Carboxy derivatives with antiinflammatory properties

Abstract

To provide compounds for use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response, as well as related compositions, methods, uses, and intermediates.SOLUTION: A compound of formula (I) is provided. In the formula, the ring A containing nitrogen represents a 5-membered heteroaryl ring which, in addition to the C=N shown, contains one or more further heteroatoms independently selected from N, O, and S, or represents a 6-membered heteroaryl ring which, in addition to the C=N shown, optionally contains one or more further N atoms.SELECTED DRAWING: None

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, R, and Schradin, C, 2016). Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications used to treat inflammatory diseases; however, these drugs do not prevent the progression of inflammation; they only treat associated symptoms. Glucocorticoids are potent anti-inflammatory agents and can provide emergency treatment for acute inflammatory flares. However, when administered long-term, these drugs can cause numerous undesirable side effects and lead to resistance (Straub, R, and 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, after 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. DMF's mechanism of action is complex and controversial. The compound's efficacy is attributed to various phenomena, including covalent protein modification and the conversion of the "prodrug" DMF to MMF.In particular, the following pathways have been highlighted as relevant to 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 its electrophilic α,β-unsaturated ester moiety with the nucleophilic cysteine ​​residue on 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) through succination 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 G. et al., 2018). al., 2015); 5) Prevention of the association of PKCθ with the costimulatory receptor CD28, which reduces IL-2 production 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 influences the cellular response to oxidative stress (Lehmann JCU et al., 2007); 7) Agonism of 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 J. Let et al., 2018); 9) Inhibition of the expression and function of hypoxia-inducible factor-1α (HIF-1α) and its target genes, such as IL-8 (Zhao G. et al. 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, with the exception of 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 indeed 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 is replenished and 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 subsequently generate itaconic acid, termed 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), resulting in succinate accumulation (Cordes T. et al., 2016). By inhibiting SDH, an enzyme critical for inflammatory responses (EL Mills et al., 2016), itaconate ameliorates macrophage activation and inflammation during ischemia-reperfusion injury in vitro and in vivo (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, induces an anti-inflammatory response and reduces the expression levels of the pro-inflammatory cytokines IL-1β, IL-6, IL-12, and IL-18 in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (WO 2017 / 142855 A1, 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, DMI regulation of IκBζ is independent of NRF2 and is mediated through upregulation of ATF3, a global negative regulator of immune activation that downregulates various cytokines, including IL-6 (Bambouskova M. et al., 2018). Furthermore, 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 therapeutic option 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).Furthermore, DMI has been reported to be useful for the prevention and treatment of ulcerative colitis and its cancer progression (CN110731955, Sun Yat-sen University Cancer Center) and 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 intracellularly (ElAzzouny M. et al., 2017). Other α,β-unsaturated esters and acids have been shown to lower IL-1β in macrophages by inhibiting the NLRP3 inflammasome (Cocco M. et al., 2017 and 2014), inhibiting the TLR4 pathway, and ultimately suppressing LPS-induced stimulation of 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 chromosome region maintenance 1 (CRM1) inhibitors. CRM-1 plays a role in 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. Because the α,β-unsaturated carboxylic acid is not esterified in 4OI, this electrophile exhibits reduced 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 that of the much more reactive DMI. In this latter case, the α,β-unsaturated carboxylic acid is esterified, and as a result, the IL-6-lowering and NRF2-activating effects of DMI are reversed by the thiol 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 1) protects neurons from hydrogen peroxide (Liu H. et al., 2018), 2) inhibits inflammatory cytokine production in peripheral blood mononuclear cells from SLE patients (Tang C. et al., 2018), 3) protects human umbilical vein endothelial cells from high glucose (Tang C. et al., 2019), 4) inhibits osteoclastogenesis by suppressing the E3 ubiquitin ligase Hrd1 and activating NRF2 signaling (Sun X. et al., 2019), and 5) induces STING suppression 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 reactive oxygen species generation (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).Furthermore, itaconate has been reported to regulate tricarboxylic acid and redox metabolism to reduce reperfusion injury (Cordes T. et al., 2020). Furthermore, elevated plasma itaconate levels have been shown to be significantly correlated with a reduction in rheumatoid arthritis disease activity scores after initiation of 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 carboxylic compounds, such as itaconate and acrylate derivatives, that have enhanced properties compared to currently available anti-inflammatory agents, such as DMF. The inventors have surprisingly discovered that certain α,β-unsaturated methacrylic acids bearing heteroaryl groups are effective in reducing cytokine release, activating NRF2 in cells, and / or improving metabolic stability. These properties are potentially more effective than those of 4-octyl itaconate, in particular. Therefore, 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 depicted 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 depicted C=N, optionally one or more further N atoms; R A1 But C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl, -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, -(CH2) 0-6 -aryl, and O-aryl; R A1 However, optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 , SF5, (CH2) 0-3 C 3-7 cycloalkyl, and 5- to 7-membered heterocyclyl; 3-7 Cycloalkyl and 5- to 7-membered heterocyclyl are 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 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 (CH2) 0-1 Phenyl and G 1 However, 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 A2But, 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 it is non-existent, 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 combine to form C 3-5 can form a cycloalkyl ring, In the compound of formula (I), [ka] represents the following: [ka] base R A1 and R A2the total number of carbon atoms, together with any substituents thereon, is 6 to 14; [ka] represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, Alternatively, a pharmaceutically acceptable salt and / or solvate thereof is provided.

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

[0010] In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt and / or solvate thereof. [Brief explanation of the drawings]

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

[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] Preferably, 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 depicted 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 depicted C=N, optionally one or more further N atoms; R A1 But C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, and -(CH2) 0-6 -aryl, and RA1 However, optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 , SF5, and C 3-7 cycloalkyl, and C 3-7 Cycloalkyl optionally includes 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 (CH2) 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 2 is selected from the group consisting of G 2 But C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6haloalkyl, 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 it is non-existent, 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 substituents thereon, is 6 to 14; [ka] represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, Alternatively, a pharmaceutically acceptable salt and / or solvate thereof is provided.

[0018] Preferably, 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 depicted 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 depicted C=N, optionally one or more further N atoms; R A1 But C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, and -(CH2) 0-6 -aryl, and R A1 However, 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, NR1 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 it is non-existent, 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 substituents thereon, is 6 to 14; [ka] represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, Alternatively, a pharmaceutically acceptable salt and / or solvate thereof is 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 depicted 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 depicted C=N, optionally one or more further N atoms; R A1 But C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH2) 1-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, and -(CH2) 0-6 -aryl, and R A1 However, 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 1-2 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 2-6Alkynyl, 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 it is non-existent, 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 substituents thereon, is 6 to 12; [ka] represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, or a pharmaceutically 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 depicted 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 depicted C=N, optionally one or more further N atoms; R A1 But C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, and -(CH2) 0-6 -aryl, and R A1 However, optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , and S(O) 0-2 G 1 and 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 1-2 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 it is non-existent, 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 substituents thereon, is 6 to 12; [ka] represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, Alternatively, a pharmaceutically acceptable salt and / or solvate thereof is provided.

[0021] "C 1-10The term "alkyl" refers to a straight-chain or branched, fully saturated hydrocarbon group having 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. Other branched variants such as heptyl-CH(CH3)- and hexyl-CH(CH3)- are also included. Other alkyl groups, such as 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, C 7-8 Alkyl, C 8-10 Alkyl, C 8-9 Alkyl, and C9-10 Alkyl is as defined above but with a different number of carbon atoms. 1-10 The term "alkyl" also refers to "C" 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 inclusive of CH=CH2, CH2CH=CH2, CH=CHCH3, CH2CH2CH=CH2, CH=CHCH2CH3, CH2CH=CHCH3, CH2CH2CH2CH=CH2, CH=CHCH2CH2CH3, CH2CH=CHCH2CH3, CH2CH2CH=CHCH3, CH=CHCH=CHCH3, and CH2CH=CHCH=CH2. Branched variants such as CH(CH3)CH=CH2 and CH=C(CH3)CH2 are also included. Other alkenyl groups, e.g., 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, C4-8 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-chain or branched hydrocarbon group having 2 to 10 carbon atoms and at least one carbon-carbon triple bond. The term is inclusive of CΞCH, CH2CΞCH, CΞC-CH3, CH2CH2CΞCH, CΞCCH2CH3, CH2CΞCCH3, CH2CH2CH2CΞCH, CΞCCH2CH2CH3, CH2CH2CΞCCH3, CΞCCΞCCH3, and CH2CΞCCΞCH. Branched variants such as CH(CH3)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 4-9Alkynyl, 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, C 7-8 Alkynyl, C 8-10 Alkynyl, C 8-9 Alkynyl, and C 9-10 Alkynyl is as defined above but containing a different number of carbon atoms.

[0024] "C 3-10 The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group having 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 5-7Cycloalkyl, 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 contains a different number 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 Spirocycloalkyls are as defined above but contain 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 encompasses pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homomorpholinyl. A 5- to 7-membered heterocyclyl group can typically be substituted with one or more (e.g., one or two) oxo groups. Preferably, 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 group --OH.

[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" refers to a C as defined above. 1-6

[0023] "(C)" refers to an alkyl group (e.g., a C alkyl group, i.e., methyl) that is substituted with one or more (e.g., one, two, or three) halo atoms. Examples include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and 1,1-difluoroethyl.

[0031] "C 1-2 The term "alkoxy" refers to the C groups defined above. 1-2 Refers to an alkyl group (e.g., a C1 alkyl group, i.e., methyl) that is specifically linked to an oxygen. The term encompasses methoxy and ethoxy.

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

[0023] refers to alkoxy 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, alkanesulfonate, e.g., methanesulfonate, or arenesulfonate, e.g., para-toluenesulfonate or benzenesulfonate.

[0034] When a substituent is shown 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, which means 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, which, in addition to the depicted C═N, contains 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 (if present) can be attached to a carbon or nitrogen atom of the imidazole moiety.

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

[0040] [ka] 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) can 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 (if present) can 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] Preferably, the 1,2,4-oxadiazole is [ka] 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, one or two) 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] 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] represents pyrazine, it is [ka] The purpose is to represent.

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

[0063] In the above representation, the substituent is not shown as being attached to a carbon atom or nitrogen atom, but instead as crossing a double or single bond of the heteroaryl compound, which means that the point of attachment is undefined 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 may 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, -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, -(CH2) 0-6 -aryl, and O-aryl (eg, O-phenyl).

[0065] In one embodiment, R A1 is C 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl, -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, and -(CH2) 0-6 -phenyl.

[0066] Preferably, R A1 is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH2) 1-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, and -(CH2) 0-6 -phenyl.

