WO2022069953A1 - Synthesis and characterization of (s)-3-(5- fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivatives and their secretory phospholipase a2 (spla2) inhibitor activity - Google Patents

Synthesis and characterization of (s)-3-(5- fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivatives and their secretory phospholipase a2 (spla2) inhibitor activity Download PDF

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WO2022069953A1
WO2022069953A1 PCT/IB2021/052556 IB2021052556W WO2022069953A1 WO 2022069953 A1 WO2022069953 A1 WO 2022069953A1 IB 2021052556 W IB2021052556 W IB 2021052556W WO 2022069953 A1 WO2022069953 A1 WO 2022069953A1
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piperidin
fluoropyridin
oxadiazol
methanone
oxadiazole
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PCT/IB2021/052556
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French (fr)
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Ranjith Siddaraj
Raghu Ningegowda
Govindappa Banuprakash
Sandeep CHANDRASHEKHARAPPA
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Ranjith Siddaraj
Raghu Ningegowda
Govindappa Banuprakash
Chandrashekharappa Sandeep
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The present invention relates to development of novel (S)-3 -(5 -fluoropyridin-2-yl)-5 -(piperidin- 3-yl)- 1,2,4-oxadiazole derivatives. It particularly relates to the development of novel compounds of (S)-3 -(5 -fluoropyridin-2-yl)-5 -(piperidin-3 -yl)- 1,2,4-oxadiazole derivatives as inhibitors of Secretory Phospholipase A2 (sPLA2). It also relates synthetic process for preparation of novel compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-1,2,4-oxadiazole derivatives as inhibitors of Secretory Phospholipase A2 (sPLA2). It further relates to the development of composition with novel compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-1, 2,4- oxadiazole derivatives for inhibition of Secretory Phospholipase A2 (sPLA2). The final compounds were characterized by 1H and 13C-NMR, IR, LC-MS and Elemental analysis. In vitro inhibitory effect of series of 7(a-s) [Formula I] on VRV-PL-8a were assessed for PLA2 inhibition studies. The tested compounds 7(a-s) [Formula I] inhibited sPLA2 in dose-dependent manner with an IC50 value ranging from 9.2 to 82μΜ which are computed and analyzed using sigmoidal 4PL curve fit.

Description

TITLE OF THE INVENTION: SYNTHESIS AND CHARACTERIZATION OF (S)-3-(5- FLUOROPYRIDIN-2-YL)-5-(PIPERIDIN-3-YL)-l,2,4-OXADIAZOLE DERIVATIVES AND THEIR SECRETORY PHOSPHOLIPASE A2 (sPLA2) INHIBITOR ACTIVITY
FIELD OF THE INVENTION
The present invention relates to development of novel (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin- 3-yl)-l,2,4-oxadiazole derivatives. It particularly relates to the development of novel compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivatives as inhibitors of Secretory Phospholipase A2 (sPLA2). It also relates synthetic process for preparation of novel compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivatives as inhibitors of Secretory Phospholipase A2 (sPLA2). It further relates to the development of composition with novel compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4- oxadiazole derivatives for inhibition of Secretory Phospholipase A2 (sPLA2).
BACKGROUND OF THE INVENTION
Oxadiazole are most important five membered heterocyclic ring systems present in a large number of biologically active molecules of various pharmacological classes. They possess good herbicidal, bactericidal and fungicidal activities [Gadaginamath G S, Shyadligeri A S, Kavali R R. Indian J Chem. 38B, 156. 1999; and Renukadevi P, Birada J S. Indian J Heterocyclic Chem. 9, 107, 1999], 1, 2,4-oxadiazoles are having extensive importance because of their chemical and biological properties. They are also known as bioisosteres for amides and esters present in various biologically active compounds.
Advanced pharmacokinetic and in vivo functions are often observed due to increased metabolic and hydrolytic stabilities of the oxadiazole ring, which makes these heterocycles as a significant structural moiety for the pharmaceutical field. Derivatives of 1,2,4-oxadiazole nucleus are widely studied by researchers because of their versatile biological applications as human tryptase inhibitory activity [Chang-Sun Lee,Weili Liu, Paul A. Sprengeler, John Somoza R, James Jane W, David Sperandio, Jeffrey Spencer R, Michael Green J, Mary E. McGrath. Bioorg. Med. Chem. Lett. 16, 4036, 2006], 0-amyloid imaging probes in Alzheimer’s disease [Masahiro Ono, Mamoru Haratake, Hideo Saji,Morio Nakayama. Bioorg. Med. Chem. 16, 6867. 2008], antimicrobial [H K Nagesh, B Padmashali, C Sandeep, T E Musturappa, M R Lokesh, Der Pharma Chemica, 7(12) (2015) 129-136], antihyperglycemic activity [Michael Malamasa, Janet Sredy, Michael McCaleb, IwanGunawan, Brenda Mihan, Donald Sullivan. Eur. J. Med. Chem. 36, 31, 2001], potential combretastatin A-4 (CA-4) analogs [Bhaskar Dasa C, Xiang-Ying Tang, Patrick Rogler, Todd Evans. Tetrahedron Lett. 53, 31, 3947. 2012], marine metabolite [Emiliano Manzo, Dario Pagano, Marianna Carbone, Letizia Ciavatta M, Margherita Gavagnin. Arkivoc. 220. 2012], antitumor activity [CatalinMaftei V, Elena Fodor, Peter Jones G, Heiko Franz M, Gerhard Kelter,HeinerFiebig, Ion Neda. Beilstein J. Org. Chem. 9, 2202, 2013] and DNA Gyrase Inhibitor Cyclothialidine activity [Peter Angehrn, Stefan Buchmann, Christoph Funk, Erwin Goetschi, Hans Gmuender, Paul Hebeisen, Dirk Kostrewa, Helmut Link, Thomas Luebbers, S chmitt-Hoffmann, Frank-Peter Theil. J. Med. Chem. 47, 1487, 2004],
Oxadiazole rings can exist in different regioisomeric forms; two 1,2,4-isomers (if asymmetrically substituted), 1,3,4- isomer and 1,2,5-isomer. The 1,2, 5 -regioisomer is significantly less common and orients the side chains in different positions relative to the other three isomers. Two 1,2,4 and 1,3,4 regioisomeric oxadiazoles exist due to vector arrangement of side chains, thus placing the side chains in very similar positions. The consequence is that matched pairs will show the same overall molecular shapes and are thus expected to bind in a similar fashion [ Bostrom, J, Hogner A, Schmitt, S. J. Med. Chem. 49, 6716-6725, 2006], Moreover, oxadiazoles show remarkable hydrogen bond acceptor properties and it will be shown that the regioisomers show significantly different hydrogen bonding capacities. Also 1 ,2,4-oxadiazole scaffold is a class of heterocycles commonly found in biologically active molecules. This motifs often used as an amide or ester bioisosterel [Diana G. D, Volkots D. L, Nitz T. J, Bailey T. R, Long M. A, Vescio N, Aldous S, Pevear D. C, Dutko F. J. J. Med. Chem. 37, 2421-2436. 1994] found in several drugs and lead molecules including the potent SI Pl agonist [Li. Z. Chen, W Hale, J. J. Lynch, C. L. Mills, S. G. Hajdu, R. Keohane, C.A. Rosenbach, M. J. Milligan, J. A. Shei, G. J. Chrebet, G. Parent, S. A. Bergstrom, J. Card, D. Forrest, M. Quackenbush, E. J Wickham, L. A. Vargas, H. Evans, R. M. Rosen, H. Mandala, S. J. Med. Chem. 48, 6169-6173. 2005] and the metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2 [Roppe J, Smith N. D, Huang D, Tehrani L, Wang B, Anderson J, Brodkin J, Chung J, Jiang X, King C, Munoz B, Vamey M. A, Prasit P, Cosford N. D. P. J. Med. Chem. 47, 4645-4648, 2004],
It has been reported that 1,2,4-oxadiazoles were synthesized by treating carboxylic acid derivatives with amidoxime. Amidoxime was obtained from the nitrile by the addition of hydroxylamine hydrochloride, these amidoximes are O-acylated by different carboxylic acid derivatives [John Kallikat Augustine, Vani Akabote, Shrivatsa Ganapati Hegde, Padma Alagarsamy, J. Org. Chem. 74, 5640-5643, 2009; and J. L Buchanan, C. B Vu, T. J Merry, E. G Corpuz, S.GPradeepan, U. N Mam, M Yang, H. R Plake, V. M. J. Med. Chem. 38, 2726-2735, 1991], Acid amides containing oxadiazole nucleus and their derivatives were evaluated for a several pharmacological activities such as antitubercular [R Ningegowda, S. Chandrashekharappa, V Singh, V Mohanlall, K N Venugopala; Chemical Data Collections, 28 (2020) 100431], anti-inflammatory, central nervous system (CNS) depressant activity and ulcergenic activity [P. L Durette, W. K Hagmann, I. E Kopka, M MacCoss, Merck Co. WO 2000, 00/71572 Al (a) T. L Deegan, T. J Nitz, D Cebzanov, D. E Pufko, J. A Porco. Jr. Bioorg. Med. Chem. Lett. 9, 209-212, 1999. (b) R. F Poulain, A. L Tartar, B. P Deprez. Tetrahedron Lett. 42, 1495, 2001; J Rudolph, H Theis, R Hanke, R Endermann, L Johannsen, F.-U Geschke. J. Med. Chem. 44, 619-626. 