70(m,2H), 1.51-1.36(m,2H).

[0323] The following compounds were synthesized using the same procedure: [Table 10-1] [Table 10-2]

[0324] Intermediate 78-9,9-Difluorononanenitrile [ka]

[0325] Step 1 Sodium cyanide (0.84 g, 17.2 mmol) was added to a solution of 8-bromooctan-1-ol (3.00 g, 14.4 mmol) in DMSO (24 mL) at room temperature. The mixture was stirred at room temperature for 18 h, then diluted with water (50 mL) and extracted with EtOAc (2x100 mL). The combined organic phase was dried (MgSO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 9-hydroxynonanenitrile (1.45 g, 9.1 mmol) as a translucent oil. 1 H NMR(400MHz,DMSO-d6)δ 4.32(t,J=5.2Hz,1H), 3.38(td,J=6.5,5.1Hz,2H), 2.48(t,J=7.1Hz,2H), 1.61-1.48(m,2H), 1.47-1.21(m,10H).

[0326] Step 2 DMP (5.54 g, 13.1 mmol) was added portionwise to a solution of 9-hydroxynonanenitrile (1.45 g, 9.1 mmol) in DCM (14 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 45 min. The reaction mixture was diluted with saturated Na 2 S 2 O 3 (15 mL). The organic layer was washed with saturated aqueous NaHCO 3 (15 mL). The aqueous layer was extracted with DCM (3x30 mL). The combined organic phase was dried (MgSO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give 9-oxopentanenitrile, which was diluted directly with DCM (35 mL) and then cooled to 0 °C. Diethylaminosulfur trifluoride (2.46 mL, 18.6 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO 3 The mixture was quenched with DCM (3x30 mL) until pH 7. The aqueous phase was extracted with DCM (3x30 mL). The combined organic extracts were dried (MgSO 4) and concentrated. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give 9,9-difluorononanenitrile (0.490 g, 2.5 mmol, 90% purity) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 6.05(tt,J=56.9,4.5Hz,1H), 2.48(t,J=7.1Hz,2H), 1.89-1.69(m,2H), 1.61-1.48(m,2H), 1.46-1.18(m,8H).

[0327] Intermediate 79-10,10,10-Trifluorodecanitrile [ka] n-Butyllithium (1.6 M in hexanes, 12 mL, 19 mmol) was added to a solution of diisopropylamine (2.8 mL, 19 mmol) in THF (19 mL) at -78 °C. The solution was stirred at 0 °C for 15 min and then cooled to -78 °C. A solution of acetonitrile (1.0 mL, 19 mmol) in THF (16 mL) was added and the mixture was stirred at -78 °C for 30 min. 8-Bromo-1,1,1-trifluorooctane (4.8 g, 19 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 20 h, then saturated aqueous NH 4 The mixture was quenched with Cl solution (50 mL). The aqueous phase was extracted with ethyl acetate (3x20 mL) and the combined organic phase was dried (MgSO 4 ), and concentrated. The crude product was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ 2.48 (t, J = 7.1 Hz, 2H), 2.30-2.14 (m, 2H), 1.60-1.42 (m, 3H), 1.41-1.22 (m, 9H).

[0328] Intermediate 80-1-Aminodecan-2-one hydrochloride [ka]

[0329] Step 1 Isopropylmagnesium chloride (2M in THF, 33 mL, 66 mmol) was added dropwise to a suspension of tert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (14.5 g, 66 mmol) in THF (150 mL) at 0 °C. Octylmagnesium bromide (2M in THF, 42 mL, 84 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C and quenched with 1 M HCl (100 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (2 x 100 mL), dried (MgSO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-40% MTBE / isohexane) to give tert-butyl (2-oxodecyl)carbamate (16.5 g, 55 mmol, 90% purity) as a clear, colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.02(t,J=5.9Hz,1H), 3.72(d,J=5.9Hz,2H), 2.37(t,J=7.3Hz,2H), 1.49-1.41(m,2H), 1.39(s,9H), 1.27-1.19(m,10H), 0.93-0.80(m,3H).

[0330] Step 2 HCl (4M in 1,4-dioxane, 46 mL, 0.18 mol) was added dropwise to a solution of tert-butyl (2-oxodecyl)carbamate (16.5 g, 56 mmol, 90% purity) in 1,4-dioxane at 0° C. The reaction was stirred at room temperature for 18 h. HCl (4M in 1,4-dioxane, 18 mL, 72 mmol) was added and the mixture was stirred at room temperature for an additional 2 h. The mixture was concentrated to give 1-aminodecan-2-one hydrochloride (13.0 g, 53 mmol, 85% purity) as a light brown solid, which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ 7.98(s,3H), 3.91(s,2H), 2.53-2.48(m,2H), 1.55-1.46(m,2H), 1.34-1.15(m,10H), 0.95-0.75(m,3H).

[0331] Intermediate 81-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid [ka]

[0332] Step 1 A solution of 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (1.00 g, 3.77 mmol) and Pd-170 (50 mg, 75 μmol) in THF (20 mL) was degassed with nitrogen for 10 min. A solution of (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.45 M in THF, 9.2 mL) was added dropwise. The reaction was stirred at room temperature for 1.5 h, then heated to 75° C. and stirred for 16 h. The reaction was cooled to room temperature and poured into water (20 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give tert-butyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetate (0.653 g, 2.2 mmol) as a clear yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.41(d,J=8.0Hz,2H), 7.31-7.20(m,2H), 3.57(s,2H), 1.41(s,9H), 1.35-1.30(m,2H), 1.14-1.08(m,2H).

[0333] Step 2 A mixture of tert-butyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetate (0.653 g, 2.2 mmol) and formic acid (4.1 mL, 109 mmol) was stirred at room temperature for 16 h. The mixture was concentrated and the residue was coevaporated with toluene (2x10 mL) to give 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid (0.625 g, 2.1 mmol, 84% purity) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 12.37(s,1H), 7.40(d,J=8.0Hz,2H), 7.28(d,J=7.9Hz,2H), 3.58(s,2H), 1.36-1.29(m,2H), 1.14-1.07(m,2H).

[0334] Intermediate 113-2-(3-propylphenyl)acetonitrile [ka] A flask was charged with 2-(4-bromophenyl)acetonitrile (1.5 g, 7.7 mmol), propylboronic acid (1.0 g, 11 mmol), potassium phosphate (3.2 g, 15 mmol), and SPhos Pd G3 (0.12 g, 0.15 mmol). The flask was evacuated / backfilled with nitrogen (3 times). Toluene (20 mL) was added and the mixture was heated to 90 °C for 2 h, then cooled to room temperature, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give 2-(4-propylphenyl)acetonitrile (0.98 g, 5.8 mmol) as a clear, colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.26(d,J=8.4Hz,2H), 7.21(d,J=8.2Hz,2H), 3.98(s,2H), 2.58-2.53(m,2H), 1.66-1.48(m,2H), 0.88(t,J=7.3Hz,3H).

[0335] Intermediate 114-4-(1,1-difluoropropyl)benzonitrile [ka] A mixture of potassium acetate (209 mg, 2.1 mmol), potassium ferrocyanide (783 mg, 2.1 mmol), and 1-bromo-4-(1,1-difluoropropyl)benzene (1.00 g, 4.3 mmol) in 1,4-dioxane (10 mL) and water (10 mL) was sparged with nitrogen for 10 min before adding Pd-174 (153 mg, 210 μmol). Sparging was continued for an additional 2 min and the mixture was heated to 100° C. for 1 h. The mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (35 mL). The aqueous layer was extracted with EtOAc (2×35 mL) and the combined organic layers were washed with brine (50 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give 4-(1,1-difluoropropyl)benzonitrile (0.780 g, 3.3 mmol, 77% purity) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 8.04-7.96(m,2H), 7.77-7.71(m,2H), 2.25(tq,J=17.0,7.4Hz,2H), 0.91(t,J=7.4Hz,3H).

[0336] The following compounds were synthesized using the same procedure: [Table 11]

[0337] Intermediate 12 1-1-Bromo-4-(1-propylcyclopropyl)benzene [ka]

[0338] Step 1 A solution of ethylmagnesium chloride (2M in THF, 14 mL, 28 mmol) was added dropwise to a solution of 1-(4-bromophenyl)cyclopropane-1-carbonitrile (5.0 g, 22.5 mmol) in THF (40 mL) at room temperature. The mixture was then stirred at 70° C. for 4 h, cooled to room temperature and diluted with saturated NH 4 Cl (75 mL). 2 SO 4 (1M, 15 mL) was added and the mixture was stirred for 10 min and then extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine and dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give 1-(1-(4-bromophenyl)cyclopropyl)propan-1-one (4.61 g, 18.2 mmol) as a clear, colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.57-7.51(m,2H), 7.39-7.32(m,2H), 2.25(q,J=7.1Hz,2H), 1.50-1.42(m,2H), 1.17-1.10(m,2H), 0.82(t,J=7.1Hz,3H).

[0339] Step 2 A solution of 1-(1-(4-bromophenyl)cyclopropyl)propan-1-one (4.61 g 18.2 mmol), hydrazine hydrate (2.7 mL, 54.6 mmol), and potassium hydroxide (3.07 g, 54.6 mmol) in diethylene glycol (35 mL) was heated to 200° C. for 3 h. The mixture was cooled to room temperature and poured into water (100 mL). The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (100 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give 1-bromo-4-(1-propylcyclopropyl)benzene (3.73 g, 15 mmol) as a clear, colorless oil. 1H NMR(400MHz,DMSO-d6)δ 7.48-7.42(m,2H), 7.25-7.19(m,2H), 1.55-1.49(m,2H), 1.26-1.15(m,2H), 0.81(t,J=7.4Hz,3H), 0.75-0.71(m,2H), 0.71-0.66(m,2H).

[0340] Intermediate 12 2-1-Bromo-4-(5,5,5-trifluoropentyl)benzene [ka]

[0341] Step 1 A mixture of 1,1,1-trifluoro-4-iodobutane (2.7 mL, 21 mmol) and triphenylphosphine (5.50 g, 21 mmol) in MeCN (20 ml) was heated to reflux for 18 h. The mixture was cooled to room temperature and concentrated. The residue was suspended in toluene (15 ml) and stirred at 85° C. for 10 min. The mixture was cooled to room temperature and the precipitate was collected by filtration. The solid was washed with toluene (2×20 mL) to give triphenyl(4,4,4-trifluorobutyl)phosphonium iodide (10.5 g, 19 mmol, 90% purity) as a white solid. LCMS m / z 373.0 (MI) + (ES + ). 1 H NMR (400MHz, DMSO-d6) δ 7.94-7.80(m,9H), 7.80-7.68(m,6H), 4.15-4.00(m,2H), 2.79-2.64(m,2H), 2.05-1.83(m,2H).

[0342] Step 2 Potassium carbonate (4.66 g, 33.7 mmol) was added to a solution of 4-bromobenzaldehyde (3.40 g, 18.3 mmol) and triphenyl(4,4,4-trifluorobutyl)phosphonium iodide (10.2 g, 18.3 mmol, 90% purity) in IPA (100 mL). The mixture was heated to 80 °C and stirred for 17 h. The mixture was cooled to room temperature and concentrated. The resulting solid was suspended in DCM (100 mL), filtered, and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (0-10% DCM / isohexane) to give (E)-1-bromo-4-(5,5,5-trifluoropent-1-en-1-yl)benzene (4.81 g, 16 mmol) as a clear, colorless oil as an 83:17 mixture of isomers. 1 H NMR (400 MHz, DMSO-d6) δ 7.54-7.48 (m, 2H), 7.39-7.31 (m, 2H), 6.53-6.47 (m, 1H), 6.36-6.31 (m, 1H), 2.49-2.37 (m, 4H) [data corresponding to the (E)-isomer].

[0343] Step 3 A suspension of (E)-1-bromo-4-(5,5,5-trifluoropent-1-en-1-yl)benzene (4.81 g, 16 mmol) and 1% Pt / C (50 wt%, 950 mg) in EtOH (75 mL) was stirred under a hydrogen atmosphere (1 bar) at room temperature for 2 h. The mixture was filtered and concentrated. The crude product was purified by chromatography on silica gel (100% iso-hexane) to give 1-bromo-4-(5,5,5-trifluoropentyl)benzene (4.33 g, 14 mmol, 90% purity) as a clear, colorless liquid. 1 H NMR(400MHz,DMSO-d6)δ 7.50-7.44(m,2H), 7.20-7.15(m,2H), 2.59(t,J=7.6Hz,2H), 2.36-2.18(m,2H), 1.69-1.55(m,2H), 1.54-1.43(m,2H).

[0344] Intermediate 12 3-1-Bromo-4-(2-cyclopropylethyl)benzene [ka]

[0345] Step 1 Potassium carbonate (5.70 g, 41.2 mmol) was added to a solution of 4-bromobenzaldehyde (4.05 g, 21.9 mmol) and triphenyl(cyclopropylmethyl)phosphonium iodide (9.72 g, 21.9 mmol) in IPA (100 mL). The mixture was heated to 80 °C and stirred for 17 h. The mixture was cooled to room temperature and concentrated. The resulting solid was suspended in DCM (100 mL), filtered, and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (0-10% DCM / isohexane) to give (E)-1-bromo-4-(2-cyclopropylvinyl)benzene (4.28 g, 18 mmol) as a white solid as a 76:24 mixture of isomers. 1 H NMR(400MHz,DMSO-d6)δ 7.49-7.42(m,2H), 7.33-7.26(m,2H), 6.44(d,J=15.9Hz,1H), 5.89(dd,J=15.9,9.1H z,1H), 1.63-1.46(m,1H), 0.87-0.74(m,2H), 0.58-0.46(m,2H) [data corresponding to (E)-isomer].

[0346] Step 2 A suspension of (E)-1-bromo-4-(2-cyclopropylvinyl)benzene (4.28 g, 18 mmol) and 1% Pt / C (50 wt%, 800 mg) in EtOH (60 mL) was stirred under a hydrogen atmosphere (1 bar) at room temperature for 6 h. The mixture was filtered and concentrated. The crude product was purified by chromatography on silica gel (100% iso-hexane) to give 1-bromo-4-(2-cyclopropylethyl)benzene (4.46 g, 12 mmol, 61% purity) as a clear, colorless liquid. 1H NMR(400MHz,DMSO-d6)δ 7.49-7.39(m,2H), 7.22-7.13(m,2H), 2.68-2.58(m,2H), 1.49-1.44(m,1H), 0.90-0.81(m,1H), 0.72-0.59(m,1H), 0.43-0.29(m,2H), 0.09--0.03(m,2H).

[0347] Intermediate 124-1-Bromo-4-(1,1-difluoropentyl)benzene [ka] A PTFE flask was charged with 1-(4-bromophenyl)pentan-1-one (2.50 g, 10.4 mmol). Deoxofluoro (50 wt% in toluene, 19 mL, 52 mmol) was added dropwise at room temperature. The mixture was heated to 80° C. for 16 h, then cooled to room temperature and saturated aqueous NaHCO 3 (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (70 mL) and dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give 1-bromo-4-(1,1-difluoropentyl)benzene (1.96 g, 7.2 mmol) as a clear, colorless oil. 1 H NMR (400MHz, DMSO-d6) δ 7.74-7.67(m,2H), 7.52-7.44(m,2H), 2.27-2.11(m,2H), 1.37-1.23(m,4H), 0.90-0.81(m,3H).

[0348] The following compounds were synthesized using the same procedure: [Table 12]

[0349] Intermediate 126-2-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)acetonitrile [ka] Sodium cyanide (1.54 g, 31.4 mmol) was added to a solution of 1-(bromomethyl)-4-(1,1,2,2-tetrafluoroethoxy)benzene (6.00 g, 20.9 mmol) in DMSO (30 mL) and the mixture was heated to 90° C. for 3 h, then cooled to room temperature and stirred for 18 h. The mixture was partitioned between EtOAc (150 mL) and 1:1 v / v water / brine (150 mL). The organic layer was washed with 1:1 v / v water / brine (2×150 mL). The combined aqueous washes were extracted with EtOAc (150 ml). The combined organic extracts were washed with 1:1 v / v water / brine (150 mL), dried (Na 2 SO 4 ) and concentrated to give 2-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)acetonitrile (4.76 g, 20 mmol) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ 7.42-7.32(m,2H), 7.24(d,J=8.4Hz,2H), 5.91(tt,J=53.0,2.8Hz,1H), 3.77(s,2H).

[0350] Intermediate 12 7-tert-Butyl 2-(diethoxyphosphoryl)-4-(hydroxyamino)-4-iminobutanoate [ka]

[0351] Step 1 Ethyl chloroformate (8.1 mL, 85 mmol) was added dropwise to a solution of 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutanoic acid (25.0 g, 80.6 mmol) and triethylamine (12.0 mL, 86 mmol) in THF (200 mL) at 0° C. The mixture was stirred for 30 min, then more triethylamine (3.0 mL, 22 mmol) and ethyl chloroformate (2.0 mL, 21 mmol) were added. After 1 h, ammonia (30% aqueous, 25 mL, 0.39 mol) was added dropwise. The mixture was stirred at room temperature for 1 h, then concentrated to approximately 50 mL. The mixture was diluted with water (300 mL) and extracted with EtOAc (5×200 mL). The combined organic phase was washed with saturated aqueous NH 4 Cl (400 mL), brine (400 mL), dried (Na 2 SO 4 ) and concentrated. The residue was triturated with MTBE (200 mL) and the resulting solid was isolated by filtration to give tert-butyl 4-amino-2-(diethoxyphosphoryl)-4-oxobutanoate (10.66 g, 34 mmol) as a white solid. LCMS m / z 254.2 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.41(s,1H), 6.89(s,1H), 4.10-3.97(m,4H), 3.21(ddd,J=23.3,11.5,3.4Hz,1H), 2.69(ddd,J= 16.3,11.5,7.2Hz,1H), 2.39(ddd,J=16.4,9.6,3.4Hz,1H), 1.38(s,9H), 1.24(q,J=7.2Hz,6H). 31 P NMR(162MHz,DMSO-d6)δ 23.19.

[0352] Step 2 Trifluoroacetic anhydride (17.9 mL, 129 mmol) was added portionwise to a stirred solution of tert-butyl 4-amino-2-(diethoxyphosphoryl)-4-oxobutanoate (12.85 g, 41.6 mmol) and triethylamine (18.0 mL, 129 mmol) in 1,4-dioxane (100 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 60 h. The reaction mixture was quenched with water (100 mL) and the mixture was partially concentrated. The mixture was extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (200 mL) and dried (MgSO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 3-cyano-2-(diethoxyphosphoryl)propanoate (6.63 g, 22 mmol) as a brown oil. LCMS m / z 236.2 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 4.14-4.03(m,4H), 3.59(ddd,J=23.8,8.1,5.9Hz,1H), 2.90-2.75(m,2H), 1.44(s,9H), 1.29-1.22(m,6H).

