Pyrazolo[1,5-a]pyrimidines: A Close Look into their Synthesis and Applications

Author(s): Amal Al-Azmi* .

Journal Name: Current Organic Chemistry

Volume 23 , Issue 6 , 2019

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Graphical Abstract:


Pyrazolo[1,5-a]pyrimidines are fused N-heterocyclic systems of a pyrazole. They are considered as a key structural motif in many vital applications, such as medicinal, pharmaceuticals, pesticides, dyes and pigments. Their synthetic routes have escalated dramatically in the last decades. The current review is a recent synthetic survey of pyrazolo[ 1,5-a]pyrimidines and their applications until recently.

Keywords: Aminopyrazoles, pyrazoles, pyrimidines, MCR, anticancer, heterocylces, antibacterial.

Drev, M.; Grošelj, U.; Mevec, Š.; Pušavec, E.; Štrekelj, J.; Golobič, A.; Dahmann, G.; Stanovnik, B.; Svete, J. Regioselective synthesis of 1-and 4-substituted 7-oxopyrazolo[1,5-a] pyrimidine-3-carboxamides. Tetrahedron, 2014, 70, 8267-8279.
Gregg, B.T.; Tymoshenko, D.O.; Razzano, D.A.; Johnson, M.R. Pyrazolo[1,5-a]pyrimidines. Identification of the Privileged Structure and Combinatorial Synthesis of 3-(Hetero)arylpyrazolo[1,5-a]pyrimidine-6-carboxamides. J. Comb. Chem., 2007, 9(3), 507-512.
Ahmed, O.M.; Mohamed, M.A.; Ahmed, R.R.; Ahmed, S.A. Synthesis and anti-tumor activities of some new pyridines and pyrazolo[1,5-a]pyrimidines. Eur. J. Med. Chem., 2009, 44, 3519-3523.
Liu, Y.; Laufer, R.; Patel, N.K.; Ng, G.; Sampson, P.B.; Li, S-W.; Lang, Y.; Feher, M.; Brokx, R.; Beletskaya, I.; Hodgson, R.; Plotnikova, O.; Awrey, D.E.; Qiu, W.; Chirgadze, N.Y.; Mason, J.M.; Wei, X.; Lin, D.C-C.; Che, Y.; Kiarash, R.; Fletcher, G.C.; Mak, T.W.; Bray, M.R.; Pauls, H.W. Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent. ACS Med. Chem. Lett., 2016, 7(7), 671-675.
Zhoa, M.; Ren, H.; Chang, J.; Zhang, D.; Yang, Y.; Yong, H.; Qi, C.; Zhang, H. Design and synthesis of novel pyrazolo[1,5-a]pyrimidine derivatives bearing nitrogen mustard moiety and evaluation of their antitumor activity in vitro and in vivo. Eur. J. Med. Chem., 2016, 119, 183-196.
Tsai, P.C.; Wang, I.J. Synthesis and solvatochromic properties of 3,6-bis-hetarylazo dyes derived from pyrazolo[1,5-a] pyrimidine. Dyes Pigm, 2008, 76, 575-581.
Sayed, A.Z.; Aboul-Fetouh, M.S.; Nassar, H.S. Synthesis, biological activity and dyeing performance of some novel azo disperse dyes incorporating pyrazolo[1,5-a] pyrimidines for dyeing of polyester fabrics. J. Mol. Struct., 2012, 1010, 146-151.
Al-Etaibi, A.M.; Al-Awadi, N.A.; El-Apasery, M.A.; Ibrahim, M.R. Synthesis of some novel pyrazolo[1,5-a]pyrimidine derivatives and their application as disperse dyes. Molecules, 2011, 16, 5182-5193.
Al-Azmi, A.; Kalarikkal, A.K. Pyrazoles versus pyrazolo[1,5-a]pyrimidines and pyridones versus enamines: Reactions of 2-aryl-3-oxopropanenitrile with nitrogen and carbonyl compounds. Curr. Org. Synth., 2017, 14(8), 1198-1213.
Tigreros, A.; Rosero, H-A.; Castillo, J-C.; Portilla, J. Integrated pyrazolo[1,5-a]pyrimidine–hemicyanine system as a colorimetric and fluorometric chemosensor for cyanide recognition in water. Talanta, 2019, 96, 395-401.
Ding, Z-C.; An, X-M.; Zeng, J-H.; Tang, Z-N. Copper(I)-catalyzed synthesis of 4,5-dihydropyrazolo[1,5-a]pyrimidines via cascade transformation of N-propargylic sulfonylhydrazones with sulfonyl azides. Adv. Synth. Catal., 2017, 359(19), 3319-3324.
Castillo, J-C.; Rosero, H-A.; Portilla, J. Simple access toward 3-halo- and 3-nitro-pyrazolo[1,5-a]pyrimidines through a one-pot sequence. RSC Advances, 2017, 7, 28483-28488.