[0067] Preferably, R A1 is C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH2) 1-6 -C 3-10 Cycloalkyl, -(CH2) 1-6 -C 5-10 Spirocycloalkyl, and -(CH2) 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 a C7 alkyl, and the alkyl group is in a linear configuration, i.e., [ka] It has.

[0071] Preferably, R A1 is a C8 alkyl, and the alkyl group is in a linear configuration, i.e., [ka] It has.

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

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

[0074] For example, preferably, R A1 is a C7 alkyl, where the alkyl group is substituted with an alkyl group. For example, a C7 alkyl can be substituted with a C1 alkyl (i.e., methyl) to form the following group: [ka]

[0075] In one embodiment, R A1 is -(CH2) 0-6 -C 3-10 Cycloalkyl, especially -(CH2) 0-6 -C 4-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Cycloalkyl, or -(CH2) 0-6 -C 5-8 In one embodiment, R A1 is -(CH2) 0-6 -cyclopropyl, -(CH2) 0-6 -cyclobutyl, -(CH2) 0-6 -Cyclopentyl, -(CH2) 0-6 -Cyclohexyl, -(CH2) 0-6 -Cycloheptyl, -(CH2) 0-6 -cyclooctyl, and -(CH2) 0-6 -bicyclo[2.2.1]heptyl, in particular -(CH2) 0-6 -Cyclopentyl, -(CH2) 0-6 -Cyclohexyl, -(CH2) 0-6 -Cycloheptyl, -(CH2) 0-6 -cyclooctyl, or -(CH2) 0-6 -bicyclo[2.2.1]heptyl.

[0076] Preferably, R A1 is -(CH2)0-C 3-10 Cycloalkyl, for example, —(CH2)0-C6 cycloalkyl, —(CH2)0-C7 cycloalkyl, or —(CH2)0-C8 cycloalkyl.

[0077] In one embodiment, R A1 is -(CH2) 1-6 -C 3-10 Cycloalkyl, especially -(CH2) 1-6 -C 4-10 Cycloalkyl, -(CH2) 1-6 -C 5-10 Cycloalkyl, or -(CH2) 1-6 -C 5-8 In one embodiment, R A1 is -(CH2) 1-6 -cyclopropyl, -(CH2) 1-6 -cyclobutyl, -(CH2) 0-6 -Cyclopentyl, -(CH2) 1-6 -Cyclohexyl, -(CH2) 1-6 -Cycloheptyl, -(CH2) 1-6 -cyclooctyl, and -(CH2) 1-6 -bicyclo[2.2.1]heptyl, in particular -(CH2) 1-6 -Cyclopentyl, -(CH2) 1-6 -Cyclohexyl, -(CH2) 1-6 -Cycloheptyl, -(CH2) 1-6 -cyclooctyl, or -(CH2) 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 a C cycloalkyl group. 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 -(CH2) 0-6 -C 5-10 Spirocycloalkyl, especially -(CH2)0-6 -spiro[3.3]heptyl. Preferably, R A1 is -(CH2) 1-6 -C 5-10 It is a spirocycloalkyl.

[0080] In one embodiment, R A1 is -(CH2) 0-6 -aryl, for example, -(CH2) 0-6 -phenyl or -(CH2) 0-6 -naphthyl. Preferably, R A1 is -(CH2) 1-6 -aryl. Preferably, R A1 is -(CH2) 0-6 -phenyl. Preferably, R A1 is -(CH2) 1-6 -phenyl.

[0081] Preferably, R A1 is -(CH2) 0-2 -phenyl, for example, -(CH2) 1-2 In one embodiment, R A1 is phenyl. In another embodiment, R A1 is CH-phenyl. In another embodiment, R A1 is (CH2)2-phenyl. Most preferably, R A1 is phenyl or -CH2-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 -(CH2) 0-2 -phenyl, e.g., C 7-8 Alkyl or -(CH2) 1-2 -phenyl.

[0084] In another embodiment, R A1 is C 7-8 Alkyl or -(CH2)0-2 -phenyl, e.g., C 7-8 Alkyl or -(CH2) 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 , SF5, (CH2) 0-3 C 3-7 cycloalkyl, and 5- to 7-membered heterocyclyl, and the C is substituted with one or more, for example, 1, 2, 3, 4, or 5, for example, 1, substituent selected from the group consisting of 3-7 Cycloalkyl and the 5- to 7-membered heterocyclyl are 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.

[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 , SF5, and (CH2) 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 optionally includes halo, C 1-3 Alkyl, and C1-3 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.

[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 bonded to the same carbon atom and optionally linked together are substituted with one or more, for example, one, two, three, or four, for example, one, substituent selected from the group consisting of: 3-7 Form a cycloalkyl or R A1 But, arbitrarily, C 1-2 Haloalkyl, C 1-2 Haloalkoxy is 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 three substituents.

[0090] In one embodiment, R A1 is substituted with halo, for example, fluoro, chloro, or bromo. In a second embodiment, R A1 is C 1-6In a third embodiment, R A1 is C 1-6 In a fourth embodiment, R A1 In a fifth embodiment, R is substituted with hydroxy. A1 is substituted with cyano. In a sixth embodiment, R A1 is an O.G. 1 In a seventh embodiment, R A1 is S(O) 0-2 G 1 In an eighth embodiment, R A1 is substituted with SF5. In a ninth embodiment, R A1 is (CH2) 0-3 C 3-7 substituted with cycloalkyl, 3-7 Cycloalkyl is optionally substituted with halo, C 1-3 Alkyl and C 1-3 In a tenth embodiment, R A1 is substituted with a 5- to 7-membered heterocyclyl, such as pyrrolidinyl, wherein the 5- to 7-membered heterocyclyl is optionally substituted with halo, C 1-3 Alkyl and C 1-3 and substituted with one or more groups selected from haloalkyl.

[0091] Preferably, R A1 is replaced by one SF5, or R A1 is one SG 1 is replaced by G 1 However, it is CF3.

[0092] In one embodiment, one or more of the substituents is 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)2G 1 Suitably, one or more (e.g., one) substituent is SG 1 is.

[0093] In one embodiment, RA1 is (CH2) 0-3 C 3-7 Cycloalkyl (e.g., one (CH2) 0-3 C 3-7 cycloalkyl), and the C 3-7 Cycloalkyl is optionally substituted with halo, C 1-3 Alkyl and C 1-3 and substituted with one or more groups selected from haloalkyl.

[0094] In one embodiment, R A1 is C 3-7 In a second embodiment, R A1 is CH2C 3-7 In a third embodiment, R A1 is (CH2)2C 3-7 In a fourth embodiment, R is substituted with cycloalkyl, for example, CHCH. A1 is (CH2)3C 3-7 It is substituted with cycloalkyl.

[0095] In one embodiment, R A1 is (CH2) 0-3 C 3-7 substituted with cycloalkyl, 3-7 The cycloalkyl is unsubstituted.

[0096] In one embodiment, R A1 is (CH2) 0-3 C 3-7 substituted with cycloalkyl, 3-7 Cycloalkyl is a group consisting of 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, for example methyl, ethyl, or n-propyl, for example n-propyl. 1-3Haloalkyl, for example, CF3.

[0098] In one embodiment, R A1 is substituted with a C3 cycloalkyl, and the C3 cycloalkyl is 1-3 Substituted with haloalkyl, for example, CF3.

[0099] In another embodiment, R A1 is substituted with a C3 cycloalkyl, which is substituted with n-propyl.

[0100] In another embodiment, R A1 is substituted with (CH2)2C3 cycloalkyl.

[0101] Preferably, one of the following portions 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, and the pyrrolidinyl is preferably connected to R via the 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 substituted with halo, C 1-3 Alkyl, and C 1-3 and substituted with one or more groups selected from haloalkyl.

[0105] In another embodiment, R A1 is optionally C 1-2 Haloalkyl, e.g., CF3, C 1-2 Haloalkoxy, e.g., OCF3, or substituted with one or more, e.g., 1, 2, 3, or 4, e.g., 1, 2, 3, or 4, phenyl rings substituted with halo atoms (e.g., bromo, chloro, and / or fluoro).

[0106] Preferably, R A1 is one C 1-6 Alternatively, R A1 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, forming a cyclopropyl ring, R A1 is further substituted with one halo atom, for example, bromo. Suitably, in these embodiments, R A1 is -(CH2) 0-1 -phenyl. Most preferably, the phenyl ring is substituted in the para position.

[0107] In one embodiment, R A1 is optionally halo (e.g., fluoro or chloro), C 1-2 Alkyl, C 1-2 Haloalkyl (e.g., CF3), hydroxy, cyano, O(C 1-2 alkyl), and S(O)C 1-2 and alkyl. A1 is substituted with C1 alkyl (i.e., methyl), fluoro, or chloro.

[0108] In another embodiment, RA1 optionally, two alkyl groups, e.g., C 1-6 Alkyl, e.g., C 1-2 The alkyl group is substituted with 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 alkyl groups (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 alkyl and two alkyl groups, they are attached to the same carbon atom and are optionally linked together to form C 3-7 A cycloalkyl ring is formed, forming a group of the following structure: [ka] wherein n is an integer selected from 1, 2, 3, 4, and 5. Preferably, n is 3.

[0110] Preferably, C 3-7 The cycloalkyl group is a C3 cycloalkyl group: [ka] is.

[0111] Preferably, C 3-7 The cycloalkyl group is a C4 cycloalkyl group: [ka] is.

[0112] Preferably, C 3-7 The cycloalkyl group is a C5 cycloalkyl group: [ka] is.

[0113] Preferably, C 3-7 The cycloalkyl group is a C6 cycloalkyl group: [ka] is.

[0114] Preferably, C 3-7 The cycloalkyl group is a C7 cycloalkyl group: [ka] is.

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

[0116] In this embodiment, preferably, R A1 is -(CH2) 1-6 -phenyl, for example, -CH-phenyl. The phenyl ring can be optionally substituted, for example, with halo, for example, chloro and / or fluoro, for example, chloro. Alternatively, the phenyl ring can be optionally substituted with bromo.

[0117] Preferably, R A1 But -(CH2) 0-2 -phenyl, for example, -(CH2) 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 -(CH2) 0-2 When it is -phenyl, for example -CH2-phenyl, the phenyl group is substituted, for example, at the para position with bromo.

[0118] Appropriately, R A1 But -(CH2) 0-2 -phenyl, for example, -(CH2)1-2 When -phenyl, the phenyl group may be substituted with an additional phenyl ring, optionally substituted with one or more (e.g., one) halo atoms. Preferably, 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 However, optionally halo, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 , SF5, (CH2) 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 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.