2001; C. D Bedford, R. A Howd, O. D Dailey, A Miller, H. W Nolen, R. A Kenley, J. R Kern, J. S Winterle. J. Med. Chem. 29, 2174-2183, 1986; (a) K Rice, J. M Nuss, Bioorg. Med. Chem. Lett. 11, 753-755, 2001; (b) A. R Gangloff, J Litvak, E. J Shelton, D Sperandio, V. R Wang, K. D Rice. Tetrahedron Lett. 42, 1441-1443. 2001; Peng-Fei Xu, Zhi- Hui Zhang, Xin-Ping Hui, Zi-Yi Zhang. Journal of the Chinese Chemical Society. 51, 315-319, 2004; and GudaDinneswara Reddy, Sae-Jin Park, Hyeon Mo Cho, Tack-Joong Kim, MyongEuyLee. J. Med. Chem.55, 6438-6444, 2012], Drug Raltegravir is one of the oxadiazole derivatives used as an antiretroviral drug for the treatment of HIV infection. It is clear that heterocyclic compounds are having a large impact on several drug discovery programs across a variety of disease including diabetes, obesity, cancer, inflection and inflammation [K. Manjunatha, BojaPoojary, Prajwal L. Lobo, Jennifer Fernandes, N. SuchethaKumari. European Journal of Medicinal Chemistry. 45, 5225-5233, 2010], Recently considerable our work [M. B. Siddesh, B. Padmashali, K. S. Thriveni,C. Sandeep, Heterocyclic Letters, 2014, 4, 503-514; K. N. Venugopala, S. Chandrashekharappa, M. Pillay, S. Bhandary, M. Morsy, D. Chopra, B. E Aldhubiab,M. Attimarad, O. I. Alwassil, S. H. Nagaraja, K. Mlisana, Medicinal Chemistry, 2019, 15, 311-326; Ranjith S. Raghu Ningegowda, European Journal of Chemistry, 9(4)2018, 353-359; Ranjith S. Raghu Ningegowda, European Journal of Chemistry, 9(4)2018, 317-321. Raghu Ningegowda, Nanjunda Swamy Shivananju, Peramiyan Rajendran, Babu Shubha Priya, Apoptosis, 22(1): 145-157, 2017; Raghu Ningegowda, Nanjunda Swamy. S, Raghu Ram Achar, Basappa, S.L. Gaonkar, S. Ranjith, George W. Yip, B.S. Priya, Asian Journal of Biochemical and Pharmaceutical Research. 2015, 2, (5), 186-197; Chandrasekhar Ashwatanarayanappa, Raghu Ningegowda, International Journal of Pharm Tech Research. 2014, 6(4), 1245-1255. Chandrasekhar Aswathanarayanappa, Raghu Ningegowda, M. C. Shiva Kumar, S. K. Peethambar, and Sandeep Telkar, Med Chem Res. 2013, 22, 78-87; Raghu Ningegowda, Amit Grover, Basappa, S. Ranjith, Kanchugarakoppal S.Rangappa, B.S.Priya.S. Nanjundaswamy, Invest New Drugs. 2010, 28, 754-765; K. N. Venugopala, M. A. Khedr, M. Pillay, S. K. Nayak, S. Chandrashekharappa, B. E. Aldhubiab , S. Harsha , M. Attimard, B. Odhav; Journal of biomolecular structure and Dynamics.2018 36, 2163-2178; S. M. Mallikarjuna, C. Sandeep, B. Padmashali, Der Pharma Chemica, 2016, 8, 262-268; K. N. Venugopala, C. Sandeep, M. Pillay, H. Hassan Abdallah, F. M. Mahomoodally, S. Bhandary, D. Chopra, M. Attimaradl, B. E. Aldhubiab, A. B. Nair, N. Sreeharsha, M. A. Morsy, S. Pottathil, R. Venugopala, B. Odhav, K. Mlisana, PLoS ONE 14 (6): e0217270; S. Chandrashekharappa, B. Padmashali, K. N. Venugopala, R. S. Kulkarni, J. Appl. Chem. (Lumami, India), 2013, 2, 1049-1056; S O. I. Alwassil, S. Chandrashekarappa, S. K. Nayak, K. N. Venugopala, PLoS ONE 14 (10): e0223413. K. Venugopala, O. Al-Attraqchi, C. Tratrat,S. Nayak, M. Morsy, B. Aldhubiab, M. Attimarad, A.Nair, N. Sreeharsha, R.Venugopala, M. Haroun, M.Girish, S. Chandrashekharappa, O. Alwassil, B.Odhav.Biomolecules 2019, 9 (11), 661; and C. Sandeep, B. Padmashali, S. K. Rashmi, S. M. Mallikarjuna, M. B. Siddesh, H. K. Nagesh, K. S. Thriveni, Heterocyclic Letters, 2014, 4, 371-376] has been directed towards the synthesis and Characterization of a novel (S)-3- (5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivatives and studied their Secretory Phospholipase A2 (SPLA2) inhibitor activity with Computational Perspective and in vitro screening.
Snakebites claim more than a hundred thousand lives a year world over, and the mainstay remedy is sero therapy. Principle toxin that many of snake venom composed is phospholipase A2 (PLA2) [Amit Nargotra & Surrinder Koul et al., In silico identification of viper phospholipaseA2 inhibitors: validation by in vitro, in vivo studies. J Mol Model, 2011], It has a large array of secreted PLA2s and their isoforms. Elapidae venoms contain group-I PLA2s and Viperidae venoms, group-II PLA2s. Snake venom phospholipases A2, in addition to their role in digestion, may be neurotoxic or myotoxic, and may interfere with coagulation or inflammation processes [Grazyna Faure. Natural inhibitors of toxic phospholipases A2. Biochimie, 82 833-840. 2000], PLA2 belong to super family is a wide class of enzymes which are defined by their ability to catalyze the hydrolysis of the sn-2 ester bond of membrane phospholipids. Products of PLA2 activity include free fatty acids, predominantly arachidonic acid and lysophospholipids. These products are further metabolized to form a variety of pro-inflammatory lipid mediators, including prostaglandins and leukotrienes, collectively called eicosanoids and platelet activating factor.
Due to the role of PLA2s in the inflammatory process, there is pharmacological interest in PLA2 inhibitors [Camila Aparecida Cotrim, Simone Cristina Buzzo de Oliveira et al., Quercetin as an inhibitor of snake venom secretory phospholipase A2. Chemico-Biological Interactions 189, 9- 16, 2011], The etiology of many inflammatory diseases has received a great deal of recent attention but remains, unresolved for the most part hindering in the development of new agents, which are curative in nature. Thus inhibition of PLA2 becomes a rate limiting step in inflammatory reaction is a key event and the inhibitor of this enzyme has potential therapeutic relevance in inflammatory disorders [Tao Chen. Genotoxicity of Aristolochic Acid: A Review. Journal of Food and Drug Analysis, 15, 4, 387-399, 2007], Inflammation is a complex process involving many factors like enzymes, hormones, toxins and trauma, regulation of PLA2 activity decreases inflammation significantly than altering any other that could contribute to inflammatory reaction [Ticli, F. K., L. I. Hage, et al. "Rosmarinic acid, a new snake venom phospholipase A2 inhibitor from Cordia verbenacea (Boraginaceae): antiserum action potentiation and molecular interaction." Toxicon 46(3): 318-327. 2005], It has been shown that PLA2 inhibitors so far screened inhibits both mammalian & snake venom PLA2 with some variations [AK Mishra, A Gupta, V Gupta, A Mishra. Design and Antiinflamatory activity of some novel Oxadiazole Derivatives - An Overview. JPRHC, 2, 3, 2010], Thus PLA2 inhibitors of group I and II has tremendous therapeutic importance and can be used in the treatment of venom toxicity as well as in chronic inflammatory disorders.
Though there prior art reports which reported the several compounds oxadiazole and their derivatives agents but none of the prior arts in the literature reported or disclosed the compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole and its derivatives which act as inhibitors of Secretory Phospholipase A2 (SPLA2) along with not having the drawbacks or limitations of the prior art or existing compounds. There exists several drawbacks or limitations with the prior art compounds to act as inhibitors of Secretory Phospholipase A2 (sPLA2). Therefore, the present inventors developed the compounds of (S)-3-(5-fluoropyridin-2-yl)-5- (piperidin-3-yl)-l,2,4-oxadiazole and its derivatives which act as inhibitors of Secretory Phospholipase A2 (SPLA2) along with the developed compounds not having the drawbacks or limitations of the prior art or existing compounds. The invention also includes the development of suitable process for synthesis of compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3- yl)-l,2,4-oxadiazole and its derivatives which act as inhibitors of Secretory Phospholipase A2 (SPLA2).
OBJECTIVES OF THE INVENTION
The primary object of the present invention is the development of compounds of (S)-3-(5- fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole and its derivatives.
The other object of the present invention is the development of compounds of (S)-3-(5- fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole and its derivatives which act as inhibitors of Secretory Phospholipase A2 (SPLA2).
The other object of the present invention is the development of synthetic process for compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole and its derivatives which act as inhibitors of Secretory Phospholipase A2 (SPLA2).
The other object of the present invention is the development of compositions with compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole and its derivatives which act as inhibitors of Secretory Phospholipase A2 (SPLA2).
The other object of the present invention is the development of compounds of (S)-3-(5- fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole and its derivatives which act as inhibitors of Secretory Phospholipase A2 (SPLA2) which are effective in treatment of several diseases, including cardiovascular diseases, atherosclerosis, immune disorders and cancer.