Golubev, P.; Karpova, E.A.; Pankova, A.S.; Sorokina, M. Kuznetsov. M.A. Regioselective Synthesis of 7-(Trimethylsilylethynyl)pyrazolo[1,5-a]pyrimidines via reaction of pyrazolamines with enynones. J. Org. Chem., 2016, 81(22), 11268-11275.
Sun, J.; Qiu, J-K.; Jiang, B.; Hao, W-J.; Guo, C.; Tu, S-J.I. 2-Catalyzed multicomponent reactions for accessing densely functionalized pyrazolo[1,5-a]pyrimidines and their disulphenylated derivatives. J. Org. Chem., 2016, 81(8), 3321-3328.
Castillo, J-C.; Tigreros, A.; Portilla, J. 3-Formylpyrazolo[1,5-a]pyrimidines as key intermediates for the preparation of functional fluorophores. J. Org. Chem., 2018, 83(18), 10887-10897.
Loubidi, M. Manga, C.; Tber, Z.; Bassoude, I.; Essassi, E.; Berteina-Raboin, S. One-pot SNAr/Direct Pd-Catalyzed CH arylation functionalization of Pyrazolo[1,5-a]pyrimidine at the C3 and C7 positions. Eur. J. Org. Chem., 2018, 2018(29), 3936-3942.
Jismy, B.; Guillaumet, G.; Allouchi, H.; Akssira, M.; Abarbri, M. Concise and efficient access to 5,7-disubstituted pyrazolo[1,5-a]pyrimidines by Pd-catalyzed sequential arylation, alkynylation and SNAr reaction. Eur. J. Org. Chem., 2017, 2017(41), 6168-6178.
Wu, Y-C. H.-J.; Li, Liu, L.; Wang, D.; H.-Z.; Yang; Chen, Y.-J. Efficient construction of pyrazolo[1,5-a]pyrimidine scaffold and its exploration as a new heterocyclic fluorescent platform. J. Fluoresc., 2008, 18(2), 357-363.
Abbas-Temirek, H.H.; Abo-Bakr, A.M. Reactions with heterocyclic amidines: Synthesis of several new pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines. Eur. J. Chem., 2016, 7(1), 107-114.
Bedford, R.B.; Durrant, S.J.; Montgomery, M. Catalyst-switchable regiocontrol in the direct arylation of remote C-H groups in pyrazolo[1,5-a]pyrimidines. Angew. Chem., 2015, 54(30), 8787-8790.
Ried, W.; Aboul-Fetouh, S. Synthesis of new substituted pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]1,3,5-triazines. Tetrahedron, 1988, 44(23), 7155-7162.
Kelada, M.; Walsh, J.M.D.; Devine, R.W.; McArdle, P.; Stephens, J.C. Synthesis of pyrazolopyrimidinones using a “one-pot” approach under microwave irradiation. Beilstein J. Org. Chem., 2018, 14, 1222-1228.
Jismy, B.; Allouchi, H.; Guillaumet, G.; Akssira, M.; Abarbri, M. An Efficient Synthesis of New 7-Trifluoromethyl-2,5-disubstituted Pyrazolo[1,5-a] pyrimidines. Synthesis, 2018, 50(08), 1675-1686.
Ahmetaj, S. Velikanje. N.; Grošelj, U.; Šterbal, I.; Prek, B.; Golobič, A.; Kočar, D.; Dahmann, G.; Stanovnik, B.; Svete, J. Parallel synthesis of 7-heteroaryl-pyrazolo[1,5-a]pyrimidine-3-carboxamides. Mol. Divers., 2013, 17(4), 731-743.
Ismail, N.S.M.; Ali, G.M.E.; Ibrahim, D.A.; Elmetwali, A.M. Medicinal attributes of pyrazolo[1,5-a]pyrimidine based scaffold derivatives targeting kinases as anticancer agents. J. Pharm. Sci., 2016, 2(2), 60-70.
Castillo, J.C.; Estupiñan, D.; Nogueras, M.; Cobo, J.; Portilla, J. 6-(Aryldiazenyl)pyrazolo[1,5-a] pyrimidines as strategic intermediates for the synthesis of pyrazolo[5,1-b]purines. J. Org. Chem., 2016, 81(24), 12364-12373.
Stepaniuk, O.O.; Matviienko, V.O.; Kontratov, I.S.; Vitruk, I.V.; Tolmachev, A.O. Synthesis of New Pyrazolo[1,5-a] pyrimidines by reaction of β,γ-unsaturated γ-alkoxy-α-keto esters with n-unsubstituted 5-aminopyrazoles. Synthesis, 2013, 45, 925-930.
El-Enany, M.M.; Kamel, M.M.; Khalil, O.M.; El-Nassan, H.B. Synthesis and antitumor activity of novel pyrazolo[1,5-a] pyrimidine derivatives. Eur. J. Chem., 2011, 2(3), 331-336.