[0120] Preferably, R A1 But C 1-10 If it is alkyl, R A1 However, 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 1-2Haloalkoxy, or substituted with one phenyl ring 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, -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, and -(CH2) 0-6 -aryl, R A1 However, optionally halo, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxy, Cyano, OG 1 , S(O) 0-2 G 1 , SF5, (CH2) 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 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, which is optionally substituted with one or more halo atoms.

[0122] Preferably, R A1 But C 2-10 Alkenyl, C 2-10 Alkynyl, -(CH2) 0-6 -C 3-10 Cycloalkyl, -(CH2) 0-6 -C 5-10 Spirocycloalkyl, and -(CH2) 0-6 -aryl, R A1 However, optionally halo, C 1-6Alkyl, 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, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, or (CH2) 0-1 phenyl (e.g., phenyl), and G 1 However, 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 C1-6 In a second embodiment, G 1 is C 3-7 In a third embodiment, G is C 1-6 haloalkyl, for example, CF. In a fourth embodiment, G 1 is (CH2) 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. 1 is 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 CH2-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 combine to form C 3-5 It may form a cycloalkyl ring.

[0130] In one embodiment, R C and R D 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 DBoth are H.

[0134] In another embodiment, R C and R D are connected, and 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 pharmaceutically 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 termed "exo."

[0136] In another embodiment, the compound of formula (I) is: [ka] or a pharmaceutically 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, so 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] Preferably, the endo double bond in the compound of formula (I) is trans.

[0140] Typically, as shown, for example, 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 equivalent compounds of formula (I) in which the carbon-carbon double bond is endo. 50 , lower EC 50 , and / or 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 the exo compound. In some cases, isomerization in an in vitro assay, for example, an in vitro hepatocyte stability assay, or in vivo after administration of the 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. Preferably, compounds of formula (I), for example, those in which the carbon-carbon double bond is exo, are stable to isomerization.

[0142] The combined group R including 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 A1The 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] represents isoxazole, R A1 does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl. [ka] represents isoxazole, R A1 is phenyl, phenyl substituted with halo, or C 1-10 In one embodiment, it does not represent phenyl substituted with alkyl. [ka] 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 -sulfanail)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 pharmaceutically 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 -sulfanail)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(pentafluoro-λ 6 -sulfanail)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 -sulfanail)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-λ 6 -sulfanail)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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 -sulfanail)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharmaceutically 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 the characterization data are shown in Figures 1-3.

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

[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, 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 readily known to those skilled in the art.

[0158] Compounds of formula (I) can 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): A compound of formula (V)—wherein X represents a leaving group, such as chloro, bromo, iodo, an alkane sulfonate, such as methane sulfonate, or an arenesulfonate, such as para-toluene sulfonate or benzene sulfonate—is reacted with a trialkyl phosphonoacetate of formula (IV)—wherein R 11 , R 12 , and R 3 are independently optionally substituted with halo; 1-4 represents alkyl, providing 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 compounds 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): Amidoximes of formula (XIII) can be obtained by reacting nitrile (XIV) with hydroxylamine hydrochloride in the presence of a base such as NaHCO3 in a solvent such as isopropanol.

[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, 1 M 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 give compounds of formula (VIII).

[0169] Step (vi): Compounds of formula (III) can be obtained by exposing compounds of formula (VIII) to basic conditions such as Cs2CO3 in the presence of tetrahydrofuran 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, wherein 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 the commercially available compound of formula (XXIII) under conditions known to one skilled in the art (such as mCPBA in DCM at low temperature) provides the epoxide of formula (XXII).

[0173] Step (ii): The epoxide of formula (XXII) undergoes nucleophilic ring opening, for example using HBr in THF, to give the haloalcohol of formula (XXI).

[0174] Step (iii): Oxidation of the alcohol in a compound of formula (XXI) under conditions readily 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 performed at room temperature, the tert-butyl ester remains intact, step (v) is unnecessary, and P is tert-butyl.

[0176] Step (v): The acid of formula (XVIII) was 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 using conditions described elsewhere herein gave compounds of formula (XVI).

[0178] Step (vii): Removal of the protecting group P under conditions known to those 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, and 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): Trifractionation of the ketone in the compound of formula (XXV) under standard conditions (strong base, e.g., LDA, and a triflating agent, e.g., Tf2NPh) 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 KCO, followed by acidification, etc.) to give the compound 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 compounds or general formulas described above. Protecting groups and means for their removal are described in "Protective Groups in Organic Synthesis" by Theodora W. Greene and Peter G.M.Wuts, 4th Rev. Ed., 2006, ISBN-10:0471697540, published by John Wiley & Sons Inc. 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 may be, for example, a pharmaceutically 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 3 is 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 its equivalent, 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 , R D , 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, This involves reacting with a base such as Cs2CO3, In the formula, R A1 , R C , R D , R 3 , R 11 , and R 12 is 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, with a compound of formula (XV): [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 or salt of formula (I), e.g., a pharmaceutically acceptable salt thereof, comprising the step of: [ka] or a salt thereof, In the formula, R A1 and RA2 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 or salt of formula (I), e.g., a pharmaceutically acceptable salt thereof, comprising the step of: [ka] or a salt thereof, reacting with carbon monoxide in the presence of a metal catalyst, for example a palladium catalyst, followed by hydrolysis (e.g. basic hydrolysis, for example aqueous KCO, 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 , RD , 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, a salt thereof, for example a pharmaceutically acceptable salt and / or solvate thereof, is provided.

[0202] In one embodiment, a compound selected from the group consisting of intermediates 13-85: Alternatively, a salt thereof, for example a pharmaceutically acceptable salt and / or solvate thereof, is provided.

[0203] In another embodiment, a compound selected from the group consisting of intermediates 86-151: Alternatively, a salt thereof, for example a pharmaceutically acceptable salt and / or solvate thereof, is provided.

[0204] In another embodiment, a compound selected from the group consisting of intermediates 152-223: Alternatively, a salt thereof, for example a pharmaceutically acceptable salt and / or solvate thereof, is 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 salts of compounds of formula (I) must be pharmaceutically acceptable for use in therapy. Suitable pharmaceutically 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 pharmaceutically acceptable salts include trifluoroacetic acid salts. Preferably, the pharmaceutically acceptable salt is a tromethamine salt. Thus, in one embodiment, a compound of formula (I) is provided in the form of a pharmaceutically acceptable salt. Alternatively, a compound of formula (I) is provided in the form of a free acid. If the compound contains a basic group, as in the free acid, it may be zwitterionic.

[0207] The compounds of formula (I) may be prepared in crystalline or amorphous form, and if crystalline, may optionally be solvated, for example as a hydrate. The present invention includes within its scope stoichiometric solvates (e.g., hydrates), as well as compounds containing variable amounts of solvent (e.g., water). Preferably, the compounds of formula (I) are not solvates.

[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, and mixtures thereof (e.g., racemic mixtures). Where noted 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). Where additional chiral centers are present in 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 one from the other by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0209] The present invention also includes all isotopic forms of the compounds provided herein, whether in the form (i) where all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is essentially predominant (referred to herein as a "natural isotopic form"), or (ii) where one or more atoms are replaced by an atom having the same atomic number but a mass number different from that of the essentially predominant atom (referred to herein as a "non-natural variant isotopic form"). It is understood that atoms may naturally exist as a mixture of mass numbers. The term "non-natural variant isotopic form" further includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers 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 an "isotopically enriched isotopic form"). 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-naturally occurring 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( 125 It may contain one or more artificial or rare isotopes, such as I), or may contain 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-naturally occurring variant isotopes incorporating H or D may offer certain therapeutic benefits due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some situations. Furthermore, non-naturally occurring variant isotope forms may 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 replaced by deuterium (i.e., 2 In one embodiment, the atoms of the compound of formula (I) are in an isotopic form that is not radioactive. In one embodiment, one or more atoms of the compound of formula (I) are in an isotopic form that is radioactive. A suitable radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0213] In one embodiment, compounds of formula (I) are provided whereby a single atom of the compound exists in a non-naturally occurring variant isotopic form. In another embodiment, compounds of formula (I) are provided whereby two or more atoms exist in a non-naturally occurring 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 similar to those described herein, e.g., 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 for the conventional reagents used in the Examples. Because 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, e.g., at least 60% pure, more preferably at least 75% pure, preferably at least 85%, and especially at least 98% pure (% being weight by weight). Impure preparations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0215] Treatment indications Compounds of formula (I) are used in therapy, particularly for the treatment or prevention of inflammatory diseases or diseases associated with an undesired immune response. As shown in Biological Example 1 below, the compounds of formula (I) of Example 1 have lower IC 50 As shown by the 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 exhibiting improved stability in both mouse and human cryopreserved hepatocytes. Other exemplary compounds of Formula (I) have lower IC values. 50 As 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 efficacy than 4-octyl itaconate and 2-(2-chlorobenzyl)acrylic acid, while also 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 pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament. Also provided is a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof. Such a pharmaceutical composition comprises a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

[0217] In a further aspect, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of inflammatory diseases or diseases 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 pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment or prevention of inflammatory diseases or diseases associated with an undesired immune response. In a further aspect, the present invention provides a method for treating or preventing inflammatory diseases or diseases associated with an undesired immune response, comprising administering a compound of formula (I) as defined herein, or a pharmaceutically 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, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of an inflammatory disease or a disease associated with an unwanted immune response. In one embodiment, the present invention provides the use of a compound of formula (I) as defined herein or a pharmaceutically 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 unwanted immune response. In one embodiment, the present invention provides a method for treating an inflammatory disease or a disease associated with an unwanted immune response comprising administering a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0220] In one embodiment, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the prevention of inflammatory diseases or diseases associated with an unwanted immune response. In one embodiment, the present invention provides the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the prevention of inflammatory diseases or diseases associated with an unwanted immune response. In one embodiment, the present invention provides a method for preventing inflammatory diseases or diseases associated with an unwanted immune response, comprising administering a compound of formula (I) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

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

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

[0223] An unwanted immune response is typically an immune response 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, erythrodermic, pustular, guttate, inverse, and onychoderma), 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 mitochondrial degeneration). 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 transplant, 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 Non-alcoholic steatohepatitis, rheumatoid arthritis, granuloma annulare, cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, drug-induced lupus, autoimmune myocarditis or myopericarditis, Dressler syndrome, giant cell myocarditis, post-pericardiotomy 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 (sciatica). chronic lymphocytic inflammation with pontine perivascular enhancement reactive 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 (including bullous pemphigoid, mucous membrane pemphigoid, cicatricial pemphigoid, gestational pemphigoid or pemphigoid, and ocular cicatricial pemphigoid), linear IgA disease, Behçet's disease, celiac disease, Chagas' disease, dermatomyositis, type 1 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 (TTH), and idiopathic thrombocytopenic purpura (TTH). 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-person 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) inflammatory bowel disease), 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 ... glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma, glaucoma Celiac disease, dermatitis herpetiformis, eosinophilic esophagitis, achalasia, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune esophagitis, autoimmune orchitis, autoimmune pancreatitis, aortitis and perivasculitis, 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, lignicin conjunctivitis, Mooren's ulcer, acute pityriasis lichenoides (PLEVA), Much-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, and thymoma-associated multisystem autoimmunity), perivenous encephalomyelitis, reflex sympathetic dystrophy, relapsing polychondritis, sperm and testicular autoimmunity, Susac syndrome, Tolosa-Hunt syndrome, and phosphatasia. Collegian-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 with 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 monogenic interferonopathies (including Aicardi-Goutieres 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 diseases (e.g., diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, kidney transplant).

