(19) TZZ_¥¥Z_T (11) EP 1 363 705 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61P 31/18 (2006.01) A61P 31/12 (2006.01) 13.06.2012 Bulletin 2012/24 A61K 31/496 (2006.01) A61K 31/501 (2006.01) A61K 31/53 (2006.01) A61K 31/506 (2006.01) (2006.01) (2006.01) (21) Application number: 02707413.7 C07D 401/14 C07D 403/14 C07D 241/02 (2006.01) C07D 253/08 (2006.01) C07D 251/02 (2006.01) C07D 241/36 (2006.01) (22) Date of filing: 02.01.2002 C07D 471/02 (2006.01) (86) International application number: PCT/US2002/000455 (87) International publication number: WO 2002/062423 (15.08.2002 Gazette 2002/33) (54) COMPOSITION AND ANTIVIRAL ACTIVITY OF SUBSTITUTED AZAINDOLEOXOACETIC PIPERAZINE DERIVATIVES ZUSAMMENSETZUNG UND ANTIVIRALE WIRKUNG SUBSTITUIERTER AZAINDOLOXOESSIGSÄUREPIPERAZIN- DERIVATIVE COMPOSITION ET ACTIVITE ANTIVIRALE DE DERIVES DE PIPERAZINE AZAINDOLEOXOACETIQUE SUBSTITUES (84) Designated Contracting States: • KADOW, John, F. AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Wallingford, CT 06492 (US) MC NL PT SE TR • YIN, Zhiwei Designated Extension States: Meriden, CT 06450 (US) AL LT LV MK RO SI (74) Representative: Reitstötter - Kinzebach (30) Priority: 02.02.2001 US 266183 P Patentanwälte 23.08.2001 US 314406 P Postfach 86 06 49 81633 München (DE) (43) Date of publication of application: 26.11.2003 Bulletin 2003/48 (56) References cited: WO-A1-00/76521 WO-A1-01/62255 (73) Proprietor: Bristol-Myers Squibb Company WO-A1-02/04440 WO-A1-96/11929 Princeton NJ 08543-4000 (US) • WANG TAO ET AL: "Discovery of 4-benzoyl-1-[(4- (72) Inventors: methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)o • WANG, Tao xoacetyl]-2- (R)-methylpiperazine (BMS-378806): Middletown, CT 06457 (US) a novel HIV-1 attachment inhibitor that interferes • ZHANG, Zhongxing with CD4-gp120 interactions." JOURNAL OF Madison, CT 06443 (US) MEDICINAL CHEMISTRY 25 SEP 2003, vol. 46, no. • MEANWELL, Nicholas, A. 20, 25 September 2003 (2003-09-25), pages East Hampton, CT 06424 (US) 4236-4239, XP002533377 ISSN: 0022-2623 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 363 705 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 363 705 B1 Description REFERENCE TO RELATED APPLICATIONS 5 [0001] This application claims the benefit of U.S. Provisional Application Serial Numbers 60/314,406 filed August 23, 2001 and 60/266,183 filed February 2, 2001. BACKGROUND OF THE INVENTION 10 Field of the Invention [0002] This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with azaindole piperazine diamide derivatives that possess unique antiviral activity. More particularly, the present invention relates to compounds useful for the treatment of HIV 15 and AIDS. Background Art [0003] HIV-1 (human immunodeficiency virus -1) infection remains a major medical problem, with an estimated 33.6 20 million people infected worldwide. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 1999, 5.6 million new infections were reported, and 2.6 million people died from AIDS. Currently available drugs for the treatment of HIV include six nucleoside reverse transcriptase (RT) inhibitors (zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir), three non-nucleoside reverse transcriptase inhibitors (nevirapine, de- lavirdine and efavirenz), and six peptidomimetic protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, amprenavir 25 and lopinavir). Each of these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs have a profound effect on viremia and disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented as a consequence of the widespread application of combination therapy. However, despite these impressive results, 30 to 50% of patients ultimately fail combination drug therapies. Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within 30 certain cell types (e.g. most nucleoside analogs cannot be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when sub- optimal drug concentrations are present (Larder and Kemp; Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al; Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref. 6-14)). Therefore, novel anti-HIV agents exhibiting distinct resistance 35 patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options. [0004] Currently marketed HIV-1 drugs are dominated by either nucleoside reverse transcriptase inhibitors or pepti- domimetic protease inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recently gained an in- creasingly important role in the therapy of HIV infections (Pedersen & Pedersen, Ref 15). At least 30 different classes of NNRTI have been described in the literature (De Clercq, Ref. 16) and several NNRTIs have been evaluated in clinical 40 trials. Dipyridodiazepinone (nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazine derivatives (delavir- dine) have been approved for clinical use. However, the major drawback to the development and application of NNRTIs is the propensity for rapid emergence of drug resistant strains, both in tissue cell culture and in treated individuals, particularly those subject to monotherapy. As a consequence, there is considerable interest in the identification of NNRTIs less prone to the development of resistance (Pedersen & Pedersen, Ref 15). 45 [0005] Several indole derivatives including indole-3-sulfones, piperazino indoles, pyrazino indoles, and 5H-indolo[3,2- b][1,5]benzothiazepine derivatives have been reported as HIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1; Williams et al, Ref. 2; Romero et al, Ref. 3; Font et al, Ref. 17; Romero et al, Ref. 18; Young et al, Ref. 19; Genin et al, Ref. 20; Silvestri et al, Ref. 21). Indole 2-carboxamides have also been described as inhibitors of cell adhesion and HIV infection (Boschelli et al, US 5,424,329, Ref. 4). Finally, 3-substituted indole natural products (Semicochliodinol A and 50 B, didemethylasterriquinone and isocochliodinol) were disclosed as inhibitors of HIV-1 protease (Fredenhagen et al, Ref. 22). Other indole derivatives exhibiting antiviral activity useful for treating HIV are disclosed in PCT WO 00/76521 (Ref. 93). Also, indole derivatives are disclosed in PCT WO 00/71535 (Ref. 94). [0006] Structurally related aza-indole amide derivatives have been disclosed previously (Kato et al, Ref. 23; Levacher et al, Ref. 24; Dompe Spa, WO-09504742, Ref. 5(a); SmithKline Beecham PLC, WO-09611929, Ref. 5(b); Schering 55 Corp., US-05023265, Ref. 5(c)). However, these structures differ from those claimed herein in that they are aza-indole mono-amide rather than unsymmetrical aza-indole piperazine diamide derivatives, and there is no mention of the use of these compounds for treating viral infections, particularly HIV. Other azaindoles have been also disclosed by Wang et al, Ref. 95. Nothing in these references can be construed to disclose or suggest the novel compounds of this invention 2 EP 1 363 705 B1 and their use to inhibit HIV infection. REFERENCES CITED 5 Patent documents [0007] 1. Greenlee, W.J.; Srinivasan, P.C. Indole reverse transcriptase inhibitors. U.S. Patent 5,124,327. 10 2. Williams, T.M.; Ciccarone, T.M.; Saari, W. S.; Wai, J.S.; Greenlee, W.J.; Balani, S.K.; Goldman, M.E.; Theohrides, A.D. Indoles as inhibitors of HIV reverse transcriptase. European Patent 530907. 3. Romero, D.L.; Thomas, R.C.; Preparation of substituted indoles as anti-AIDS pharmaceuticals. PCT WO 93 15 /01181. 4. Boschelli, D.H.; Connor, D.T.; Unangst, P.C. Indole-2-carboxamides as inhibitors of cell adhesion. U.S. Patent 5,424,329. 20 5. (a) Mantovanini, M.; Melillo, G.; Daffonchio, L. Tropyl 7-azaindol-3-ylcarboxyamides as antitussive agents. PCT WO 95/04742 (Dompe Spa). (b) Cassidy, F.; Hughes, I.; Rahman, S.; Hunter, D. J. Bisheteroaryl-carbonyl and carboxamide derivatives with 5HT 2C/2B antagonists activity. PCT WO 96/11929. (c) Scherlock, M. H.; Tom, W. C. Substituted 1H-pyrrolopyridine-3-carboxamides. U. S. Patent 5,023,265. 25 Other Publications [0008] 6. Larder, B.A.; Kemp, S.D. Multiple mutations in the HIV-1 reverse transcriptase confer high-level resistance to 30 zidovudine (AZT). Science, 1989, 246,1155-1158. 7. Gulick, R.M. Current antiretroviral therapy: An overview. Quality of Life Research, 1997, 6, 471-474. 8. Kuritzkes, D.R. HIV resistance to current therapies. Antiviral Therapy, 1997, 2 (Supplement 3), 61-67. 35 9. Morris-Jones, S.; Moyle, G.; Easterbrook, P.J. Antiretroviral therapies in HIV-1 infection. Expert Opinion on Investigational Drugs, 1997, 6(8),1049-1061. 10. Schinazi, R.F.; Larder, B.A.; Mellors, J.W. Mutations in retroviral genes associated with drug resistance. Inter- 40 national Antiviral News, 1997, 5,129-142,. 11. Vacca, J.P.; Condra, J.H. Clinically effective HIV-1 protease inhibitors. Drug Discovery Today, 1997, 2, 261-272. 12. Flexner, D. HIV-protease inhibitors. Drug Therapy, 1998, 338, 1281-1292. 45 13. Berkhout, B. HIV-1 evolution under pressure of protease inhibitors: Climbing the stairs of viral fitness. J. Biomed. Sci., 1999, 6, 298-305. 14. Ren, S.; Lien, E.