Gavrin, L.K.; Lee, A.; Provencher, B.A.; Massefski, W.W.; Huhn, S.D.; Ciszewski, G.M.; Cole, D.C.; McKew, J.C. Synthesis of Pyrazolo[1,5-a]pyrimidinone Regioisomers. J. Org. Chem., 2007, 72(3), 1043-1046.
Tian, Y.; Du, D.; Rai, D.; Wang, L.; Liu, H.; Zhan, P.; De Clercq, E.; Pannecouque, C.; Liu, X. Fused heterocyclic compounds bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 1: Design, synthesis and biological evaluation of novel 5,7-disubstituted pyrazolo[1,5-a] pyrimidine derivatives. Bioorg. Med. Chem., 2014, 22, 2052-2059.
Al-Adiwish, W.M.; Tahir, M.I.M.; Adnalizawati, A.S-N.; Hashim, S.F.; Ibrahim, N.; Yaacob, W.A. Synthesis, antibacterial activity and cytotoxicity of new fused pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-c][1,2,4]triazine derivatives from new 5-aminopyrazoles. Eur. J. Med. Chem., 2013, 64, 464-476.
Ammar, Y.A.; Thabet, H.K.; Aly, M.M.; Mohamed, Y.A.; Ismail, M.A.; Salem, M.A. Cyanothioacetanilide intermediates in heterocyclic synthesis, Part 1: Synthesis and biological evaluation of some novel thiazole, thiophene, pyrazole, and pyrazolo[1,5-a] pyrimidine derivatives. Phosphorus Sulfur Silicon, 2010, 185, 743-753.
Shiota, T.; Yamamori, T.; Sakai, K.; Kiyokawa, M.; Honma, T.; Ogawa, M.; Hayashi, K.; Ishizuka, N.; Matsumura, K.; Hara, M.; Fujimoto, M.; Kawabata, T.; Nakajima, S. Synthesis and structure-activity relationship of a new series of potent angiotensin II receptor antagonists: Pyrazolo[1,5-a]pyrimidine derivatives. Chem. Pharm. Bull., 1999, 47(7), 928-938.
Elnagdi, M.H.; Elmoghayar, M.R.H.; Elgemeie, G.E.H. Chemistry of Pyrazolopyrimidines. Adv. Heterocycl. Chem., 1987, 41, 319-376.
Mukaiyama, H.; Nishimura, T.; Shiohara, H.; Kobayashi, S.; Komatsu, Y.; Kukuchi, S.; Tsuji, E.; Kamada, N.; Ohnota, H.; Kusama, H. Discovery of novel 2-Anilinopyrazolo[1,5-a]pyrimidine derivatives as c-Src kinase inhibitors for the treatment of acute ischemic stroke. Chem. Pharm. Bull., 2007, 55(6), 881-889.
Popovici-Muller, J. Shipps Jr.; G.W.; Rosner, K.E.; Deng, Y.; Wang, T.; Curran, P.J.; Brown, M.A.; Siddiqui, M.A.; Cooper, A.B.; Duca, J.; Cable, M.; Girijavallabhan, V. Pyrazolo[1,5-a]pyrimidine-based inhibitors of HCV polymerase. Bioorg. Med. Chem. Lett., 2009, 19, 6331-6336.
Xu, J.; Liu, H.; Li, G.; He, Y.; Ding, R.; Wang, X.; Feng, M.; Zhang, S.; Chen, Y.; Li, S.; Zhao, M.; Qi, C.; Dang, Y. Synthesis and biological evaluation of novel F-18 labeled pyrazolo[1,5-a]pyrimidine derivatives: Potential PET imaging agents for tumor detection. Bioorg. Med. Chem. Lett., 2011, 21, 4736-4741.
Ding, R.; He, Y.; Xu, J.; Liu, H.; Wang, X.; Feng, M.; Qi, C.; Zhang, J. Synthesis and biological evaluation of pyrazolo[1,5-a]-pyrimidine-containing 99mTc Nitrido Radiopharmaceuticals as imaging agents for Tumors. Molecules, 2010, 15, 8723-8733.
Elnagdi, M.H.; Sadek, K.U.; Galil, F.M.A.; Hassan, S.M.E. Studies on Heterocyclic Amidines: Synthesis of new Azaindene derivatives. Arch. Pharm., 1988, 321, 851-854.
El-Mekabaty, A.; Habib, O.M.O.; Moawad, E.B.; Hasel, A.M. Synthesis and antioxidant activity of new pyrazolo[1,5-a]pyrimidine Derivatives Incorporating a Thiazol-2-yldiazenyl moiety. J. Heterocycl. Chem., 2015, 53(6), 1820-1826.
Anwar, H.F.; Fleita, D.H.; Kolshorn, H.; Meier, H.; Elnagdi, M.H. 2H-Pyrazol-3-ylamines as precursors for the synthesis of polyfunctionally substituted pyrazolo[1,5-a]pyrimidines. ARKIVOC, 2006, 15, 133-141.