[0353] Step 3 A mixture of hydroxylamine hydrochloride (2.30 g, 33.1 mmol) and sodium bicarbonate (2.78 g, 33.1 mmol) in 2-propanol (45 mL) was stirred for 15 min, after which tert-butyl 3-cyano-2-(diethoxyphosphoryl)propanoate (6.63 g, 22.1 mmol) was added and the mixture was stirred under reflux for 18 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated. The crude product was purified by chromatography on silica gel (0-20% MeOH / DCM) to give tert-butyl 2-(diethoxyphosphoryl)-4-(hydroxyamino)-4-iminobutanoate (4.83 g, 15 mmol) as a waxy pale green solid. LCMS m / z 325.3 (M+H) + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 8.93(s,1H), 5.40(s,2H), 4.10-3.96(m,4H), 3.25(ddd,J=23.0,11.8,3.1Hz,1H), 2.57(ddd,J= 15.9,11.7,6.8Hz,1H), 2.37(ddd,J=15.9,10.2,3.1Hz,1H), 1.38(s,9H), 1.24(q,J=7.0Hz,6H).

[0354] Intermediate 128-2-(4-bromophenyl)-2,2-difluoroacetonitrile [ka]

[0355] Step 1 A mixture of ethyl 2-(4-bromophenyl)-2,2-difluoroacetate (3.5 g, 13 mmol) and ammonia (7 M in methanol, 20 mL, 0.92 mol) was stirred at room temperature for 16 h. The mixture was concentrated to give 2-(4-bromophenyl)-2,2-difluoroacetamide (3.0 g, 10 mmol, 90% purity) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 8.38(s,br.1H), 8.05(s,br.1H), 7.80-7.70(m,2H), 7.57-7.47(m,2H).

[0356] Step 2 TFAA (1.2 mL, 8.6 mmol) was added dropwise to a solution of 2-(4-bromophenyl)-2,2-difluoroacetamide (2.0 g, 7.2 mmol, 90% purity) and pyridine (1.7 mL, 22 mmol) in THF (30 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for an additional 20 min. The mixture was poured into water (80 mL) and extracted with EtOAc (3x80 mL). The combined organic layers were dried (MgSO 4 ) and concentrated to give 2-(4-bromophenyl)-2,2-difluoroacetonitrile (1.9 g, 7.2 mmol, 90% purity) as a clear, pale orange oil.1 H NMR (400MHz, DMSO-d6) δ 7.93-7.84 (m, 2H), 7.82-7.73 (m, 2H).

[0357] Intermediate 129-2,2-difluoro-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka]

[0358] Step 1 1-Iodo-4-(trifluoromethyl)benzene (8.0 mL, 54.4 mmol) and ethyl 2-bromo-2,2-difluoroacetate (7.0 mL, 54.4 mmol) were added to a suspension of copper (8.99 g, 142 mmol) in DMSO (100 mL). The mixture was heated to 60° C. and stirred for 18 h. The mixture was cooled to room temperature and washed with saturated aqueous NH 4 Cl (200 mL) and EtOAc (200 mL). The mixture was filtered and the phases were separated. The aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine (200 mL) and dried (MgSO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-20% MTBE / isohexane) to give ethyl 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)acetate (13.17 g, 45 mmol, 92% purity) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.95(d,J=8.2Hz,2H), 7.85(d,J=8.2Hz,2H), 4.32(q,J=7.1Hz,2H), 1.23(t,J=7.1Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-61.64,-102.28.

[0359] Step 2 Prepared from ethyl 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)acetate (8.00 g, 29.8 mmol) according to the procedure described in Intermediate 128, step 1 to give 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)acetamide (5.25 g, 22 mmol) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.47 (br.s, 1H), 8.12 (br.s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H). 19 F NMR (376MHz, DMSO-d6) δ-61.49,-102.79.

[0360] Step 3 Prepared from 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)acetamide (5.25 g, 22 mmol) according to the procedure described in Intermediate 128, step 2 to give 2,2-difluoro-2-(4-(trifluoromethyl)phenyl)acetonitrile (3.35 g, 15 mmol) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ 8.07 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H). 19 F NMR (376MHz, DMSO-d6) δ -61.90, -83.33.

[0361] The following compounds were synthesized using the same procedure: [Table 13-1] [Table 13-2]

[0362] Intermediate 131-2-(4-(1,1-difluoropentyl)phenyl)acetonitrile [ka]

[0363] Step 1 A solution of 1-bromo-4-(1,1-difluoropentyl)benzene (1.00 g, 3.80 mmol) and Pd-170 (51 mg, 76 μmol) in THF (20 mL) was sparged with nitrogen for 10 min. (2-ethoxy-2-oxoethyl)zinc(II) bromide (0.34 M in THF, 25 mL, 8.4 mmol) was added dropwise. The mixture was heated to 75° C. and stirred for 16 h, then cooled to room temperature and poured into water (20 mL). The mixture was separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give ethyl 2-(4-(1,1-difluoropentyl)phenyl)acetate (0.651 g, 2.4 mmol) as a clear yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.46(d,J=8.2Hz,2H), 7.37(d,J=8.1Hz,2H), 4.09(q,J=7.1Hz,2H), 3.73(s,2H) , 2.26-2.10(m,2H), 1.34-1.25(m,4H), 1.18(t,J=7.1Hz,3H), 0.87-0.81(m,3H). 19 F NMR (376MHz, DMSO-d6) δ-92.45.

[0364] Step 2 A large Biotage microwave vial was charged with ethyl 2-(4-(1,1-difluoropentyl)phenyl)acetate (0.65 g, 2.4 mmol) and ammonia (7M in MeOH, 6.9 mL, 48 mmol). The vial was sealed and heated at 75 °C for 16 h. The mixture was cooled to room temperature and concentrated. The vessel was recharged with ammonia (7M in MeOH, 6.9 mL, 48 mmol) and heated at 75 °C for 16 h. The mixture was concentrated. The crude product was purified by chromatography on silica gel (0-10% MeOH / DCM) to give 2-(4-(1,1-difluoropentyl)phenyl)acetamide (0.471 g, 1.9 mmol) as a white solid. LCMS m / z 242.1 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.50(s,1H), 7.43(d,J=8.3Hz,2H), 7.35(d,J=8.0Hz,2H), 6.91(s,1H), 3.42(s,2H), 2.25-2.09(m,2H), 1.35-1.25(m,4H), 0.88-0.81(m,3H). 19 F NMR (376MHz, DMSO-d6) δ-92.25.

[0365] Step 3 Prepared from 2-(4-(1,1-difluoropentyl)phenyl)acetamide (0.471 g, 1.9 mmol) following the procedure described in Intermediate 62, step 2. The crude product was purified by chromatography on silica gel (0-10%, 0-10% EtOAc / isohexane) to give 2-(4-(1,1-difluoropentyl)phenyl)acetonitrile (0.394 g, 1.7 mmol) as a clear, colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.54(d,J=8.3Hz,2H), 7.46(d,J=8.1Hz,2H), 4.11(s,2H), 2.26-2.10(m,2H), 1.34-1.22(m,4H), 0.90-0.80(m,3H). 19 F NMR(376MHz,DMSO-d6)δ-92.67.

[0366] The following compounds were synthesized using the same procedure: [Table 14]

[0367] Intermediate 132-7,7,9,9,9-Pentafluorononanenitrile [ka]

[0368] Step 1 A suspension of NaH in mineral oil (60 wt%, 16 g, 408 mmol) was added to a solution of hex-5-yn-1-ol (40 g, 408 mmol) in THF (340 mL) at 0° C. and the mixture was stirred until effervescence subsided. Tetrabutylammonium iodide (12.6 g, 34 mmol) and benzyl bromide (58.2 g, 340 mmol) were added and the mixture was stirred at room temperature for 18 h. Saturated aqueous NH 4 Cl solution was added and the reaction mixture was diluted with Et 2 The combined organic phase was washed with brine and extracted with MgSO 4 The mixture was dried at 40° C., filtered and the filtrate was concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (120 g silica, 10-20% EtOAc / petroleum ether) to give ((hex-5-yn-1-yloxy)methyl)benzene (70 g, 372 mmol, 91%) as a pale yellow oil. LCMS: (System 2, Method C) m / z 189.4 (M+H). + (ES + ).

[0369] Step 2 CuI (15.2 g, 79.8 mmol) in dimethylformamide (540 mL), K 2 CO 3 A mixture of TMSCF (36 g, 266 mmol) and N,N,N',N'-tetramethylethylenediamine (9.4 g, 79.8 mmol) was vigorously stirred at room temperature under a dry air atmosphere for 15 minutes. 3(15.2 g, 106 mmol) was added and the resulting deep green mixture was stirred for an additional 5 min and then cooled to 0° C. A solution of ((hex-5-yn-1-yloxy)methyl)benzene (10 g, 53.2 mmol) and TMSCF in dimethylformamide (540 mL) pre-cooled to 0° C. was then added. 3 A solution of (15.2 g, 106 mmol) was added in one portion. After 30 min at 0° C., the reaction mixture was warmed to room temperature and stirred for 24 h under a dry air atmosphere. Water was then added and the mixture was extracted with Et 2 O. The combined organic phases were washed with water and brine, then with MgSO 4 The mixture was dried at 40° C. under reduced pressure and the residue was purified by flash column chromatography (120 g silica, 10-20% EtOAc / petroleum ether) to give (((7,7,7-trifluorohept-5-yn-1-yl)oxy)methyl)benzene (6.8 g, 26.5 mmol, 50%) as a pale yellow oil. LCMS: (System 2, Method A) m / z 274.4 (M+NH 4 ) + (ES + ).

[0370] Step 3 THF (13.5 mL) and H 2 To a solution of (((7,7,7-trifluorohept-5-yn-1-yl)oxy)methyl)benzene (2.5 g, 9.8 mmol) in a mixture of 2,4-dimethylformamide (1.5 mL), JohnPhos AuCl (CAS: 854045-93-5) (265 mg, 0.5 mmol) and silver trifluoromethanesulfonate (128 mg, 0.5 mmol) were added, the vial was wrapped in aluminum foil and heated to 70 °C. After 18 h, the reaction mixture was cooled to room temperature and saturated aqueous NaHCO 3 The solution was diluted with DCM (x3) and the combined organic phase was washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (80 g silica, 10-30% EtOAc / petroleum ether) to give 7-(benzyloxy)-1,1,1-trifluoroheptan-3-one (2.0 g, 7.3 mmol, 75%) as a pale yellow oil. LCMS: (System 2, Method A) m / z 275.3 (M+H). + (ES + ).

[0371] Step 4 A solution of 7-(benzyloxy)-1,1,1-trifluoroheptan-3-one (6.0 g, 21.9 mmol) and DAST (50 g, 313 mmol) in DCE (60 mL) was stirred at 50° C. overnight. The reaction mixture was poured onto ice (50 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and diluted with Na 2 SO 4 The filtrate was concentrated under reduced pressure at 40 °C and the residue was purified by flash column chromatography (80 g silica, 10-40% EtOAc / petroleum ether) to give (((5,5,7,7,7-pentafluoroheptyl)oxy)methyl)benzene (5.5 g, 18.6 mmol, 85%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ:7.39-7.25(m,5H), 4.50(s,2H), 3.49(t,J=5.9Hz,2H), 2.81-2.62(m,2H), 2.07-1.88(m,2H), 1.73-1.57(m,4H). 19 F NMR (376 MHz, CDCl 3 )δ: -61.93(t,J=8.9Hz), -95.16(q,J=8.9Hz).

[0372] Step 5 A solution of (((5,5,7,7,7-pentafluoroheptyl)oxy)methyl)benzene (7.0 g, 23.6 mmol) in MeOH (50 mL) was diluted with 5% Pd(OH) 2A / C catalyst (50 wt % in water, 3.5 g) and AcOH (0.5 mL) were added and the reaction mixture was heated to H 2 The mixture was stirred under atmosphere overnight at 60° C. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure at 40° C. to give 5,5,7,7,7-pentafluoroheptan-1-ol (4.8 g, 23.3 mmol, 98%) as a pale yellow oil, which was used directly in the next step.

[0373] Step 6 To a solution of 5,5,7,7,7-pentafluoroheptan-1-ol (4.8 g, 23.3 mmol) in dichloromethane (80 mL) was added Dess-Martin periodinane (14.8 g, 35 mmol) and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with aqueous Na 2 S 2 O 3 (100 mL), diluted with dichloromethane (50 mL) and separated. The aqueous phase was extracted with dichloromethane (2x50 mL) and the combined organic phase was washed with water (2x60 mL) and brine, and MgSO 4 The filtrate was concentrated under reduced pressure at 40 °C and the residue was purified by flash column chromatography (40 g silica, 10-50% EtOAc / petroleum ether) to give 5,5,7,7,7-pentafluoroheptanal (3.6 g, 17.6 mmol, 75%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ:9.78(s,1H), 2.83-2.65(m,2H), 2.60-2.51(m,2H), 2.08-1.92(m,2H), 1.92-1.82(m,2H).

[0374] Step 7 A solution of potassium tert-butoxide in THF (20 wt%, 15.0 g, 26.4 mmol) was added dropwise to a solution of diethyl cyanomethylphosphonate (4.7 g, 26.4 mmol) in tetrahydrofuran (50 mL) at 0° C. The reaction mixture was allowed to warm to room temperature for 30 min, then cooled to 0° C. and a solution of 5,5,7,7,7-pentafluoroheptanal (3.6 g, 17.6 mmol) in tetrahydrofuran (40 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and Na 2 SO 4 The filtrate was concentrated under reduced pressure at 40 °C and the residue was purified by flash column chromatography (40 g silica, 10-40% EtOAc / petroleum ether) to give 7,7,9,9,9-pentafluoronon-2-enenitrile (3.5 g, 15.4 mmol, 88%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ:6.75-6.63(m,0.4H), 6.52-6.41(m,0.6H), 5.43-5.32(m,1H), 2.83-2.64(m, 2H), 2.55-2.45(m,1H), 2.36-2.25(m,1H), 2.08-1.89(m,2H), 1.79-1.66(m,2H). Mixture of E / Z isomers.

[0375] Step 8 A mixture of 7,7,9,9,9-pentafluoronon-2-enenitrile (3.5 g, 15.4 mmol) and 20% Pd / C (50 wt % in water, 700 mg) in EtOAc (30 mL) was diluted with H 2 The mixture was stirred at room temperature overnight under an atmosphere of 0.1%. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure at 40° C. to give 7,7,9,9,9-pentafluorononanenitrile (3.1 g, 13.5 mmol, 88%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3)δ:2.82-2.64(m,2H), 2.37(t,J=7.0Hz,2H), 2.06-1.89(m,2H), 1.75-1.65(m,2H), 1.64-1.47(m,4H). 19 F NMR (376 MHz, CDCl 3 )δ: -61.97(t,J=8.9Hz), -95.23(q,J=8.9Hz).

[0376] Intermediate 13 3-tert-butyl 2-(diethoxyphosphoryl)-3-(5-octylisoxazol-3-yl)propanoate [ka]

[0377] Step 1 Et at 0 °C 2 To a solution of ethyl 2-chloro-2-(hydroxyimino)acetate (2.00 g, 13.2 mmol) and dec-1-yne (5.48 g, 39.7 mmol) in 2O (25 mL) was added triethylamine (1.79 mL, 13.2 mmol) and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 12 h. The reaction was quenched with water (40 mL), the phases were separated and the aqueous phase was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and filtered. The filtrate was concentrated under reduced pressure at 35° C. and the residue was purified by flash column chromatography (1:50 to 1:10 EtOAc / petroleum ether) to give ethyl 5-octylisoxazole-3-carboxylate (3 g, 11.8 mmol, 90%) as a pale yellow oil. LCMS: (System 2, Method B) m / z 286.3 (M+H). + (ES + ).

[0378] Step 2 To a solution of ethyl 5-octylisoxazole-3-carboxylate (3 g, 11.8 mmol) in MeOH (30 mL) at 0 °C was added NaBH 4(887 mg, 23.7 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was quenched with water (20 mL), concentrated to remove methanol, and the residue was extracted with ethyl acetate (4x10 mL). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and filtered. The filtrate was concentrated under reduced pressure at 30° C. and the residue was purified by flash column chromatography (40 g silica, 0-30% MTBE / petroleum ether) to give (5-octylisoxazol-3-yl)methanol (2 g, 9.47 mmol, 80%) as a pale yellow oil. LCMS: (System 2, Method C) m / z 212.4 (M+H). + (ES + ).

[0379] Step 3 To a solution of (5-octylisoxazol-3-yl)methanol (750 mg, 3.6 mmol) and triethylamine (1 mL, 7.2 mmol) in DCM (10 mL) at 0° C., methanesulfonyl chloride (0.41 mL, 5.4 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was concentrated under reduced pressure at 30° C. to give crude (5-octylisoxazol-3-yl)methyl methanesulfonate (878 mg, 3.0 mmol, 84%) as a pale yellow oil, which was used directly in the next step. LCMS: (System 2, Method C) m / z 290.2 (M+H) + (ES + ).

[0380] Step 4 To a solution of (5-octylisoxazol-3-yl)methyl methanesulfonate (878 mg, 3.0 mmol) in acetone (10 mL) was added LiBr (779 mg, 9.0 mmol) and the mixture was stirred at 65° C. for 2 h. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (4×10 mL). The combined organic phase was washed with brine and diluted with Na 2 SO 4The mixture was dried at 40° C. under reduced pressure and the residue was purified by flash column chromatography (25 g silica, 0-30% MTBE / petroleum ether) to give 3-(bromomethyl)-5-octylisoxazole (600 mg, 2.2 mmol, 73%) as a pale yellow oil. LCMS: (System 2, Method C) m / z 274.2 / 276.2 (M+H). + (ES + ).

[0381] Step 5 To a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (55 mg, 2.2 mmol) in THF (15 mL) at 0° C. was added a suspension of NaH in mineral oil (60 wt%, 96 mg, 2.4 mmol) and the mixture was stirred at 0° C. for 0.5 h. Then a solution of 3-(bromomethyl)-5-octylisoxazole (600 mg, 2.2 mmol) in THF (5 mL) at 0° C. was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with water (20 mL), the phases were separated and the aqueous phase was extracted with ethyl acetate (4×10 mL). The combined organic layers were washed with brine and Na 2 SO 4 The mixture was dried at 40° C. under reduced pressure and the residue was purified by flash column chromatography (25 g silica, 0-80% MTBE / petroleum ether) to give tert-butyl 2-(diethoxyphosphoryl)-3-(5-octylisoxazol-3-yl)propanoate (500 mg, 1.1 mmol, 50%) as a pale yellow oil. LCMS: (System 2, Method C) m / z 446.2 (M+H). + (ES + ).