[0226] In one embodiment, the inflammatory disease or disease associated with an unwanted 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 with aphthous stomatitis (PFA). or is associated with a disorder selected from the group consisting of: 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 (including Aicardi-Goutieres syndrome, retinal vasculopathy with cerebral leukodystrophy, spondylochondrodysplasia, infantile-onset STING [stimulator of interferon genes]-associated vasculopathy, proteasome-associated autoinflammatory syndrome, familial chilblains, hereditary symmetrical 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 excessive NF-κB or gain of function of the NF-κB signaling pathway (including non-canonical NF-κB signaling), or significantly contributes 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 IC 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 activity compared to 4-octyl itaconate when tested in an 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 an NRF2 assay, e.g., as described in Biological Example 2.max In one embodiment, the compound of formula (I) exhibits a lower EC50 activity compared to 4-octyl itaconate when tested in an 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 activity compared to 4-octyl itaconate when tested in an 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 2 + 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, preferably the hepatocytes are human cryopreserved hepatocytes.

[0232] Administration Compound of formula (I) is usually administered as a pharmaceutical composition. Thus, in one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically 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, such as polyethylene glycol or oil.The formulation may also contain suspending agents, preservatives, flavorings and / or coloring agents.

[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 conventional 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 filling the dispersion or suspension into a soft gelatin capsule.

[0239] A typical parenteral composition will consist of a solution or suspension of a 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, droplets, gels, and powders. Aerosol formulations usually contain a solution or fine suspension of a compound of formula (I) in a pharmaceutically acceptable aqueous or non-aqueous solvent, and are usually presented in a sterile form in a sealed container, which can be in the form of a cartridge or refill for use in a spray device, in single or multiple doses. 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 includes an aerosol dispenser, it will contain a propellant, which can be compressed gas, air, or an organic propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). The aerosol dosage form can also be in 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 lung 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 contain 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 topically 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 suppositories or enemas, including, for example, aqueous or oily solutions, suspensions, emulsions, and foams.Such compositions are prepared according to standard procedures well known to those skilled in the art.For example, suppositories can be prepared by mixing active ingredients with conventional suppository bases such as cocoa butter or other glycerides.In this case, the drug is mixed with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the 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 can also contain various other ingredients, including but not limited to tonicity agents, buffers, surfactants, stabilizing polymers, preservatives, cosolvents, and viscosity building agents.Suitable pharmaceutical compositions of the present invention include the compounds of the present invention formulated with tonicity agents and buffers.Pharmaceutical compositions of the present invention can optionally further contain surfactants and / or emollients and / or stabilizing polymers.

[0248] Various tonicity agents can be used to adjust the tonicity of the composition, preferably to that of natural tears. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, and 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 specific agent added. However, generally, the composition will contain a sufficient amount of tonicity agent to ensure that the final composition has an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm, and 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. Specific concentrations will vary depending on the agent used. Preferably, however, the buffer will be selected to maintain a target pH within the range of pH 5-8, more preferably a target pH of pH 5-7.

[0250] Surfactants can optionally be used to deliver higher concentrations of the compounds of the present invention. Surfactants function to solubilize the compounds and stabilize colloidal dispersions such as micellar solutions, microemulsions, emulsions, and suspensions. Examples of optional surfactants include polysorbates, poloxamers, polyoxysilane 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants for use in the present invention have a hydrophilic / lipophilic balance (HLB) value 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 ophthalmic compositions of the compounds of the present invention is a mucilage, which functions as a stabilizing polymer. The stabilizing polymer must be an ionic / charged example, preferably for topical ocular use; more specifically, the polymer must have a negative surface charge, a zeta potential of (-)10-50 mV for physical stability, and be dispersible in water (i.e., water-soluble). Preferred stabilizing polymers of the present invention are polyelectrolytes, or, if more than one, polyelectrolytes from the family of crosslinked polyacrylates, such as Carbomer and Pemulen®, particularly Carbomer 974p (polyacrylic acid), at 0.1-0.5% w / w.

[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-increasing agents 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 typically packaged in multi-dose form. Therefore, preservatives are necessary to prevent microbial contamination during use. Suitable preservatives include benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically used at levels of 0.001 to 1.0% w / v. The unit dose compositions of the present invention are sterile but typically will not be preserved. Therefore, 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, e.g., 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, e.g., 40% to 90% by weight, of the carrier depending on the method of administration. The composition may contain 0.05 mg to 1000 mg, e.g., 1.0 mg to 500 mg, e.g., 1.0 mg to 50 mg, e.g., about 10 mg, of the compound of formula (I) depending on the method of administration. The composition may contain 50 mg to 1000 mg, e.g., 100 mg to 400 mg, of the carrier depending on the method of administration. The dosage of the compound used to treat the aforementioned disorders will vary in the usual manner depending on the severity of the disorder, the patient's weight, and other similar factors. However, as a general guide, suitable unit doses may be 0.05 to 1000 mg, more preferably 1.0 to 500 mg, for example 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 multiple drugs.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), and the like. , adalimumab, certolizumab, golimumab, and biosimilars), phosphodiesterase-4 (PDE4) inhibitors (e.g., apremilast, crisaborole), anti-IL-17 agents (e.g., brodalumab, ixekizumab, secukinumab), anti-IL-12 / 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 analogs (e.g., mitoxantrone), cladribine, sphingosine 1-phosphate receptor modulators or sphingosine analogs (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 analogs (e.g., pentostatin), mTOR (mechanistic target of rapamycin) pathway inhibitors (e.g., sirolimus, everolimus), antithymocyte 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, BLyS, also known as 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 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 muscarinic agents (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), acetic acids (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), topical / 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; - reduced dose and dosing frequency through improved pharmacokinetics, particularly 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 the 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 due to different electrophilicities, which result in differential targeting of the cysteine ​​proteome (van der Reest J. et al., 2018) and therefore alter the 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] [Example]

[0260] Analyzer NMR spectra were recorded using a Bruker 400 MHz Avance III spectrometer equipped with a BBFO 5 mm probe or a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5 mm SmartProbe™. Spectra were measured at 298 K and referenced to the solvent resonance unless otherwise noted. 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 (2.1 x 30 mm), maintained at 40 °C and eluted with a linear acetonitrile gradient appropriate for the lipophilicity of the compound 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 to 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 (4.6 x 30 mm), maintained at 40 °C and eluted with a linear acetonitrile gradient appropriate for the compound's lipophilicity over 4 or 15 min at a constant flow rate of 2.5 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 at 254 nm 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 heated at 20°C for 1 min. -1 Heat to 30-350°C or change according to the experimental instructions. -1 A purge of dry nitrogen at 100°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 alloys. A predefined amount of 1–5 mg of 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 1 min. -1 A nitrogen purge of 0.05 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 (½”), 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 PANalytical X'Pert PRO. The data collection range was 2.994–35° 2θ, with a continuous scan rate of 0.202004° s. -1 It was.

[0267] General method All reactions were stirred unless otherwise stated.

[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 warmed 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 x). The combined organic extracts were washed with brine, dried (Na2SO4), 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 diethylphosphonoacetate (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 a mixture of phosphonoacetate and sodium hydride. The reaction was heated to 70 °C, stirred for 3 h, and then cooled to room temperature before partitioning between EtOAc and water. The phases were separated, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried (MgSO4), 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 the THF. The mixture was diluted with water and EtOAc. The phases were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried (MgSO4), 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% by weight, 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. Next, chloromethylheteroarene (1 equiv.) was added, and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous NH Cl solution and extracted with EtOAc (3 x). The combined organic phases were washed with brine, dried (Na SO ), 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 warmed to room temperature and stirred for 45 min. The reaction was quenched with saturated aqueous NaHCO3, and the mixture was extracted with EtOAc (3 x). The combined organic extracts were washed with brine, dried (Na2SO4), 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 phases were washed with brine, dried (MgSO4), and 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% by weight, 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×) or MTBE (3×). The combined organic phases were washed with brine, dried (NaSO), and concentrated, and the crude product was then purified by chromatography on silica gel to give the desired compound.

[0276] Step 3 TFA (10–350 equiv.) was added to a solution of the tert-butyl ester (1 equiv.) in DCM (to achieve 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 (twice). 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×). The combined organic phases were washed with 1 M HCl (200 mL), brine (200 mL), dried (MgSO4), 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×). The combined organic phases were washed with 1 M HCl (aqueous) (3×), dried (MgSO4), 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×). The combined organic phases were dried (MgSO4) 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, stirred for 1–5 h, cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic phases were dried (MgSO4) and concentrated. The crude product was purified by chromatography on silica gel to give the desired 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 minutes, then nonanenitrile (10 mL, 57 mmol) was added, and the mixture was heated to reflux for 12 hours before being 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) at 0 °C. 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), dried (MgSO), 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 x 20 mL) to give nonanehydrazide (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 nonanehydrazide (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 (NaSO), 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) so 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 (NaSO) 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 warmed to room temperature and stirred for 5 h, then poured into water (250 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (2 × 40 mL), dried (NaSO), and concentrated. The 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), then extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (2 × 100 mL), dried (NaSO), 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 (NaSO), 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. After the mixture was stirred for 30 minutes, 1-iodooctane (9.92 g, 7.46 mL, 41.3 mmol) was added dropwise over 10 minutes at 0° C. The reaction was allowed to warm to room temperature and stirred for 16 hours. 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 (NaSO), 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 quenched with saturated aqueous NH4Cl (50 mL). 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 (Na2SO4), 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 washed with saturated NaHCO (2 x 25 mL), water (25 mL), and brine (25 mL). The organic layer was then dried (NaSO) 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 + ). 1H 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 minutes. 8,8-Difluorononanenitrile (2.00 g, 11.4 mmol) was added, and the mixture was heated to 85° C. and stirred for 16 hours. The reaction was cooled to room temperature and filtered. The filtrate was concentrated and co-evaporated 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 + ). 1 H NMR(400MHz,DMSO-d6)δ 8.69(s,1H), 5.34(s,2H), 1.94(t,J=7.6Hz,2H), 1.90-1.76(m,2H), 1.58( t,J=18.9Hz,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] [Table 4-15]