Anwar, H.F.; Elnagdi, M.H. Recent developments in aminopyrazole chemistry. ARKIVOC, 2009, I, 198-250.
Elfahham, H.A.; Abdel-Galil, F.M.; Ibraheim, Y.R.; Elnagdi, M.H. Activated nitriles in heterocyclic synthesis. A novel synthesis of pyrazolo[1,5-a]pyrimidines and pyrano[2,3-c]pyrazoles. J. Heterocycl. Chem., 1983, 20, 667-670.
Quiroga, J.; Trilleras, J.; Insuasty, B.; Abonía, R.; Nogueras, M.; Cobo, J. Regioselective formylation of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine systems using Vilsmeier–Haack conditions. Tetrahedron Lett., 2008, 49, 2689-2691.
Quiroga, J.; Insuasty, B.; Rincon, R.; Larrahondo, M.; Hanold, N.; Meier, H. The formation of pyrazolo[1,5-a]pyrimidines by the reaction of 3-(4-chlorophenyl)pyrazol-5-amine with chalcones. J. Heterocycl. Chem., 1994, 31, 1333-1335.
Buriol, L.; München, T.S.; Frizzo, C.P.; Marzari, M.R.B.; Zanatta, N.; Bonacorso, H.G.; Martins, M.A.P. Resourceful synthesis of pyrazolo[1,5-a]pyrimidines under ultrasound irradiation. Ultrason. Sonochem., 2013, 20, 1139-1143.
Hussein, A.M. Novel synthesis of some new pyrimido[1,6‐a] pyrimidine and pyrazolo[1,5-a] pyrimidine derivatives. J. Heterocycl. Chem., 2012, 49, 446-451.
Abdelhamid, A.O.; El-Idreesy, T.T.; Abdelriheem, N.A.; Dawoud, H.R.M. Green one-pot solvent-free synthesis of pyrazolo[1,5-a] pyrimidines, Azolo[3,4-d]pyridiazines, and Thieno[2,3-b]pyridines containing triazole moiety. J. Heterocycl. Chem., 2016, 53, 710-718.
Hussein, A.M. Novel synthesis of some new pyrimido[1,6-a]pyrimidine and Pyrazolo[1,5-a]pyrimidine Derivatives. J. Heterocycl. Chem., 2012, 49, 446-451.
Bel Abed, H.; Mammoliti, O.; Van Lommen, G.; Herdewijn, P. Simple approach to the synthesis of 3-fluoro pyrazolo[1,5-a] pyrimidine analogues. Tetrahedron Lett., 2013, 54, 2612-2614.
Wu, Y-C.; Chen, Y-J.; Li, H-J.; Zou, X-M.; Hu, F-Z.; Yang, H-Z. Synthesis of trifluoromethyl-promoted functional pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones. J. Fluor. Chem., 2006, 127, 409-416.
Médran-Navarrete, V.; Damont, A.; Peyronneau, M-A.; Kuhnast, B.; Bernards, N.; Pottier, G.; Marguet, F.; Puech, F.; Boisgard, R.; Dollé, F. Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18 kDa with PET. Bioorg. Med. Chem. Lett., 2014, 24, 1550-1556.
Reynoldsa, A.; Hanania, R.; Hibbsb, D.; Damontc, A.; Da Pozzod, E.; Sellerie, S.; Dolléc, F.; Martinid, C.; Kassiou, M. Pyrazolo[1,5-a] pyrimidine acetamides: 4-Phenyl alkyl ether derivatives as potent ligands for the 18 kDa translocator protein (TSPO). Bioorg. Med. Chem. Lett., 2010, 20, 5799-5802.
Labroli, M.A.; Dwyer, M.P.; Poker, C.; Keertikar, K.M.; Rossman, R.; Guzi, T.J. A convergent preparation of the CHK1 inhibitor MK-8776 (SCH 900776). Tetrahedron Lett., 2016, 57, 2601-2603.
Griffith, D.A.; Hargrove, D.M.; Maurer, T.S.; Blum, C.A.; De Lombaert, S.; Inthavongsay, J.K.; Klade, L.E.; Mack, C.M.; Rose, C.R.; Sanders, M.J.; Carpino, P.A. Discovery and evaluation of pyrazolo[1,5-a] pyrimidines as neuropeptide Y1 receptor antagonists. Bioorg. Med. Chem. Lett., 2011, 21, 2641-2645.
Kamal, A.; Faazil, S. A. Hussaini, S.M.; Ramaiah, M.J.; Balakrishna, M.; Patel, N.; Pushpavalli, S.N.C.V.L.; Pal-Bhadra, M. Synthesis and mechanistic aspects of 2-anilinonicotinyl-pyrazolo[1,5-a] pyrimidine conjugates that regulate cell proliferation in MCF-7 cells via estrogen signaling. Bioorg. Med. Chem. Lett., 2016, 26, 2077-2083.