[0382] Intermediate 134-2-Bromo-1-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)ethan-1-one [ka]

[0383] Step 1 EtOH (15 mL) and H2 A solution of 1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile (3.00 g, 14.2 mmol) and KOH (2.38 g, 42.6 mmol) in 2O (15 mL) was stirred at 100° C. for 16 h. The mixture was concentrated under reduced pressure at 35° C. and the residue was washed with EtOAc (2×20 mL). The aqueous layer was adjusted to pH=4 using dilute aqueous HCl (1 M) and then extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine and Na 2 SO 4 The mixture was dried at 40° C. and filtered, and the filtrate was concentrated under reduced pressure at 35° C. to give 1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (3.2 g, 13.9 mmol, 94%) as a yellow oil, which was used directly in the next step. 1 H NMR(400MHz,DMSO-d6)δ:12.50(br,1H), 7.66(d,J=8.1Hz,2H), 7.55(d,J=8.0Hz,2H), 1.49(q,J=4.0Hz,2H), 1.20(q,J=4.0Hz,2H).

[0384] Step 2 To a solution of 1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (3.2 g, 13.9 mmol), N,O-dimethylhydroxylamine hydrochloride (4.07 g, 41.7 mmol), and HATU (10.56 g, 27.8 mmol) in dimethylformamide (70 mL) at 0 °C was added Et 3 N (9.83 g, 97.3 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then saturated aqueous NH 4 The mixture was quenched with Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4The mixture was dried at 4° C., filtered and concentrated under reduced pressure at 35° C. The residue was purified by flash column chromatography (20-33% EtOAc / petroleum ether) to give N-methoxy-N-methyl-1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxamide (3.5 g, 12.8 mmol, 92%) as a colorless oil. LCMS: (System 2, Method C) m / z 274.2 (M+H). + (ES + ).

[0385] Step 3 To a mixture of N-methoxy-N-methyl-1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxamide (3.00 g, 11.0 mmol) in THF (55 mL) at 0° C., a solution of methylmagnesium bromide in diethyl ether (3 M, 5.1 mL, 15.3 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NH 4 The mixture was quenched with Cl solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure at 30° C. The residue was purified by flash column chromatography (25 g silica, 0-10% MTBE / petroleum ether) to give 1-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)ethan-1-one (2.5 g, 11.0 mmol, 99%) as a colorless oil. LCMS: (System 2, Method C) m / z 229.3 (M+Na). + (ES + ).

[0386] Step 4 To a solution of 1-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)ethan-1-one (2.2 g, 9.64 mmol) in MeOH (50 mL) at room temperature, Br 2 (2.31 g, 14.46 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO 3The mixture was adjusted to pH=7 using 100 mL of 100% NaOH and then concentrated under reduced pressure at 30° C. to remove MeOH. The remaining aqueous mixture was extracted with EtOAc (2×50 mL) and the combined organic phases were 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure at 35° C. The residue was purified by flash column chromatography (40 g silica, 0-10% MTBE / petroleum ether) to give 2-bromo-1-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)ethan-1-one (1.4 g, 4.56 mmol, 47%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ:7.72(d,J=8.0Hz,2H), 7.67(d,J=8.2Hz,2H), 4.22(s,2H), 1.65(q,J=4.1Hz,2H,1.35(q,J=4.2Hz,2H).

[0387] Intermediate 135-2-(chloromethyl)-4-octylpyridine [ka]

[0388] Step 1 Methyl 4-bromopicolinate (2.80 g, 13.0 mmol), oct-1-yne (5.70 g, 51.8 mmol), Pd(PPh) in DIPEA (65 mL) 3 ) 2 Cl 2 A mixture of (0.92 g, 1.30 mmol) and CuI (492 mg, 2.60 mmol) was stirred at 85° C. for 3 h. The mixture was cooled to room temperature, filtered, and the filtrate was diluted with water (60 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with dilute aqueous HCl solution (0.5 M, 3×30 mL), water (2×30 mL), and brine, and extracted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (120 g silica, 0-30% EtOAc / petroleum ether) to give methyl 4-(oct-1-yn-1-yl)picolinate (2.40 g, 9.78 mmol, 75%) as a dark oil. LCMS: (System 2, Method C) m / z 246.4 (M+H). + (ES + ).

[0389] Step 2 A mixture of methyl 4-(oct-1-yn-1-yl)picolinate (2.40 g, 9.78 mmol) and Pd / C catalyst (10 wt%, 240 mg) in MeOH (20 mL) was heated with H 2 The mixture was stirred at room temperature for 12 h under an atmosphere of 0.05%. The mixture was filtered and concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (80 g silica, 0-30% EtOAc / petroleum ether) to give methyl 4-octylpicolinate (2.20 g, 8.82 mmol, 90%) as a brown oil. LCMS: (System 2, Method C) m / z 250.4 (M+H). + (ES + ).

[0390] Step 3 To a solution of methyl 4-octylpicolinate (2.20 g, 8.82 mmol) in MeOH (44 mL) at 0 °C was added NaBH 4 (3.35 g, 88.2 mmol) was added and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (40 mL) and concentrated under reduced pressure at 40° C. to remove MeOH. The aqueous residue was extracted with ethyl acetate (3×40 mL) and the combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and filtered. The filtrate was concentrated under reduced pressure at 40° C. and the residue was purified by flash column chromatography (40 g silica, 0-30% EtOAc / petroleum ether) to give (4-octylpyridin-2-yl)methanol (1.20 g, 5.42 mmol, 61%) as a yellow oil. LCMS: (System 2, Method C) m / z 222.4 (M+H).+ (ES + ).

[0391] Step 4 To a solution of (4-octylpyridin-2-yl)methanol (1.20 g, 5.42 mmol) in DCM (27 mL) at room temperature was added SOCl 2 (1.90 g, 16.3 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The solvent was then removed under reduced pressure at 30 °C and the residue was purified by H 2 The mixture was diluted with HO (10 mL), adjusted to pH = 4 using dilute aqueous HCl (2 M), and extracted with MTBE (3 x 10 mL). 2 Wash with 2×2 mL of HO and brine. 2 SO 4 The mixture was dried at 4° C., filtered and concentrated under reduced pressure at 30° C. The residue was purified by flash column chromatography (20 g silica, 0-30% MTBE / petroleum ether) to give 2-(chloromethyl)-4-octylpyridine (1.30 g, 5.42 mmol, 100%) as a brown oil. LCMS: (System 2, Method C) m / z 240.4 / 242.4 (M+H). + (ES + ). 1 H NMR (400 MHz, CDCl 3 )δ:8.44(d,J=5.1Hz,1H), 7.28(s,1H), 7.05(dd,J=5.1,1.7Hz,1H), 4.65(s,2H), 2 .62(t,J=7.8Hz,2H), 1.68-1.57(m,2H), 1.37-1.20(m,10H), 0.88(t,J=6.8Hz,3H).

[0392] The following compounds were prepared by a similar procedure: [Table 15]

[0393] Intermediate 138-1-(4-cyclobutoxyphenyl)cyclopropane-1-carbonitrile [ka] 1-(4-hydroxyphenyl)cyclopropane-1-carbonitrile (1.20 g, 7.54 mmol) in dimethylformamide (14 mL), Cs 2 CO 3 A mixture of (7.35 g, 22.6 mmol), KI (125 mg, 0.75 mmol), and bromocyclobutane (4.04 g, 30.2 mmol) was stirred at 60 °C overnight. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with saturated aqueous NH 4 Wash with Cl solution (2x30mL) and brine, then add Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (40 g silica, 0-20% MTBE / petroleum ether) to give 1-(4-cyclobutoxyphenyl)cyclopropane-1-carbonitrile (1.10 g, 5.16 mmol, 68%) as a pale yellow liquid. LCMS: (System 2, Method C) m / z 214.4 (M+H). + (ES + ).

[0394] Intermediate 140-2-(4-cyclopentylphenyl)acetonitrile [ka] A mixture of 2-(4-bromophenyl)acetonitrile (1.00 g, 5.10 mmol), potassium cyclopentyltrifluoroborate (988 mg, 5.61 mmol), palladium(II) acetate (115 mg, 0.51 mmol), cataCXium A (CAS: 321921-71-5) (366 mg, 1.02 mmol), and cesium carbonate (3.32 g, 10.2 mmol) in toluene (25 mL) was stirred at 110 °C overnight. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure at 40 °C. The residue was purified by flash column chromatography (25 g silica, 0-10% EtOAc / petroleum ether) to give 2-(4-cyclopentylphenyl)acetonitrile (470 mg, 2.54 mmol, 50%) as a colorless oil.1 H NMR (400 MHz, CDCl 3 )δ:7.26-7.22(m,4H), 3.71(s,2H), 3.06-2.92(m,1H), 2.13-1.99(m,2H), 1.88-1.75(m,2H), 1.75-1.63(m,2H), 1.63-1.49(m,2H).

[0395] Intermediate 14 3-1-(4-cyclopropoxyphenyl)cyclopropane-1-carbonitrile [ka] Prepared by a similar procedure to Intermediate 138, except the reaction mixture was heated to 200° C. in a microwave reactor for 1.5 h. LCMS: (System 2, Method C) m / z 200.2 (M+H). + (ES + ).

[0396] Intermediate 145-1-(4-cyclopentylphenyl)cyclopropane-1-carbonitrile [ka] Prepared by a similar procedure as intermediate 140. LCMS: (System 2, Method C) m / z 212.4 (M+H). + (ES + ).

[0397] Intermediate 15 2-2-(4-cyclobutylphenyl)acetonitrile [ka] 1-(Chloromethyl)-4-cyclobutylbenzene (2.7 g, 15 mmol) in MeCN (50 mL) at room temperature, K 2 CO 3To a solution of (3.1 g, 22.5 mol), KF (1.3 g, 22.5 mmol), TMSCN (2.2 g, 22.5 mmol) was slowly added dropwise and the resulting mixture was stirred at 60 °C for 6 h. The reaction mixture was then diluted with water (30 mL) and MTBE (20 mL), the phases were separated, and the aqueous layer was extracted with MTBE (2 x 50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure at 35° C. The residue was purified by flash column chromatography (40 g silica, 0-15% MTBE / petroleum ether) to give 2-(4-cyclobutylphenyl)acetonitrile (1.9 g, 11.1 mmol, 74%) as a colorless oil. LCMS: (System 2, Method C) m / z 172.3 (M+H). + (ES + ).

[0398] Intermediate 15 4-4-Butoxy-3-fluorobenzonitrile [ka] 3-Fluoro-4-hydroxybenzonitrile (1.00 g, 7.29 mmol) in acetone (15 mL), K 2 CO 3 A mixture of 4-butoxy-3-fluorobenzonitrile (2.01 g, 14.6 mmol), and 1-iodobutane (2.01 g, 10.94 mmol) was stirred at 60 °C for 16 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure at 40 °C. The residue was purified by flash column chromatography (40 g silica, 20-40% EtOAc / petroleum ether) to give 4-butoxy-3-fluorobenzonitrile (1.20 g, 6.21 mmol, 85%) as a colorless oil. LCMS: (System 2, Method C) m / z 194.3 (M+H) + (ES + ).

[0399] Intermediate 15 6-3-chloro-4-propoxybenzonitrile [ka] Prepared by a similar procedure as intermediate 154 using 3-chloro-4-hydroxybenzonitrile (1.40 g, 9.12 mmol) and 1-iodopropane (1.69 g, 10.0 mmol). Yield: 1.50 g, 7.67 mmol, 84%. LCMS: (System 2, Method C) m / z 196.3 / 198.3 (M+H). + (ES + ).

[0400] Intermediate 158-1-(4-cyclobutylphenyl)cyclopropane-1-carbonitrile [ka] To a solution of 2-(4-cyclobutylphenyl)acetonitrile (Intermediate 152, 1.00 g, 5.84 mmol) in THF (20 mL) at -78 °C was added a solution of KHMDS in THF (1 M, 13.4 mL, 13.4 mmol) and the resulting mixture was stirred at -78 °C for 1 h. Then, a solution of 1,2-dibromoethane (1.21 g, 6.42 mmol) in THF (3 mL) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NH 4 It was quenched with Cl solution (20 mL), the phases were separated and the aqueous layer was extracted with MTBE (2×20 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure at 30° C. The residue was purified by flash column chromatography (25 g silica, 0-10% MTBE / petroleum ether) to give 1-(4-cyclobutylphenyl)cyclopropane-1-carbonitrile (350 mg, 1.77 mmol, 30%) as a colorless oil. LCMS: (System 2, Method C) m / z 198.4 (M+H). + (ES + ). 1 H NMR (400 MHz, CDCl 3 )δ:7.25-7.16(m,4H), 3.59-3.46(m,1H), 2.40-2.27(m,2H), 2.20-1.93(m,3H), 1.91-1.78(m,1H), 1.73-1.65(m,2H), 1.41-1.33(m,2H).

[0401] Intermediate 16 1-1-(3,5-dichloro-4-fluorophenyl)cyclopropane-1-carbonitrile [ka]

[0402] Step 1 To a solution of 3,5-dichloro-4-fluorobenzoic acid (9.00 g, 43.1 mmol) in THF (10 mL) at 0 °C was added BH 3 .Me 2 A solution of S complex (2M, 130 mL, 260 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with MeOH (20 mL), concentrated under reduced pressure at 30° C. and the residue was diluted with MTBE (30 mL) and water. The phases were separated and the aqueous phase was extracted with MTBE (3×30 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (80 g silica, 0-40% MTBE / petroleum ether) to give (3,5-dichloro-4-fluorophenyl)methanol (8.00 g, 41.0 mmol, 95%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.32 (d, J = 6.2 Hz, 2H), 4.64 (s, 2H). Not a single exchangeable proton is observed.

[0403] Step 2 To a solution of (3,5-dichloro-4-fluorophenyl)methanol (8.00 g, 41.0 mmol) in DCM (100 mL) at 0 °C, SOCl 2 (24.2 g, 205 mmol) was added and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was quenched with water (40 mL), the phases were separated and the aqueous phase was extracted with DCM (4x30 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, and concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (80 g silica, 0-5% MTBE / petroleum ether) to give 1,3-dichloro-5-(chloromethyl)-2-fluorobenzene (7.60 g, 35.6 mmol, 87%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ:7.35(d,J=6.1Hz,2H), 4.48(s,2H).

[0404] Step 3 1,3-Dichloro-5-(chloromethyl)-2-fluorobenzene (7.20 g, 33.7 mmol), TMSCN (5.00 g, 50.6 mmol), K 2 CO 3 A mixture of (7.00 g, 50.6 mmol) and KF (2.90 g, 50.6 mmol) was stirred at 80° C. for 12 h. The mixture was concentrated under reduced pressure at 40° C., the residue was diluted with DCM (30 mL) and water (20 mL), the phases were separated and the aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (80 g silica, 0-20% MTBE / petroleum ether) to give 2-(3,5-dichloro-4-fluorophenyl)acetonitrile (3.20 g, 15.7 mmol, 46%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ:7.31(d,J=6.0Hz,2H), 3.71(s,2H).

[0405] Step 4 To a solution of 2-(3,5-dichloro-4-fluorophenyl)acetonitrile (1.00 g, 4.90 mmol) in THF (10 mL) at 0° C. was added a suspension of sodium hydride in mineral oil (60 wt %, 431 mg, 10.8 mmol) and the mixture was stirred at 0° C. for 30 min. 1,2-Dibromoethane (1.00 g, 5.39 mmol) was added and the resulting suspension was stirred at room temperature for 16 h. The mixture was washed with saturated aqueous NH 4 The mixture was quenched with Cl (10 mL), the phases were separated, and the aqueous phase was extracted with MTBE (3×20 mL). The combined organic layers were washed with H 2 2×20 mL) and brine. 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (25 g silica, 0-20% MTBE / petroleum ether) to give 1-(3,5-dichloro-4-fluorophenyl)cyclopropane-1-carbonitrile (800 mg, 3.48 mmol, 71%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ:7.25(d,J=6.2Hz,2H),1.80-1.74(m,2H),1.43-1.36(m,2H).

[0406] Intermediate 16 4-1-(4-chloro-3,5-difluorophenyl)cyclopropane-1-carbonitrile [ka] Prepared by a similar procedure to Intermediate 161 starting from 4-chloro-3,5-difluorobenzoic acid (2.00 g, 10.39 mmol) except step 2 was heated at 40° C. for 2 h. Yield: 400 mg. White solid. 1 H NMR (400 MHz, CDCl 3 )δ:6.96-6.89(m,2H), 1.86-1.78(m,2H), 1.46-1.37(m,2H).

[0407] Intermediate 16 6-1-(3-chloro-4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile [ka] Prepared by a similar procedure to intermediate 161, steps 2 to 4, starting from (3-chloro-4-(trifluoromethyl)phenyl)methanol (5.8 g, 27.5 mmol), except that step 2 was stirred at room temperature overnight and step 4 was stirred at room temperature for 3 hours. Yield: 480 mg. Off-white solid. 1 H NMR (400 MHz, CDCl 3 )δ:7.67(d,J=8.3Hz,1H), 7.39(d,J=1.4Hz,1H), 7.31-7.26(m,1H), 1.89-1.82(m,2H), 1.52-1.45(m,2H).

[0408] Intermediate 16 9-1-(4-bromo-3-chlorophenyl)cyclopropane-1-carbonitrile [ka] Prepared in a similar manner to Intermediate 161, step 2 to step 4, starting from (4-bromo-3-chlorophenyl)methanol (6.00 g, 27.2 mmol), except that step 2 was stirred at 0 °C for 2 h and step 4 was stirred at room temperature for 3 h. Yield: 1.0 g. White solid. 1 H NMR (400 MHz, CDCl 3 )δ 7.59(d,J=8.4Hz,1H), 7.36(d,J=2.3Hz,1H), 7.06(dd,J=8.4,2.4Hz,1H), 1.81-1.74(m,2H), 1.44-1.37(m,2H).

[0409] Intermediate 17 2-1-(3-chloro-4-methoxyphenyl)cyclopropane-1-carbonitrile [ka] Prepared in a similar manner to Intermediate 161, steps 2 to 4, starting from (3-chloro-4-methoxyphenyl)methanol (3.30 g, 19.1 mmol), except that step 2 was stirred at room temperature for 2 h and step 4 was stirred at room temperature for 3 h. Yield: 425 mg. White solid. 1 H NMR (400 MHz, CDCl 3 )δ:7.26(d,J=2.4Hz,1H), 7.22(dd,J=8.5,2.4Hz,1H), 6.89(d,J=8.5Hz,1H), 3.90(s,3H), 1.72-1.65(m,2H),1.37-1.30(m,2H).

[0410] Intermediate 17 4-1-(3-chloro-4-methylphenyl)cyclopropane-1-carbonitrile [ka] Prepared in a similar manner to intermediate 161, steps 2 to 4, starting from (3-chloro-4-methylphenyl)methanol (8.50 g, 54.3 mmol). Yield: 800 mg. Yellow oil. LCMS: (System 2, Method C) m / z 192.2 / 194.2 (M+H). + (ES + ).

