Journal of the American Chemical Society
Article
(5) This inhibitor is relevant to treating obesity, diabetes, stress, and
alcoholism. NPY is the most abundant peptide present in the
mammalian central nervous system; for critical reviews on NPY, see:
Reichmann, F.; Holzer, P. Neuropeptides 2016, 55, 99−109.
(6) Kotian, P. L.; Babu, Y. S.; Kumar, V. S.; Zhang, W.; Vogeti, L.
Preparation of pyrrolidinecarboxamide derivatives as human plasma
kallikrein inhibitors. Patent WO 2017059178 A1, April 6, 2017.
(7) Human plasma kallikrein inhibitors are relevant to treating
cardiovascular diseases: Bryant, J. W.; Shariat-Madar, Z. Human
plasma kallikrein-kinin system: Physiological and biochemical
parameters. Cardiovasc. Hematol. Agents Med. Chem. 2009, 7, 234−
250.
(8) (a) Minatti, A. E.; Cheng, Y.; Zhong, W. Preparation of
pyridinylspirochromenopyridineiosindolamine derivatives and analogs
for use as beta-secretase modulators. Patent WO 2012019056 A1,
February 9, 2012. (b) Minatti, A. E.; Cheng, Y.; Zhong, W.
Derivatives of 1 H-isoindol-3-amine, 1 H-iso-aza-indol-3amine, 3,4-
dihydroisoquinolin-1-amine, and 1,4-dihydroisoquinolin-3-amine as
beta-secretase inhibitors. U.S. Patent US 8921363 B2, December 30,
2014.
(9) BACE 1 inhibitors are potentially relevant to treating
Alzheimer’s disease: Vassar, R.; Bennett, B. D.; Babu-Khan, S.;
Kahn, S.; Mendiaz, E. A.; Denis, P.; Teplow, D. B.; Ross, S.;
Amarante, P.; Loeloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.;
Lile, J.; Jarosinski, M. A.; Biere, A. L.; Curran, E.; Burgess, T.; Louis, J.
C.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M. Beta-secretase
cleavage of Alzheimer’s amyloid precursor protein by the trans-
membrane aspartic protease BACE. Science 1999, 286, 735−741.
(10) Biswas, K.; Brown, J.; Chen, J. J.; Gore, V. K.; Harried, S.;
Horne, D. B.; Kaller, M. R.; Ma, V. V.; Nguyen, T. T.; Sham, K.;
Zhong, W. Chroman derivatives as TRPM8 inhibitors and their
preparation. Patent WO 2014025651 A1, February 13, 2014.
(11) Hu, Y.; Cai, D.; Zhu, J.; Dong, P.; Li, M.; Greenman, K. L.;
Dong, J.; Wang, T.-L. Aromatic ring-containing compound,
preparation method therefor, pharmaceutical composition, and use.
Patent WO 2018130227 A1, July 19, 2018.
(21) For analysis of heterocycles in drugs, see: (a) Taylor, R. D.;
MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845−5859.
(b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med.
Chem. 2014, 57, 10257−10274.
(22) For selected examples, see: (a) Marzo, L.; Pagire, S. K.; Reiser,
̈
O.; Konig, B. Visible-Light Photocatalysis: Does It Make a Difference
in Organic Synthesis? Angew. Chem., Int. Ed. 2018, 57, 10034−10072.
(b) Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.;
MacMillan, D. W. C. Science 2016, 352, 1304−1308. (c) Jain, P.;
Verma, P.; Xia, G.; Yu, J.-Q. Enantioselective amine α-functionaliza-
tion via palladium-catalysed C−H arylation of thioamides. Nat. Chem.
2017, 9, 140−144. (d) Lei, Y.; Yang, J.; Qi, R.; Wang, S.; Wang, R.;
Xu, Z. Arylation of benzyl amines with aromatic nitriles. Chem.
Commun. 2018, 54, 11881−11884. (e) Patel, N. R.; Kelly, C. B.;
Siegenfeld, A. P.; Molander, G. A. Mild, Redox-Neutral Alkylation of
Imines Enabled by an Organic Photocatalyst. ACS Catal. 2017, 7,
1766−1770. (f) Remeur, C.; Kelly, C. B.; Patel, N. R.; Molander, G.
A. Aminomethylation of Aryl Halides Using α-Silylamines Enabled by
Ni/Photoredox Dual Catalysis. ACS Catal. 2017, 7, 6065−6069.
(23) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913−9914. (b) Robak, M. T.; Herbage, M. A.; Ellman, J. A.
Chem. Rev. 2010, 110, 3600−3740.
(24) For reviews on atom economy, minimizing step count and
redox manipulations, and avoiding protecting groups in synthesis, see:
(a) Trost, B. M. On Inventing Reactions for Atom Economy. Acc.
Chem. Res. 2002, 35, 695−705. (b) Gaich, T.; Baran, P. S. Aiming for
the Ideal Synthesis. J. Org. Chem. 2010, 75, 4657−4673. (c) Burns, N.
Z.; Baran, P. S.; Hoffmann, R. W. Redox Economy in Organic
Synthesis. Angew. Chem., Int. Ed. 2009, 48, 2854−2867. (d) New-
house, T.; Baran, P. S.; Hoffmann, R. W. The economies of synthesis.
Chem. Soc. Rev. 2009, 38, 3010−3021. (e) Young, I. S.; Baran, P. S.
Protecting-group-free synthesis as an opportunity for invention. Nat.