[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 NH4Cl (50 mL) was added and the resulting mixture was extracted with DCM (3 x 50 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 hours and quenched with saturated aqueous NaHCO (50 mL). The mixture was extracted with MTBE (3 × 50 mL), and the combined organic phases were dried (MgSO) and concentrated. The 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 hours. The mixture was cooled to room temperature, diluted with MTBE (200 mL), and washed with water (3 × 40 mL). The combined organic phases were dried (MgSO4) 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. 1H 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-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 62-2-(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 co-evaporated with toluene (2 x 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 x 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 (NaSO), 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. 1H 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, then quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (300 mL), dried (MgSO4), 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 + ). 1H 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 approximately 250 mL and then extracted with EtOAc (3 × 100 mL). The aqueous phase was acidified to pH 1 with concentrated HCl and extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine (250 mL), dried (MgSO), 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(PPh3)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 (MgSO4) 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. 1 H 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 x 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 x 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 warmed 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 afford 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 72-1-bromodecan-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 (NaSO), 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 NaHCO3 (2x20 mL), brine (20 mL), dried (Na2SO4) 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 73-(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 warmed to room temperature and stirred for 18 h. The mixture was quenched with ice, and then water (100 mL) was added. The mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with 10% citric acid (3×100 mL), water (100 mL), dried (MgSO4), 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 × 100 mL). The combined organic phases were washed with brine (3 × 100 mL), dried (MgSO), 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 (400MHz, CDCl3) 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 (3 × 75 mL). The combined organic phases were washed with 1 M HCl (2 × 100 mL), water (100 mL), dried (MgSO), 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 (400MHz, CDCl3) 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 hours, then diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried (MgSO4) 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 warmed to room temperature and stirred for 45 min. The reaction mixture was quenched with saturated NaSO (15 mL). The organic layer was washed with saturated aqueous NaHCO (15 mL). The aqueous layer was extracted with DCM (3 × 30 mL). The combined organic phases were dried (MgSO) 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 warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 to pH 7. The aqueous phase was extracted with DCM (3 x 30 mL). The combined organic extracts were dried (MgSO4) 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 minutes 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 minutes. 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 hours, then quenched with saturated aqueous NH4Cl solution (50 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phases were dried (MgSO4) 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 (2 M 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 (2 M 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 × 100 mL). The combined organic phases were washed with brine (2 × 100 mL), dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography (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 (4 M 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 for 18 h at room temperature. HCl (4 M 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 minutes. 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 hours, then heated to 75° C. and stirred for 16 hours. 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 (NaSO), 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 hours. The mixture was concentrated, and the residue was co-evaporated with toluene (2 × 10 mL) to give 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid (0.625 g, 2.1 mmol, 84% purity) as a colorless oil. 1H 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 and backfilled with nitrogen (three 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 minutes, after which Pd-174 (153 mg, 210 μmol) was added. Sparging was continued for an additional 2 minutes, and the mixture was heated to 100° C. for 1 hour. 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 (NaSO), 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 121-1-Bromo-4-(1-propylcyclopropyl)benzene [ka]

[0338] Step 1 A solution of ethylmagnesium chloride (2 M 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 poured into saturated NH Cl (75 mL). Dilute H SO (1 M, 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, dried (Na SO ), 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 (NaSO), 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 122-1-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 hours. The mixture was cooled to room temperature and concentrated. The residue was suspended in toluene (15 ml) and stirred at 85° C. for 10 minutes. 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-d) 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 (£)-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 123-1-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 (£)-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). Deoxofluorobenzene (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, poured into saturated aqueous NaHCO (100 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (70 mL), dried (NaSO), 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 (NaSO), 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 (400MHz, CDCl3) 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 additional 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 and then concentrated to approximately 50 mL. The mixture was diluted with water (300 mL) and extracted with EtOAc (5 x 200 mL). The combined organic phase was washed with saturated aqueous NH4Cl (400 mL), brine (400 mL), dried (Na2SO4), 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 hours. The reaction mixture was quenched with water (100 mL) and the mixture was partially concentrated. The mixture was extracted with EtOAc (2×150 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSO4), 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 minutes, 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 hours. 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 hours. 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 (3 × 80 mL). The combined organic layers were dried (MgSO4) and concentrated to give 2-(4-bromophenyl)-2,2-difluoroacetonitrile (1.9 g, 7.2 mmol, 90% purity) as a clear, pale orange oil. 1H 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 poured into saturated aqueous NH4Cl (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), dried (MgSO4), 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 = 8.2 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 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 minutes. (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 hours, 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 (NaSO), 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 (7 M 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 (7 M 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) according to 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 NH₄Cl solution was added, and the reaction mixture was extracted with Et₂O. The combined organic phases were washed with brine, dried over MgSO₄, 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 A mixture of CuI (15.2 g, 79.8 mmol), K2CO3 (36 g, 266 mmol), and N,N,N',N'-tetramethylethylenediamine (9.4 g, 79.8 mmol) in dimethylformamide (540 mL) was vigorously stirred at room temperature under a dry air atmosphere for 15 min. TMSCF3 (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. Next, a solution of ((hex-5-yn-1-yloxy)methyl)benzene (10 g, 53.2 mmol) and TMSCF3 (15.2 g, 106 mmol) in dimethylformamide (540 mL) precooled to 0 °C was added in one portion. After 30 min at 0 °C, the reaction mixture was warmed to room temperature and stirred under a dry air atmosphere for 24 h. Water was then added, and the mixture was extracted with Et2O. The combined organic phase was washed with water and brine, then dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure at 40 °C, 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+NH4). + (ES + ).

[0370] Step 3 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 THF (13.5 mL) and HO (1.5 mL) was added JohnPhos AuCl (CAS: 854045-93-5) (265 mg, 0.5 mmol) and silver trifluoromethanesulfonate (128 mg, 0.5 mmol), and the vial was wrapped in aluminum foil and heated to 70 °C. After 18 h, the reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO solution, and extracted with DCM (3 times). The combined organic phases were dried over NaSO, 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), dried over NaSO, and filtered. 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 afford (((5,5,7,7,7-pentafluoroheptyl)oxy)methyl)benzene (5.5 g, 18.6 mmol, 85%) as a pale yellow oil. 1 H NMR (400MHz, CDCl3)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). 19F NMR (376MHz, CDCl3) δ: -61.93 (t, J = 8.9 Hz), -95.16 (q, J = 8.9 Hz).

[0372] Step 5 To a solution of (((5,5,7,7,7-pentafluoroheptyl)oxy)methyl)benzene (7.0 g, 23.6 mmol) in MeOH (50 mL) was added 5% Pd(OH)2 / C catalyst (50 wt% in water, 3.5 g) and AcOH (0.5 mL), and the reaction mixture was stirred under a H2 atmosphere at 60 °C overnight. 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 quenched with aqueous NaSO (100 mL), diluted with dichloromethane (50 mL), and separated. The aqueous phase was extracted with dichloromethane (2 x 50 mL), and the combined organic phase was washed with water (2 x 60 mL) and brine, dried over MgSO, and filtered. 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 afford 5,5,7,7,7-pentafluoroheptanal (3.6 g, 17.6 mmol, 75%) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) 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 warmed to room temperature for 30 minutes, 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 warmed to room temperature and stirred overnight. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. 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(400MHz,CDCl3)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 stirred at room temperature overnight under an atmosphere of H. 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(400MHz, CDCl3)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). 19F NMR (376MHz, CDCl3) δ: -61.97 (t, J = 8.9 Hz), -95.23 (q, J = 8.9 Hz).

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

[0377] Step 1 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 EtO (25 mL) at 0 °C, triethylamine (1.79 mL, 13.2 mmol) was added, 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, dried over NaSO, 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, NaBH (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 (4 × 10 mL). The combined organic phases were washed with brine, dried over NaSO, 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 phases were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure at 40 °C, 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, a suspension of NaH in mineral oil (60 wt%, 96 mg, 2.4 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. Next, 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, dried over Na SO , and filtered. The filtrate was concentrated under reduced pressure at 40 °C, 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 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 EtOH (15 mL) and HO (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, dried over NaSO, and filtered. 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 EtN (9.83 g, 97.3 mmol). The reaction mixture was stirred at room temperature for 2 h, then quenched with saturated aqueous NHCl solution and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, 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 quenched with saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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 afford 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 (2.31 g, 14.46 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was adjusted to pH = 7 using saturated aqueous NaHCO and then concentrated under reduced pressure at 30 °C to remove MeOH. The residual aqueous mixture was extracted with EtOAc (2 × 50 mL), and the combined organic phases were dried over NaSO, 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 A mixture of methyl 4-bromopicolinate (2.80 g, 13.0 mmol), oct-1-yne (5.70 g, 51.8 mmol), Pd(PPh)Cl (0.92 g, 1.30 mmol), and CuI (492 mg, 2.60 mmol) in DIPEA (65 mL) 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, dried over NaSO, 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 stirred under an atmosphere of H2 at room temperature for 12 h. 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, NaBH (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 phases were washed with brine, dried over NaSO, 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 afford (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, SOCl (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 diluted with HO (10 mL), adjusted to pH = 4 using dilute aqueous HCl (2 M), and extracted with MTBE (3 × 10 mL). The combined organic layers were washed with HO (2 × 2 mL) and brine, dried over NaSO, 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 + ). 1H NMR(400MHz,CDCl3)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] A mixture of 1-(4-hydroxyphenyl)cyclopropane-1-carbonitrile (1.20 g, 7.54 mmol), CsCO (7.35 g, 22.6 mmol), KI (125 mg, 0.75 mmol), and bromocyclobutane (4.04 g, 30.2 mmol) in dimethylformamide (14 mL) was stirred at 60 °C overnight. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with saturated aqueous NH Cl solution (2 × 30 mL) and brine, dried over Na SO , 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(400MHz,CDCl3)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 143-1-(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 hours. 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 for Intermediate 140. LCMS: (System 2, Method C) m / z 212.4 (M+H) + (ES + ).