[0411] Intermediate 206-4-Cyclobutylbenzonitrile [ka] Cyclobutanol (1.2 mL, 15 mmol) was added dropwise to a suspension of NaH (60% suspension in mineral oil, 0.69 g, 17 mmol) in 1,4-dioxane (15 mL). After the mixture was stirred for 30 min, 4-fluorobenzonitrile (0.50 g, 4.1 mmol) was added and the mixture was heated at 100° C. for 30 min. It was then cooled to room temperature. The mixture was quenched with EtOH (1 mL), then diluted with brine (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO 4) and concentrated. The crude product was purified by chromatography on silica gel (0-20% MTBE / isohexane) to give 4-cyclobutoxybenzonitrile (0.74 g, 3.8 mmol, 90% purity) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.80-7.68(m,2H), 7.05-6.98(m,2H), 4.84-4.72(m,1H), 2.49-2.39(m,2H), 2.11-1.98(m,2H), 1.86-1.73(m,1H), 1.71-1.58(m,1H).

[0412] The following compounds were synthesized using the same procedure: [Table 16]

[0413] Intermediate 211-4,6-Dichloro-2,3-dihydro-1H-indene-1-carbonitrile [ka] Potassium tert-butoxide (1.67 g, 14.9 mmol) was added portionwise to a solution of 4,6-dichloro-2,3-dihydro-1H-inden-1-one (1.00 g, 4.97 mmol) and TosMIC (2.91 g, 14.9 mmol) in DME (50 mL) and ethanol (2 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give 4,6-dichloro-2,3-dihydro-1H-indene-1-carbonitrile (0.207 g, 0.93 mmol) as an orange solid. 1H NMR(400MHz,DMSO-d6)δ 7.58-7.54(m,1H), 7.52-7.48(m,1H), 4.65-4.56(m,1H), 3.08-2.98(m,1H), 2.96-2.86(m,1H), 2.63-2.52(m,1H), 2.37-2.26(m,1H).

[0414] Intermediate 212-2-(3,5-dichloro-4-fluorophenyl)-2,2-difluoro-N-hydroxyacetimidamide [ka] Hydroxylamine (50% in water, 1.0 mL, 17.6 mmol) was added to a solution of 2-(3,5-dichloro-4-fluorophenyl)-2,2-difluoroacetonitrile (2.818 g, 11.74 mmol) in IPA (20 mL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was coevaporated with toluene (3x10 mL) to give 2-(3,5-dichloro-4-fluorophenyl)-2,2-difluoro-N-hydroxyacetimidamide (3.06 g, 11 mmol) as an orange solid. LCMS m / z 273.0 / 275.0 (M+H) + (ES + ). 1 H NMR (400MHz, DMSO-d6) δ 7 10.09 (s, 1H), 7.74 (d, J = 6.3Hz, 2H), 6.16 (s, 2H). 19 F NMR (376MHz, DMSO) δ-96.06(d,J=2.5Hz), -113.42--116.00(m).

[0415] The following compounds were synthesized using the same procedure: [Table 17]

[0416] Intermediate 215-4-Butoxy-3-chlorobenzonitrile [ka] Prepared in a similar procedure to intermediate 154 using 3-chloro-4-hydroxybenzonitrile (1.00 g, 6.54 mmol). Yield: 1.20 g, 5.72 mmol, 88%. LCMS: (System 2, Method C) m / z 210.3 / 212.2 (M+H). + (ES + ).

[0417] Intermediate 217-4-Butoxy-3-(trifluoromethyl)benzonitrile [ka] Prepared in a similar procedure to intermediate 154 using 4-hydroxy-3-(trifluoromethyl)benzonitrile (1.40 g, 7.48 mmol). Yield: 1.50 g, 6.17 mmol, 82%. LCMS: (System 2, Method C) m / z 244.2 (M+H). + (ES + ).

[0418] Intermediate 219-4-Butoxy-3,5-difluorobenzonitrile [ka] 3,5-Difluoro-4-hydroxybenzonitrile (750 mg, 4.84 mmol), butan-1-ol (393 mg, 5.32 mmol), and PPh in THF (15 mL) at 0 °C 3 To a solution of (2.54 g, 9.68 mmol) was added DIAD (1.96 g, 9.68 mmol) and the resulting pale yellow mixture was stirred at room temperature for 4 h. The reaction was quenched with water (10 mL), the phases were separated and the aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (25 g silica, 0-2% MTBE / petroleum ether) to give 4-butoxy-3,5-difluorobenzonitrile (750 mg, 3.55 mmol, 73%) as a pale yellow liquid. LCMS: (System 2, Method C) m / z 212.3 (M+H). + (ES + ).

[0419] Intermediate 220-tert-Butyl 3-(6-bromopyridin-2-yl)-2-(diethoxyphosphoryl)propanoate [ka] Tert-Butyl 2-(diethoxyphosphoryl)acetate (0.94 mL, 4.0 mmol) was added dropwise to a suspension of NaH (60 wt%, 0.18 g, 4.5 mmol) in THF (12 mL). The mixture was stirred at room temperature for 30 min. 2-Bromo-6-(bromomethyl)pyridine (1.0 g, 4.0 mmol) was added in portions and the mixture was then heated to 60 °C for 1 h. The mixture was cooled to room temperature and then poured into brine (40 mL) and extracted with EtOAc (3x50 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated. The crude product was purified by chromatography on a RP Flash C18 (5-75% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give tert-butyl 3-(6-bromopyridin-2-yl)-2-(diethoxyphosphoryl)propanoate (1.07 g, 2.4 mmol) as a colorless oil. LCMS: m / z 442.2 / 444.4 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.67(t,J=7.7Hz,1H), 7.48(d,J=7.8Hz,1H), 7.38(d,J=7.5Hz,1H), 4.15-3.99(m,4H), 3 .54-3.37(m,1H), 3.29-3.19(m,1H), 3.18-3.06(m,1H), 1.32(s,9H), 1.29-1.20(m,6H).

[0420] Example 1-2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0421] Step 1 Prepared from 5-(chloromethyl)-3-octyl-1,2,4-oxadiazole (intermediate 1, 0.60 g, 2.6 mmol) following general procedure A, step 1, method A. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-octyl-1,2,4-oxadiazol-5-yl)propanoate (0.413 g, 0.92 mmol) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 4.15-4.04(m,4H), 3.56(ddd,J=23.4,11.1,4.4Hz,1H), 3.41-3.32(m,1H), 3.28-3.17(m,1H), 2.64(t,J=7.4Hz,2H), 1.71-1.55(m,2H), 1.37(s,9H), 1.32-1.19(m,16H), 0.90-0.82(m,3H). LCMS m / z 469.3(M+Na) + (ES + ).

[0422] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-octyl-1,2,4-oxadiazol-5-yl)propanoate (0.413 g, 0.93 mmol) following general procedure A, step 2, method A. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give tert-butyl 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.105 g, 0.322 mmol) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ 6.23(d,J=1.3Hz,1H), 5.93-5.86(m,1H), 3.91(s,2H), 2.64(t,J=7.3Hz,2 H), 1.68-1.57(m,2H), 1.34(s,9H), 1.28-1.21(m,10H), 0.91-0.78(m,3H). LCMS m / z 323.2(M+H) + (ES + ).

[0423] Step 3 Prepared from tert-butyl 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.105 g, 0.33 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give the title compound (0.059 g, 0.22 mmol) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 12.81(s,1H), 6.28(d,J=1.2Hz,1H), 5.94-5.83(m,1H), 3.91(s,2H), 2.64( t,J=7.5Hz,2H), 1.66-1.56(m,2H), 1.33-1.19(m,10H), 0.90-0.81(m,3H). LCMS m / z 267.2(M+H) + (ES + ).

[0424] Example 1 can also be prepared using the following route: [ka]

[0425] Step 1 A solution of hydroxylamine hydrochloride (72.9 g, 1.05 mol) in isopropanol (420 mL) was added to the flask with NaHCO 3(150 g, 1.78 mol) was added in one portion at a time. The mixture was stirred at room temperature for 10 min, then nonanenitrile (73.0 g, 524 mmol) was added in one portion at a time to the mixture. The mixture was heated to 85° C. and stirred for 12 h. The mixture was filtered and the filter cake was washed with isopropanol (2×200 mL). The filtrate was concentrated under reduced pressure at 45° C. to give crude N-hydroxynonanimidamide (80 g, 464 mmol, 89%) as a white solid. The crude product was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ:8.65(s,1H), 5.27(s,2H), 1.92(t,J=7.2Hz,2H), 1.51-1.40(m,2H), 1.31-1.19(m,10H), 0.86(t,J=6.0Hz,3H).

[0426] Step 2 Five reactions were carried out in parallel. To a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (300 g, 1.19 mol) in THF (3 L) was added a suspension of NaH in mineral oil (60 wt%, 50.4 g, 1.26 mol) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then ethyl bromoacetate (179 g, 1.07 mol) was added dropwise to the mixture at such a rate as to keep the internal temperature below 10 °C. The mixture was stirred at 10 °C for 1 h, then aqueous NH 4 The five batches of reactions were combined and the combined mixture was extracted with ethyl acetate (3×2 L). The combined organic layers were washed with brine (500 mL) and poured into Na 2 SO 4 The mixture was dried at 45° C., filtered, and concentrated under reduced pressure at 45° C. to give 1-(tert-butyl) 4-ethyl 2-(diethoxyphosphoryl)succinate (1.80 kg, 5.32 mol, 89% crude) as a colorless oil. The crude product was used directly in the next step without further purification. 1H NMR (400MHz, DMSO-d6) δ: 4.12-3.98(m,6H), 3.34-3.21(m,1H), 2.84-2.71(m,1H), 2.68-2.57(m,1H), 1.40(s,9H), 1.29-1.14(m,9H).

[0427] Step 3 Four reactions were carried out in parallel. To a solution of 1-(tert-butyl)4-ethyl 2-(diethoxyphosphoryl)succinate (300 g, 887 mmol) in tetrahydrofuran (1.48 L) was added aqueous NaOH solution (1 M, 1.21 L, 1.21 mmol) in one portion at a time. The mixture was stirred at room temperature for 12 h. The four reactions were combined for workup. The reaction mixture was concentrated under reduced pressure at 45° C. to remove tetrahydrofuran and the residue was extracted with ethyl acetate (2×500 mL). The pH of the aqueous phase was adjusted to 1 with concentrated aqueous HCl (12 M) and the aqueous phase was extracted with ethyl acetate (3×2 L). The combined organic layers were washed with brine (5 L) and Na 2 SO 4 The crude product was triturated with isopropyl ether (1.1 L) and stirred at room temperature for 30 min. The suspension was filtered and the filter cake was washed with isopropyl ether (2x300 mL) and dried under vacuum to give 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutanoic acid (840 g, 2.70 mmol, 76%) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ:10.04(br.s,1H), 4.22-4.08(m,4H), 3.43-3.29(m,1H), 3.08-2.94(m,1H), 2.85-2.73(m,1H), 1.45(s,9H), 1.37-1.27(m,6H).

[0428] Steps 4 and 5 To a solution of 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutanoic acid (100 g, 322 mmol) in THF (600 mL) was added 4-methylmorpholine (32.6 g, 322 mmol) in one portion at room temperature. The mixture was cooled to -15 °C and ethyl chloroformate (35.0 g, 322 mmol) was added dropwise to the mixture at such a rate as to keep the internal temperature at -15 to -10 °C. The mixture was stirred at -15 to -10 °C for 2 h, then N-hydroxynonanimidamide (55.5 g, 322 mmol) and triethylamine (54.5 g, 538 mmol) were added dropwise at -15 to -10 °C. The mixture was stirred at room temperature for 12 h and then quenched by the addition of dilute aqueous HCl (1 M, 500 mL) at room temperature. The mixture was extracted with ethyl acetate (3×500 mL) and the combined organic layers were washed with brine (500 mL) and sodium 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure at 45° C. to give a brown oil. The crude product was purified by flash column chromatography on silica (5-100% ethyl acetate / n-heptane) to give tert-butyl 2-(diethoxyphosphoryl)-4-((1-(hydroxyamino)nonylidene)amino)-4-oxobutanoate (140 g, 301 mmol, 94%) as a yellow oil. LCMS m / z 465.1 (M+H). + (ES + ). 1 H NMR (400 MHz, DMSO-d6) δ: 6.35 (s, 1H), 4.12-3.98 (m, 4H), 3.45-3.33 (m, 1H), 2.97-2.83 (m, 1H), 2.79-2.66 (m, 1H), 2.06-1.95 (m, 2H), 1.57-1.44 (m, 2H), 1.39 (s, 9H), 1.31-1.19 (m, 16H), 0.89-0.81 (m, 3H). Not a single exchangeable proton was observed.

[0429] Step 6 To a solution of tert-butyl 2-(diethoxyphosphoryl)-4-((1-(hydroxyamino)nonylidene)amino)-4-oxobutanoate (140 g, 301 mmol) in THF (840 mL) was added Cs 2CO 3 (196 g, 603 mmol) was added in one portion at room temperature. The mixture was stirred at 70° C. for 3 h and then quenched by adding water (1 L) at room temperature. The mixture was extracted with ethyl acetate (3×1 L) and the combined organic layers were washed with brine (500 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure at 45° C. to give a brown oil. The crude product was purified by flash column chromatography on silica (5-100% ethyl acetate / n-heptane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-octyl-1,2,4-oxadiazol-5-yl)propanoate (109 g, 244 mmol, 81%) as a yellow oil. LCMS m / z 469.2 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ:4.14-4.04(m,4H), 3.60-3.48(m,1H), 3.39-3.28(m,1H), 3.27-3.17(m,1 H), 2.62(t,J=7.6Hz,2H), 1.66-1.55(m,2H), 1.36(s,9H), 1.29-1.20(m,16H), 0.87-0.82(m,3H).

[0430] Step 7 To a solution of tert-butyl 2-(diethoxyphosphoryl)-3-(3-octyl-1,2,4-oxadiazol-5-yl)propanoate (100 g, 192 mmol) in THF (600 mL), 2 CO 3 (79.9 g, 578 mmol) and paraformaldehyde (3.30 g, 193 mmol) were added in one portion at room temperature. The mixture was stirred at 65 °C for 12 h, then the mixture was concentrated under reduced pressure at 45 °C to give the crude product. The crude product was purified by flash column chromatography on silica (5-100% ethyl acetate / n-heptane) to give tert-butyl 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylate (48 g, 149 mmol, 61%) as a yellow oil. LCMS m / z 323.1 (M+Na).+ (ES + ). 1 H NMR(400MHz,DMSO-d6)δ:6.22(s,1H), 5.89(d,J=1.2Hz,1H), 3.90(s,2H), 2.63(t,J=7 .2Hz,2H), 1.67-1.55(m,2H), 1.34(s,9H), 1.31-1.18(m,10H), 0.85(t,J=7.2Hz,3H).

[0431] Step 8 To a solution of tert-butyl 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylate (48 g, 149 mmol) in DCM (160 mL) was added TFA (170 g, 1.49 mol) portionwise. The mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure at 45° C. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 10 μm 100x250 mm; solvent system: MeCN / (0.1% TFA / water) gradient: 40-70% MeCN) to give the product, which was lyophilized under vacuum at room temperature. The product, still containing some MeCN, was coevaporated three times with MTBE (100 mL) and then concentrated under reduced pressure at 45° C. for 3 h to give 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (28 g, 105 mmol, 69%) as a yellow oil. LCMS m / z 267.1 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ:12.8(s,1H), 6.27(s,1H), 5.90(d,J=0.8Hz,1H), 3.90(s,2 H), 2.67-2.60(m,2H), 1.66-1.56(m,2H), 1.32-1.18(m,10H), 0.85(t,J=6.8Hz,3H).

[0432] Isolation of the tromethamine (TRIS) salt of Example 1 Example 1 (38.4 mg, 1 molar equivalent) was loaded into a vial and dissolved in ACN (400 μL). Tromethamine (17.5 mg, 0.99 molar equivalent) was loaded into the solution and stirred at 300 rpm for 2 hours at ambient temperature. The resulting solution was evaporated under a nitrogen flow to give a solid, which was analyzed by XRPD, DSC, TGA, and NMR. 1 Analyzed by H NMR. mp 122°C. 1 H NMR (400 MHz, DMSO-d6) δ 5.88 (s, 1H), 5.23 (s, 1H), 3.73 (s, 2H), 3.45 (s, 6H), 2.59 (t, J = 7.4 Hz, 2H), 1.63-1.53 ​​(m, 2H), 1.27-1.12 (m, 10H), 0.80 (t, J = 6.6 Hz, 3H). Six exchangeable protons not observed.

[0433] The XRPD data for the tromethamine salt of Example 1 is shown in Table 1. [Table 18]

[0434] TGA data (Figure 1) showed a weight loss of approximately 0.037% from 25 to 100° C. DSC analysis (Figure 1) showed an onset of melting at 122° C.

[0435] The isolation of the tromethamine salt of Example 1 was scaled up as follows:

[0436] Example 1 (2 g, 1 molar equivalent) was loaded into a round bottom flask and dissolved in ACN (20 mL). TRIS (0.91 g, 1 molar equivalent) was dissolved in water (5 mL) and then charged to the solution containing Example 1. The mixture was stirred at ambient temperature for approximately 1 hour, at which point all material had dissolved. The resulting solution was first evaporated using a rotary evaporator to isolate an oil. ACN (10 mL) was added to the oil. The system was mixed for 10 minutes and a white solid was observed. The material was collected and 1 Analysis was performed by 1 H NMR. 1The H NMR spectrum showed the formation of the tromethamine salt of Example 1, with the ratio between Example 1 and the salt being 1:1.04, respectively. No double bond isomerization was observed. The XRPD pattern of the crystalline tromethamine salt of Example 1 is shown in FIG. 1 The H NMR spectrum is shown in Figure 3.

[0437] Example 2-2-((5-octyl-1,3,4-oxadiazol-2-yl)methyl)acrylic acid [ka]

[0438] Step 1 Prepared from 2-(chloromethyl)-5-octyl-1,3,4-oxadiazole (intermediate 2, 0.86 g, 3.7 mmol) following general procedure A, step 1, method A. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(5-octyl-1,3,4-oxadiazol-2-yl)propanoate (1.23 g, 1.1 mmol, 40% purity) as a yellow oil. LCMS m / z 469.3 (M+Na). + (ES + ).

[0439] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(5-octyl-1,3,4-oxadiazol-2-yl)propanoate (1.23 g, 1.1 mmol, 40% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-((5-octyl-1,3,4-oxadiazol-2-yl)methyl)acrylate (0.197 g, 0.60 mmol) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ 6.20(d,J=1.1Hz,1H), 5.87-5.79(m,1H), 3.86-3.76(m,2H), 2.80(t,J=7.4Hz ,2H), 1.70-1.57(m,2H), 1.38(s,9H), 1.34-1.20(m,10H), 0.93-0.80(m,3H). LCMS m / z 323.2(M+H) + (ES + ).