Chem. 2009, 1, 193−205.
(25) For selected examples, see: (a) Koos, M.; Mosher, H. S. α-
Amino-α-trifluoromethyl-phenylacetonitrile: A potential reagent for
19F NMR determination of enantiomeric purity of acids. Tetrahedron
1993, 49, 1541. (b) Rassukana, Y. V. Methyl α-Iminotrifluoropropi-
onate: A Novel Convenient Building Block for the Preparation of
Functionalized Derivatives Bearing a Trifluoroalanine Residue.
Synthesis 2011, 2011, 3426. (c) Rassukana, Y. V.; Yelenich, I. P.;
Synytsya, A. D.; Onys’ko, P. P. Fluorinated NH-iminophosphonates
and iminocarboxylates: novel synthons for the preparation of
biorelevant α-aminophosphonates and carboxylates. Tetrahedron
2014, 70, 2928. (d) Morisaki, K.; Morimoto, H.; Ohshima, T. Direct
access to N-unprotected tetrasubstituted propargylamines via direct
catalytic alkynylation of N-unprotected trifluoromethyl ketimines.
Chem. Commun. 2017, 53, 6319−6321. (e) Yonesaki, R.; Kondo, Y.;
Akkad, W.; Sawa, M.; Morisaki, K.; Morimoto, H.; Ohshima, T. 3-
Mono-Substituted BINOL Phosphoric Acids as Effective Organo-
catalysts in Direct Enantioselective Friedel−Crafts-Type Alkylation of
N-Unprotected α-Ketiminoester. Chem. - Eur. J. 2018, 24, 15211−
15214. (f) Sawa, M.; Miyazaki, S.; Yonesaki, R.; Morimoto, H.;
Ohshima, T. Catalytic Enantioselective Decarboxylative Mannich-
Type Reaction of N-Unprotected Isatin-Derived Ketimines. Org. Lett.
2018, 20, 5393−5397.
(12) TRPM8 inhibitors are relevant to treating migraines and
neuropathic pain: (a) Andersen, H.H.; Olsen, R.V.; Møller, H.G.;
Eskelund, P.W.; Gazerani, P.; Arendt-Nielsen, L. A review of topical
high-concentration L-menthol as a translational model of cold
allodynia and hyperalgesia. Eur. J. Pain 2014, 18, 315−325.
(13) Salvati, M. E.; Finlay, H.; Harikrishnan, L. S.; Jiang, J.; Johnson,
J. A.; Kamau, M. G.; Lawrence, R. M.; Miller, M. M.; Qiao, J. X.;
Wang, T. C.; Wang, Y.; Yang, W. Preparation of heterocyclic and
aromatic ureas and amides as CETP inhibitors. Patent WO
2007062314 A2, May 31, 2007.
(14) CETP inhibitors are relevant to treating cardiovascular
diseases: (a) Tall, A. R.; Rader, D. J. Trials and Tribulations of
CETP Inhibitors. Circ. Res. 2018, 122, 106−112. (b) Tall, A. R.
CETP inhibitors to increase HDL cholesterol levels. N. Engl. J. Med.
2007, 356, 1364−1366.
(15) Dally, R. D.; Woods, T. A. Preparation of isoindolinone
compounds as CDC7 inhibitors in treating cancer. Patent WO
2014143601 A1, September 18, 2014.
(16) CDC7 inhibitors are relevant to treating cancer: Montagnoli,
A.; Moll, J.; Colotta, F. Targeting Cell Division Cycle 7 Kinase: A
New Approach for Cancer Therapy. Clin. Cancer Res. 2010, 16,
4503−4508.
(17) Hough, T. L.; Gates, P. S. Pyrimidine derivative herbicides.
Patent WO 9405644 A1, March 17, 1994.
(26) Wu, Y.; Hu, L.; Li, Z.; Deng, L. Catalytic asymmetric umpolung
reactions of imines. Nature 2015, 523, 445−450.
(27) (a) Sun, Z.-M.; Chen, S.-P.; Zhao, P. Tertiary Carbinamine
Synthesis by Rhodium-Catalyzed [3 + 2] Annulation of N-
Unsubstituted Aromatic Ketimines and Alkynes. Chem. - Eur. J.
2010, 16, 2619−2627. (b) Tran, D. N.; Cramer, N. syn-Selective
Rhodium(I)-Catalyzed Allylations of Ketimines Proceeding through a
Directed CH Activation/Allene Addition Sequence. Angew. Chem.,
Int. Ed. 2010, 49, 8181−8184. (c) Tran, D. N.; Cramer, N.
Enantioselective Rhodium(I)-Catalyzed [3 + 2] Annulations of
Aromatic Ketimines Induced by Directed CH Activations. Angew.
Chem., Int. Ed. 2011, 50, 11098−11102. (d) Zhang, J.; Ugrinov, A.;
̌
̌
́
̌
̌
́
(18) Budesínsky, Z.; Vavrina, J.; Langsadl, L.; Holubek, J. On the
synthesis of 4- and 5-pyrimidinyl-diphenyl-(1-imidazolyl)methanes
and their antifungal activity. Collect. Czech. Chem. Commun. 1980, 45,
539−547.
(19) Kraehmer, H.; Laber, B.; Rosinger, C.; Schulz, A. Herbicides as
Weed Control Agents: State of the Art: I. Weed Control Research and
Safener Technology: The Path to Modern Agriculture. Plant Physiol.
2014, 166, 1119−1131.
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