[0397] Intermediate 152-2-(4-cyclobutylphenyl)acetonitrile [ka] To a solution of 1-(chloromethyl)-4-cyclobutylbenzene (2.7 g, 15 mmol), K2CO3 (3.1 g, 22.5 mol), and KF (1.3 g, 22.5 mmol) in MeCN (50 mL) at room temperature, 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 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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] A mixture of 3-fluoro-4-hydroxybenzonitrile (1.00 g, 7.29 mmol), K2CO3 (2.01 g, 14.6 mmol), and 1-iodobutane (2.01 g, 10.94 mmol) in acetone (15 mL) 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 156-3-chloro-4-propoxybenzonitrile [ka] Prepared by a procedure similar to that for 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, a solution of KHMDS in THF (1 M, 13.4 mL, 13.4 mmol) was added, and the resulting mixture was stirred at −78 °C for 1 h. Next, 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 quenched with saturated aqueous NH4Cl 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, dried over anhydrous Na2SO4, 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 + ). 1H NMR(400MHz, CDCl3)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, a solution of BH3.Me2S complex in THF (2 M, 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, dried over anhydrous Na2SO4, 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, CDCl3) δ: 7.32 (d, J = 6.2 Hz, 2H), 4.64 (s, 2H). One exchangeable proton is not 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 (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 (4 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, 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 (400MHz, CDCl3) δ: 7.35 (d, J = 6.1 Hz, 2H), 4.48 (s, 2H).

[0404] Step 3 A mixture of 1,3-dichloro-5-(chloromethyl)-2-fluorobenzene (7.20 g, 33.7 mmol), TMSCN (5.00 g, 50.6 mmol), K2CO3 (7.00 g, 50.6 mmol), and KF (2.90 g, 50.6 mmol) in MeCN (80 mL) 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, dried over anhydrous Na2SO4, 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 (400MHz, CDCl3) δ: 7.31 (d, J = 6.0 Hz, 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, a suspension of sodium hydride in mineral oil (60 wt%, 431 mg, 10.8 mmol) was added, 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 quenched with saturated aqueous NH 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 HO (2 × 20 mL) and brine, dried over anhydrous Na SO , 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 (400MHz, CDCl3) 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 hours. Yield: 400 mg. White solid. 1 H NMR (400MHz, CDCl3) δ: 6.96-6.89 (m, 2H), 1.86-1.78 (m, 2H), 1.46-1.37 (m, 2H).

[0407] Intermediate 166-1-(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 (400MHz, CDCl3) 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 169-1-(4-bromo-3-chlorophenyl)cyclopropane-1-carbonitrile [ka] Prepared similarly to Intermediate 161, Steps 2 to 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 (400MHz, CDCl3) 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 similarly 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 hours and Step 4 was stirred at room temperature for 3 hours. Yield: 425 mg. White solid. 1H NMR(400MHz, CDCl3)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 174-1-(3-chloro-4-methylphenyl)cyclopropane-1-carbonitrile [ka] Prepared similarly 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 stirring the mixture 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 (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (0–20% MTBE / isohexane) to give 4-cyclobutoxybenzonitrile (0.74 g, 3.8 mmol, 90% purity) as a colorless oil. 1H 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 warmed 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 SO ), 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. 1 H 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 co-evaporated with toluene (3 x 10 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] To a solution of 3,5-difluoro-4-hydroxybenzonitrile (750 mg, 4.84 mmol), butan-1-ol (393 mg, 5.32 mmol), and PPh3 (2.54 g, 9.68 mmol) in THF (15 mL) at 0 °C, DIAD (1.96 g, 9.68 mmol) was added, 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 (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, 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, then poured into brine (40 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were dried (MgSO4) 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) according to General Procedure A, Step 1, Method A. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to afford 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) according to 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. 1 H 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 silica gel chromatography (0-100% EtOAc / isohexane) to afford 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 To a solution of hydroxylamine hydrochloride (72.9 g, 1.05 mol) in isopropanol (420 mL) was added NaHCO3 (150 g, 1.78 mol) in one portion. The mixture was stirred at room temperature for 10 minutes, and then nonanenitrile (73.0 g, 524 mmol) was added to the mixture in one portion. The mixture was heated to 85 °C and stirred for 12 hours. 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. 1H 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, and then ethyl bromoacetate (179 g, 1.07 mol) was added dropwise to the mixture at a rate that kept the internal temperature below 10 °C. The mixture was stirred at 10 °C for 1 h and then poured into aqueous NH4Cl solution (2 L) in portions at 0–10 °C. 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), dried over NaSO, 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. 1 H 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. The mixture was stirred at room temperature for 12 hours. 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), dried over Na2SO4, filtered, and concentrated under reduced pressure at 45 °C. The crude product was triturated with isopropyl ether (1.1 L) and stirred at room temperature for 30 minutes. The suspension was filtered, and the filter cake was washed with isopropyl ether (2×300 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(400MHz,CDCl3)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 a rate that maintained the internal temperature at -15 to -10 °C. The mixture was stirred at -15 to -10 °C for 2 h, and 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 x 500 mL), and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, 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 to 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 CsCO (196 g, 603 mmol) 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), dried over NaSO, 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) was added KCO (79.9 g, 578 mmol) and paraformaldehyde (3.30 g, 193 mmol) in one portion at room temperature. The mixture was stirred at 65 °C for 12 h, and 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 to 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 100 × 250 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 co-evaporated 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 stream of nitrogen to give a solid, which was analyzed by XRPD, DSC, TGA, and HPLC. 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% between 25 and 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 loaded into 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. 1 The H NMR spectrum showed the formation of the tromethamine salt of Example 1, with the ratio of Example 1 to 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 Figure 2. 1 The 1 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) according to 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) according to 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. 1 H 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 silica gel chromatography (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) according to General Procedure A, Step 1, Method A. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to afford 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) according to 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. 1H 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 afford 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) according to 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) according to 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 from tert-butyl 2-((3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.468 g, 1.40 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-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) according to 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 afford 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 + ). 1H 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) according to 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 from tert-butyl 2-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.41 g, 1.40 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-(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 + ). 1H 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) according to 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) according to 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) according to 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. 1 H 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) according to 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)acrylic acid (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) according to 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 + ). 1 H 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) according to 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 from tert-butyl 2-((3-(octan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.38 g, 1.1 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-(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) according to 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) according to 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 + ). 1 H 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 hours. Potassium iodide (123 mg, 0.74 mmol) was added and stirring continued at 80 °C for 1 h. The mixture was cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (30 mL), dried (Na2SO4) 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 + ). 1 H 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) according to 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 from tert-butyl 2-((3-(1-(4-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.394 g, 1.1 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)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) according to 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 afford 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 + ). 1 H 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 from tert-butyl 2-(diethoxyphosphoryl)-3-(3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)propanoate (4.30 g, 8.59 mmol) according to 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-(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 from tert-butyl 2-((3-(8,8,8-trifluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (1.84 g, 4.89 mmol) according to General Procedure A, Step 3. 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)acrylic acid (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 from 5-(chloromethyl)-3-(2-methylheptan-2-yl)-1,2,4-oxadiazole (0.60 g, 2.5 mmol) according to General Procedure A, Step 1, Method B, except that sodium iodide was not 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 afford 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) according to 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 + ). 1 H 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 from tert-butyl 2-((3-(2-methylheptan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.30 g, 0.93 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-(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) according to 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) according to 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 from tert-butyl 2-((1-octyl-1H-1,2,4-triazol-3-yl)methyl)acrylate (1.60 g, 4.98 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-((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) according to 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) according to 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)acrylic acid (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) according to 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 + ). 1H 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) according to General Procedure A, Step 2, Method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to afford 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, 30 x 100 mm column, 40-70% MeCN in water with 0.1% formic acid) 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 + ). 1 H 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 from 5-(chloromethyl)-3-(3,5-dichlorobenzyl)-1,2,4-oxadiazole (4.18 g, 9.2 mmol, 61% purity) according to General Procedure A, Step 1, Method B, 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) according to General Procedure A, Step 2, Method B. The crude product was purified by chromatography on silica gel (0-100% EtOAc / isohexane) to afford 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 from tert-butyl 2-((3-(3,5-dichlorobenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (610 mg, 1.57 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-(3,5-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 from 5-(chloromethyl)-3-(7,7,8,8,8-pentafluorooctyl)-1,2,4-oxadiazole (2.74 g, 8.53 mmol) according to General Procedure A, Step 1, Method C, 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) according to 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 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) 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-(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 + ). 1 H 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) according to 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) according to 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 + ). 1H 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 + ). 1 H 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 from 3-(4-butylbenzyl)-5-(chloromethyl)-1,2,4-oxadiazole (1.10 g, 3.9 mmol) according to General Procedure A, Step 1, Method B, 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) according to 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 + ). 1H 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 + ). 1 H 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) according to 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 + ). 1H 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 from tert-butyl 2-((3-(1-(3-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.88 g, 2.3 mmol) according to General Procedure A, Step 3. 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 from N-hydroxy-1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboximidamide (1.12 g, 1.5 equiv., 4.59 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-(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) according to 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 + ). 1H 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 from tert-butyl 2-((3-(1-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.107 g, 0.27 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-(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) according to 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 + ). 1H 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 + ). 1 H 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) according to 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 + ). 1H 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 from tert-butyl 2-((3-(1-(2-chlorophenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.300 g, 0.79 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-(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 from 1-(4-chlorophenyl)-N-hydroxycyclobutane-1-carboximidamide (596 mg, 1 equiv., 2.18 mmol, 82% purity) 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 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) according to 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 + ). 1H 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 + ). 1 H 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 viscous 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 + ). 1 H 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) according to 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 from tert-butyl 2-((3-(2-methyloctan-2-yl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (504 mg, 1.5 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-(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 from 3-butyl-N-hydroxybenzimidamide (728 mg, 1.1 equiv., 3.37 mmol, 89% purity) according to General Procedure B, Method A. 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 + ). 1 H 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) according to 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 from tert-butyl 2-((3-(3-butylphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.400 g, 1.1 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-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 + ). 1H 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 from N-hydroxy-2-(4-pentylphenyl)acetimidamide (780 mg, 1.05 equiv., 3.22 mmol, 91% 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 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 + ). 1 H 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) according to 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 from tert-butyl 2-((3-(4-pentylbenzyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.12 g, 0.31 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-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 + ). 1H 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) according to 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) according to 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 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) 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-(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) according to 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 from tert-butyl 2-((3-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (0.650 g, 1.8 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-(7,7-difluorooctyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid (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] Step 1 Prepared from 2-cyclohexyl-N-hydroxyacetimidamide (553 mg, 2.90 mmol, 82% 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-(cyclohexylmethyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (356 mg, 0.78 mmol, 94% purity) as a light brown oil. LCMS m / z 431.1 (M+H) + (ES + ). 1 H NMR(400MHz,DMSO-d6)δ .67(m,1H), 4.17-4.01(m,4H), 3.56(m,1H), 3.41-3.17(m,2H), 2.53(s,1H), 1.72-1.54(m, 6H), 1.41(t,J=7.1Hz,1H), 1.37(s,9H), 1.26(m,6H), 1.19-1.08(m,2H), 1.03-0.91(m,2H).