[0440] Step 3 Prepared from tert-butyl 2-((5-octyl-1,3,4-oxadiazol-2-yl)methyl)acrylate (0.197 g, 0.60 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give the title compound (0.132 g, 0.49 mmol) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 12.78(s,1H), 6.25(d,J=1.1Hz,1H), 5.86-5.80(m,1H), 3.83(s,2H), 2.80( t,J=7.5Hz,2H), 1.71-1.60(m,2H), 1.34-1.23(m,10H), 0.90-0.83(m,3H). LCMS m / z 267.1(M+H) + (ES + ).

[0441] Example 3-2-((5-octyl-1,2,4-oxadiazol-3-yl)methyl)acrylic acid [ka]

[0442] Step 1 Prepared from 3-(chloromethyl)-5-octyl-1,2,4-oxadiazole (intermediate 3, 3.18 g, 13.8 mmol) following general procedure A, step 1, method A. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(5-octyl-1,2,4-oxadiazol-3-yl)propanoate (3.70 g, 7.3 mmol, 88% purity) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 4.14-4.03(m,4H), 3.42-3.33(m,1H), 3.24-3.12(m,1H), 3.07-2.98(m,1H), 2.89(t, J=7.4Hz,2H), 1.73-1.65(m,2H), 1.36(s,9H), 1.29-1.22(m,16H), 0.89-0.83(m,3H). LCMS m / z 469.3(M+Na) + (ES + ).

[0443] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(5-octyl-1,2,4-oxadiazol-3-yl)propanoate (3.70 g, 7.3 mmol, 88% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give tert-butyl 2-((5-octyl-1,2,4-oxadiazol-3-yl)methyl)acrylate (1.75 g, 5.4 mmol) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 6.16(d,J=1.3Hz,1H), 5.78-5.70(m,1H), 3.68(s,2H), 2.88(t,J=7.4Hz,2 H), 1.74-1.64(m,2H), 1.38(s,9H), 1.34-1.19(m,10H), 0.89-0.81(m,3H). LCMS m / z 267.2(M-tBu+H) + (ES + ).

[0444] Step 3 Prepared from tert-butyl 2-((5-octyl-1,2,4-oxadiazol-3-yl)methyl)acrylate (1.65 g, 5.12 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give the title compound (1.32 g, 4.9 mmol) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 12.57(s,1H), 6.22(d,J=1.3Hz,1H), 5.75(d,J=1.5Hz,1H), 3.68(s,2H), 2.8 8(t,J=7.5Hz,2H), 1.78-1.59(m,2H), 1.37-1.18(m,10H), 0.93-0.78(m,3H). LCMS m / z 267.1(M+H) + (ES + ).

[0445] Example 4-2-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0446] Step 1 Prepared from 3-(4-chlorobenzyl)-5-(chloromethyl)-1,2,4-oxadiazole (intermediate 5, 5.65 g, 23.2 mmol) following general procedure A, step 1, method A. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 3-(3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (7.27 g, 9.0 mmol, 57% purity) as a yellow oil. LCMS m / z 481.2 / 483.3 (M+Na). + (ES + ).

[0447] Step 2 Prepared from tert-butyl 3-(3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (7.27 g, 9.0 mmol, 57% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-30% EtOAc / isohexane) to give tert-butyl 2-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.468 g, 1.40 mmol) as a colorless oil. LCMS m / z 279.1 / 281.0 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.42-7.35(m,2H), 7.35-7.26(m,2H), 6.21(d,J=1.2Hz,1H), 5.94-5.84(m,1H), 4.06(s,2H), 3.91(s,2H), 1.25(s,9H).

[0448] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.468 g, 1.40 mmol). The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (0.265 g, 0.94 mmol) as a colorless gum. LCMS m / z 279.5 / 281.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.80(s,1H), 7.44-7.35(m,2H), 7.35-7.28(m,2H), 6.27(d,J=1.2Hz,1H), 5.95-5.87(m,1H), 4.08(s,2H), 3.91(s,2H).

[0449] Example 5-2-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0450] Step 1 Prepared from 5-(chloromethyl)-3-(4-chlorophenethyl)-1,2,4-oxadiazole (Intermediate 6, 2.11 g, 8.21 mmol) following General Procedure A, Step 1, Method C, except the reaction was not heated above room temperature. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(5-octyl-1,3,4-oxadiazol-2-yl)propanoate (1.87 g, 1.7 mmol, 44% purity) as a yellow oil. LCMS m / z 495.1 / 497.1 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.35-7.20(m,4H), 4.15-4.01(m,4H), 3.64-3.49(m,1H), 3.41-3.32(m,1 H), 3.29-3.19(m,1H), 2.98-2.96(m,4H), 1.37(s,9H), 1.27-1.22(m,6H).

[0451] Step 2 Prepared from tert-butyl 3-(3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.87 g, 1.7 mmol, 44% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give tert-butyl 2-((3-pentyl-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.413 g, 1.2 mmol) as a yellow oil. LCMS m / z 293.1 / 295.1 (M-tBu+H). + (ES+ ). 1 H NMR(400MHz,DMSO-d6)δ 7.36-7.29(m,2H), 7.29-7.22(m,2H), 6.24(d,J=1.2Hz,1H), 5.92-5.85(m,1H), 3.92(s,2H), 2.97(s,4H), 1.34(s,9H).

[0452] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.41 g, 1.40 mmol). The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give 2-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (0.275 g, 0.93 mmol) as a colorless gum. LCMS m / z 293.1 / 295.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.83(s,1H), 7.37-7.28(m,2H), 7.27-7.19(m,2H), 6.29(d,J=1.3Hz,1H), 5.97-5.86(m,1H), 3.92(s,2H), 2.97(m,4H).

[0453] Example 6-2-((3-heptyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0454] Step 1 Prepared from 5-(chloromethyl)-3-heptyl-1,2,4-oxadiazole (intermediate 4, 7.00 g, 31 mmol) following general procedure A, step 1, method C. The crude product was purified by chromatography on silica gel (0-70% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-heptyl-1,2,4-oxadiazol-5-yl)propanoate (5.84 g, 13 mmol) as a colorless oil. LCMS m / z 455.2 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 4.15-4.05(m,4H), 3.56(ddd,J=23.3,11.1,4.4Hz,1H), 3.40-3.29(m,1H), 3.23(ddd,J=16.8,8.6,4.3 Hz,1H), 2.64(t,J=7.3Hz,2H), 1.68-1.56(m,2H), 1.37(s,9H), 1.31-1.20(m,14H), 0.90-0.83(m,3H).

[0455] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-heptyl-1,2,4-oxadiazol-5-yl)propanoate (5.84 g, 13.5 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-30% EtOAc / isohexane) to give tert-butyl 2-((3-heptyl-1,2,4-oxadiazol-5-yl)methyl)acrylate (3.42 g, 11 mmol) as a colorless oil. LCMS m / z 253.2 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 6.23(d,J=1.2Hz,1H), 5.90(d,J=1.3Hz,1H), 3.91(s,2H), 2.64(t,J=7.4 Hz,2H), 1.62(s,2H), 1.34(s,9H), 1.30-1.21(m,8H), 0.89-0.82(m,3H).

[0456] Step 3 Prepared from tert-butyl 2-((3-heptyl-1,2,4-oxadiazol-5-yl)methyl)acrylate (1.00 g, 3.24 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give 2-((3-heptyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (0.746 g, 2.9 mmol) as a colorless gum. LCMS m / z 253.3 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.79(br.s,1H), 6.28(d,J=1.2Hz,1H), 5.92(d,J=1.2Hz,1H), 3.91(s,2H), 2 .65(t,J=7.5Hz,2H), 1.71-1.54(m,2H), 1.35-1.19(m,8H), 0.95-0.78(m,3H).

[0457] Example 7-2-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0458] Step 1 Prepared from 5-(chloromethyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole (intermediate 7, 4.00 g, 17 mmol) following general procedure A, step 1, method A using THF instead of NMP. The crude product was purified by chromatography on a RP Flash C18 (5-75% MeCN / water 0.1% formic acid) to give tert-butyl 3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (3.06 g, 6.2 mmol, 90% purity) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ 8.03-7.95(m,2H), 7.71-7.62(m,2H), 4.17-4.05(m,4H), 3.75-3.61(m,1H), 3.53-3.34(m,2H), 1.38(s,9H), 1.27(q,J=6.8Hz,6H). LCMS m / z 445.1(M+H) + (ES + ).

[0459] Step 2 Prepared from tert-butyl 3-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (3.06 g, 6.2 mmol, 90% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on RP Flash C18 (5-75% MeCN / water 0.1% formic acid) followed by chromatography on silica gel (0-50% EtOAc / isohexane) to give tert-butyl 2-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.30 g, 0.89 mmol) as a clear, colorless oil. LCMS m / z 265.1 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 8.04-7.94(m,2H), 7.69-7.60(m,2H), 6.29(d,J=1.2Hz,1H), 6.03-5.95(m,1H), 4.05(s,2H), 1.34(s,9H).

[0460] Step 3 Prepared from tert-butyl 2-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.30 g, 0.89 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on RP Flash C18 (5-75% MeCN / water 0.1% formic acid) to give 2-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.232 g, 0.83 mmol) as a white solid. LCMS m / z 265.1 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.88(s,br.1H), 8.07-7.91(m,2H), 7.70-7.56(m,2H), 6.33(d,J=1.2Hz,1H), 6.07-5.90(m,1H), 4.04(s,2H).

[0461] Example 8 - 2-((3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0462] Step 1 Prepared from 5-(chloromethyl)-3-(octan-2-yl)-1,2,4-oxadiazole (intermediate 8, 1.16 g, 4.78 mmol) following general procedure A, step 1, method A using THF instead of NMP. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)propanoate (0.62 g, 1.2 mmol, 90% purity) as a colorless oil. LCMS m / z 469.1 (M+Na). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 4.14-4.03(m,4H), 3.63-3.47(m,1H), 3.40-3.32(m,1H), 3.28-3.16(m,1H), 2.94-2. 82(m,1H), 1.68-1.44(m,2H), 1.37(s,9H), 1.32-1.08(m,17H), 0.84(t,J=6.8Hz,3H).

[0463] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)propanoate (0.62 g, 1.2 mmol, 90% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-10% EtOAc / isohexane) to give tert-butyl 2-((3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.36 g, 1.1 mmol) as a colorless oil. LCMS m / z 267.2 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 6.25-6.21(m,1H), 5.92-5.88(m,1H), 3.92(s,2H), 2.97-2.81(m,1H), 1.69-1.45(m,2H), 1.34(s,9H), 1.29-1.09(m,11H), 0.90-0.80(m,3H).

[0464] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.38 g, 1.1 mmol). The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give 2-((3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (0.32 g, 1.1 mmol) as a colorless oil. LCMS m / z 267.2 (M+H). + (ES +). 1 H NMR(400MHz,DMSO-d6)δ 12.80(s,br.1H), 6.30-6.26(m,1H), 5.92-5.88(m,1H), 3.91(s,2H), 3.02-2.81(m ,1H), 1.69-1.57(m,1H), 1.57-1.46(m,1H), 1.33-1.06(m,11H), 0.91-0.79(m,3H).

[0465] Example 9 - 2-((3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0466] Step 1 Prepared from 5-(chloromethyl)-3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazole (intermediate 9, 1.00 g, 3.7 mmol) following general procedure A, step 1, method A using THF instead of NMP. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazol-5-yl)propanoate (1.01 g, 1.8 mmol, 84% purity) as an orange oil. LCMS m / z 497.3 (M+Na). + (ES + ).

[0467] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazol-5-yl)propanoate (1.01 g, 1.8 mmol, 84% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-((3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.30 g, 0.85 mmol) as a pale yellow oil. LCMS m / z 295.2 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.92-7.83(m,3H), 7.81(d,J=1.7Hz,1H), 7.54-7.45(m,2H), 7.42(dd,J=8.5,1.8Hz,1H ), 6.20(d,J=1.3Hz,1H), 5.88(t,J=1.2Hz,1H), 4.22(s,2H), 3.91(s,2H), 1.20(s,9H).

[0468] Step 3 Prepared from tert-butyl 2-((3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.30 g, 0.85 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give 2-((3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (180 mg, 0.58 mmol) as a white solid. LCMS m / z 295.1 (M+H). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 12.82(s,1H), 7.93-7.84(m,3H), 7.80(d,J=1.7Hz,1H), 7.54-7.46(m,2H), 7.43(dd,J= 8.5,1.8Hz,1H), 6.26(d,J=1.2Hz,1H), 5.90(d,J=1.3Hz,1H), 4.23(s,2H), 3.91(s,2H).

[0469] Example 10-2-((3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0470] Step 1 Tert-Butyl 2-(diethoxyphosphoryl)acetate (1.92 mL, 8.17 mmol) was added to a suspension of 5-(chloromethyl)-3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazole (Intermediate 10, 2.00 g, 7.43 mmol) and cesium carbonate (2.66 g, 8.17 mmol) in DME (20 mL) at room temperature. The reaction was heated to 80° C. and stirred for 18 h. Potassium iodide (123 mg, 0.74 mmol) was added and stirring was continued at 80° C. for 1 h. The mixture was cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (30 mL), dried (Na 2 SO 4 ) and concentrated. The crude product was purified by chromatography on silica gel (0-60% EtOAc / isohexane) to give tert-butyl 3-(3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.12 g, 1.6 mmol, 71% purity) as a yellow oil. LCMS m / z 507.1 (M+Na). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 7.40(s,4H), 4.15-3.99(m,4H), 3.52(ddd,J=23.3,10.9,4.4Hz,1H), 3.37-3.28(m,1H), 3 .20(ddd,J=16.8,8.8,4.4Hz,1H), 1.56-1.37(m,4H), 1.36(s,9H), 1.25(q,J=6.8Hz,6H).

[0471] Step 2 Prepared from tert-butyl 3-(3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.12 g, 1.6 mmol, 71% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-30% EtOAc / isohexane) to give tert-butyl 2-((3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (396 mg, 1.1 mmol) as a colorless oil. LCMS m / z 305.1 / 307.1 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.40(s,4H), 6.21(d,J=1.2Hz,1H), 5.88(d,J=1.3Hz,1H), 3.89(s,2H), 1.50-1.41(m,2H), 1.41-1.34(m,2H), 1.33(s,9H).

[0472] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.394 g, 1.1 mmol). The crude product was purified by chromatography on silica gel (0-60% EtOAc / isohexane) to give 2-((3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (206 mg, 0.67 mmol) as a colorless gum. LCMS m / z 305.1 / 307.1 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.82(s,1H), 7.60-7.27(m,4H), 6.27(d,J=1.2Hz,1H), 5.90(d,J=1.2Hz,1H), 3.89(s,2H), 1.51-1.34(m,4H).

[0473] Example 11-2-((3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0474] Step 1 Prepared from 5-(chloromethyl)-3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazole (Intermediate 11, 4.30 g, 15.1 mmol) following General Procedure A, Step 1, Method C, except the reaction was not heated above room temperature. The crude product was purified by chromatography on silica gel (0-60% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)propanoate (4.30 g, 1.7 mmol, 44% purity) as a yellow oil. LCMS m / z 523.2 (M+Na). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 4.21-3.90(m,4H), 3.69-3.48(m,1H), 3.39-3.30(m,1H), 3.23(ddd,J=16.8,8.7,4.4Hz,1H), 2 .69-2.60(m,2H), 2.29-2.13(m,2H), 1.68-1.55(m,2H), 1.50-1.42(m,2H), 1.41-1.14(m,21H)

[0475] Step 2 Prepared according to General Procedure A, step 2, method B from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)propanoate (4.30 g, 8.59 mmol) and the crude product was purified by chromatography on silica gel (0-30% EtOAc / isohexane) to give tert-butyl 2-((3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (1.84 g, 4.6 mmol) as a clear, colorless oil. LCMS m / z 321.2 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 6.23(d,J=1.2Hz,1H), 5.92-5.86(m,1H), 3.91(s,2H), 2.65(t,J=7.4Hz,2H), 2.29-2.12(m,2H), 1.69-1.57(m,2H), 1.49-1.41(m,2H), 1.36-1.28(m,15H).

[0476] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (1.84 g, 4.89 mmol). The crude product was purified by chromatography on silica gel (0-30% EtOAc / isohexane) to give 2-((3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (1.39 g, 4.33 mmol) as a clear, colorless oil. LCMS m / z 321.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.80(s,1H), 6.30-6.25(m,1H), 5.94-5.87(m,1H), 3.91(s,2H), 2.65(t,J=7.5Hz ,2H), 2.30-2.15(m,2H), 1.68-1.56(m,2H), 1.51-1.40(m,2H), 1.37-1.25(m,6H). 19 F NMR(376MHz,DMSO-d6)δ-64.76.

[0477] Example 12-2-((3-(2-methylheptan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0478] Step 1 Prepared according to general procedure A, step 1, method B from 5-(chloromethyl)-3-(2-methylheptan-2-yl)-1,2,4-oxadiazole (0.60 g, 2.5 mmol), except that no sodium iodide was used and the reaction was not heated above room temperature. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(2-methylheptan-2-yl)-1,2,4-oxadiazol-5-yl)propanoate (0.55 g, 1.1 mmol, 90% purity) as a yellow oil. LCMS m / z 447.4 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 4.15-4.03(m,4H), 3.54(ddd,J=23.3,11.1,4.3Hz,1H), 3.40-3.32(m,1H), 3.31-3.17(m,1H), 1.60-1. 52(m,2H), 1.37(s,10H), 1.31-1.12(m,16H), 1.08(ddd,J=13.8,7.5,5.3Hz,1H), 0.82(t,J=7.0Hz,3H).

[0479] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(2-methylheptan-2-yl)-1,2,4-oxadiazol-5-yl)propanoate (0.55 g, 1.1 mmol, 90% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-((3-(2-methylheptan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.30 g, 0.93 mmol) as a colorless oil. LCMS m / z 267.0 (M-tBu+H). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 6.22(d,J=1.3Hz,1H), 5.89(q,J=1.3Hz,1H), 3.90(s,2H), 1.60-1.52(m,2H) , 1.34(s,9H), 1.27-1.12(m,10H), 1.11-1.01(m,2H), 0.81(t,J=7.0Hz,3H).

[0480] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(2-methylheptan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.30 g, 0.93 mmol). The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give 2-((3-(2-methylheptan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (0.16 g, 0.57 mmol) as a white waxy solid. LCMS m / z 267.0 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.78(s,1H), 6.27(d,J=1.2Hz,1H), 5.88(q,J=1.3Hz,1H), 3.90(s,2H), 1.6 1-1.50(m,2H), 1.28-1.11(m,10H), 1.11-1.00(m,2H), 0.81(t,J=7.0Hz,3H).

