202
K.-S. Yeung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 198–202
6. Part 1: (a) Wang, T.; Zhang, Z.; Wallace, O. B.; Deshpande, M.; Fang, H.; Yang, Z.;
Zadjura, L. M.; Tweedie, D. L.; Huang, S.; Zhao, F.; Ranadive, S.; Robinson, B. S.;
Gong, Y.-F.; Ricarrdi, K.; Spicer, T. P.; Deminie, C.; Rose, R.; Wang, H.-G. H.; Blair,
W. S.; Shi, P.-Y.; Lin, P.-F.; Colonno, R. J.; Meanwell, N. A. J. Med. Chem. 2003, 46,
4236; Part 2: (b) Meanwell, N. A.; Wallace, O. B.; Fang, H.; Wang, H.;
Deshpande, M.; Wang, T.; Yin, Z.; Zhang, Z.; Pearce, B. C.; James, J.; Yeung, K.-S.;
Qiu, Z.; Wright, J. J. K.; Yang, Z.; Zadjura, L.; Tweedie, D. L.; Yeola, S.; Zhao, F.;
Ranadive, S.; Robinson, B. A.; Gong, Y.-F.; Wang, H.-G. H.; Blair, W. S.; Shi, P.-Y.;
Colonno, R. J.; Lin, P.-F. Bioorg. Med. Chem. Lett. 2009, 19, 1977; Part 3: (c)
Meanwell, N. A.; Wallace, O. B.; Wang, H.; Deshpande, M.; Pearce, B. C.; Trehan,
A.; Yeung, K.-S.; Qiu, Z.; Wright, J. J. K.; Robinson, B. A.; Gong, Y.-F.; Wang, H.-G.
H.; Blair, W. S.; Shi, P.-Y.; Lin, P.-F. Bioorg. Med. Chem. Lett. 2009, 19, 5136; Part
4: (d) Wang, T.; Kadow, J. F.; Zhang, Z.; Yin, Z.; Gao, Q.; Wu, D.; Digiugno Parker,
D.; Yang, Z.; Zadjura, L.; Robinson, B. A.; Gong, Y.-F.; Blair, W. S.; Shi, P.-Y.;
Yamanaka, G.; Lin, P.-F.; Meanwell, N. A. Bioorg. Med. Chem. Lett. 2009, 19, 5140;
Part 5: (e) Wang, T.; Yin, Z.; Zhang, Z.; Bender, J. A.; Yang, Z.; Johnson, G.; Yang,
Z.; Zadjura, L. M.; D’Arienzo, C. J.; Parker, D. D.; Gesenberg, C.; Yamanaka, G. A.;
Gong, Y.-F.; Ho, H.-T.; Fang, H.; Zhou, N.; McAuliffe, B. V.; Eggers, B. J.; Fan, L.;
Nowicka-Sans, B.; Dicker, I. B.; Gao, Q.; Colonno, R. J.; Lin, P-F.; Meanwell, N. A.;
Kadow, J. F. J. Med. Chem. 2009, 52, 7778; Part 6: (f) Kadow, J. F.; Ueda, Y.;
Meanwell, N. A.; Connolly, T. P.; Wang, T.; Chen, C.-P.; Yeung, K.-S.; Zhu, J.;
Bender, J. A.; Yang, Z.; Parker, D.; Lin, P.-F.; Colonno, R. J.; Mathew, M.; Morgan,
D.; Zheng, M.; Chien, C.; Grasela, D. J. Med. Chem. 2012, 55, 2048.
7. Hanna, G. J.; Lalezari, J.; Hellinger, J. A.; Wohl, D. A.; Nettles, R.; Persson, A.;
Krystal, M.; Lin, P.; Colonno, R.; Grasela, D. M. Antimicrob. Agents Chemother.
2011, 55, 722.
8. (a) Nettles, R.; Schurmann, D.; Zhu, L.; Stonier, M.; Huang, S.-P.; Chien, C.;
Krystal, M.; Wind-Rotolo, M.; Bertz, R.; Grasela, D. 18th Conference Retroviruses
Opportunistic Infections, Boston, MA, February 27–March 2, 2011, Abstract 49.;
(b) Nettles, R.; Schürmann, D.; Zhu, L.; Stonier, M.; Huang, S.-P.; Chang, I.;
Chien, C.; Krystal, M.; Wind-Rotolo, M.; Ray, N.; Hanna, G. J.; Bertz, R.; Grasela,