The other object of the present invention is the development of compounds of (S)-3-(5- fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivatives as inhibitors of Secretory Phospholipase A2 (sPLA2) which are easy to use with little technical expertise.
The other object of the present invention is the development of compounds of (S)-3-(5- fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivatives as inhibitors of Secretory Phospholipase A2 (SPLA2) which are safe and practical to use. BRIEF DESCRIPTION OF THE FIGURE S/DRAWINGS
Fig-1 : sPLA2 inhibition by 7k, Inhibitor concentration-dependent activity plot. The activity buffer contained 50 mM Tris (pH 7.5), lOpl of ImM DMPC with 2 mM Triton X-100, and lOmM CaCb, and varied concentrations of 7k were added (0-100pM). The reaction was initiated by adding 10 ng of enzyme. The reaction was terminated by adding quenching solution. Values represent arithmetical means and standard deviations (n = 3).
Fig- 2 : sPLA2 inhibition by 7k, sigmoidal 4PL fit of 7k (0-100pM). Values represent arithmetical means and standard deviations (n = 3).
Fig- 3 : Neutralization of hemolytic activity of VRV-PL-8a by 7k. All data values represent mean ± SEM (n = 4).
Fig. 4: In silico analysis of sPLA2 with 7k. Docking pose of 7k with sPLA2 showing molecular interaction.
Fig. 5 : Three dimensional binding geometry of 7k (Red wired model) with hydrophobic core residing at active site of sPLA2 represented as secondary ribbon structure.
STATEMENT OF THE INVENTION
Compound of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I:
Figure imgf000006_0001
Formula I
Wherein R is selected from 6a to 6s:
Figure imgf000006_0002
Pharmaceutical composition for inhibition of Secretory Phospholipase A2 (SPLA2) comprising the compound (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I and pharmaceutically acceptable excipients or carriers.
A process for synthesis of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I as claimed in claim 1 comprising: i. converting the 2-bromo- 5 -fluoropyridine (1) into 5-fluoropicolinonitrile (2); ii. then the compound (2) of step (i) is treated with hydroxylamine hydrochloride to get (Z)-5-fluoro-N'-hydroxypicolinimidamide (3); iii. then the compound (3) of is treated with (S)-l-(tert-butoxy carbonyl) piperidine-3- carboxylic acid to yield Boc protected oxadiazole (4); iv. then the Boc group was cleaved from the oxadiazole (4) in the presence of HC1 to give the scaffold (5); and v. then the scaffold (5) is reacted with compounds of 6 a to 6s to form the compounds of formula I.
The compound 5-fluoropicolinonitrile (2) is synthesized using potassium ferricyanide.
The step (v) reaction is carried in the presence of EDCI.HC1 as coupling agent.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivatives by using the starting material 2-bromo-5-fluoropyridine (1) is converted into 5- fluoropicolinonitrile (2) which was synthesized using potassium ferricyanide. The obtained compound (2) was treated with hydroxylamine hydrochloride to get (Z)-5-fluoro-N'- hydroxypicolinimidamide (3), which was further treated with (S)-l -(tert- butoxy carbonyl) piperidine-3-carboxylic acid to yield Boc protected oxadiazole (4). Further Boc group was cleaved from the oxadiazole (4) in the presence of HC1 in ether to give the scaffold (5) which was made to react with different carboxylic aids 6(a-s) in the presence of EDCI.HC1 as coupling agent to get amides containing oxadiazole nucleus Formula I [7(a-s)] in good yield.
Figure imgf000007_0001
Where R is selected from any of the following from 6a to 6s:
Figure imgf000008_0001
Scheme-1: synthesis of oxadiazole derivative of Formula I [7(a-s)J
In IR spectrum of compound 7b CH stretching, CO stretching, C=N stretching and CF3 bending frequencies appears in the range of 2927.41, 1650.77, 1555.31 and 1252.54 cm'1 respectively.
In proton-NMR spectrum of compound 7b, protons of fluoropyridine appear in the range 8.79- 7.9 ppm. One proton of pyrazole ring appears at 6.24ppm and NCH2 group appears as quartet at 4.0 ppm whereas methyl protons appear at 2.13 ppm.
In carbon- 13 NMR spectrum of compound 7b, aromatic carbons of fluoropyridine nucleus appears in the range of 180-147 ppm and carbonyl carbon appears at 165.50ppm. Remaining carbons appears in the range 77.64-22.80 ppm. All these data complies the assigned structure for the compound (7b). Similarly all the newly synthesized compounds were characterized.
Pharmacology- SPLA2 inhibitory activity o yl)-l,2,4-oxadiazole derivatives of Formula
Figure imgf000008_0002
Catalytic mechanism of both the sPLA2 being the same it is composed of a hydrophobic region wherein the fatty acid tails of substrates bind, and a hydrophilic region which is useful for substrate cleavage. In vitro inhibitory effect of series of 7(a-s) on VRV-PL-8a were assessed for PLA2 inhibition studies. The tested 7(a-s) inhibited sPLA2 in dose-dependent manner with an IC50 value ranging from 9.2 to 82pM which are computed and analyzed using sigmoidal 4PL curve fit. Among the tested compounds, A12 showed significant inhibition against VRV-PL-8a with IC50 of 9.2pM (Fig. 1 and Fig. 2), when compared to other structurally related molecules. In situ indirect hemolytic activity of VRV-PL-8a, in presence of compound 7k was evaluated using egg yolk. 7k showed comparatively significant dose-dependent inhibition, induced by VRV-PL-8a compared to positive control (Fig. 3).
Ligand 7k forms a good bonding with hnpsPLA2, wherein it binds near His47 and Gly29, 7k forms 7r-7r stacking with His8 and 7r-cation bond with Ca2+ which a cofactor during catalysis of sPLA2 (Fig. 4 and Fig. 5). His48/His47 Calcium ion which is present at the active site confers the strong bonding with the ligand resulting in high binding affinity when compared to the known one (Table 2.2). The possible reason for this may be due to the more electronegative cloud around the nucleus might have assisted the ligand 7k. Moreover the role of functional groups helps the best pose for the ligands to fit into the catalytic site lined with hydrophobic amino acids of PLA2 which mimics perhaps a competitive inhibition. Our docking results (Table 1) showed that 7k found more potent for hnpsPLA2. ADME result showed that the ligands 7(a-s) possess good ADME values as compared to standard drugs of an value of 95% possess by them on in silico analysis keeping the same drug like criteria as subjected in QikProp module of Schrodinger (Table 2)
Table 1: Docking result for Human non-pancreatic sPLA2
Figure imgf000009_0001
Table 2: ADME evaluation of 7(a-s) derivatives
Figure imgf000010_0001
The present invention focused on the efficient synthesis of amides containing oxadiazole nucleus. The scaffold 5 was synthesized using easily available reagents and reactions performed were ecofriendly as they were carried out at moderate temperature. Using scaffold 5 various (S)-3-(5- fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole amide derivatives 7(a-s) with good yield and purity.. The newly synthesized compounds were used to conclude their biological effectiveness with special reference to PLA2 enzyme inhibition. Among all the compound screened compound 7k given better results than known drugs.
The present research validates that 7k; a oxadiazole derivative can be a potent candidate in PLA2 enzyme inhibition.
Experimental: All the chemicals were purchased from Merck India, Sigma Aldrich, SD Fine chemicals, Spectrochem and were used without further purifications. Melting points reported were determined in open capillary, purification of the newly synthesized amides of oxadiazole piperazine derivatives was done by column chromatography using silica gel 60-120 mesh size using appropriate solvents. Reaction completion was confirmed by thin layer chromatography (TLC), visualization was done using UV light (254 nm) chamber. Characterization was done by FT-IR Spectra which was recorded on Jasco FT-IR Spectrometer, NMR and 13C NMR were recorded at 399.6 MHz and 100 MHz on JEOL ECX NMR spectrometer respectively using CDCI3 Or DMSO-t/e as solvent and tetra methyl silane (TMS) as internal standard, liquid chromatography mass spectra (LC-MS) was recorded using Waters Alliance 2795 separations module and Waters Micromass LCT mass detector and Elemental analysis (CHN) was performed on an Elementar vario Micro cube analyzer.
Procedure for the synthesis of 5-fluoropicolinonitrile (2):
2-Bromo-5-fluoropyridine (1) (20g, 0.114 mol) was dissolved in DMA(200 mL) was purged with nitrogen for 15 minutes, finely powdered potassium ferricyanide (11.29 g, 0.034 mol) was added and stirred vigorously at room temperature for 10 minutes and then heated to 140 °C for three hours. Completion of the reaction was confirmed by thin layer chromatography. Reaction mass was filtered through the celite plug and washed with ethanol (2x50 mL), concentrated and the crude material obtained was purified by column chromatography over silica gel using 30-70 % DCM in petroleum ether as an eluent to yield cyano compound (2).
Colour: White solid; M.p.: 107-108 °C; Yield: 89.6%; *H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.8 (m, 1H, Ar-H), 8.19-8.22 (s, 1H, .7=2,5 Hz, Ar-H), 8.01-8.06 (m, 1H, Ar-H); 13C NMR (100 MHz, DMSO-t/j, 5 ppm):160.6 (1C, Ar-C), 135.3(1C, Ar-C), 13O.2(1C, Ar-C), 129.7(1C, Ar-C), 122. l(Ar-C), 117.1(1C, CN); MS (m/z) 123.1 (M+); Anal, calcd. for C6H3FN2: C, 52.09 ; H, 2.48; N, 22.94%; Found: C, 51.92; H, 2.52; N, 22.64%.