[0481] Example 13-2-((1-octyl-1H-1,2,4-triazol-3-yl)methyl)acrylic acid [ka]

[0482] Step 1 Prepared from 3-(chloromethyl)-1-octyl-1H-1,2,4-triazole (2.40 g, 10.4 mmol) following general procedure A, step 1, method C. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(1-octyl-1H-1,2,4-triazol-3-yl)propanoate (3.72 g, 5.4 mmol, 65% purity) as an orange oil. LCMS m / z 466.3 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 8.36(s,1H), 4.10-4.03(m,6H), 3.39-3.29(m,1H), 3.13(ddd,J=15.5,11.8,7.1Hz,1H), 2.92(ddd ,J=15.5,9.6,3.3Hz,1H), 1.74-1.69(m,2H), 1.33(s,9H), 1.27-1.21(m,16H), 0.86-0.83(m,3H).

[0483] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(1-octyl-1H-1,2,4-triazol-3-yl)propanoate (3.72 g, 5.4 mmol, 65% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-((1-octyl-1H-1,2,4-triazol-3-yl)methyl)acrylate (1.60 g, 4.98 mmol) as a colorless oil. LCMS m / z 344.3 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 8.36(s,1H), 6.05(d,J=1.6Hz,1H), 5.61-5.49(m,1H), 4.07(t,J=6.9Hz,2H), 3.5 7(s,2H), 1.80-1.63(m,2H), 1.37(s,9H), 1.30-1.14(m,10H), 0.88-0.82(m,3H).

[0484] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((1-octyl-1H-1,2,4-triazol-3-yl)methyl)acrylate (1.60 g, 4.98 mmol). The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((1-octyl-1H-1,2,4-triazol-3-yl)methyl)acrylic acid (1.17 g, 4.40 mmol) as a colorless oil. LCMS m / z 266.2 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.48(s,1H), 8.37(s,1H), 6.12(d,J=1.6Hz,1H), 5.53(q,J=1.6Hz,1H), 4.08(t,J=7.0 Hz,2H), 3.57(s,2H), 1.73(p,J=7.1Hz,2H), 1.31-1.15(m,10H), 0.85(t,J=6.8Hz,3H).

[0485] Example 14-2-((3-(3,4-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0486] Step 1 Prepared from 5-(chloromethyl)-3-(3,4-dichlorobenzyl)-1,2,4-oxadiazole (5.00 g, 18.0 mmol) following general procedure A, step 1, method C. The crude product was purified by chromatography on silica gel (0-60% EtOAc / isohexane) to give tert-butyl 3-(3-(3,4-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (2.74 g, 3.1 mmol, 55% purity) as an orange oil. LCMS m / z 437.1 / 439.1 (M-tBu+H). + (ES+ ).

[0487] Step 2 Prepared from tert-butyl 3-(3-(3,4-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (2.74 g, 3.1 mmol, 55% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% MTBE / isohexane) to give tert-butyl 2-((3-(3,4-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.39 g, 0.80 mmol, 76% purity) as a colorless oil. LCMS m / z 315.6 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.62-7.54(m,2H), 7.29(dd,J=8.2,2.1Hz,1H), 6.21(s,1H), 5.89(s,1H), 4.10(s,2H), 3.91(s,2H), 1.23(s,9H).

[0488] Step 3 Prepared from tert-butyl 2-((3-(3,4-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.39 g, 0.80 mmol, 76% purity) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-100% MTBE / isohexane) to give 2-((3-(3,4-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (239.91 mg, 0.76 mmol) as a colorless oil. LCMS m / z 314.8 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.83(s,1H), 7.65-7.54(m,2H), 7.29(dd,J=8.3,2.1Hz,1H), 6.28(s,1H), 5.92(s,1H), 4.12(s,2H), 3.92(s,2H).

[0489] Example 15-2-((3-(4-(tert-butyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0490] Step 1 Prepared from 3-(4-(tert-butyl)benzyl)-5-(chloromethyl)-1,2,4-oxadiazole (2.33 g, 6.51 mmol, 74% purity) following general procedure A, step 1, method B. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give tert-butyl 3-(3-(4-(tert-butyl)benzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.0 g, 2.0 mmol) as an orange oil. LCMS m / z 503.3 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.35-7.29(m,2H), 7.22-7.15(m,2H), 4.12-4.01(m,5H), 3.98(d,J=1.6Hz,2H), 3.54( ddd,J=23.4,10.9,4.5Hz,1H), 3.22(ddd,J=16.8,8.7,4.5Hz,1H), 1.30-1.20(m,24H).

[0491] Step 2 Prepared from tert-butyl 3-(3-(4-(tert-butyl)benzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.0 g, 2.1 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-((3-(4-(tert-butyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.30 g, 0.58 mmol, 69% purity) as a pale yellow oil. LCMS m / z 300.8 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.33-7.30(m,2H), 7.21-7.17(m,2H), 6.21(d,J=1.2Hz,1H), 5.88(q,J=1 .3Hz,1H), 3.98(s,2H), 3.90(d,J=1.0Hz,2H), 1.25(s,9H), 1.24(s,9H).

[0492] Step 3 Prepared from tert-butyl 2-((3-(4-(tert-butyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.30 g, 0.58 mmol, 69% purity) according to general procedure A, step 3. The crude product was purified by preparative HPLC (Waters X-Select Prep-C18, 5 μm, 30x100 mm column, 40-70% MeCN 0.1% formic acid in water) to give 2-((3-(4-(tert-butyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (100 mg, 0.33 mmol) as a sticky yellow oil. LCMS m / z 300.8 (M+H) + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 12.84(s,1H), 7.40-7.28(m,2H), 7.25-7.14(m,2H), 6.26(d,J=1.2Hz,1H ), 5.90(d,J=1.4Hz,1H), 4.00(s,2H), 3.90(d,J=1.0Hz,2H), 1.26(s,9H).

[0493] Example 16-2-((3-(3,5-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0494] Step 1 Prepared according to general procedure A, step 1, method B from 5-(chloromethyl)-3-(3,5-dichlorobenzyl)-1,2,4-oxadiazole (4.18 g, 9.2 mmol, 61% purity), except that sodium iodide was not used. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give tert-butyl 3-(3-(3,5-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.0 g, 2.0 mmol) as an orange oil. LCMS m / z 503.3 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.35-7.29(m,2H), 7.22-7.15(m,2H), 4.12-4.01(m,5H), 3.98(d,J=1.6Hz,2H), 3.54( ddd,J=23.4,10.9,4.5Hz,1H), 3.22(ddd,J=16.8,8.7,4.5Hz,1H), 1.30-1.20(m,24H).

[0495] Step 2 Prepared from tert-butyl 3-(3-(3,5-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.0 g, 2.0 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-((3-(3,5-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.61 g, 1.6 mmol) as a colorless oil. LCMS m / z 313.0 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.52(t,J=2.0Hz,1H), 7.38(d,J=2.0Hz,2H), 6.22(d,J=1.2Hz,1H), 5.90(q,J=1.3Hz,1H), 4.13(s,2H), 3.93(d,J=1.1Hz,2H), 1.25(s,9H).

[0496] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(3,5-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (610 mg, 1.57 mmol). The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((3-(3,5-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (230 mg, 0.71 mmol) as a pale yellow oil. LCMS m / z 313.5 / 315.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.82(s,1H), 7.52(t,J=1.9Hz,1H), 7.39(d,J=1.9Hz,2H), 6.28(d,J=1.2Hz,1H), 5.93(q,J=1.2Hz,1H), 4.14(s,2H), 3.93(d,J=1.2Hz,2H).

[0497] Example 17-2-((3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0498] Step 1 Prepared according to general procedure A, step 1, method C from 5-(chloromethyl)-3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazole (2.74 g, 8.53 mmol), except the reaction was heated to 60 °C. The crude product was purified by chromatography on silica gel (0-100% MTBE / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)propanoate (0.754 g, 1.3 mmol, 90% purity) as a colorless oil. LCMS m / z 558.9 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 4.17-3.95(m,4H), 3.55(ddd,J=23.3,11.0,4.4Hz,1H), 3.42-3.28(m,2H), 3.22(ddd,J=16.8,8.6,4.4Hz,1H), 2.6 5(t,J=7.4Hz,2H), 2.15(tq,J=16.2,7.8Hz,2H), 1.68-1.55(m,2H), 1.48(p,J=7.6,6.8Hz,14H), 1.29-1.19(m,6H).

[0499] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)propanoate (0.754 g, 1.3 mmol, 90% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give tert-butyl 2-((3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.326 g, 0.78 mmol) as a colorless oil. LCMS m / z 357.6 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 6.23(s,1H), 5.90(s,1H), 3.91(s,2H), 2.66(t,J=7.4Hz,2H), 2.27-2.0 7(m,2H), 1.63(p,J=7.4Hz,2H), 1.55-1.43(m,3H), 1.43-1.27(m,12H).

[0500] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.326 g, 0.78 mmol). The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give 2-((3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.188 g, 0.52 mmol) as a colorless oil. LCMS m / z 357.0 (M+H) + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 12.81(s,1H), 6.28(s,1H), 5.91(s,1H), 3.91(s,2H), 2.66(t,J=7.5Hz,2H), 2.17(t t,J=19.3,7.8Hz,2H), 1.64(p,J=7.4Hz,2H), 1.56-1.44(m,2H), 1.44-1.27(m,4H).

[0501] Example 18-2-((3-(4-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0502] Step 1 Prepared according to general procedure A, step 1, method B from 3-(4-butylphenyl)-5-(chloromethyl)-1,2,4-oxadiazole (2.80 g, 7.37 mmol, 66% purity), except that sodium iodide was not used. The crude product was purified by chromatography on silica gel (0-50% EtOAc / isohexane) to give tert-butyl 3-(3-(4-butylphenyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.72 g, 3.5 mmol) as a yellow oil. LCMS m / z 489.3 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.92-7.85(m,2H), 7.41-7.35(m,2H), 4.11(qdd,J=7.9,6.6,5.0Hz,4H), 3.67(ddd,J=23.4,10.8,4.6Hz,1H), 3. 52-3.33(m,2H), 2.69-2.62(m,2H), 1.64-1.53(m,2H), 1.38(s,9H), 1.27(q,J=6.9Hz,8H), 0.91(t,J=7.3Hz,3H).

[0503] Step 2 Prepared from tert-butyl 3-(3-(4-butylphenyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.72 g, 3.5 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-((3-(4-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (1.0 g, 2.8 mmol) as a pale yellow oil. LCMS m / z 287.1 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.92-7.86(m,2H), 7.42-7.34(m,2H), 6.28(d,J=1.2Hz,1H), 5.97(q,J=1.3Hz,1H), 4. 03(s,2H), 2.69-2.61(m,2H), 1.63-1.53(m,2H), 1.34(m,11H), 0.91(t,J=7.3Hz,3H).

[0504] Step 3 Prepared from tert-butyl 2-((3-(4-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (1.0 g, 2.8 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((3-(4-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (775 mg, 2.7 mmol) as a white solid. LCMS m / z 286.7 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.81(s,1H), 7.94-7.83(m,2H), 7.41-7.34(m,2H), 6.33(d,J=1.2Hz,1H), 6.00(d,J=1.3Hz,1H) , 4.02(s,2H), 2.69-2.61(m,2H), 1.64-1.53(m,2H), 1.32(h,J=7.4Hz,2H), 0.90(t,J=7.4Hz,3H).

[0505] Example 19-2-((3-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0506] Step 1 Prepared according to general procedure A, step 1, method C from 3-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-5-(chloromethyl)-1,2,4-oxadiazole (1.52 g, 1 equiv, 4.76 mmol), except the reaction was heated to 60 °C. The crude product was purified by chromatography on silica gel (0-100% MTBE / isohexane) to give tert-butyl 3-(3-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.529 g, 0.89 mmol, 90% purity) as a colorless oil. LCMS m / z 559.5 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.71-7.56(m,4H), 7.55-7.47(m,2H), 7.42-7.32(m,2H), 4.14-3.96(m,6H), 3.55(ddd,J=23.3,10.9,4.5Hz,1H), 3.42-3.18(m,2H), 1.31-1.18(m,15H).

[0507] Step 2 Prepared from 3-(3-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.529 g, 0.89 mmol, 90% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give tert-butyl 2-((3-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.178 g, 0.39 mmol, 91% purity) as a colorless oil. LCMS m / z 355.6 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.70-7.64(m,2H), 7.64-7.58(m,2H), 7.54-7.48(m,2H), 7.41-7.35(m ,2H), 6.22(s,1H), 5.89(s,1H), 4.10(s,2H), 3.91(s,2H), 1.25(s,9H).

[0508] Step 3 Prepared from tert-butyl 2-((3-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.178 g, 0.39 mmol, 91% purity) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((3-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (72 mg, 0.20 mmol) as a pale yellow oil. LCMS m / z 355.0 (M+H) + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 12.84(s,1H), 7.72-7.66(m,2H), 7.66-7.58(m,2H), 7.54-7.48(m,2H), 7.42-7.3 4(m,2H), 6.27(d,J=1.2Hz,1H), 5.91(d,J=1.3Hz,1H), 4.11(s,2H), 3.92(s,2H).

[0509] Example 20-2-((3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0510] Step 1 Prepared according to general procedure A, step 1, method B from 3-(4-butylbenzyl)-5-(chloromethyl)-1,2,4-oxadiazole (1.10 g, 3.9 mmol), except that sodium iodide was not used. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 3-(3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.85 g, 1.8 mmol) as a colorless oil. LCMS m / z 481.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.16(d,J=8.2Hz,2H), 7.11(d,J=8.2Hz,2H), 4.13-4.01(m,4H), 3.98(s,2H), 3.64-3.46(m,1H), 3.31-3.27(m,1H) ), 3.27-3.16(m,1H), 2.56-2.53(m,2H), 1.58-1.45(m,2H), 1.28(s,9H), 1.26-1.18(m,8H), 0.88(t,J=7.3Hz,3H).

[0511] Step 2 Prepared from 3-(3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.85 g, 1.8 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / cyclohexane) to give tert-butyl 2-((3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.62 g, 1.74 mmol) as a colorless oil. LCMS m / z 301.1 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.17(d,J=8.0Hz,2H), 7.11(d,J=8.1Hz,2H), 6.23-6.19(m,1H), 5.90-5.86(m,1H), 3.99(s,2H), 3.90 (s,2H), 2.57-2.52(m,2H), 1.59-1.46(m,2H), 1.33-1.26(m,2H), 1.25(s,9H), 0.88(t,J=7.3Hz,3H).

[0512] Step 3 Prepared from tert-butyl 2-((3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.62 g, 1.74 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-50% EtOAc / heptane) to give 2-((3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (0.523 g, 1.72 mmol) as a white solid. LCMS m / z 301.1 (M+H). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 12.81(s,br.1H), 7.17(d,J=8.2Hz,2H), 7.13(d,J=8.1Hz,2H), 6.29-6.25(m,1H), 5.93-5.89(m,1H), 4. 00(s,2H), 3.90(s,2H), 2.57-2.53(m,2H), 1.57-1.47(m,2H), 1.34-1.23(m,2H), 0.89(t,J=7.3Hz,3H).

[0513] Example 21-2-((3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0514] Step 1 Prepared according to general procedure A, step 1, method B from 5-(chloromethyl)-3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazole (2.24 g, 7.41 mmol, 89% purity), except that sodium iodide was not used. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 3-(3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.60 g, 3.3 mmol) as a sticky yellow oil. LCMS m / z 501.2 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.43-7.39(m,1H), 7.40-7.32(m,3H), 4.14-3.99(m,4H), 3.53(ddd,J=23.3,10.9,4.4Hz,1H), 3.38- 3.27(m,1H), 3.21(ddd,J=16.8,8.9,4.5Hz,1H), 1.54-1.39(m,4H), 1.36(s,9H), 1.29-1.21(m,6H).

[0515] Step 2 Prepared from tert-butyl 3-(3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.60 g, 3.3 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / cyclohexane) to give tert-butyl 2-((3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.88 g, 2.3 mmol) as a colorless oil. LCMS m / z 383.1 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.44-7.41(m,1H), 7.41-7.32(m,3H), 6.22(d,J=1.1Hz,1H), 5.89(q,J=1.3Hz,1H), 3.90(s,2H), 1.48-1.39(m,4H), 1.34(s,9H).

[0516] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.88 g, 2.3 mmol). The crude product was purified by chromatography on silica gel (0-100% EtOAc / heptane) to give 2-((3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (670 mg, 2.1 mmol) as a colorless gum. LCMS m / z 305.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.84(s,1H), 7.46-7.43(m,1H), 7.40-7.33(m,3H), 6.27(d,J=1.2Hz,1H), 5.91(d,J=1.2Hz,1H), 3.89(s,2H), 1.51-1.38(m,4H).

[0517] Example 22-2-((3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0518] Step 1 Prepared according to general procedure B, method A from N-hydroxy-1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboximidamide (1.12 g, 1.5 equiv, 4.59 mmol). The crude product was purified by chromatography on silica gel (0-100% MTBE / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)propanoate (0.532 g, 0.93 mmol, 91% purity) as a colorless oil. LCMS m / z 541.1 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.69(dd,J=11.6,8.1Hz,2H), 7.57(dd,J=18.7,8.0Hz,2H), 4.14-3.99(m,4H), 3.52(ddd,J=23. 3,10.9,4.4Hz,1H), 3.39-3.26(m,1H), 3.20(ddd,J=16.8,8.9,4.4Hz,1H), 1.57-1.14(m,19H).

[0519] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)propanoate (0.532 g, 0.93 mmol, 91% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give tert-butyl 2-((3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.107 g, 0.27 mmol) as a colorless oil. LCMS m / z 339.1 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.70(d,J=8.1Hz,2H), 7.60(d,J=8.1Hz,2H), 6.21(s,1H), 5.88(s,1H), 3.90(s,2H), 1.56-1.39(m,4H), 1.32(s,9H).

[0520] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.107 g, 0.27 mmol). The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give 2-((3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (70 mg, 0.20 mmol) as a colorless oil. LCMS m / z 339.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.82(s,1H), 7.71(d,J=8.2Hz,2H), 7.61(d,J=8.1Hz,2H), 6.27(d,J=1.2Hz,1H), 5.91(d,J=1.3Hz,1H), 3.90(s,2H), 1.58-1.39(m,4H).

[0521] Example 23-2-((3-(4-pentylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0522] Step 1 Prepared from N-hydroxy-4-pentylbenzimidamide (0.95 g, 1.5 equiv, 4.6 mmol) according to general procedure B, method A. The crude product was purified by chromatography on silica gel (0-100% MTBE / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(4-pentylphenyl)-1,2,4-oxadiazol-5-yl)propanoate (0.509 g, 1.0 mmol) as a colorless oil. LCMS m / z 503.3 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.93-7.84(m,2H), 7.43-7.34(m,2H), 4.18-4.04(m,4H), 3.67(ddd,J=23.4,10.8,4.6Hz,1H), 3.52-3.27(m ,2H), 2.65(t,J=7.7Hz,2H), 1.61(p,J=7.5Hz,2H), 1.38(s,9H), 1.34-1.22(m,10H), 0.88(t,J=7.1Hz,3H).