Aggarwal, R.; Kumar, V.; Singh, G.; Sanz, D.; Claramunt, R.M.; Alkorta, I.; Sánchez-Sanz, G.; Elguero, J. An NMR and computational study of azolo[a]pyrimidines with special emphasis on pyrazolo[1,5-a] pyrimidines. J. Heterocycl. Chem., 2015, 52, 336-345.
Frey, R.R.; Curtin, M.L.; Albert, D.H.; Glaser, K.B.; Pease, L.J.; Soni, N.B.; Bouska, J.J.; Reuter, D.; Stewart, K.D.; Marcotte, P.; Bukofzer, G.; Li, J.; Davidsen, S.K.; Michaelides, M.R. 7-Aminopyrazolo[1,5-a] pyrimidines as Potent multitargeted receptor tyrosine kinase inhibitors. J. Med. Chem., 2008, 51, 3777-3787.
Kosugi, T.; Mitchell, D.R.; Fujino, A.; Imai, M.; Kambe, M.; Kobayashi, S.; Makino, H.; Matsueda, Y.; Oue, Y.; Komatsu, K.; Imaizumi, K.; Sakai, Y.; Sugiura, S.; Takenouchi, O.; Unoki, G.; Yamakoshi, Y.; Cunliffe, V.; Frearson, J.; Gordon, R.; Harris, C.J.; Kalloo-Hosein, H.; Le, J.; Patel, G.; Simpson, D.J.; Sherborne, B.; Thomas, P.S.; Suzuki, N.; Takimoto-Kamimuraand, M.; Ichiro-Kataoka, K. Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) as an antiinflammatory target: Discovery and in Vivo activity of selective pyrazolo[1,5-a]pyrimidine inhibitors using a focused library and structure-based optimization approach. J. Med. Chem., 2012, 55, 6700-6715.
Engers, D.W.; Frist, A.Y.; Lindsley, C.W.; Hong, C.C.; Hopkins, C.R. Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: The discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Bioorg. Med. Chem. Lett., 2013, 23, 3248-3252.
Abdel-Aziz, H.A.; Hamdy, N.A.; Farag, A.M.; Fakhr, I.M.I. Synthesis of some novel pyrazolo[1,5-a]pyrimidine, 1,2,4-triazolo[1,5-a]pyrimidine, pyrido[2,3-d]pyrimidine, pyrazolo[5,1-c]-1,2,4-triazine and 1,2,4-triazolo[5,1-c]-1,2,4-triazine derivatives incorporating a thiazolo[3,2-a]benzimidazole moiety. J. Heterocycl. Chem., 2008, 45, 1033-1037.
Wang, Y.D.; Honores, E.; Wu, B.; Johnson, S.; Powell, D.; Miranda, M.; McGinnis, J.P.; Discafani, C.; Rabindran, S.K.; Cheng, W.; Krishnamurthy, G. Synthesis, SAR study and biological evaluation of novel pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as anti-proliferative agents. Bioorg. Med. Chem., 2009, 17, 2091-2100.
Elkholy, A.; Al-Qalaf, F.; Elnagdi, M.H. Regio-orientation in condensation of aminopyrazoles with 1,3-difunctional reagents: synthesis of new pyrazolo[1,5-a]pyrimidines, pyrazolo[3,4-d]pyridazines and 2,4-dihydropyrano[2,3-c]pyrazoles. ARKIVOC, 2008, 14, 124-131.
Behbehani, H.; Ibrahim, H.M.; Makhseed, S.; Mahmoud, H. Applications of 2-arylhydrazononitriles in synthesis: Preparation of new indole containing 1,2,3-triazole, pyrazole and pyrazolo[1,5-a]pyrimidine derivatives and evaluation of their antimicrobial activities. Eur. J. Med. Chem., 2011, 46, 1813-1820.
Kaping, S.; Kalita, U.M.; Sunn, M.; Singha, L.I.; Vishwakarma, J.N. A facile, regioselective synthesis of pyrazolo[1,5-a]pyrimidine analogs in the presence of KHSO4 in aqueous media assisted by ultrasound and their anti-inflammatory and anti-cancer activities. Monatsh. Chem., 2016, 147, 1257-1276.
Gopalsamy, A.; Ciszewski, G.; Hu, Y.; Lee, F.; Feldberg, L.; Frommer, E.; Kim, S.; Collins, K.; Wojciechowicz, D.; Mallon, R. Identification of pyrazolo[1,5-a]pyrimidine-3-carboxylates as B-Raf kinase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 2735-2738.
Gopalsamy, A.; Ciszewski, G.; Shi, M.; Berger, D.; Hu, Y.; Lee, F.; Feldberg, L.; Frommer, E.; Kim, S.; Collins, K.; Wojciechowicz, D.; Mallon, R. Hit to lead optimization of pyrazolo[1,5-a]pyrimidines as B-Raf kinase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19, 6890-6892.