Procedure for the synthesis 5-fluoro-N'-hydroxypicolininudanude (3):
To the solution of cyano compound (2) (10 g, 0.082 mol) was dissolved in 250 ml methyl alcohol to this added hydroxylamine hydrochloride (NH2OH.HCI) (8.52 g, 0.123 mol) in presence of TEA (12.44 g, 0.123 mol) and then the reaction mixture was stirred at RT for 10 h. Reaction was monitored by thin layer chromatography, under reduced pressure solvent was removed. Obtained residue was further dissolved in methylene dichloride (DCM) solvent and washed with water. By using separating funnel the organic layer was separated, again which is washed with the brine solution, separated organic layer was dried with anhydrous Na2SO4 and concentrated to get title compound (3).
Colour: Off White crystalline solid; M.p.: 190-191 °C; Yield: 98.42 %; *H-NMR (400 MHz, CDCI3, 5 ppm): 8.55 (d, 1H, .7=2,8 Hz, Ar-H), 7.89-7.92 (m, 1H, Ar-H), 7.72-7 ,77(m, 1H, Ar-H), 5.84(s, 2H, NH2); 13C NMR (100 MHz, CDCI3, 5 ppm): 163.1(1C, C=N-OH), 158.4(1C, Ar-H), 150.3(lC, Ar-H) 134.0(lC, Ar-C), 121.6(1C, Ar-C), 12O.6(1C, Ar-C); MS (m/z): 156.1 (M+); Anal, calcd. for C6H6FN3O: C, 46.45 ; H, 3.90; N, 27.09%; Found: C, 46.28; H, 3.92; N, 27.21%.
Procedure for the synthesis (S)-tert-butyl 3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5- yl)piperidine-l -carboxylate (4):
(S)-l -(tert-butoxycarbonyl) piperidine-3 -carboxylic acid (9g, 0.0541 mol), aldoxime (8 g, 0.0 0515 mol), EDCI.HC1 (10.87 g, 0.056 mol) and HOBt (1.39 g, 0.0013 mol) were taken in Dry DMF(100 mL) . Reaction mixture was stirred at room temperature for 10 hrs. Then diluted with water (500 mL) and extracted with EtOAc (2x100 mL). the combined organic layer was Organic layer was washed with water(2xl00 mL), brine (2x 100 mL). Organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product as pale pink colour solid. The solid obtained was dissolved in DMF (100 mL), and stirred at 120°C for four hrs. Reaction mixture diluted with water (500 mL) and extracted with EtOAc (2x100 mL). The combined organic layer was washed with water (2x100 mL), brine (2x100 mL), dire dove anhydrous NaoSO-i, filtered and concentrated. The residue was crystallized in DCM and diethyl ether and dried under vacuum to afford compound (4).
Colour: White solid; M.p.: 211-213 °C; Yield: 83.51 %; 'H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.65(d, 1H, .7=2,8 Hz, Ar-H), 8.14-8.19(m, 1H, Ar-H), 7.53-7.6(m, 1H, Ar-H), 4.3(m, 1H, N- CH2), 3.99-4.02(m, 1H, N-CH2), 3.17-3.24(m, 2H, N-CH2), 2.92-2.99(m, 1H, CH), 2.26-2.31(m, 1H, CH2), 1.82-1.99(m, 2H, CH2), 1.54-1.68(m, 1H, CH), 1.46(s, 9H, C(CH3)3); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole-C), 163.5(1C, Oxadiazole-C), 159.3(1C, Ar-C), 153.9(1C, CO), 151.1(1C, Ar-C), 134.1(1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 79.8(1C, C(CH3)3), 56.7(1C, CH2), 49.0(lC, CH2), 33.9(1C, Chiral C), 3O.2(1C, CH2), 28.4(3C, CH3), 22.7(1C, CH2); MS (m/z) 349.2 (M+); Anal, calcd. for CI7H2IFN4O3: C, 58.61 ; H, 6.08; N, 16.08%; Found: C, 58.74; H, 6.38; N, 15.89%.
Procedure for the synthesis of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4- oxadiazole( 5):
Compound (4) (5 g, 0.0143 mol) was dissolved in HC1 in diethyl ether(50 mL) and stirred at room temperature for 2 hrs. The reaction was monitored by thin layer chromatography, after the completion, reaction mixture was concentrated under reduced pressure to obtain scaffold (6); Colour: Off white solid; M.p.: 197-198 °C; Yield: 98.51 %; *H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.65(d, 1H, .7=2,8 Hz, Ar-H), 8.14-8.19(m, 1H, Ar-H), 7.53-7.6(m, 1H, Ar-H), 3.89(brd, 1H, CH2 ), 3.53-3.57(m, 1H, CH2), 3.33-3.41(m, 2H, CH2), 3.14-3.21(m, 1H, CH2), 2.79-2.88(m, 1H, CH2), 2.29-2.34(m, 2H, CH2), 1.75-2.02(m, 1H, CH2); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole-C), 163.5(1C, Oxadiazole-C), 159.3(1C, Ar-C), 151.1(1C, Ar-C), 134.1(1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 52.1(1C, CH2), 48.6 (1C, CH2), 36.7 (1C, Chiral C),30.1(lC, CH2), 25.5(1C, CH2); MS (m/z) 249.1 (M+); Anal, calcd. for CI2HI3FN4O: C, 58.06; H, 5.28; N, 22.57%; Found: C, 58.22; H, 5.14; N, 22.48%.
General Procedure for the preparation of oxadiazole derivatives 7(a-s):
The scaffold (5) (1 mmol) was taken in 8 mL dry methylene dichloride to this added EDCI.HC1 (1.5 mmol), HOBt (0.005 mmol) in the presence of base TEA (3 mmol) and the reaction mixture was stirred at room temperature for 15 min. To this reaction mixture added different acids (1.1 mol) and reaction mixture was stirred under nitrogen at room temperature for 12 h. The reaction was monitored by thin layer chromatography. Using 10% NaHCO3, the reaction mixture was washed for the removal of traces of acidic impurities further organic layer was washed with water and brine, then dried over anhydrous Na2SO4 and evaporated the solvent under reduced pressure. The crude mass was purified by column chromatography using MDC/MeOH as an eluent (9:1) to get novel amides containing piperidine oxadiazole moiety 7(a-s) in good yield. Physical data of all the newly synthesized compounds are entered in Table 3.
Table 3: List of Oxadiazole derivatives (7a-s)
Figure imgf000013_0001
Figure imgf000014_0001
Procedure for the synthesis of (S)-3-(3-(5-fluoropyridin-2-yl)-l, 2, 4-oxadiazol-5-yl) piperidin- l-yl)(l, 2, 3, 4-tetrahydronaphthalen-2-yl) methanone (7a):
The general experimental procedure described above afforded 7a as Off white solid from the reaction of 5 (250 mg, 1 mmol) with l,2,3,4-tetrahydronaphthalene-2-carboxylic acid 6a (193.8 mg, 1.1 mmol )
Colour: Off white sohd^H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.79(s, 1H), 8.18-8.15(brd, 1H), 7.95-7.99(brd, 1H), 7.02(m, 4H), 4.13-4.43(m, 1H), 3.72-3.95(brd, 2H), 3.21-3.45 (brd, 4H), 3.01 -3.21 (brd, 1H), 2.78-2.90(brd, 4H), 2.1-2.5(m, 1H), 1.89-1.91(m, 1H), 1.67(m, 1H), 1.4- 1.5(m, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 178.8(1C, CO),
163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 137.0(lC, Ar-C), 135.5 (1C, Ar-C), 134.1(1C, Ar-C), 127.9(2C, Ar-C), 125.7(2C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 55.5(1C, N-CH2), 45.5(1C, CH), 34.0(lC, chiral C), 33.0(lC, CH2), 32.7(1C, Ar-CH2), 3O.2(1C, CH2), 27.8(1C, CH2) 27.5(1C, Ar-CH2), 22.8(1C, CH2); MS (m/z) 407.0 (M+); Anal, calcd. for C23H23FN4O2: C, 67.97; H, 5.70; N, 13.78%; Found: C, 67.59; H, 5.5; N, 13.6%.
Procedure for the synthesis of (S)-(l-ethyl-3-methyl-lH-pyrazol-5-yl)(3-(3-(5-fluoropyridin-2- yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)methanone (7b):
The general experimental procedure described above afforded 7b as Off white solid from the reaction of 5 (250 mg, 1 mmol) with -ethyl-3-methyl-lH-pyrazole-5-carboxylic acid 6b ( 169.47 mg, 1.1 mmol ); Colour: White solid; 'H-NMR (400 MHz, DMSO-t/e, 5 ppm): 8.79(s, 1H), 8.15(brd, 1H), 7.95-7.99(m, 1H), 6.20-6.24(brd, 1H), 4.1-4.4(m, 1H), 4.0(q, J=7.6, 2H), 3.67(brd, 2H), 3.46(brd, 2H), 2.1-2.2(m, 1H), 2.07(s, 3H), 1.89-1.91(m, 1H), 1.67(m, 1H), 1.4- 1.5(m, 1H), 1.24(s, 3H); 13C NMR (100 MHz, CDC13, 5 ppm): 180.3(1 C, Oxadiazole C), 165.3(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 147.0(lC, Ar-C), 134.1 (1C, Ar-C), 133.4(1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 1O5.4(1C, Ar-C) 55.3(1C, N-CH2), 47.8(1C, N-CH2), 47.6(1C, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2), 14.9(1C, CH3), 12.8(1C, CH3); MS (m/z) 385.0 (M+); Anal, calcd. for CI9H2IFN6O2: C, 59.36; H, 5.51; N, 21.86%; Found: C, 59.19; H, 5.63; N, 21.75%.