[0523] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(4-pentylphenyl)-1,2,4-oxadiazol-5-yl)propanoate (0.509 g, 1.0 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give tert-butyl 2-((3-(4-pentylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.268 g, 0.74 mmol) as a colorless oil. LCMS m / z 301.5 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.93-7.86(m,2H), 7.42-7.35(m,2H), 6.28(d,J=1.2Hz,1H), 5.97(d,J=1.3Hz,1H), 4.03(s, 2H), 2.66(t,J=7.8Hz,2H), 1.60(p,J=7.4Hz,2H), 1.40-1.22(m,13H), 0.87(t,J=6.9Hz,3H).

[0524] Step 3 Prepared from tert-butyl 2-((3-(4-pentylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.268 g, 0.74 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give 2-((3-(4-pentylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (185 mg, 0.61 mmol) as a colorless oil. LCMS m / z 301.0 (M+H) + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 12.87(s,1H), 7.95-7.84(m,2H), 7.44-7.32(m,2H), 6.33(d,J=1.2Hz,1H), 6.00(s,1H), 4.02(d, J=1.1Hz,2H), 2.65(t,J=7.6Hz,2H), 1.70-1.52(m,2H), 1.41-1.19(m,4H), 0.87(t,J=6.9Hz,3H).

[0525] Example 24-2-((3-(1-(2-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0526] Step 1 Prepared from 1-(2-chlorophenyl)-N-hydroxycyclopropane-1-carboximidamide (729 mg, 2.77 mmol, 80% purity) according to general procedure B, method A. The crude product was purified by chromatography on a RP Flash C18 (5-75% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give tert-butyl 3-(3-(1-(2-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.43 g, 0.84 mmol) as a clear, colorless gum. LCMS m / z 485.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.55-7.43(m,2H), 7.41-7.29(m,2H), 4.14-4.01(m,4H), 3.59-3.45(m,1H), 3.36- 3.13(m,2H), 1.66-1.50(m,2H), 1.43-1.39(m,2H), 1.37(s,9H), 1.30-1.20(m,6H).

[0527] Step 2 Prepared from tert-butyl 3-(3-(1-(2-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.43 g, 0.84 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give tert-butyl 2-((3-(1-(2-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.300 g, 0.79 mmol) as a clear, colorless oil. LCMS m / z 305.1 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.56-7.44(m,2H), 7.41-7.32(m,2H), 6.24-6.19(m,1H), 5.90-5.86(m ,1H), 3.89(s,2H), 1.61-1.54(m,2H), 1.44-1.37(m,2H), 1.34(s,9H).

[0528] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(1-(2-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.300 g, 0.79 mmol). The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give 2-((3-(1-(2-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (0.225 g, 0.70 mmol) as a colorless gum. LCMS m / z 305.0 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.83(s,br.1H), 7.56-7.50(m,1H), 7.49-7.43(m,1H), 7.41-7.30(m,2H), 6.28-6 .23(m,1H), 5.91-5.86(m,1H), 3.89(s,2H), 1.66-1.51(m,2H), 1.47-1.28(m,2H).

[0529] Example 25-2-((3-(1-(4-chlorophenyl)cyclobutyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0530] Step 1 Prepared according to general procedure B, method A from 1-(4-chlorophenyl)-N-hydroxycyclobutane-1-carboximidamide (596 mg, 1 equiv., 2.18 mmol, 82% purity). The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 3-(3-(1-(4-chlorophenyl)cyclobutyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (602 mg, 0.72 mmol, 60% purity) as a clear, colorless oil. LCMS m / z 520.5 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.41-7.36(m,2H), 7.32-7.26(m,2H), 4.10-4.00(m,4H), 3.52(ddd,J=23.3,10.9,4.6Hz,1H ), 3.38-3.17(m,2H), 2.80-2.57(m,4H), 2.09-1.86(m,2H), 1.27(s,9H), 1.25-1.20(m,6H).

[0531] Step 2 Prepared from tert-butyl 3-(3-(1-(4-chlorophenyl)cyclobutyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (602 mg, 0.72 mmol, 60% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-30% EtOAc / isohexane) to give tert-butyl 2-((3-(1-(4-chlorophenyl)cyclobutyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (250 mg, 0.64 mmol) as a colorless oil. LCMS m / z 319.2 / 321.2 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.41-7.35(m,2H), 7.33-7.26(m,2H), 6.21(d,J=1.3Hz,1H), 5.87(d,J=1.3Hz,1H), 3.90(s,2H), 2.80-2.71(m,2H), 2.68-2.57(m,2H), 2.09-1.85(m,2H), 1.20(s,9H).

[0532] Step 3 Prepared from tert-butyl 2-((3-(1-(4-chlorophenyl)cyclobutyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (250 mg, 0.64 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-60% EtOAc / isohexane) to give 2-((3-(1-(4-chlorophenyl)cyclobutyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (164 mg, 0.50 mmol) as a sticky colorless gum. LCMS m / z 319.1 / 321.1 (M+H). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 12.81(s,1H), 7.44-7.36(m,2H), 7.34-7.27(m,2H), 6.26(d,J=1.2Hz,1H), 5.88(d,J=1.3Hz, 1H), 3.90(s,2H), 2.81-2.70(m,2H), 2.68-2.56(m,2H), 2.09-1.98(m,1H), 1.97-1.83(m,1H).

[0533] Example 26-2-((3-(2-methyloctan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0534] Step 1 A mixture of hydroxylamine hydrochloride (1.22 g, 17.6 mmol) and sodium bicarbonate (1.48 g, 17.6 mmol) in IPA (20 mL) was stirred for 15 min. 2,2-Dimethyloctanitrile (2.50 g, 14.7 mmol, 90% purity) was added and the mixture was heated to 85° C. and stirred for 22 h. The mixture was cooled to room temperature, filtered, and washed with IPA (3×20 mL). The filtrate was concentrated to give N-hydroxy-2,2-dimethyloctanimidamide (2.70 g, 14 mmol) as a sticky orange oil, which was used directly in the next step.

[0535] Step 2 Prepared from crude N-hydroxy-2,2-dimethyloctanimidamide (1.44 g, 7.35 mmol) according to general procedure B, method A. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(2-methyloctan-2-yl)-1,2,4-oxadiazol-5-yl)propanoate (1.92 g, 2.1 mmol, 50% purity) as a light brown oil. LCMS m / z 483.3 (M+Na). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 4.15-3.99(m,4H), 3.54(ddd,J=23.3,11.1,4.3Hz,1H), 3.40-3.28(m,1H), 3.23(ddd,J=16.7,8.7, 4.3Hz,1H), 1.40(t,J=7.0Hz,3H), 1.37(s,9H), 1.29-1.16(m,10H), 1.03(s,6H), 0.88-0.81(m,6H).

[0536] Step 3 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(2-methyloctan-2-yl)-1,2,4-oxadiazol-5-yl)propanoate (1.92 g, 2.1 mmol, 50% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-((3-(2-methyloctan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (504 mg, 1.5 mmol) as a colorless oil. LCMS m / z 337.2 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 6.23(d,J=1.2Hz,1H), 5.89(d,J=1.4Hz,1H), 3.91(s,2H), 1.61-1.53(m,2H), 1.34 (s,9H), 1.25(s,6H), 1.23-1.13(m,6H), 1.13-1.01(m,2H), 0.83(t,J=6.9Hz,3H).

[0537] Step 4 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(2-methyloctan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (504 mg, 1.5 mmol). The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((3-(2-methyloctan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (405 mg, 1.4 mmol) as a yellow oil. LCMS m / z 281.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.67(s,1H), 6.27(d,J=1.2Hz,1H), 5.88(d,J=1.3Hz,1H), 3.90(s,2H), 1.6 1-1.50(m,2H), 1.30-1.10(m,12H), 1.10-0.99(m,2H), 0.83(t,J=6.8Hz,3H).

[0538] Example 27-2-((3-(3-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0539] Step 1 Prepared according to general procedure B, method A from 3-butyl-N-hydroxybenzimidamide (728 mg, 1.1 equiv., 3.37 mmol, 89% purity). The crude product was purified by chromatography on a RP Flash C18 (5-85% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give tert-butyl 3-(3-(3-butylphenyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.65 g, 1.3 mmol, 90% purity) as a clear, colorless gum. LCMS m / z 411.1 (M-tBu+H). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 7.85-7.73(m,2H), 7.54-7.37(m,2H), 4.18-4.07(m,4H), 3.76-3.59(m,1H), 3.53-3.38(m,2H) , 2.72-2.61(m,2H), 1.65-1.52(m,2H), 1.40(s,9H), 1.36-1.21(m,8H), 0.91(t,J=7.3Hz,3H).

[0540] Step 2 Prepared from tert-butyl 3-(3-(3-butylphenyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.65 g, 1.3 mmol, 90% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give tert-butyl 2-((3-(3-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.400 g, 1.1 mmol) as a clear, colorless oil. LCMS m / z 287.1 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.84-7.76(m,2H), 7.53-7.37(m,2H), 6.31-6.25(m,1H), 6.00-5.93(m,1H), 4.04(s, 2H), 2.73-2.61(m,2H), 1.64-1.52(m,2H), 1.38-1.26(m,11H), 0.91(t,J=7.3Hz,3H).

[0541] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(3-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.400 g, 1.1 mmol). The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((3-(3-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (190 mg, 0.66 mmol) as a white solid. LCMS m / z 287.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.87(s,1H), 7.82-7.75(m,2H), 7.49-7.38(m,2H), 6.33(d,J=1.2Hz,1H), 6.00(d,J=1.3Hz,1H ), 4.03(s,2H), 2.71-2.60(m,2H), 1.63-1.51(m,2H), 1.38-1.25(m,2H), 0.90(t,J=7.4Hz,3H).

[0542] Example 28-2-((3-(4-pentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0543] Step 1 Prepared according to general procedure B, method A from N-hydroxy-2-(4-pentylphenyl)acetimidamide (780 mg, 1.05 equiv., 3.22 mmol, 91% purity). The crude product was purified by chromatography on a RP Flash C18 (5-75% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(4-pentylbenzyl)-1,2,4-oxadiazol-5-yl)propanoate (0.27 g, 0.52 mmol) as a clear light brown gum. LCMS m / z 495 (M+H). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 7.18-7.14(m,2H), 7.13-7.09(m,2H), 4.13-4.01(m,4H), 3.98(s,2H), 3.61-3.48(m,1H), 3. 32-3.16(m,4H), 1.60-1.49(m,2H), 1.28(s,9H), 1.26-1.19(m,10H), 0.85(t,J=6.9Hz,3H).

[0544] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(4-pentylbenzyl)-1,2,4-oxadiazol-5-yl)propanoate (0.27 g, 0.52 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give tert-butyl 2-((3-(4-pentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.12 g, 0.31 mmol) as a clear, colorless oil. LCMS m / z 315.1 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.17(d,J=8.1Hz,2H), 7.11(d,J=8.2Hz,2H), 6.25-6.16(m,1H), 5.92-5.81(m,1H), 3.99(s,2H) , 3.90(s,2H), 2.56-2.52(m,2H), 1.60-1.46(m,2H), 1.34-1.18(m,13H), 0.85(t,J=7.0Hz,3H).

[0545] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(4-pentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.12 g, 0.31 mmol). The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((3-(4-pentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (50 mg, 0.16 mmol) as a yellow oil. LCMS m / z 315.1 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.84(s,1H), 7.17(d,J=8.1Hz,2H), 7.13(d,J=8.0Hz,2H), 6.26(s,1H), 5.90(d,J=1.4Hz,1H), 4.00(s,2H), 3.90(s ,2H), 2.54(d,J=7.7Hz,2H), 1.54(p,J=7.4Hz,2H), 1.28(dddd,J=14.9,9.3,6.8,2.1Hz,4H), 0.86(t,J=6.9Hz,3H).

[0546] Example 29-2-((3-(3-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0547] Step 1 Prepared from 2-(3-butylphenyl)-N-hydroxyacetimidamide (2.66 g, 1 equiv, 11.2 mmol, 87% purity) according to general procedure B, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 3-(3-(3-butylbenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.68 g, 2.9 mmol, 84% purity) as a dark orange oil. LCMS m / z 503.3 (M+Na). + (ES + ).

[0548] Step 2 Prepared from tert-butyl 3-(3-(3-butylbenzyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (1.68 g, 2.9 mmol, 84% purity) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-((3-(3-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.98 g, 2.6 mmol) as a yellow oil. LCMS m / z 300.7 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.20(t,J=7.5Hz,1H), 7.07(td,J=7.9,1.9Hz,3H), 6.21(d,J=1.3Hz,1H), 5.88(t,J=1.3Hz,1H), 4.00(s,2H), 3.90 (s,2H), 2.54(d,J=7.6Hz,2H), 1.52(tt,J=8.3,6.5Hz,2H), 1.32-1.26(m,2H), 1.25(s,9H), 0.89(t,J=7.3Hz,3H).

[0549] Step 3 Prepared from tert-butyl 2-((3-(3-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.98 g, 2.6 mmol) according to general procedure A, step 3. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((3-(3-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (700 mg, 2.2 mmol) as a sticky yellow oil. LCMS m / z 301.6 (M+H). + (ES + ). 1H NMR(400MHz,DMSO-d6)δ 12.81(s,1H), 7.21(t,J=7.5Hz,1H), 7.10(d,J=1.8Hz,1H), 7.09-7.02(m,2H), 6.27(d,J=1.2Hz,1H), 5.90(d,J=1.4Hz,1H) , 4.01(s,2H), 3.91(s,2H), 2.54(t,J=7.7Hz,2H), 1.53(tt,J=7.9,6.4Hz,2H), 1.30(h,J=7.3Hz,2H), 0.89(t,J=7.3Hz,3H).

[0550] Example 30 - 2-((3-(2-(4-chlorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0551] Step 1 Prepared from 2-(4-chlorophenyl)-N-hydroxy-2-methylpropanimidamide (0.98 g, 4.6 mmol) according to general procedure B, method A. The crude product was purified by chromatography on silica gel (0-100% MTBE / isohexane) to give tert-butyl 3-(3-(2-(4-chlorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.320 g, 0.65 mmol) as a colorless oil. LCMS m / z 509.2 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.33(m,2H), 7.32-7.25(m,2H), 4.15-3.98(m,4H), 3.51(ddd,J=23.3,10.9,4.4Hz,1H), 3.40-3 .27(m,1H), 3.22(ddd,J=16.8,8.7,4.4Hz,1H), 1.65(d,J=3.7Hz,6H), 1.28(s,9H), 1.26-1.20(m,6H).

[0552] Step 2 Prepared from tert-butyl 3-(3-(2-(4-chlorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.320 g, 0.65 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-50% MTBE / isohexane) to give tert-butyl 2-((3-(2-(4-chlorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.133 g, 0.36 mmol) as a colorless oil. LCMS m / z 307.5 (M-tBu+H). + (ES + ). 1 H NMR (400MHz, DMSO-d6) δ 7.40-7.26(m,4H), 6.20(s,1H), 5.87(s,1H), 3.90(s,2H), 1.66(s,6H), 1.27(s,9H).

[0553] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(2-(4-chlorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.133 g, 0.36 mmol). The crude product was purified by chromatography on silica gel (0-100% MTBE / isohexane) to give 2-((3-(2-(4-chlorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (78 mg, 0.25 mmol) as a colorless oil. LCMS m / z 307.5 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.83(s,br.1H), 7.56-7.50(m,1H), 7.49-7.43(m,1H), 7.41-7.30(m,2H), 6.28-6 .23(m,1H), 5.91-5.86(m,1H), 3.89(s,2H), 1.66-1.51(m,2H), 1.47-1.28(m,2H).

[0554] Example 31-2-((3-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0555] Step 1 Prepared from 8,8-difluoro-N-hydroxynonanimidamide (1.06 g, 5.07 mmol) according to general procedure B, method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give tert-butyl 2-(diethoxyphosphoryl)-3-(3-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)propanoate (1.28 g, 2.6 mmol) as a clear yellow oil. LCMS m / z 505.2 (M+Na). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 4.15-4.02(m,4H), 3.56(ddd,J=23.3,11.1,4.4Hz,1H), 3.39-3.33(m,1H), 3.23(ddd,J=16.8,8 .6,4.4Hz,1H), 2.65(t,J=7.4Hz,2H), 1.90-1.76(m,2H), 1.66-1.46(m,5H), 1.43-1.19(m,21H).

[0556] Step 2 Prepared from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)propanoate (1.28 g, 2.6 mmol) following general procedure A, step 2, method B. The crude product was purified by chromatography on silica gel (0-20% EtOAc / isohexane) to give tert-butyl 2-((3-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.650 g, 1.8 mmol) as a clear, colorless oil. LCMS m / z 303.2 (M-tBu+H). +(ES + ). 1 H NMR(400MHz,DMSO-d6)δ 6.23(d,J=1.3Hz,1H), 5.96-5.83(m,1H), 3.91(s,2H), 2.65(t,J=7.4Hz,2H), 1.90-1.76(m,2H), 1.67-1.51(m,5H), 1.34(s,15H).

[0557] Step 3 Prepared according to general procedure A, step 3 from tert-butyl 2-((3-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.650 g, 1.8 mmol). The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to give 2-((3-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.479 g, 1.6 mmol, 86%, 98% purity) as a clear, colorless oil. LCMS m / z 303.6 (M+H). + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ 12.81(s,1H), 6.28(d,J=1.2Hz,1H), 5.91(d,J=1.4Hz,1H), 3.91(s,2H), 2.6 5(t,J=7.5Hz,2H), 1.92-1.75(m,2H), 1.70-1.51(m,5H), 1.44-1.25(m,6H).

[0558] Example 32-2-((3-(cyclohexylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid [ka]

[0559] ...