Behbehani, H.; Ibrahim, H.M.; Makhseed, S. Synthesis of 7-substituted pyrazolo[1,5-a] pyrimidine-3carboxamides as potential non benzodiazepine hypnotics. ARKIVOC, 2010, 2, 267-282.
Dwyer, M.P.; Keertikar, K.; Paruch, K.; Alvarez, C.; Labroli, M.; Poker, C.; Fischmann, T.O.; Mayer-Ezell, R.; Bond, R.; Wang, Y.; Azevedo, R.; Guzi, T.J. Discovery of pyrazolo[1,5-a]pyrimidine-based Pim inhibitors: A template-based approach. Bioorg. Med. Chem. Lett., 2013, 23, 6178-6182.
Xu, Y.; Brenning, B.G.; Kultgen, S.G.; Foulks, J.M.; Clifford, A.; Lai, S.; Chan, A.; Merx, S.; McCullar, M.V.; Kanner, S.B.; Ho, K-K. Synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective pim-1 inhibitors. Med. Chem. Lett., 2015, 6, 63-67.
Saikia, P.; Gogoi, S.; Boruah, R.C. Carbon–carbon bond cleavage reaction: Synthesis of multisubstituted pyrazolo[1,5-a] pyrimidines. J. Org. Chem., 2015, 80, 6885-6889.
Shekarrao, K.; Kaishap, P.P.; Saddanapu, V.; Addlagatta, A.; Gogoi, S.; Boruah, R.C. Microwave-assisted palladium mediated efficient synthesis of pyrazolo[3,4-b]pyridines, pyrazolo[3,4-b]quinolines, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]quinazolines. RSC Advances, 2014, 4, 24001-24006.
Zhang, X.; Song, Y.; Gao, L.; Guo, X.; Fan, X. Highly facile and regio-selective synthesis of pyrazolo[1,5-a]pyrimidines via reactions of 1,2-allenic ketones with aminopyrazoles. Org. Biomol. Chem., 2014, 12, 2099-2107.
Ghotekar, B.K.; Jachak, M.N.; Toche, R.B. New one-step synthesis of pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]quinazoline derivatives via multicomponent reactions. J. Heterocycl. Chem., 2009, 46, 708-713.
Rahmati, A. One-pot synthesis of 2-alkyl-7-amino-5-aryl-pyrazolo[1,5-a]pyrimidine-6-carbonitriles via a domino three-component condensation-oxidation reaction. C. R. Chim., 2012, 15, 647-652.
Kolosov, M.A.; Beloborodov, D.A.; Orlov, V.D.; Dotsenko, V.V. Catalyst-free Biginelli-type synthesis of new functionalized 4,7-dihydropyrazolo[1,5-a]pyrimidines. New J. Chem., 2016, 40, 7573-7579.
Marugan, J.J.; Southall, N.; Goldin, E.; Zheng, W.; Patnaik, S.; Sidransky, E.; Motabar, O.; Westbroek, W. Substituted pyrazolopyrimidines as glucocerebrosidase activators US, 2014. /0249145 A1.
Yamazaki, H.; Kuribayashi, S.; Inoue, T.; Tateno, C.; Nishikura, Y.; Oofusa, K.; Harada, D.; Naito, S.; Horie, T.; Ohta, S. Approach for in vivo protein binding of 5-n-butyl-pyrazolo[1,5-a]pyrimidine bioactivated in chimeric mice with humanized liver by two-dimensional electrophoresis with accelerator mass spectrometry. Chem. Res. Toxicol., 2010, 23(1), 152-158.
Brahmkshatriya, P.S.; Dobes, P.; Fanfrlik, J.; Rezac, J.; Paruch, K.; Bronowska, A.; Lepsík, M.; Hobza, P. Quantum mechanical scoring: structural and energetic insights into cyclin-dependent kinase 2 inhibition by pyrazolo[1,5-a]pyrimidines. Curr. Comput. Aided, Drug. Des., 2013, 9(1), 118-129.
Zhang, F.; Mi, Y.; Qi, J.L.; Li, J.W.; Si, M.; Guan, B.C.; Du, X.N.; An, H.L.; Zhang, H.L. Modulation of Kv7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin-7(4H)-one compound QO-58. Br. J. Pharmacol., 2013, 168(4), 1030-1042.
Popik, P.; Kostakis, E.; Krawczyk, M.; Nowak, G.; Szewczyk, B.; Krieter, P.; Chen, Z.; Russek, S.J.; Gibbs, T.T.; Farb, D.H.; Skolnick, P.; Lippa, A.S.; Basile, A.S. The anxioselective agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) is more efficacious than diazepam at enhancing GABA-Gated currents at α1 subunit-containing GABAA receptors. J. Pharmacol. Exp. Ther., 2007, 319(3), 1244-1252.