Procedure for the synthesis of (S)-benzo[d]thiazol-6-yl(3-(3-(5-fluoropyridin-2-yl)-l,2,4- oxadiazol-5-yl)piperidin-l-yl)methanone (7c):
The general experimental procedure described above afforded 7c as pale yellow solid from the reaction of 5 (250 mg, 1 mmol) with benzo[d]thiazole-6-carboxylic acid 6c (191.6 mg, 1.1 mmol); Colour: Pale yellow solid; 'H-NMR (400 MHz, DMSO-t/e, 5 ppm): 9.24(s, 1H), 8.79(s, 1H), 8.15(m, 1H), 8.4(s, 1H), 7.95-7.99(m, 1H), 7.85-7.9(m, 2H), 4.13-4.43(m, 1H), 3.72-3.95fm, 2H), 3.32-3.45 (brd, 2H), 2.1-2.5(m, 1H), 1.89-1.91(m, 1H), 1.67(m, 1H), 1.4-1.52(m, 1H); bC NMR (100 MHz, CDC13, 5 ppm): 180.3(lC, Oxadiazole C), 172.5(1C, CO), 163.5(1C, Oxadiazole C), 155.5(1C, Benzothiazole C), 153.9(1C, Ar-C), 151.6(1C, Ar-C), 151.1(1C, Ar- C), 134.1 (1C, Ar-C), 133.5(1C, Ar-C), 138.8(1C, Ar-C) 125.1(1C, Ar-C), 123.6(1C, Ar-C), 121.7(1C, Ar-C), 121.4(1C, Ar-C), 12O.7(1C, Ar-C), 55.7(1C, N-CH2), 48.0(lC, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2); MS m/z) 410.0 (M*); Anal, calcd. for C20HI6FN5O2S: C, 58.67; H, 3.94; N, 17.10%; Found: C, 58.25; H, 3.91; N, 17.02%.
Procedure for the synthesis of (S)-l-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin- 1 -yl)-2- (thiophen-2-yl) ethanone ( 7d) :
The general experimental procedure described above afforded 7d as white solid from the reaction of 5 (250 mg, 1 mmol) with 2-(thiophen-3-yl)acetic acid 6d (156.2 mg, 1.1 mmol); Colour: White sohd^H-NMR (400 MHz, DMSO-t76, 8 ppm):8.79(s, 1H), 8.14-8.16(dd, f =8.76 Hz, J2= 4.48 Hz, 1H), 7.95-7.99(m, 1H), 7.43-7.48(m, 1H), 7.42(s, 1H), 6.95-6.99(m, 1H), 4.1-4.4(m, 1H), 3.6- 4.0(m, 3H), 3.74-3.89(m, 2H), 3.23-3.33(m, 2H), 2.1-2.5(m, 1H), 1.89-1.91(m, 1H), 1.67(m, 1H), 1.4-1.5(m, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 164.0(lC, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 138.2(1C, Ar-C), 134.1 (1C, Ar-C), 128.6((1C, Ar-C), 127.0((lC, Ar-C), 125.5((1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 55.2(1C, N-CH2), 49.2(1C, CH2), 36.6(Ar-CH2) 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2); MS (m/z): 373.0 (NT); Anal, calcd. for CI8HI7FN4O2S: C, 58.05; H, 4.60; N, 15.04%; Found: C, 57.86; H, 4.36; N, 14.92%. Procedure for the synthesis of (S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)(2-(trifluoromethyl)phenyl)methanone (7e):
The general experimental procedure described above afforded 7e as Brown gummy solid from the reaction of 5 (250 mg, 1 mmol) with 2-(trifluoromethyl) benzoic acid 6e (209 mg, 1.1 mmol); Colour: Brown gummy solid; 3H-NMR (400 MHz, DMSO-t/e, 5 ppm): 8.79(s, 1H), 8.56(s, 1H), 8.15(m, 1H), 7.95-7.99(m, 2H), 7.71-7.76(m, 2H),7. 4.13-4.43(m, 1H), 3.72-3.83(m, 2H), 3.32- 41 (m, 2H), 2.1-2.5(m, 1H), 1.89-1.91(brd, 1H), 1.65-1.67(m, 1H), 1.4-1.5(m, 1H); 13C NMR (100 MHz, CDC13, 5, ppm): 180.3(lC, Oxadiazole C), 17O.O(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 136.5(1C, Ar-C), 134.7(1C, Ar-C), 134.1 (1C, Ar-C), 130.0(lC, Ar-C), 127.5(1C, Ar-C), 126.7(1C, Ar-C), 126.1( 1C, Ar-C), 125.1(1C, Ar-C), 123.8(1C, Ar-CF3), 121.7(1C, Ar-C), 55.7(1C, N-CH2), 48.0(lC, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2); MS (m/z) 420.0 (NT); Anal, calcd. for C2oHi6F4N402: C, 57.14;
H, 3.84; N, 13.33%; Found: C, 57.02; H, 3.75; N, 13.12%.
Procedure for the synthesis of (S)-l-(3-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5- yl)piperidine-l-carbonyl)pyrazin-2-yl)ethanone (7f):
The general experimental procedure described above afforded 7f as white solid from the reaction of 5 (250 mg, 1 mmol) with 3-acetylpyrazine-2-carboxylic acid 6f (183.7 mg, 1.1 mmol); Colour: White solid; *H-NMR (400 MHz, DMSO-t76, 8 ppm): 9.1(d, J=6.12 Hz, 1H), 8.9(d, J=5.9 Hz), 8.79(s, 1H), 8.15(m, 1H), 7.95-7.99(m, 1H), 4.13-4.43(m, 1H), 3.72-3.95(brd, 2H), 3.32-3.52 (brd, 2H), 2.24(1H, 3H) , 2.1-2.5(m, 1H), 1.89-1.91(m, 1H), 1.69- 1.75 (brd, 1H), 1.4-1.5(m, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 195.9(1C, CO), (165.3(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C),150.0(lC, Pyrazine C)149.O(1C, Pyrazine C), 148.0(lC, Pyrazine C), 142.2(Pyrazine C), 134.1 (1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 54.9(1C, N-CH2), 47.2(1C, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 27.1(1C, CH3), 22.8(1C, CH2); MS (m/z) 396.0 (M+); Anal, calcd. for CI9HI7FN6O3: C, 57.57; H, 4.32; N, 21.20%; Found: C, 57.28; H, 4.23; N, 21.25%.
Procedure for the synthesis of (S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)(l-methyl-lH-pyrrol-2-yl)methanone (7g):
The general experimental procedure described above afforded 7g as pale brown solid from the reaction of 5 (250 mg, 1 mmol) with 1 -methyl- lH-pyrrole-2-carboxylic acid 6g (137.5 mg, 1.1 mmol); Colour: Pale brown solid^H-NMR (400 MHz, DMSO-t/e, 8 ppm): 8.79(s, 1H), 8.15(m, 1H), 7.95-7.99(m, 1H), 7.85(d, .7=4,72 Hz, 1H), 7,57(d, .7=5,2 Hz, 1H), 6.5(d, J=4.8, 1H), 4.13- 4.43(m, 1H), 4.05(s, 3H), 3.71-3.93(brd, 2H), 3.33-3.51 (brd, 2H), 2.15-2.52(m, 1H), 1.89-
I.91(m, 1H), 1.67(m, 1H), 1.4-1.5(brd, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 165.3(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 134.1 (1C, Ar-C), 133.1(1C, pyrrole C), 126.0(lC, pyrrole C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 113.3(1 C, pyrrole C), 111.8(1C, pyrrole C), 55.3(1C, N-CH2), 47.6(1C, CH2), 37.3(1C, N-CH3), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2); MS m/z) 356.0 (NT); Anal, calcd. for CI8HI8FN5O2: C, 60.84; H, 5.11; N, 19.71%; Found: C, 60.91; H, 5.2; N, 19.65%.
Procedure for the synthesis of (S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl) (2-methyloxazol-5-yl) methanone (7h):
The general experimental procedure described above afforded 7h as pale yellow solid from the reaction of 5 (250 mg, 1 mmol) with 4-methyloxazole-5-carboxylic acid 6h (139.7 mg, 1.1 mmol); Colour: Pale yellow solid; 'H-NMR (400 MHz, DMSO-t/e, 8 ppm): 8.79(s, 1H), 8.15(m, 1H), 7.95-7.99(m, 1H), 7.32(s, 1H), 4.13-4.43(m, 1H), 3.72-3.95(m, 2H), 3.32-3.52 (m, 2H), 2.73(s, 3H), 2.1-2.5(m, 1H), 1.89-1.91(m, 1H), 1.67(m, 1H), 1.4-1.5(m, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 172.5(1C, CO), 163.5(1C, Oxadiazole C), 157.8(1C, Oxazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 141.9(1C, Oxazole C), 136.1(1C, (Oxazole C), 134.1 (1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 55.3(1C, N-CH2), 47.5(1C, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2), 13.5(1C, CH3); MS (m/z) 358.0 (M+); Anal, calcd. for CI7HI6FN5O3: C, 57.14; H, 4.51; N, 19.60%; Found: C, 57.02; H, 4.32; N, 19.45%.