[0560] Step 2 Prepared from tert-butyl 3-(3-(cyclohexylmethyl)-1,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (356 mg, 0.78 mmol, 94% purity) according to 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-(cyclohexylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (125 mg, 0.39 mmol) as a colorless oil. LCMS m / z 251.1 (M-tBu+H). + (ES + ). 1 H NMR(400MHz,CD3OD)δ 6.34(s,1H), 5.86(s,1H), 3.90(s,2H), 2.58(d,J=6.9Hz,2H), 1.77-1.65(m,6H), 1.43(s,9H), 1.35-1.17(m,3H), 1.09-0.97(m,2H).

[0561] Step 3 Prepared from tert-butyl 2-((3-(cyclohexylmethyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (125 mg, 0.39 mmol) according to General Procedure A, Step 3. The crude product was purified by chromatography on sil...

Claims

1. A compound of formula (I) 【Chemical 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 depicted 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 , SF 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 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, and 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 with R １ and R ２ may combine to form a 5- to 7-membered heterocycle; or R Ａ２ But it is non-existent, 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 are connected, and C ３－５ can form a cycloalkyl ring, In the compound of formula (I), 【Chemistry 4】 represents the following: 【Chemistry 5】 group R Ａ１ and R Ａ２ the total number of carbon atoms in, together with any optional substituents thereof, is 6 to 14; 【Chemistry 6】 represents isoxazole, R Ａ１ does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, or a pharmaceutically acceptable salt and / or solvate thereof.

2. The compound of formula (I) 【Chemistry 7】 or a pharmaceutically acceptable salt and / or solvate thereof; In the formula, A, R Ａ１ , R Ａ２ , R Ｃ , and R Ｄ 2. The compound of claim 1, wherein:

3. The compound of formula (I) 【Chemistry 8】 or a pharmaceutically acceptable salt and / or solvate thereof; In the formula, A, R Ａ１ , R Ａ２ , and R Ｃ 2. The compound of claim 1, wherein:

4. A compound of formula (I) 【Chemistry 9】 During the ceremony, 【Chemistry 10】 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 11】 represents a 6-membered heteroaryl ring containing, in addition to the depicted 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 Optionally, halo, C １－６ Alkyl, C １－６ Haloalkyl, hydroxy, cyano, OG １ , S(O) ０－２ G １ , SF ５ , and (CH ２ ) ０－３ C ３－７ cycloalkyl, wherein said C ３－７ Cycloalkyl optionally includes 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 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, 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 with R １ and R ２ may combine to form a 5- to 7-membered heterocycle; or R Ａ２ But it is non-existent, R Ｃ and R Ｄ are each independently H, C １－２ Alkyl, hydroxy, fluoro, or C １－２ is an alkoxy; group R Ａ１ and R Ａ２ the total number of carbon atoms in, together with any optional substituents thereof, is 6 to 14; 【Chemistry 12】 represents isoxazole, R Ａ１ does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, or a pharmaceutically acceptable salt and / or solvate thereof.

5. A compound of formula (I) 【Chemistry 13】 During the ceremony, 【Chemistry 14】 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 15】 represents a 6-membered heteroaryl ring containing, in addition to the depicted 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 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 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 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 with R １ and R ２ may combine to form a 5- to 7-membered heterocycle; or R Ａ２ But it is non-existent, R Ｃ and R Ｄ are each independently H, C １－２ alkyl, hydroxy, or fluoro; group R Ａ１ and R Ａ２ the total number of carbon atoms in, together with any optional substituents thereof, is 6 to 14; 【Chemistry 16】 represents isoxazole, R Ａ１ does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, or a pharmaceutically acceptable salt and / or solvate thereof.

6. A compound of formula (I) 【Chemistry 17】 During the ceremony, 【Chemistry 18】 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 19】 represents a 6-membered heteroaryl ring containing, in addition to the depicted 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 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 １－２ 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 is alkyl, or R Ａ２ But it is non-existent, R Ｃ and R Ｄ are each independently H, C １－２ alkyl, hydroxy, or fluoro; group R Ａ１ and R Ａ２ the total number of carbon atoms in, together with any optional substituents thereof, is 6 to 12; 【Chemistry 20】 represents isoxazole, R Ａ１ does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, or a pharmaceutically acceptable salt and / or solvate thereof.

7. A compound of formula (I) 【Chemical 21】 During the ceremony, 【Chemical Formula 22】 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 【Chemical 23】 represents a 6-membered heteroaryl ring containing, in addition to the depicted 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 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 １－２ 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 it is non-existent, R Ｃ and R Ｄ are each independently H, C １－２ alkyl, hydroxy, or fluoro; group R Ａ１ and R Ａ２ the total number of carbon atoms in, together with any optional substituents thereof, is 6 to 12; 【Chemistry 24】 represents isoxazole, R Ａ１ does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl, or a pharmaceutically acceptable salt and / or solvate thereof.

8. 【Catalog 25】 represents a 5-membered heteroaryl ring that contains, in addition to the depicted C═N, one or more (e.g., 1 or 2) further heteroatoms independently selected from N, O, and S.

9. 【Catalog 26】 represents a 6-membered heteroaryl ring containing, in addition to the depicted C═N, optionally one or more (e.g., one or two) further N atoms.

10.

27. 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.

11.

28. 11. The compound of claim 10, wherein represents oxadiazole, in particular 1,2,4-oxadiazole.

12. 【Catalog 29】 10. The compound of claim 9, wherein represents a 6-membered heteroaryl ring selected from the group consisting of pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

13. 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 -phenyl.

14. R Ａ１ But C １－１０ Alkyl, for example, C ７－８ The compound of claim 13, wherein the alkyl is n-octyl.

15. R Ａ１ But -(CH ２ ) ０－６ -C ３－１０ Cycloalkyl, especially —(CH ２ ) ０－６ -C ４－１０ Cycloalkyl, -(CH ２ ) ０－６ -C ５－１０ cycloalkyl, or -(CH ２ ) ０－６ -C ５－８ represents cycloalkyl, or R Ａ１ But -(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.

16. R Ａ１ But -(CH ２ ) ０ -C ３－１０ 16. The compound of claim 15, which is cycloalkyl.

17. R Ａ１ But -(CH ２ ) ０－２ -phenyl, for example, -(CH ２ ) ０－１ -phenyl.

18. R Ａ１ The compound of any one of claims 1 to 17, wherein is unsubstituted.

19. R Ａ１ But, Halo, C １－６ Alkyl, C １－６ Haloalkyl, hydroxy, cyano, OG １ , S(O) ０－２ G １ , SF ５ , C ３－７ cycloalkyl, and 5- to 7-membered heterocyclyl, and is substituted by one or more, for example, one, two, three, or four, for example, one, substituent selected from the group consisting of ３－７ Cycloalkyl and said 5- to 7-membered heterocyclyl are optionally halo (e.g., F), C １－３ alkyl (e.g., methyl or n-propyl), and C １－３ Haloalkyl (e.g., CF ３ 18. The compound of claim 1, wherein the compound is substituted with one or more groups selected from the group consisting of:

20. R Ａ１ is halo (e.g., chloro or bromo), C １－６ Alkyl, C １－６ Haloalkyl (e.g., CF ３ ), hydroxy, cyano, OG １ , S(O) ０－２ G １ (For example, SG １ ), SF ５ , and (CH ２ ) ０－３ C ３－７ cycloalkyl (e.g., cyclopropyl or cyclopentyl), and ３－７ Cycloalkyl is optionally halo (e.g., F), C １－３ alkyl (e.g., methyl or n-propyl), and C １－３ Haloalkyl (e.g., CF ３ 18. The compound of claim 1, wherein the compound is substituted with one or more groups selected from the group consisting of:

21. R Ａ１ is halo (e.g., chloro or bromo), C １－２ Alkyl, C １－２ Haloalkyl (e.g., CF ３ ), hydroxy, cyano, O(C １－２ alkyl), and S(O) ２ C １－２ 21. The compound of any one of claims 1 to 17, 19 or 20, substituted with one or more, e.g., one, two, three or four, e.g., one, substituent selected from the group consisting of alkyl.

22. R Ａ１ However, optionally C １－２ Haloalkyl (e.g., CF ３ ), C １－２ Haloalkoxy (e.g., OCF ３ 22. A compound according to any one of claims 1 to 17 or 19 to 21, wherein the compound is substituted with one phenyl ring, which is substituted with one or more, e.g., one, two, three or four, e.g., one halo atom (e.g., chloro and / or fluoro).

23. R Ａ１ is a group having two alkyl groups, e.g., C １－６ Alkyl, for example, C １－２ and the two alkyl groups are substituted by R Ａ１ bonded to the same carbon atom in C ３－７ A compound according to any one of claims 1 to 17 or 19 to 22, which forms a cycloalkyl group, for example a cyclopropyl ring.

24. R Ａ１ But one C １－６ A compound according to any one of claims 1 to 17, which is substituted with an alkyl group, for example n-butyl.

25. R Ａ１ But one OG １ The compound of any one of claims 1 to 17, substituted with a group.

26. G １ But C １－６ 26. The compound of claim 25, wherein the alkyl is n-butyl.

27. R Ａ１ But one SF ５ The compound of any one of claims 1 to 17, substituted with a group.

28. R Ａ１ But one SG １ The compound of any one of claims 1 to 17, substituted with a group.

29. G １ But C １－６ Haloalkyl, for example, CF ３ 29. The compound of claim 28, wherein:

30. R Ａ２ The compound of any one of claims 1 to 29, wherein is absent.

31. R Ａ２ But C １－６ The compound of any one of claims 1 to 29, which is alkyl.

32. R Ｃ is H, and / or R Ｄ The compound of any one of claims 1 to 31, wherein is H.

33. 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 -sulfanail)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 -sulfanail)phenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 2-((3-(4-(pentafluoro-λ ６ -sulfanail)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 -sulfanail)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-λ ６ -sulfanail)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 pharmaceutically acceptable salt and / or solvate thereof.

34. 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 pharmaceutically acceptable salt and / or solvate thereof.

35. 35. The compound of claim 34, which is 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharmaceutically acceptable salt and / or solvate thereof.

36. 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, 2-((3-(4-butoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, 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 -sulfanail)phenyl)cyclopropyl)-1,2,4-oxadiazol-5-yl)methyl)acrylic acid, or a pharmaceutically acceptable salt and / or solvate thereof.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 and one or more pharmaceutically acceptable diluents or carriers.

38. A compound according to any one of claims 1 to 36 or a pharmaceutical composition according to claim 37 for use as a medicament.