Claims

1. A compound of formula (I) 【Chemistry 1】 During the ceremony, 【Chemistry 2】 represents a 5-membered heteroaryl ring that contains, in addition to the depicted C═N, one or more additional heteroatoms independently selected from N, O, and S; or 【Chemistry 3】 represents a 6-membered heteroaryl ring containing, in addition to the indicated C=N, optionally one or more further N atoms; R Ａ１ But, C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, -(CH ２ ) ０－６ -C ３－１０ Cycloalkyl, -(CH ２ ) ０－６ -C ５－１０ Spirocycloalkyl, -(CH ２ ) ０－６ -aryl, and O-aryl; R Ａ１ Optionally, halo, C １－６ Alkyl, C １－６ Haloalkyl, Hydroxy, Cyano, OG １ , S(O) ０－２ G １ , S.F. ５ , (CH ２ ) ０－３ C ３－７ cycloalkyl, and 5- to 7-membered heterocyclyl; ３－７ Cycloalkyl and said 5- to 7-membered heterocyclyl are optionally selected from halo, C １－３ Alkyl, and C １－３ haloalkyl, and two alkyl groups bonded to the same carbon atom are optionally linked to form C ３－７ Forms a cycloalkyl ring, C ３－１０ The cycloalkyl group is optionally fused to a phenyl ring, said phenyl ring being optionally substituted with one or more halo atoms, or R Ａ１ However, optionally C １－２ Haloalkyl, C １－２ optionally substituted with haloalkoxy, or one phenyl ring substituted with one or more halo atoms; G １ But, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Haloalkyl, or (CH ２ ) ０－１ Phenyl, G １ Optionally, halo, C １－２ Alkyl, C １－２ Haloalkyl, hydroxy, cyano, nitro, C １－２ Alkoxy, and C １－２ substituted with one or more substituents selected from the group consisting of haloalkoxy; R Ａ２ But, Halo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, hydroxy, cyano, nitro, NR １ R ２ , O.G. ２ , and S(O) ０－２ G ２ is selected from the group consisting of G ２ But, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ haloalkyl, or phenyl, which is optionally halo, C １－２ Alkyl, C １－２ Haloalkyl, hydroxy, cyano, nitro, C １－２ Alkoxy, and C １－２ substituted with one or more substituents selected from the group consisting of haloalkoxy; R １ and R ２ are independently H or C １－２ alkyl, or together, R １ and R ２ can be combined to form a 5- to 7-membered heterocycle; Or R Ａ２ But non-existence, R Ｃ and R Ｄ each independently represents H, C １－２ Alkyl, hydroxy, fluoro, or C １－２ Alkoxy or R Ｃ and R Ｄ are connected, C ３－５ may form a cycloalkyl ring, group R Ａ１ and R Ａ２ the total number of carbon atoms in, together with any optional substituents thereof, is 6 to 14; 【Chemistry 4】 When represents isoxazole, R Ａ１ does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, Or a pharma- ceutically acceptable salt and / or solvate thereof.

2. the below described 【Chemistry 5】 2. The compound of claim 1, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: represents oxadiazole.

3. the below described 【Chemistry 6】 The compound according to claim 2, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: represents 1,2,4-oxadiazole.

4. R Ａ１ But -(CH ２ ) ０－２ -phenyl, where R Ａ１ But one OG １ group, １ But, C １－６ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is an alkyl group.

5. R Ａ２ is non-existent, and R Ｃ is H, and R Ｄ The compound according to any one of claims 1 to 4, wherein is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

6. 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-octyl-1,3,4-oxadiazol-2-yl)methyl)acrylic acid, 2-((5-octyl-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-heptyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(naphthalen-2-ylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(2-methylheptan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((1-octyl-1H-1,2,4-triazol-3-yl)methyl)acrylic acid, 2-((3-(3,4-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(tert-butyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3,5-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-pentylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(2-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-chlorophenyl)cyclobutyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(2-methyloctan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-pentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(2-(4-chlorophenyl)propan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(cyclohexylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-(4-chlorophenyl)propyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(octyl-d17)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(oct-7-yn-1-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-propylphenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-octyl-1,3,4-thiadiazol-2-yl)methyl)acrylic acid, 2-((4-octylthiazol-2-yl)methyl)acrylic acid, 2-((4-octyloxazol-2-yl)methyl)acrylic acid, (R)-2-((3-(octan-2-yl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-ethylphenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, (S)-2-((3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-methoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(trifluoromethoxy)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(7,7,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1-(trifluoromethyl)cyclopropyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-bromophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxybenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-chloro-3-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-nonyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(8,8,8-trifluorooctan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-octylthiazol-2-yl)methyl)acrylic acid, 2-((3-undecyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(oct-3-yn-1-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(8,8-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-octyloxazol-2-yl)methyl)acrylic acid, 2-((3-(9,9,9-trifluorononyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(dispiro[3.1.3 ６ .1 ４ ]decan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-cyclooctyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-cyclohexyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-cycloheptyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(adamantan-1-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3,5-dichlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(6-methylheptyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-neopentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-propylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1,1-difluoropropyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1-propylcyclopropyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(3,3,3-trifluoropropyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4-chlorophenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(5,5,5-trifluoropentyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(2-cyclopropylethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(pentafluoro-λ ６ -sulfanyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(difluoromethoxy)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1,1-difluoropentyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-butoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-(1,1-difluorooctyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((5-((4-chlorophenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((5-((4-bromophenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((3-(1-(4-((trifluoromethyl)thio)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(6,6,8,8,8-pentafluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1,1-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-((4-chlorophenyl)difluoromethyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((3-((4-bromophenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4-butylphenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(difluoro(4-(trifluoromethyl)phenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1,1-difluoropentyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(difluoro(4-(trifluoromethoxy)phenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-(4-butylbenzyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((5-(4-butoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((5-(difluoro(4-(trifluoromethyl)phenyl)methyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((3-(4-(1,1-difluorobutyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-(1-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)methyl)acrylic acid, 2-((3-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((4-(4-butylphenyl)oxazol-2-yl)methyl)acrylic acid, 2-((5-octylisoxazol-3-yl)methyl)acrylic acid, 2-((4-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)oxazol-2-yl)methyl)acrylic acid, 2-((4-octylpyridin-2-yl)methyl)acrylic acid trifluoroacetate, 2-((5-octylpyridin-2-yl)methyl)acrylic acid trifluoroacetate, 2-((5-octylpyrimidin-2-yl)methyl)acrylic acid, 2-((5-octylpyrazin-2-yl)methyl)acrylic acid, 2-((6-octylpyridazin-3-yl)methyl)acrylic acid, 2-((5-methyl-4-octyloxazol-2-yl)methyl)acrylic acid, 2-(hydroxy(3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((5-butyl-4-(4-chlorophenyl)oxazol-2-yl)methyl)acrylic acid, 2-(methoxy(3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-cyclobutoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-cyclopentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-cyclopropoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-cyclopentylphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-iodophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-iodophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(difluoro(4-iodophenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(pentafluoro-λ ６ -sulfanyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(pentafluoro-λ ６ -sulfanyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((4,5-dibutyloxazol-2-yl)methyl)acrylic acid, 2,2-((3-(difluoro(4-(pentafluoro-λ ６ -sulfanyl)phenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2,2-((3-(difluoro(4-fluorophenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butylphenoxy)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((4-(4-butylbenzyl)oxazol-2-yl)methyl)acrylic acid, 2-((3-(4-cyclobutylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxy-3-fluorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-cyclobutylphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(pyrrolidin-1-yl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3,5-dichloro-4-fluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3,5-dichloro-4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-chloro-3,5-difluorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3-chloro-4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-chloro-4-(trifluoromethyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(4-bromo-3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-bromo-3-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3-chloro-4-methoxyphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(1-(3-chloro-4-methylphenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-cyclobutoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-cyclopentyloxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, (R)-2-((3-(4-(sec-butoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, (S)-2-((3-(4-(sec-butoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(4,4,4-trifluorobutoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(1-propylcyclopropyl)benzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-propoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((3-chloro-4-methoxyphenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((3-chloro-4-methylphenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4-chlorophenyl)fluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((3,5-dichloro-4-fluorophenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-((4-bromo-3-chlorophenyl)difluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(difluoro(4-((trifluoromethyl)thio)phenyl)methyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-(1-(3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)acrylic acid, 3-methyl-2-methylene-3-(3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)butanoic acid, 2-((3-(1-(4-((trifluoromethyl)sulfinyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-((trifluoromethyl)thio)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(3-methoxypropoxy)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxy-3-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-butoxy-3,5-difluorophenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-chloro-4-methoxybenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-chloro-3,5-difluorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(3-chloro-4-methylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((6-(4-chlorobenzyl)pyridin-2-yl)methyl)acrylic acid trifluoroacetate, 2-(1-(3-(difluoro(4-(trifluoromethyl)phenyl)methyl)-1,2,4-oxadiazol-5-yl)cyclopropyl)acrylic acid, 2-methylene-3-(3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)butanoic acid, 2-((6-(1-(4-chlorophenyl)cyclopropyl)pyridin-2-yl)methyl)acrylic acid, and 2-((3-(1-(4-bromo-3,5-dichlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2. The compound of claim 1, selected from the group consisting of: or a pharma- ceutically acceptable salt and / or solvate thereof.

7. The compound according to claim 5, which is 2-((3-(4-butylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

8. The compound according to claim 5, which is 2-((3-(1-(4-bromophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

9. The compound according to claim 5, which is 2-((3-(4-butoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

10. The compound according to claim 5, which is 2-((3-(1-(4-((trifluoromethyl)thio)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

11. 2-((3-(1-(4-(pentafluoro-λ ６ 6. The compound according to claim 5, which is 1,2,4-oxadiazol-5-yl)methyl)-4-sulfanyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharma- ceutically acceptable salt and / or solvate thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt and / or solvate thereof, for use as a medicament.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of an inflammatory disease or a disease associated with an undesired immune response.

14. The inflammatory disease or disease associated with an undesired immune response is selected from the group consisting of psoriasis (including chronic plaque, erythroderma, pustular, guttate, inverse and nail variants), asthma, chronic obstructive pulmonary disease (including COPD, chronic bronchitis and emphysema), heart failure (including left ventricular failure), myocardial infarction, angina pectoris, other atherosclerosis and / or atherothrombosis related disorders (including peripheral vascular disease and ischemic stroke), mitochondrial and neurodegenerative diseases, autoimmune paraneoplastic retinopathies, transplant rejection (including antibody-mediated and T-cell mediated), multiple sclerosis, transverse myelitis, ischemia-reperfusion injury, AGE-induced genomic damage, inflammatory bowel disease, primary sclerosing cholangitis (PSC), PSC-autoimmune hepatitis overlap syndrome, nonalcoholic fatty liver disease (nonalcoholic steatohepatitis), rheumatoid, granuloma annulare, cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, drug-induced lupus, autoimmune myocarditis or myopericarditis, Dressler's syndrome, giant cell myocarditis, post-pericardiotomy syndrome, drug-induced hypersensitivity syndrome (including hypersensitivity myocarditis), eczema, sarcoidosis, erythema nodosum, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectroscopy ram disorder, MOG (myelin oligodendrocyte glycoprotein) antibody-associated disorders (including MOG-EM), optic neuritis, CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids), diffuse spinal fragmentation sclerosis, Addison's disease, alopecia areata, ankylosing spondylitis, other spondyloarthritis (including peripheral spondyloarthritis associated with psoriasis, inflammatory bowel disease, reactive arthritis or juvenile-onset forms), antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid (bullous pemphigoid, mucous membrane pemphigoid, cicatricial pemphigoid, pemphigoid of pregnancy) or pemphigoid, ocular cicatricial pemphigoid), linear IgA disease, Behcet's disease, celiac disease, Chagas' disease, dermatomyositis, type I diabetes mellitus, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome and its subtypes (including acute inflammatory demyelinating polyneuropathy, AIDP, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), pharyngeal-cervical-brachial plexus variant, Miller Fisher variant and Bickerstaff brainstem encephalitis), progressive inflammatory neuropathies, Hashimoto's disease, hidradenitis suppurativa, inclusion body myositis,Necrotizing myopathy, Kawasaki disease, IgA nephropathy, Henoch-Schönlein purpura, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura (TTP), Evans syndrome, interstitial cystitis, mixed connective tissue disease, undifferentiated connective tissue disease, morphea, myasthenia gravis (including MuSK antibody positive and seronegative variants), narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriatic arthritis, polymyositis, primary biliary cholangitis (also known as primary biliary cirrhosis), rheumatoid arthritis, palindromic rheumatism, schizophrenia, autoimmune (meningo)encephalitis syndromes, scleroderma, Sjögren's syndrome, stiff-body syndrome, polymyalgia rheumatica, giant cell arteritis (temporal arteritis), Takayasu's arteritis, polyarteritis nodosa, Kawasaki disease, granulomatosis with polyangiitis (GPA; formerly known as Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome), microscopic polyarteritis / polyangiitis, hypocomplementemic urticarial vasculitis, hypersensitivity vasculitis, cryoglobulinemia, thromboangiitis obliterans (Buerger's disease), vasculitis, leukocytoclastic vasculitis, vitiligo, acute disseminated encephalomyelitis, adrenoleukodystrophy -, Alexander disease, Alper's disease, Baroconcentric sclerosis or Marburg disease, idiopathic organizing pneumonia (previously known as obliterative bronchitis organizing pneumonia), Canavan disease, central nervous system vasculitis syndromes, Charcot-Marie-Tooth disease, childhood ataxia with central nervous system hypomyelination, chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic retinopathy, globoid cell leukodystrophy (Krabbe disease), graft-versus-host disease (GVHD) (including acute and chronic forms, and intestinal GVHD), hepatitis C (HCV) infection or complications, herpes simplex virus Infection or complications, human immunodeficiency virus (HIV) infection or complications, lichen planus, Hirayama disease, cystic fibrosis, pulmonary arterial hypertension (PAH, including idiopathic PAH), pulmonary sarcoidosis, idiopathic pulmonary fibrosis, childhood asthma, atopic dermatitis, allergic dermatitis, contact dermatitis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca, dry eye, xerophthalmia, glaucoma, macular edema, diabetic macular edema, central retinal vein occlusion (CRVO), macular degeneration (including dry and / or wet age-related macular degeneration, AMD), postoperative cataract inflammation,Uveitis (including posterior, anterior, intermediate and panuveitis), iridocyclitis, scleritis, corneal graft and keratocyte graft rejection, gluten-sensitive enteropathy (celiac disease), dermatitis herpetiformis, eosinophilic esophagitis, achalasia, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune esophagitis, autoimmune orchitis, autoimmune pancreatitis, aortitis and perivascular inflammation, autoimmune retinopathy, autoimmune urticaria, Behçet's disease, (idiopathic) Castleman's disease, Cogan's syndrome, IgG4-related disease, retroperitoneal fibrosis, juvenile idiopathic arthritis including systemic juvenile idiopathic arthritis (Still's disease) Idiopathic arthritis, adult-onset Still's disease, lignified conjunctivitis, Mooren's ulcer, acute pityriasis lichenoides (PLEVA, also known as Much-Habermann disease), multifocal motor neuropathy (MMN), childhood acute-onset neuropsychiatric syndromes (PANS) (including pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)), paraneoplastic syndromes (including paraneoplastic cerebellar degeneration, Lambert-Eaton myoneuropathy syndrome, limbic encephalitis, brainstem encephalitis, opsoclonus-myoclonus ataxia, anti-NMDA receptor encephalitis, thymoma-associated multisystem autoimmunity), perivenous encephalomyelitis, anti ... Sympathetic dystrophy, relapsing polychondritis, sperm and testicular autoimmunity, Susac syndrome, Tolosa-Hunt syndrome, Vogt-Koyanagi-Harada syndrome, antisynthetase syndrome, autoimmune enteropathy, immunodysregulatory polyendocrinopathy enteropathy X-linked (IPEX), microscopic colitis, autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APEX), gout, pseudogout, amyloid (including AA or secondary amyloidosis), eosinophilic fasciitis (Schulman syndrome), progesterone hypersensitivity (progestin hypersensitivity), teron dermatitis), familial mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), hyperimmunoglobulinemia D with periodic fever (HIDS), PAPA (septic arthritis, pyoderma gangrenosum, severe prurigo cystica) syndrome, interleukin-1 receptor antagonist (DIRA) deficiency, interleukin-36 receptor antagonist (DITRA) deficiency, cryopyrin-associated periodic syndromes (CAPS) (including familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome, neonatal-onset multisystem inflammatory disease [NOMID]),NLRP12-associated autoinflammatory disease (NLRP12AD), periodic febrile aphthous stomatitis (PFAPA), chronic atypical neutrophilic dermatosis with lipodystrophy and hypertension (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold autoinflammatory syndrome, mutant adenosine deaminase 2 and monogenic interferonopathies (Aicardi-Goutières syndrome, retinal vascular disease with cerebral leukodystrophy, spondylochondrodysplasia) 14. The pharmaceutical composition of claim 13, wherein the disease is or is associated with a disease selected from the group consisting of: inflammatory bowel disease, STING [stimulator of interferon genes]-associated vasculopathy of infancy, proteasome-associated autoinflammatory syndrome, familial chilblains, hereditary symmetric dyschromia), Schnitzler syndrome; familial cylindromatosis, congenital B-cell lymphocytosis, otulin-associated autoinflammatory syndrome, type 2 diabetes, insulin resistance and metabolic syndrome (including obesity-associated inflammation), atherosclerosis, and renal inflammatory disease.

15. Further therapeutic agents include corticosteroids (glucocorticoids), retinoids, anthralin, vitamin D analogs, calcineurin inhibitors, cyclosporines, thiopurines, methotrexate, anti-TNFα agents, phosphodiesterase-4 (PDE4) inhibitors, anti-IL-17 agents, anti-IL12 / IL-23 agents, anti-IL-23 agents, JAK (Janus kinase) inhibitors, intravenous immunoglobulin (IVIG), cyclophosphamide, anti-CD20B cell depleting agents, anthracycline analogs, cladribine, sphingosine 1-phosphate receptor modulators or sphingosine analogs, interferon beta agents (including interferon beta 1b / 1a), glatiramer, anti-CD52 targeted agents, leflunomide, teriflunomide, gold compounds, laquinimod, potassium channel blockers, mycophenolic acid, mycophenolate mofetil, purine analogs, mTOR (mechanistic target of rapamycin) pathway inhibitors, antithymocyte globulin (ATG), IL-2 receptor (CD25 ) inhibitors, anti-IL-6 receptor or anti-IL-6 agents, Bruton's tyrosine kinase (BTK) inhibitors, tyrosine kinase inhibitors, ursodeoxycholic acid, hydroxychloroquine, chloroquine, B-cell activating factor (also known as BAFF, BLyS, B-lymphocyte stimulator) inhibitors, PI3K inhibitors including pan-inhibitors or inhibitors targeting p110δ and / or p110γ including isoforms, interferon alpha receptor inhibitors, T-cell costimulation blockers, thalidomide and its derivatives, dapsone, clofazidazole, amines, leukotriene antagonists, theophylline, anti-IL-5 agents, long-acting muscarinics, riluzole, free radical scavengers, proteasome inhibitors, complement cascade inhibitors including those directed against C5, immunoadsorbents, antithymocyte globulin, 5-aminosalicylic acid and its derivatives, anti-integrin agents including those targeting α4β1 and / or α4β7 integrins, anti-CD11-α agents, nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates, oxicams, fenamates, selective or A pharmaceutical composition according to any one of claims 12 to 14 for use in combination with a therapeutic agent selected from relatively selective COX-2 inhibitors, colchicine, IL-4 receptor inhibitors, IL-1β inhibitors, chlorambucil, certain antibiotics having immunomodulatory properties and / or the ability to modulate NRF2, pentoxifylline, ursodeoxycholic acid, obeticholic acid, fibrates, cystic fibrosis transmembrane conductance (CFTR) regulators, VEGF (vascular endothelial growth factor) inhibitors, pirfenidone, and mizoribine.

16. 12. The compound of claim 1 or a pharma- ceutically acceptable salt and / or solvate thereof, wherein the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is a compound of formula (I).

17. The compound of any one of claims 1 to 11, wherein the compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof is a pharma- ceutically acceptable salt of the compound of formula (I).

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