Procedure for the synthesis of (S)-2-(2,3-dihydro-lH-inden-2-yl)-l-(3-(3-(5-fluoropyridin-2-yl)- l,2,4-oxadiazol-5-yl)piperidin-l-yl)ethanone (7i):
The general experimental procedure described above afforded 7i as ellow Gummy solid from the reaction of 5 (250 mg, 1 mmol) with 2-(2,3-dihydro-lH-inden-2-yl)acetic acid 6i (193.6 mg, 1.1 mmol ); Colour: Yellow Gummy solid; 3H-NMR (400 MHz, DMSO-t/e, 8 ppm): 8.79(s, 1H), 8.15(m, 1H), 7.95-7.99(m, 1H), 7.21-7.32(m, 4H), 4.13-4.43(m, 1H), 3.72-3.95(brd, 2H), 3.32- 3.52 (brd, 2H), 3.1-3.3(brd, 4H), 2.1-2.5(m, 4H), 1.89-1.91(m, 1H), 1.67(m, 1H), 1.4-1.5(m, 1H);13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 174.6(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1 C, Ar-C), 144.7(2C, Ar-C), 134.1 (1C, Ar-C), 127.6(2C, Ar-C) , 125.1(1C, Ar-C), 124.6(2c, Ar-C), 121.7(1C, Ar-C), 55.2(1C, N-CH2), 49.2(1C, CH2), 41.6(1C, CH2), 39.1(2C, CH2), 34.0(1 C, Chiral C), 31.5(1 C, CH), 3O.2(1C, CH2), 22.8(1C, CH. 2); MS (m/z) 407.0 (M+); Anal, calcd. for C23H23FN4O2: C, 67.97; H, 5.70; N, 13.78%; Found: C, 67.77; H, 5.55; N, 13.56%.
Procedure for the synthesis of (S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)(quinolin-3-yl)methanone ( 7j) :
The general experimental procedure described above afforded 7j as brown solid from the reaction of 5 (250 mg, 1 mmol) with quinoline-3-carboxylic acid 6j (190.3 mg, 1.1 mmol); Colour: Brown solid; *H-NMR (400 MHz, DMSO-76, 8 ppm): 9.2(s, 1H), 8.86(s, 1H), 8.79(s, 1H), 8.15(m, 1H), 7.95-7.99(m, 1H), 7.95-8. l(m, 2H), 7.6-7.7(m, 2H), 4.13-4.43(m, 1H), 3.72-3.95(brd, 2H), 3.32- 3.52 (brd, 2H), 2.1-2.5(m, 1H), 1.89-1.91(m, 1H), 1.67(m, 1H), 1.4-1.5(m, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 172.5(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 149.0(lC, Ar-C), 147.2(1C, Ar-C), 136.5(1C, Ar-C), 134.1 (1C, Ar-C), 132.2(1C, Ar-C), 128.5(1C, Ar-C), 129.7(1C, Ar-C), 127.7(1C, Ar-C), 126.8(1C, Ar- C), 126.6(1C, Ar-C ), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 55.3(1C, N-CH2), 47.6(1C, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2); MS m/z) 404.0 (M+); Anal, calcd. for
C22HI8FN5O2: C, 65.50; H, 4.50; N, 17.36%; Found: C, 65.35; H, 4.23; N, 17.21%.
Procedure for the synthesis of (S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- y I) (quinolin- 5-yl) methanone ( 7k) :
The general experimental procedure described above afforded 7k as brown gummy solid from the reaction of 5 (250 mg, 1 mmol) with quinoline-5-carboxylic acid 6k (190.3 mg, 1.1 mmol); Colour: Brown gummy solid; *H-NMR (400 MHz, DMSO-t/e, 8 ppm): 9.91(d, 7=5.3 Hz, 1H), 8.96(d, 7=5.3 Hz, 1H), 8.79(s, 1H), 8.3(d, 7=4.8, 1H), 8.15(m, 1H), 7.95-7.99(m, 1H), 7.81- 7.85(m, 3H), 4.13-4.43(m, 1H), 3.72-3.95(brd, 2H), 3.31-3.5 (m, 2H), 2.1-2.5(m, 1H), 1.89- 1.91(m, 1H), 1.67(m, 1H), 1.4-1.5(m, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 172.5(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 150.3(lC, Ar-C), 148.4(1C, Ar-C), 137.1(1C, Ar-C), 134.1 (1C, Ar-C), 137.1(1C, Ar-C), 136.5(1C, Ar-C), 129.8(1C, Ar-C), 129.1(1C, Ar-C), 125.1(1C, Ar-C),124.8(lC, Ar-C), 122.5(1C, Ar-C), 121.7(1C, Ar-C), 55.6(1C, N-CH2), 47.9(1C, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2); MS (m/z) 404.0 (M+); Anal, calcd. for C22HI8FN5O2: C, 65.50; H, 4.50; N, 17.36%.
Found: C, 65.25; H, 4.36; N, 17.26%.
Procedure for the synthesis of (S)-(2,5-dimethyloxazol-4-yl)(3-(3-(5-fluoropyridin-2-yl)-l,2,4- oxadiazol-5-yl)piperidin-l-yl)methanone (71):
The general experimental procedure described above afforded 71 as white solid from the reaction of 5 (250 mg, 1 mmol) with 2,5-dimethyloxazole-4-carboxylic acid 61 (155.1 mg, 1.1 mmol ); Colour: White solid; 'H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.79(s, 1H), 8.15(m, 1H), 7.95- 7.99(m, 1H), 4.13-4.43(m, 1H), 3.72-3.95(m, 2H), 3.32-3.52 (brd, 2H), 2.65(s, 3H), 2.5(s, 3H), 2.1-2.5(m, 1H), 1.88-1.91(m, 1H), 1.64-1.68(brd, 1H), 1.4-1.53(brd, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 172.5(1C, CO), 163.5(1C, Oxadiazole C), 16O.1(1C, Oxazole C), 153.9(1C, Ar-C), 153.6(1C, Oxazole C), 151.1(1C, Ar-C), 134.1 (1C, Ar-C), 128.7(1C, Oxazole C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 55.3(1C, N-CH2), 48.0(lC, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2),13.8(1C, CH3), 11.7(1C, CH3); MS (m/z) 372.0 (M+); Anal, calcd. for CI8HI8FN5O3: C, 58.22; H, 4.89; N, 18.86%; Found: C, 58.31; H, 4.69; N, 18.66%.
Procedure for the synthesis of (S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)(l-phenylcyclopropyl)methanone (7m):
The general experimental procedure described above afforded 7m as white solid from the reaction of 5 (250 mg, 1 mmol) with 1 -phenylcyclopropanecarboxylic acid 6m (178.3 mg, 1.1 mmol); Colour: White solid; *H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.79(s, 1H), 8.15(m, 1H), 7.95-7.99(m, 1H), 7.25-7.35(m, 5H), 4.13-4.43(m, 1H), 3.72-3.95 (brd, 2H), 3.32-3.52 (brd, 2H), 2.1-2.5(m, 1H), 1.89-1.91(m, 1H), 1.67(m, 1H), 1.4-1.5(m, 1H), 0.65-0.85(brd, 4H); 13C NMR (100 MHz, CDC13, 8 ppm): 18O.7(1C, Oxadiazole C), 180.3(lC, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 143.7(1C, Ar-C), 134.1 (1C, Ar-C), 128.1(2C, Ar-C), 125.1(2C, Ar-C), 125.0(2C, Ar-C), 121.7(1C, Ar-C), 55.3(1C, N-CH2), 48.0(lC, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 27.6(1C, CH) 22.8(1C, CH2), 16.9(2C, CH2); MS (m/z): 393.4 (M*); Anal, calcd. for C22H2IFN4O2: C, 67.33; H, 5.39; N, 14.28%; Found: C, 67.25; H, 5.25; N, 14.18%.
Procedure for the synthesis of (S)-(l,3-dihydrobenzo[c][l,2,5]oxadiazol-5-yl)(3-(3-(5- fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)methanone (7n):
The general experimental procedure described above afforded 7n as yellow solid from the reaction of 5 (250 mg, 1 mmol) with l,3-dihydrobenzo[c][l,2,5]oxadiazole-5-carboxylic acid 6n (180.4 mg, 1.1 mmol); Colour: Yellow solid; *H-NMR (400 MHz, DMSO-t/e, 8 ppm): 8.9(s, 1H), 8.79(s, 1H), 8.15(m, 1H), 8.05(m, 1H), 7.95-7.98(m, 1H), 7.85(m, 1H), 4.2-4.4(m, 1H), 3.72- 3.95(m, 2H), 3.32-3.52 (m, 2H), 2.1-2.5(brd, 1H), 1.89-1.91(brd, 1H), 1.67(brd, 1H), 1.4-1.5(m, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 172.5(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 135.2((1C, Ar-C), 134.1 (1C, Ar-C), 129.5(1C, Ar-C), 129.4(1C, Ar-C), 128.3(1C, Ar-C), 127.2(1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 112.7(1C, Ar-C), 55.7(1C, N-CH2), 48.0(lC, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2); MS (m/z) 397.2 (M+); Anal, calcd. for CI9HI7FN6O3: C, 57.57; H, 4.32; N, 21.20%; Found: C, 57.39; H, 4.42; N, 21.15%.