39. A compound according to any one of claims 1 to 36 or a pharmaceutical composition according to claim 37 for use in the treatment or prevention of an inflammatory disease or a disease associated with an unwanted immune response.

40. A compound of formula (I) for use in the treatment or prevention of inflammatory diseases or diseases associated with an unwanted immune response, 【Chemistry 30】 During the ceremony, 【Chemical Formula 31】 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 【Chemical 32】 represents a 6-membered heteroaryl ring containing, in addition to the depicted 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 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 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 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 with R １ and R ２ may combine to form a 5- to 7-membered heterocycle; or R Ａ２ But it is non-existent, R Ｃ and R Ｄ are each independently H, C １－２ alkyl, hydroxy, or fluoro; or a pharmaceutically acceptable salt and / or solvate thereof.

41. A compound of formula (I) for use in the treatment or prevention of inflammatory diseases or diseases associated with an unwanted immune response, 【Chemical 33】 During the ceremony, 【Chemical 34】 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 35】 represents a 6-membered heteroaryl ring containing, in addition to the depicted 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 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 １－２ 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 it is non-existent, R Ｃ and R Ｄ are each independently H, C １－２ alkyl, hydroxy, or fluoro; or a pharmaceutically acceptable salt and / or solvate thereof.

42. R Ａ１ But -(CH ２ ) １－６ -C ３－１０ 42. The compound for use according to claim 40 or 41, which is cycloalkyl.

43. R Ａ１ 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 The compound for use according to any one of claims 40 to 42, which forms a cycloalkyl ring.

44. group R Ａ１ and R Ａ２ The compound for use according to any one of claims 40 to 43, wherein the total number of carbon atoms in the group consisting of (a) and (b) together including any optional substituents thereof is 6 to 14, for example 6 to 12.

45.

36. represents isoxazole, R Ａ１ 45. The compound for use according to any one of claims 40 to 44, wherein does not represent phenyl, phenyl substituted with bromo, or phenyl substituted with methyl.

46. Use of a compound according to any one of claims 1 to 36 or a pharmaceutical composition according to claim 37 in the manufacture of a medicament for treating or preventing an inflammatory disease or a disease associated with an undesired immune response.

47. 38. A method for treating or preventing an inflammatory disease or a disease associated with an unwanted immune response, comprising administering a compound according to any one of claims 1 to 36 or a pharmaceutical composition according to claim 37.

48. 48. A compound, pharmaceutical composition, compound, use or method for use according to any one of claims 1 to 47 for the treatment of inflammatory diseases or diseases associated with an unwanted immune response.

49. A compound, pharmaceutical composition, compound, use or method for use according to any one of claims 1 to 47 for the prevention of inflammatory diseases or diseases associated with an undesired immune response.

50. A compound, pharmaceutical composition, compound, use or method for use according to any one of claims 1 to 47 for the treatment or prevention of inflammatory diseases.

51. A compound, pharmaceutical composition, compound, use or method for use according to any one of claims 1 to 47 for the treatment or prevention of a disease associated with an unwanted immune response.

52. The inflammatory disease or disease associated with an unwanted immune response is selected from the group consisting of psoriasis (including chronic plaque, erythrodermic, pustular, guttate, inverse and onychoderma), 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 mitochondrial encephalomyopathies). ), 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 treatment of acute ST-segment elevation myocardial infarction or ischemic stroke, organ transplant, or 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, non-alcoholic fatty liver disease (NALHD), steatohepatitis), rheumatoid arthritis, 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 spectrum disorder, MOG (myelin oligodendrocyte glycoprotein) antibody-related disorder (including MOG-EM), optic neuritis, CLIPPERS (steroid-resistant chronic lymphocytic inflammation with corresponding pontine perivascular enhancement), 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 (including bullous pemphigoid, mucous membrane pemphigoid, cicatricial pemphigoid, gestational pemphigoid or pemphigoid, ocular cicatricial pemphigoid), linear IgA disease, Behcet's disease, celiac disease, Chagas' disease, dermatomyositis, type I diabetes, 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 (TTP), Eva encephalitis, 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-person syndrome, polymyalgia rheumatica, giant cell arteritis (temporal arteritis), Takayasu's arteritis, polyarteritis nodosa, Kawasaki disease, granulomatosis with polyangiitis Granulomatosis (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 obliterative bronchitis organizing pneumonia) ), 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, 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 perivasculitis, 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, lignicin conjunctivitis, Mooren's ulcer, acute pityriasis lichenoides (PLEVA, also known as Much-Habermann's 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, reflex sympathetic dystrophy, relapsing polychondritis, sperm and testicular autoimmunity, Susac syndrome, Tolosa-Hunt syndrome, Vogt syndrome Koyanagi-Harada syndrome, antisynthetase syndrome, autoimmune enteropathy, immunodysregulated 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 (Shulman syndrome), progesterone hypersensitivity (including progesterone 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, and Neonatal-Onset Multisystem Inflammatory Disease [NOMID]), NLR P12-related autoinflammatory disease (NLRP12AD), periodic fever aphthous stomatitis (PFAPA), 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 interferonopathy (Aicardi 52. The compound, pharmaceutical composition, compound for use, use, or method of any one of claims 1 to 51, which is or is associated with a disease selected from the group consisting of Gouthieres syndrome, retinal vasculopathy associated with cerebral leukodystrophy, spondylochondrodysplasia, STING [stimulator of interferon genes]-associated vasculopathy of infantile onset, 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 transplant). ,

53. 53. The compound or pharmaceutical composition for use according to claim 52, wherein the inflammatory disease or disease associated with an unwanted immune response 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.

54. 54. The compound, pharmaceutical composition, compound for use, use, or method of any one of claims 1 to 53, wherein said compound is for administration to a human subject.

55. additional therapeutic agents, such as 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, or 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 analogs (e.g., mitoxantrone), cladribine, sphingosine 1-phosphate receptor modulators or sphingosine analogs (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, tetanus, riflunomide, gold compounds, laquinimod, potassium channel blockers (e.g., dalfampridine / 4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogs (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, siltuximab),Other B-cell targeted therapies, including Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), tyrosine kinase inhibitors (e.g., imatinib), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B-cell activating factor (BAFF, BLyS, also known as 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 p110δ and / or p110δ including isoforms Inhibitors targeting 10γ (e.g., idelalisib, copanlisib, duvelisib), interferon α 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 muscarinic agents (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 relatively selective COX-2 inhibitors (e.g., celecoxib, etroxicoxib, valdecoxib, etodolac, meloxicam, nabumetone), colchicine, IL-4 receptor inhibitors (e.g.,dupilumab), topical / 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 neutralizing 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), anti-androgen therapy (e.g., 55. The compound, pharmaceutical composition, compound for use, use, or method of any one of claims 1 to 54, for use in combination with an anti-inflammatory drug (e.g., cyproterone, spironolactone, finasteride), pentoxifylline, ursodeoxycholic acid, obeticholic acid, a fibrate, a cystic fibrosis transmembrane conductance (CFTR) regulator, a VEGF (vascular endothelial growth factor) inhibitor (e.g., bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone, or mizoribine.

56. A compound of formula (II), 【Chemical 37】 or a salt thereof, wherein 【Chemical Formula 38】 R Ａ１ , R Ａ２ , R Ｃ , and R Ｄ is defined in any one of claims 1 to 36, and R ３ C optionally substituted with halo １－４ Representing an alkyl, compound, or salt thereof.

57. A compound of formula (III), 【Chemical 39】 or a salt thereof, wherein 【Chemistry 40】 R Ａ１ , R Ａ２ , R Ｃ , and R Ｄ is defined in any one of claims 1 to 36, and R ３ , R １１ , and R １２ are independently optionally substituted with halo; １－４ Representing an alkyl, compound, or salt thereof.

58. A compound of formula (V), 【Chemistry 41】 or a salt thereof, wherein 【Chemistry 42】 R Ａ１ , R Ａ２ , R Ｃ , and R Ｄ A compound, or a salt thereof, wherein: is defined in any one of claims 1 to 36, and X represents a leaving group.

59. A compound of formula (VIII), 【Chemistry 43】 or a salt thereof, In the formula, R Ａ１ , R Ｃ , and R Ｄ is as defined in any one of claims 1 to 36, and R ３ , R １１ , and R １２ are independently optionally substituted with halo; １－４ A compound, or a salt thereof, which represents alkyl, for example, methyl or tert-butyl.

60. A compound of formula (XVI), 【Chemical 44】 or a salt thereof, In the formula, R Ａ１ and R Ａ２ 37. A compound, or a salt thereof, wherein: is defined in any one of claims 1 to 36, and P is a carboxylic acid protecting group, for example para-methoxybenzyl.

61. A compound of formula (XXIV), 【Chemistry 45】 or a salt thereof, In the formula, R Ａ１ A compound, or a salt thereof, wherein:

62. A compound of formula (I), 【Chemistry 46】 or a salt thereof, such as a pharmaceutically acceptable salt thereof, comprising a compound of formula (II): 【Chemistry 47】 or a salt thereof, During the ceremony, 【Chemistry 48】 R Ａ１ , R Ａ２ , R Ｃ , and R Ｄ , and R ３ is defined in any one of claims 1 to 36, and R ３ C optionally substituted with halo １－４ Representing alkyl, process.

63. A process for preparing a compound of formula (I), or a salt thereof, such as a pharmaceutically acceptable salt, comprising reacting a compound of formula (XVI): 【Chemistry 49】 or a salt thereof, In the formula, R Ａ１ and R Ａ２ is defined in any one of claims 1 to 36 and P is a carboxylic acid protecting group, for example para-methoxybenzyl.

64. A process for preparing a compound of formula (I), or a salt thereof, such as a pharmaceutically acceptable salt, comprising reacting a compound of formula (XXIV): 【Chemistry 50】 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 in any one of claims 1 to 36.

65. 65. The compound of any one of claims 1 to 64, in natural isotopic form.

66. 66. The compound, pharmaceutical composition, compound for use, use, method, or process according to any one of claims 1 to 65, wherein the compound of formula (I) is in the form of a salt, for example a pharmaceutically acceptable salt thereof (e.g. a tromethamine salt).

67. The compound of claim 1 which is the tromethamine salt of 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid.

68. 68. The compound of claim 67, wherein the tromethamine salt of 2-((3-octyl-1,2,4-oxadiazol-5-yl)methyl)acrylic acid is in crystalline form.

69. 69. The compound of claim 68, wherein the crystalline form has an X-ray powder diffraction pattern with at least one peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) 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 values), e.g., at least one peak (e.g., 1, 2, 3, 4, 5, or 6) selected from peaks at 12.9, 17.0, 19.9, 20.1, 23.0, and 23.4 (±0.2 degrees, 2-theta values).

Images