Ramaiah, M.J.; Pushpavalli, S.N.C.V.L.; Lavanya, A.; Bhadra, K.; Haritha, V.; Patel, N.; Tamboli, J.R.; Kamal, A.; Bhadra, U.; Pal-Bhadra, M. Novel anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates modulate the expression of p53-MYCN associated micro RNAs in neuroblastoma cells and cause cell cycle arrest and apoptosis. Bioorg. Med. Chem. Lett., 2013, 23(20), 5699-5706.
Qu, C.; Ding, M.; Zhu, Y.; Lu, Y.; Du, J.; Miller, M.; Tian, J.; Zhu, J.; Xu, J.; Wen, M.; Er-Bu, A.G.A.; Wang, J.; Xiao, Y.; Wu, M.; McManus, O.B.; Li, M.; Wu, J.; Luo, H-R.; Cao, Z.; Shen, B.; Wang, H.; Zhu, M.X.; Hong, X. Pyrazolopyrimidines as potent stimulators for transient receptor potential canonical 3/6/7 channels. J. Med. Chem., 2017, 60(11), 4680-4692.
Kuribayashi, S.; Goto, K.; Naito, S.; Kamataki, T.; Yamazaki, H. Human cytochrome P450 1A2 involvement in the formation of reactive metabolites from a species-specific hepatotoxic pyrazolopyrimidine derivative, 5-n-butyl-7-(3,4,5-trimethoxybenzoylamino) pyrazolo[1,5-a] pyrimidine. Chem. Res. Toxicol., 2009, 22(2), 323-331.
Portilla, J.; Estupiñan, D.; Cobo, J.; Glidewell, C. 7-Amino-5-methyl-2-phenyl-6-(phenyldiazenyl) pyrazolo[1,5-a]pyrimidine crystallizes with Z′ = 2: Pseudosymmetry and the formation of complex sheets built from N-H⋯N and C-H⋯π(arene) hydrogen bonds. Acta Crystallogr., 2010, C66, o133-o136.
Ivachtchenko, A.V.; Dmitriev, D.E.; Golovina, E.S.; Kadieva, M.G.; Koryakova, A.G.; Kysil, V.M.; Mitkin, O.D. okun, I.M.; Tkachenko, S.E.; Vorobiev, A.A. (3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines: Potent and selective antagonists of the serotonin 5-HT6 receptor. J. Med. Chem., 2010, 53, 5186-5196.
Hwang, J.Y.; Windisch, M.P.; Jo, S.; Kim, H.C.; Kim, S.; Kim, H.; Lee, M.E.; Park, D-S.; Park, E.; Ahn, S.; Cechetto, J.; Kim, J.; Liuzzi, M.; No, Z.; Lee, J. Discovery and characterization of a novel 7-aminopyrazolo[1,5-a]pyrimidine analog as a potent hepatitis C virus inhibitor. J. Bioorg. Med. Chem. Lett, 2012, 22, 7297-7301.
Ivashchenko, A.V.; Golovina, E.S.; Kadieva, M.G.; Kysil, V.M.; Mitkin, O.D.; Okun, I.M. Antagonists of serotonin 5-HT6 receptors. III. Pyridine-substituted 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidines: Synthesis and structure-activity relationship. Pharm. Chem. J., 2012, 46, 406-410.
Hanan, E.J.; van Abbema, A.; Barrett, K.; Blair, W.S.; Blaney, J.; Chang, C.; Eigenbrot, C.; Flynn, S.; Gibbons, P.; Hurley, C.A.; Kenny, J.R.; Kulagowski, J.; Lee, L.; Magnuson, S.R.; Morris, C.; Murray, J.; Pastor, R.M.; Rawson, T.; Siu, M.; Ultsch, M.; Zhou, A.; Sampath, D.; Lyssikatos, J.P. Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors. J. Med. Chem., 2012, 55, 10090-10107.
Lopez, L.C.; Dos-Reis, S.; Espargaro, A.; Carrodeguas, J.A.; Maddelein, M-L.S. Ventura, Sancho, J. Discovery of novel inhibitors of amyloid β-peptide 1-42 aggregation. J. Med. Chem., 2012, 55, 9521-9530.
Asano, T.; Yamazaki, H.; Kasahara, C.; Kubota, H.; Kontani, T.; Harayama, Y.; Ohno, K.; Mizuhara, H.; Yokomoto, M.; Misumi, K.; Kinoshita, T.; Ohta, M.; Takeuchi, M. Identification, synthesis, and biological evaluation of 6-[(6R)-2-(4-Fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyra-zolo[1,5-a]pyrimidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one (AS1940 477), a potent p38 MAP kinase inhibitor. J. Med. Chem., 2012, 55, 7772-7785.