Procedure for the synthesis of (S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)(5-methylisoxazol-3-yl)methanoneOxadiazole (7o):
The general experimental procedure described above afforded 7o as buff solid from the reaction of 5 (250 mg, 1 mmol) with 5 -methylisoxazole-3 -carboxylic acid 6o (139.7 mg, 1.1 mmol); Colour: Buff solid; 'H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.79(s, 1H), 8.15(m, 1H), 7.95- 7.99(m, 1H), 4.13-4.43(m, 1H), 3.72-3.95(m, 2H), 3.30-3.51 (m, 2H),2.45(s, 3H), 6.3(s, 1H) 2.1- 2.5(m, 1H), 1.89-1.91(m, 1H), 1.67(brd, 1H), 1.4-1.5(brd, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 169.9(1C, Oxazole C), 165.3(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 150.0(lC, Oxazole C), 134.1 (1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 100.5(lC, Oxazole C), 55.3(1C, N-CH2), 47.6(1C, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2), 22.8(1C, CH2), 12.0(lC, CH3); MS (m/z) 358.0 (M+); Anal, calcd. For CI7HI6FN5O3: C, 57.14; H, 4.51; N, 19.60%; Found: C, 57.02; H, 4.35; N, 19.45%.
Procedure for the synthesis of (S)-3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)((lR,2S)-2-phenylcyclopropyl)methanoneOxadiazole (7p):
The general experimental procedure described above afforded 7p as white solid from the reaction of 5 (250 mg, 1 mmol) with (lS,2S)-2-phenylcyclopropanecarboxylic acid 6p (178.3 mg, 1.1 mmol); Colour: White solid;
*H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.78(s, 1H), 8.14-8.17(m, 1H), 7.95-7.99(m, 1H), 7.28- 7.35(m, 5H) 4.13-4.43(m, 1H), 3.72-3.95(m, 2H), 3.32-3.52 (brd, 2H), 2.0-2.5(m, 1H), 1.89- 1.91(m, 1H), 1.64-1.72(brd, 2H), 1.43-1.55(brd, 2H), 0.7-0.85(m, 2H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 168.9(1C, CO), 163.5(1C, Oxadiazole C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 138.8(1C, Ar-C), 134.1 (1C, Ar-C), 128.1(2C, Ar-C), 125.1(2C, Ar-C), 125.0(2C, Ar-C), 121.7(1C, Ar-C), 55.5(1C, N-CH2), 49.5(1C, CH2), 34.0(lC, Chiral C), 3O.2(1C, CH2),26.O(1C, CH), 23.5(1C, CH), 22.8(1C, CH2), 13.5(1C, CH2); MS m/z) 393.0 (NT); Anal, calcd. for C22H2IFN4O2: C, 67.33; H, 5.39; N, 14.28%; Found: C, 67.13; H, 5.29; N, 14.18%.
Procedure for the synthesis of (S)-l-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin- l-yl)-2-((4-methylpyrimidin-2-y I) thio) ethanone (7q) :
The general experimental procedure described above afforded 7q as yellow gummy solid from the reaction of 5 (250 mg, 1 mmol) with -((4-methylpyrimidin-2-yl)thio)acetic acid 6q (202.4 mg, l.lmmol); Colour: Yellow gummy solid;
*H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.79(s, 1H), 8.58(d, J= 5.2 Hz, 1H), 8.15(m, 1H), 7.95- 7.99(m, 1H), 7.6(d, J=4.8 Hz, 1H), 4.32(s, 2H), 4.15-4.42(m, 1H), 3.70-3.93 (brd, 2H), 3.31-3.49 (brd, 2H), 2.41(s, 3H) 2.1-2.4(m, 1H), 1.88-1.91(m, 1H), 1.65(m, 1H), 1.4-1.5(m, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 171.8(1 C, CO), 171.5(1 C, Pynmidime C), 167.2(1C, Pyrimidime C), 163.5(1C, Oxadiazole C), 156.3(1C, Pyrimidime C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 134.1 (1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 111.2(1C, Pyrimidine C), 55.3(1C, N-CH2), 48.0(lC, CH2), 34.0(lC, Chiral C), 37.0(lC, CH2), 3O.2(1C, CH2),
23.5(1C, CH3), 22.8(1C, CH2); MS (m/z): 415.0 (M+); Anal, calcd. for CI9HI9FN6O2S: C, 55.06; H, 4.62; N, 20.28%; Found: C, 55.16; H, 4.32; N, 20.08%. Procedure for the synthesis of (S)-(2-(difluoromethoxy)phenyl)(3-(3-(5-fluoropyridin-2-yl)- l,2,4-oxadiazol-5-yl)piperidin-l-yl)methanone (7r):
The general experimental procedure described above afforded 7r as brown gummy solid from the reaction of 5 (250 mg, 1 mmol) with 2-(difluoromethoxy) benzoic acid 6r (206.8 mg, 1.1 mmol); Colour: Brown gummy solid;
*H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.79(s, 1H), 8.15(m, 1H), 7.95-7.99(m, 1H), 7.92(d, .7=4,2 Hz, 1H), 7.59(m, 1H), 7.19-7.32(m, 3H), 4.13-4.43(m, 1H), 3.72-3.95(brd, 2H), 3.32-3.52 (brd, 2H), 2.1-2.5(m, 1H), 1.89-1.91(m, 1H), 1.67(m, 1H), 1.4-1.5(m, 1H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 172.5(1C, CO), 166.9(1C, OCF2), 163.5(1C, Oxadiazole C), 158.4(1C, Ar-C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 134.1 (1C, Ar-C), 13O.7(1C, Ar-C), 128.2(1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C), 12O.8(1C, Ar-C), 119.2(1C, Ar-C), 114.1(1C, Ar-C), 55.7(1C, N-CH2), 48.0(lC, CH2), 34.0(lC, chiral C), 3O.2(1C, CH2), 22.8(1C, CH2); MS (m/z) 419.0 (M+); Anal, calcd. for C2OHI7F3N403: C, 57.42; H, 4.10; N, 13.39%; Found: C, 57.51; H, 4.12; N, 13.19%.
Procedure for the synthesis of (S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)(2,4,6-trifluorophenyl)methanone (7s):
The general experimental procedure described above afforded 7s as brown gummy solid from the reaction of 5 (250 mg, 1 mmol) with 2,4,6-trifluorobenzoic acid 6s (209 mg, 1.1 mmol); Colour: Yellow solid; *H-NMR (400 MHz, DMSO-t76, 8 ppm): 8.79(s, 1H), 8.15(m, 1H), 7.95-7.99(m, 1H), 7.10-7.16(m, 1H), 4.13-4.43(m, 1H), 3.72-3.95(brd, 2H), 3.32-3.52 (brd, 2H), 2.1-2.3(brd, 1H), 1.5-2. l(brd, 3H); 13C NMR (100 MHz, CDC13, 8 ppm): 180.3(lC, Oxadiazole C), 172.5(1C, CO), 167.1(1C, Ar-C), 163.5(1C, Oxadiazole C), 160.8(2C, Ar-C), 153.9(1C, Ar-C), 151.1(1C, Ar-C), 134.1 (1C, Ar-C), 125.1(1C, Ar-C), 121.7(1C, Ar-C),l 10.8(2C, Ar-C), 107.9(2C, Ar-C), 55.3(1C, N-CH2), 48.0(lC, CH2), 34.0(lC, chiral C), 3O.2(1C, CH2), 22.8(1C, CH2); MS (m/z) 407.1(M+).
Anal, calcd. for Ci9Hi4F4N4O2: C, 56.16; H, 3.47; N, 13.79%; Found: C, 56.16; H, 3.47; N, 13.79%.
Pharmacology-C/reww'ca/s and Reagents:
Lyophilized powder of V. russelli venom was purchased from Irula Co-operative Society Ltd., Chennai, India. Calcium chloride, 8-anilino-l naphthalenesulfonic acid (ANS), 1 ,2-dimyristoyl- s«-glycero3 -phosphocholine (DMPC), Sephadex G-75, Sephadex G-50 and CM-Sephadex C-25 were purchased from Sigma-Aldrich, India. l-myristoyl-2-hydroxy-sn-glycero-3 -phosphocholine (LPC) was purchased from Avanti Polar Lipids. HPLC grade Methanol and analytical grade HC1 were obtained from Fisher Scientific. Tris (hydroxymethyl) aminomethane, fatty acid-free bovine serum albumin (BSA) fraction V, Triton X-100 was obtained from HiMedia Laboratories. Sodium acetate, glycine, and EGTA were purchased from SRL Chemicals. Milli-Q water was used throughout the experiments. All chemicals were of analytical grade, and solvents were of HPLC grade. Nanodrop ND3300 Fluorospectrometer from Thermo Scientific was used to record the fluorescence.
In vitro Secretary Phospholipase A2 (SPLA2) assay-Phospholipase A2 Assay:
The assay for VRV-VP-PLA2 Villa was carried out in a Nanodrop ND3300 using 1- anilinonaphthalene-8-sulfonate (ANS) as an “interfacial probe” Huang C, el al. First, 50 //L of l,2-dimyristoyl-577-glycero-3-phosphocholine (DMPC) solution (40 mM in methanol) and 50 //L of deoxycholic acid (40 mM in methanol) were mixed and quickly pipetted into doubly distilled water (1 mL). The solution was stirred for 1 min, sonicated in a water bath for 2 min, and used as the stock substrate solution. Then 75 /L of reaction buffer (50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 2 mM NaN3, 5 /g/mL bovine serum albumin (BSA), and 10 mM ANS), 10 //L of substrate stock solution, 5 //L of CaCl2 stock solution (100 mM), were incubated at 37°C for 10 min. Reactions were started by adding 5 //L of sPLA2 stock solution (3.2 //g/mL) and monitored by excitation at UV LED and emission was monitored at 477 nm using Nanodrop ND3300. Enzyme activity was calculated by
ARFU = RFU(Controi)-RFU(test)
Where ARFU is the change in RFU of test (with sPLA2) with respect to control (without sPLA2 or sPLA2 in the presence of inhibitor(s). The resultant RFU was compared with the standard LPC curve to determine the sPLA2 activity in the presence of inhibitor (Vivek Et al 2014). 4PL IC50 were calculated for 7(a-s) ligands accordingly.