D. J. Infect. Dis. 2012, 206, 1002.
9. Kadow, J. F.; Ueda, Y.; Connolly, T. P.; Wang, T.; Chen, C. P.; Yeung, K. -S.;
Bender, J.; Yang, Z.; Zhu, J.; Matiskella, J.; Regueiro-Ren, A.; Yin, Z.; Zhang, Z.;
Farkas, M.; Yang, X.; Wong, H.; Smith, D.; Raghaven, K. S.; Pendri, Y.; Staab, A.;
Soundararajan, N.; Meanwell, N.; Zheng, M.; Parker, D. D.; Adams, S.; Ho, H-T.;
Yamanaka, G.; Nowicka-Sans, B.; Eggers, B.; McAuliffe, B.; Fang, H.; Fan, L.;
Zhou, N.; Gong, Y.-F.; Colonno, R. J.; Lin, P.-F.; Brown, J.; Grasela, D. M.; Chen, C.;
Nettles, R. E. 241st ACS National Meeting & Exposition, Anaheim, CA, United
States, March 27–31, 2011, MEDI 29.
ability which translated into favorable pharmacokinetic properties
in rat, dog and monkey. The insight that the intramolecular hydro-
gen bonding-stabilized, coplanar conformation of the secondary
methyl amide 4 apparently contributed to the dramatic increase
in potency compared to the dimethyl amide 5 was subsequently
assimilated into the design of second generation inhibitors in
related heterocycle core series. That work ultimately led to the
identification of BMS-626529,
a 6-azaindole analog that is
currently in clinical studies as the phosphonoxymethyl prodrug,
BMS-663068.8,9
Chemistry
The synthesis of the methyl amide 4 is depicted in Scheme 1.
Cyanation of 7-bromo-4-fluoroindole 40 was followed by hydro-
lytic conversion of the 7-cyanoindole 41 to the methyl ester 42.
Installation of the diketo moiety on 42 by a Friedel–Crafts acylation
using oxalyl chloride provided the acid chloride 43, which was cou-
pled with benzoylpiperazine to form the penultimate intermediate
44. Direct conversion of the 7-methyl ester to the methylamide
was achieved by using 40% aqueous methylamine to furnish analog
4. Basic hydrolysis of the methyl ester 44 gave the pivotal acid 45,
which was coupled with various amines under common amide
coupling conditions to provide the C7-carboxamide analogs ( 3–
20 and27–39) in Tables 2 and 4, as previously described.14 Analogs
21–26 in Table 3 were prepared in a similar manner.
References and notes
1. De Clercq, E. Int. J. Antimicrob. Agents 2009, 33, 307.
2. Taiwo, B.; Hicks, C.; Eron, J. J. Antimicrob. Chemother. 2010, 65, 1100.
3. Mehellou, Y.; De Clercq, E. J. Med. Chem. 2010, 53, 521.
10. Doms, R. W.; Trono, D. Genes Dev. 2000, 14, 2677.
11. The EC50 for inhibition of the single cycle infectivity assay against HIV JRFL
pseudotyped virus and the CC50 of the inhibitors were determined previously
as described in Ref. 5. The data reported are the mean of two or more
experiments.
4. Kadow, J. F.; Wang, H.-G. H.; Lin, P.-F. Curr. Opin. Invest. Drugs 2006, 7, 721.
5. (a) Lin, P.-F.; Blair, W.; Wang, T.; Spicer, T.; Guo, Q.; Zhou, N.; Gong, Y.-F.; Wang,
H.-G. H.; Rose, R.; Yamanaka, G.; Robinson, B.; Li, C.-B.; Fridell, R.; Deminie, C.;
Demers, G.; Zhang, Z.; Zadjura, L.; Meanwell, N.; Colonno, R. Proc. Natl. Acad. Sci.
U.S.A. 2003, 100, 11013; (b) Ho, H.-T.; Fan, L.; Nowicka-Sans, B.; McAuliffe, B.;
Li, C.-B.; Yamanaka, G.; Zhou, N.; Fang, H.; Dicker, I.; Dalterio, R.; Gong, Y.-F.;
Wang, T.; Yin, Z.; Ueda, Y.; Matiskella, J.; Kadow, J.; Clapham, P.; Robinson, J.;
Colonno, R.; Lin, P.-F. J. Virol. 2006, 80, 4017.
12. Kuhn, B.; Mohr, P.; Stahl, M. J. Med. Chem. 2010, 53, 2601.
13. The resolution of this issue will be the subject of a separate report.
14. Wallace, O. B.; Wang, T.; Yeung, K.-S.; Pearce, B. C.; Meanwell, N. A.; Qiu, Z.;
Fang, H.; Xue, Q. M.; Yin Z. U.S. Patent 6,573,262, June 3, 2003.