Xu, J.; Liu, H.; Li, G.; He, Y.; Ding, R.; Wang, X.; Feng, M.; Zhang, S.; Chen, Y.; Li, S.; Zhao, M.; Li, Y.; Qi, C. Synthesis and biological evaluation of 7-(2-Chlorophenylamino)-5-((2[18F]fluoro-ethyoxy)methyl)pyra-zolo[1,5-a]pyrimidine -3-carbonitrile as PET tumor imaging agent. Naturforsch, 2012, 67B, 827-834.
Petek, N.; Štefane, B.; Novinec, M.; Svete, J. Synthesis and biological evaluation of 7-(aminoalkyl)pyrazolo[1,5-a]pyrimidine derivatives as cathepsin K inhibitors. Bioorg. Chem., 2018.
Labroli, M.; Paruch, K.; Dwyer, M.P.; Alvarez, C.; Keertikar, K.; Poker, C.; Rossman, R.; Fischmann, T.O.; Madison, V.; Parry, D.; Davis, N.; Seghezzi, W.; Wiswell, D.; Guzi, T.J. Discovery of pyrazolo[1,5-a] pyrimidine-based CHK1 inhibitors: A template-based approach-Part 2. Bioorg. Med. Chem. Lett., 2011, 21(1), 471-474.
Sun, L.; Gao, P.; Zhan, P.; Liu, X. Pyrazolo[1,5-a]pyrimidine-based macrocycles as novel HIV-1 inhibitors: A patent evaluation of WO2015123182. Expert Opin. Ther. Pat., 2016, 26, 979-986.
Childress, E.S.; Wieting, J.M.; Felts, A.S.; Breiner, M.M.; Long, M.F.; Luscombe, V.B.; Rodriguez, A.L.; Cho, H.P.; Blobaum, A.L.; Niswender, C.M.; Emmitte, K.A.; Jeffrey Conn, P.; Lindsley, C.W. Discovery of novel central nervous system penetrant metabotropic glutamate receptor subtype 2 (mGlu) negative allosteric modulators (NAMs) based on functionalized Pyrazolo[1,5-a]pyrimidine-5-carboxamide and thieno[3,2-b] pyridine-5-carboxamide cores. J. Med. Chem., 2018, 62, 378-384.
Liu, Y.; Laufer, R.; Patel, N.K.; Ng, G.; Sampson, P.B.; Li, S-W.; Lang, Y.; Feher, M.; Brokx, R.; Beletskaya, I.; Hodgson, R.; Plotnikova, O.; Awrey, D.E.; Qiu, W.; Chirgadze, N.Y.; Mason, J.M.; Wei, X.; Lin, D.C-C.; Che, Y.; Kiarash, R.; Fletcher, G.C.; Mak, T.W.; Bray, M.R.; Pauls, H.W. Discovery of Pyrazolo[1,5-a]pyrimidine TTK inhibitors: CFI-402257 is a Potent, selective, bioavailable anticancer agent. ACS Med. Chem. Lett., 2016, 7(7), 671-675.
Dowling, J.E.; Alimzhanov, M.; Bao, L. H.M.; Block, Chuaqui, C.; Cooke, E.L.; Denz, C.R.; Hird, A.; Huang, S.; Larsen, N.A.; Peng, B.; Pontz, T.W.; Rivard-Costa, C.; Saeh, J.C.; Thakur, K.; Ye, Q.; Zhang, T.; Lyne, P.D.; Structure and property based design of pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 kinase with activity in vivo. ACS Med. Chem. Lett., 2013, 4(8), 800-805.
Lim, J.; Altman, M.D.; Baker, J.; Brubaker, J.D.; Chen, H.; Chen, Y.; Fischmann, T.; Gibeau, C.; Kleinschek, M.A.; Leccese, E.; Lesburg, C.; Maclean, J.K.F.; Moy, L.Y.; Mulrooney, E.F.; Presland, J.; Rakhilina, L.; Smith, G.F.; Steinhuebel, D.; Yang, R. Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4. ACS Med. Chem. Lett., 2015, 6(6), 683-688.
Kumar, A.K.; Nair, K.B.; Bodke, Y.D. Design, synthesis, and evaluation of the anticancer properties of a novel series of carboxamides, sulfonamides, ureas, and thioureas derived from 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl substituted with pyrazolo[1,5-a]pyrimidine derivatives. Monatsh. Chem., 2016, 147, 2221-2234.
Ren, L.; Laird, E.R.; Buckmelter, A.J.; Dinkel, V.; Gloor, S.L.; Grina, J.; Newhouse, B.; Rasor, K.; Hastings, G.; Gradl, S.N.; Rudolph, J. Potent and selective pyrazolo[1,5-a]pyrimidine based inhibitors of B-RafV600E kinase with favorable physicochemical and pharmacokinetic properties. Bioorg. Med. Chem. Lett., 2012, 22(2), 151165-151168.

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Year: 2019
Page: [721 - 743]
Pages: 23
DOI: 10.2174/1385272823666190410145238
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