Inhibition of indirect hemolytic activity by 7(a-s)
Indirect hemolytic activity was assayed according to the method of Boman and Kalletta. Briefly, packed human erythrocytes, egg yolk, and phosphate-buffered saline pH 7.5 were mixed in the ratio of 1 :1:8 (v/v). 1 ml of this suspension was incubated separately for 60 min at 37°C with 8pg of sPLA2 alone or pre-incubated with different concentrations of inhibitor 7k ranging from 0 to lOOpM for 5 min at RT. Reaction was stopped by adding 9 ml of ice-cold PBS with pH 7.5; reaction mixtures were centrifuged at 4 °C for 10 min at 1500g. The resultant % of hemoglobin released in supernatant was measured spectrophotometrically at 540 nm.
Structure Based Design and In-Silico Molecular Docking
Molecular docking was done as mentioned by Vivek et al. Briefly, The co-ordinates of sPLA2 5G3N was obtained from the Brookhaven Protein Data Bank. Ligands were drawn using the Maestro 2D sketcher and energy minimization was computed by OPLS 2005. Proteins were prepared by retrieving into the Maestro 9.3 platform (Schrodinger, Inc.). Prime software module of Schrodinger was used to correct the missing loops in the proteins. Water molecules from sPLA2 were removed which were beyond 5 A from the hetero atoms. Water molecules that are thought to be important in aiding the interaction between the receptor and the ligand were optimized during protein pepwizard. Automated, necessary bonds, bond orders, hybridization, explicit hydrogens, and charges were assigned. OPLS 2005 force field was applied to the proteins to restrain minimization and RMSD of 0.30A was set to converge heavy atoms during the preprocessing of protein before starting docking. Using extra-precision (XP) docking each compound was docked into the receptor grid of radii 20A and the docking calculations were judge based on the docking score, and Glide energy. ADME evaluation of was done by qikprop and accessed by comparing 95% of known drugs which possesses similar ADME properties.
Reagents and conditions: (a) K3[Fe(CN)6], DMA, 140 °C, 3 hr; (b) NH2OH.HC1, TEA, MeOH, RT, 10 hrs; (c) (S)-l-(tert-butoxycarbonyl)piperidine-3 -carboxylic acid, EDCI, HOBt, 10 hrs, DMF, 120 °C, 4 hrs; (d) HC1 in ether, RT, 2 hrs; (e) R-COOH(6a-s), EDCI.HC1, HOBt, TEA, MDC, RT, 12 hrs.

Claims

We Claim,
Compound of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I:
Figure imgf000022_0001
Formula I
Wherein R is selected from 6a to 6s:
Figure imgf000022_0002
The compound of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I as claimed in claim 1 wherein the compound is
(S)-3-(3-(5-fluoropytidin-2-yl)-l, 2, 4-oxadiazol-5-yl) piperidin-l-yl)(l, 2, 3, 4-tetrahydronaphthalen-2- yl) methanone;
(S)-(l-ethyl-3-methyl-lH-pyrazol-5-yl)(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)methanone ;
(S)-benzo[d]thiazol-6-yl(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)methanone;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(2-
(trifluoromethyl)phenyl)methanone;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(l-methyl-lH-pyrrol-2- yl)methanone ;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(2-methyloxazol-5-yl)methanone;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(quinolin-3-yl)methanone;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(quinolin-5-yl)methanone; (S)-(2,5-dimethyloxazol-4-yl)(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)methanone ;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(l-phenylcyclopropyl)methanone;
(S)-(l,3-dihydrobenzo[c][l,2,5]oxadiazol-5-yl)(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5- yl)piperidin-l-yl)methanone; . The compound of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I as claimed in claim 1 wherein the compound is
(S)-l-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)-2-(thiophen-2-yl)ethanone;
(S)-l-(3-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidine-l-carbonyl)pyrazin-2- yl)ethanone;
(S)-2-(2,3-dihydro-lH-inden-2-yl)-l-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)ethanone;
(S)-l-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)-2-((4-methylpyrimidin-2- y I) thio) ethanone. . The compound of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I as claimed in claim 1 wherein the compound is
(S)-(3-(3-(5-fhioropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(5-methylisoxazol-3-yl)methanone Oxadiazole;
(S)-3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)((lR,2S)-2- phenylcyclopropyl)methanone Oxadiazole;
(S)-(2-(difluoromethoxy)phenyl)(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)methanone ; and
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(2,4,6-trifluorophenyl)methanone. . Pharmaceutical composition for inhibition of Secretory Phospholipase A2 (SPLA2) comprising the compound as claimed in claim 1 or 2 and pharmaceutically acceptable excipients or carriers. . A process for synthesis of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I as claimed in claim 1 comprising: i. converting the 2-bromo-5-fluoropyridine (1) into 5-fluoropicolinonitrile (2); ii. then the compound (2) of step (i) is treated with hydroxylamine hydrochloride to get (Z)-5-fluoro-N'- hydroxypicolinimidamide (3); iii. then the compound (3) of is treated with (S)-l-(tert-butoxy carbonyl) piperidine-3-carboxylic acid to yield Boc protected oxadiazole (4); iv. then the Boc group was cleaved from the oxadiazole (4) in the presence of HC1 to give the scaffold (5); and v. then the scaffold (5) is reacted with compounds of 6 a to 6s to form the compounds of formula I. . The process for synthesis of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I as claimed in claim 6 wherein the compound 5-fluoropicolinonitrile (2) is synthesized using potassium ferricyanide. The process for synthesis of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I as claimed in claim 6 wherein the step (v) reaction is carried in the presence of EDCI.HC1 as coupling agent. The rocess for synthesis of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I as claimed in claim wherein the compound is
(S)-3-(3-(5-fluoropyridin-2-yl)-l, 2, 4-oxadiazol-5-yl) piperidin-l-yl)(l, 2, 3, 4-tetrahydronaphthalen-2- yl) methanone;
(S)-(l-ethyl-3-methyl-lH-pyrazol-5-yl)(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)methanone ;
(S)-benzo[d]thiazol-6-yl(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)methanone;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(2- (trifluoromethyl)phenyl)methanone;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(l-methyl-lH-pyrrol-2- yl)methanone ;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(2-methyloxazol-5-yl)methanone;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(quinolin-3-yl)methanone;
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(quinolin-5-yl)methanone;
(S)-(2,5-dimethyloxazol-4-yl)(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)methanone. The process for synthesis of (S)-3-(5-fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivative of formula I as claimed in claim 6 wherein the compound is
(S)-(3-(3-(5-fhioropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(l-phenylcyclopropyl)methanone;
(S)-(l ,3-dihydrobenzo[c] [1 ,2,5]oxadiazol-5-yl)(3-(3-(5-fluoropyridin-2-yl)-l ,2,4-oxadiazol-5- yl)piperidin-l-yl)methanone;
(S)-l-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)-2-(thiophen-2-yl)ethanone;
(S)-l-(3-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidine-l-carbonyl)pyrazin-2- yl)ethanone;
(S)-2-(2,3-dihydro-lH-inden-2-yl)-l-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)ethanone;
(S)-l-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)-2-((4-methylpyrimidin-2- y I) thio) ethanone.
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(5-methylisoxazol-3-yl)methanone Oxadiazole;
(S)-3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)((lR,2S)-2- phenylcyclopropyl)methanone Oxadiazole;
(S)-(2-(difluoromethoxy)phenyl)(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l- yl)methanone ; and
(S)-(3-(3-(5-fluoropyridin-2-yl)-l,2,4-oxadiazol-5-yl)piperidin-l-yl)(2,4,6-trifluorophenyl)methanone.
PCT/IB2021/052556 2020-09-29 2021-03-27 Synthesis and characterization of (s)-3-(5- fluoropyridin-2-yl)-5-(piperidin-3-yl)-l,2,4-oxadiazole derivatives and their secretory phospholipase a2 (spla2) inhibitor activity WO2022069953A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044797A1 (en) * 2003-11-06 2005-05-19 Addex Pharmaceuticals Sa Allosteric modulators of metabotropic glutamate receptors
WO2006123257A2 (en) * 2005-05-18 2006-11-23 Addex Pharma Sa Phenyl-3-{(3-(1h-pyrrol-2-yl)-[1, 2 , 4]0xadiaz0l-5-yl]piperidin-1-yl}-methanone derivatives and related compounds as positive allosteric modulators of metabotropic glutamate receptors
WO2006123255A2 (en) * 2005-05-18 2006-11-23 Addex Pharma Sa Substituted oxadiazole derivatives as positive allosteric modulators of metabotropic glutamate receptors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044797A1 (en) * 2003-11-06 2005-05-19 Addex Pharmaceuticals Sa Allosteric modulators of metabotropic glutamate receptors
WO2006123257A2 (en) * 2005-05-18 2006-11-23 Addex Pharma Sa Phenyl-3-{(3-(1h-pyrrol-2-yl)-[1, 2 , 4]0xadiaz0l-5-yl]piperidin-1-yl}-methanone derivatives and related compounds as positive allosteric modulators of metabotropic glutamate receptors
WO2006123255A2 (en) * 2005-05-18 2006-11-23 Addex Pharma Sa Substituted oxadiazole derivatives as positive allosteric modulators of metabotropic glutamate receptors

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