USOO7915283B2 (12) United States Patent (10) Patent No.: US 7,915,283 B2 Wang et al. (45) Date of Patent: *Mar. 29, 2011 (54) INDOLE, AZAINDOLE AND RELATED W W g ? 2. 4. 12: HETEROCYCLIC 4-ALKENYL PPERDINE WO WO 98.28292 7, 1998 AMIDES WO WOO2.04440 1, 2002 WO WO O2/O62423 8, 2002 (75) Inventors: Tao Wang, Farmington, CT (US); John F. Kadow, Wallingford, CT (US); OTHER PUBLICATIONS Nhel R St. Ret M. Font, et al., “Indoles and Pyridazino4,5-b]Indoles as Non (U ); ap. un Yeung, a. 1SOn, nucleoside Analog Inhibitors of HIV-1 Reverse Transcriptase.” Eur, (US). Zhongxing Zhang, Madison, CT J. Med. Chem., 30, pp.963-971, 1995. (US); Zhiwei Yin, Glastonbury, CT D.L. Romero, et al., J. Med. Chem., 36, pp. 1505-1508, 1993. (US); Zhilei Qui, Parsippany, NJ (US); S.D. Young, et al., “2-Heterocyclic indole-3-Sulfones as Inhibitors of Daniel H. Deon, Candiac (CA); Clint A. HIV-1 Reverse Transcriptase.” Bioorganic & Medicinal Chemistry James, Laprairie (CA); Edward H. Letters, 5(5), pp. 491–496, 1995. Ruediger, Greenfield Park (CA); Carol MJ . Genin, et al., “Synthesis and Bioactivity of Novel Bachand, Candiac (CA) Bis(Heteroaryl)Piperazine (BHAP) Reverse Transcriptase Inhibi s tors: Structure-Activity Relationships and Increased Metabolic Sta (73) Assignee: Bristol-Myers Squibb Company, by Nesbstituted Pyridine Analogs,” J. Med. Chem, 39, pp. Princeton, NJ (US) R. Silvestri, et al., Antiviral Chemistry & Chemotherapy, 9, pp. 139-148, 1998. (*) Notice: Subject to any disclaimer, the term of this A. Fredenhagen, et al., "Semicochiliodinol A and B: Inhibitors of patent is extended or adjusted under 35 HIV-1 Protease and EGF-RProtein Tyrosine Kinase Related to Aster U.S.C. 154(b) by 532 days. riquinones Produced by the Fungus Chrysosporium merdarium.” This patent is Subject to a terminal dis- Journal of Antibiotics, 50(5), pp. 395-401, 1997. claimer M. Kato, et al., “New 5-HT (Serotonin-3) Receptor Antagonists. IV. Synthesis and Structure-Activity Relationships of Azabicycloalkaneacetamide Derivatives.” Chem. Pharm. Bull. (21) Appl. No.: 12/015,767 43(8), pp. 1351-1357, 1995. V. Levacher, et al., "Broadening in the Scope of NADH Models by (22) Filed: Jan. 17, 2008 Using Chiral and Non-Chiral Pyrrolo 2,3-bPyridine Derivatives.” Tetrahedron, 47(3), pp. 429-440, 1991. (65) Prior Publication Data US 2008/O188481 A1 Aug. 7, 2008 * cited by examiner Related U.S. Application Data Primary Examiner — Bernard Dentz (60) Division of application No. 10/762,108, filed on Jan. (74) Attorney, Agent, or Firm — John F. Levis 21, 2004, now Pat. No. 7,348,337, which is a continuation-in-part of application No. 107425,370, (57) ABSTRACT filed on Apr. 29, 2003, now abandoned. (60) Provisional application No. 60/383,509, filed on May This invention provides compounds having drug and bio 28, 2002 affecting properties, their pharmaceutical compositions and s method of use. In particular, the invention is concerned with (51) Int. Cl. new piperidine 4-alkenyl derivatives that possess unique anti A6 IK3 L/454 (2006.01) viral activity. More particularly, the present invention relates A6 IK3 L/4545 (2006.01) to compounds useful for the treatment of HIV and AIDS. The (52) U.S. Cl. ........................................ 514/300: 514/323 COmpoundSpounds ofOf ththe 1nVent1On forOr the general FormulaFormula: I (58) Field of Classification Search .................. 514/300, 514/323 (I) See application file for complete search history. Zn W (56) References Cited U.S. PATENT DOCUMENTS wherein: 5,023,265 A 6/1991 Scherlocket al. Z is 5,124,327 A 6, 1992 Greenlee et al. 5,424,329 A 6, 1995 Boschelli et al. 6,469,006 B1 10/2002 Blair et al. O 6,476,034 B2 11/2002 Wang et al. 6,573,262 B2 6, 2003 Wallace et al. 7,348,337 B2 * 3/2008 Wang et al. ................... 514,300 Q FOREIGN PATENT DOCUMENTS EP O530907 A1 3, 1993 WO WO 93.01181 1, 1993 WO WO95/04742 2, 1995 Q is selected from the group consisting of: US 7,915,283 B2 Page 2 -continued —W– is R7 Riis P R16 R15 21 NA N R22 R19 R20 R21 18 Claims, No Drawings US 7,915,283 B2 1. 2 INDOLE, AZAINDOLE AND RELATED Ren et al: (Ref. 6-14)). Therefore, novel anti-HIV agents HETEROCYCLIC 4-ALKENYL PPERDINE exhibiting distinct resistance patterns, and favorable pharma AMIDES cokinetic as well as safety profiles are needed to provide more treatment options. CROSS REFERENCE TO RELATED Currently marketed HIV-1 drugs are dominated by either APPLICATIONS nucleoside reverse transcriptase inhibitors or peptidomimetic protease inhibitors. Non-nucleoside reverse transcriptase This is a Divisional application of U.S. application Ser. No. inhibitors (NNRTIs) have recently gained an increasingly 10 important role in the therapy of HIV infections (Pedersen & 10/762,108 filed Jan. 21, 2004, now allowed, which is a Pedersen, Ref 15). At least 30 different classes of NNRTI Continuation in Part application of U.S. Non-Provisional have been described in the literature (De Clercq Ref. 16) and application Ser. No. 10/425,370 filed Apr. 29, 2003, now several NNRTIs have been evaluated in clinical trials. Dipy abandoned, which claims the benefit of U.S. Provisional ridodiazepinone (nevirapine), benzoxazinone (efavirenz) and Application Ser. No. 60/383,509 filed May 28, 2002. 15 bis(heteroaryl)piperazine derivatives (delavirdine) have been approved for clinical use. However, the major drawback to the FIELD OF THE INVENTION development and application of NNRTIs is the propensity for rapid emergence of drug resistant strains, both in tissue cell This invention provides compounds having drug and bio culture and in treated individuals, particularly those subject to affecting properties, their pharmaceutical compositions and monotherapy. As a consequence, there is considerable inter method of use. In particular, the invention is concerned with est in the identification of NNRTIs less prone to the develop new piperidine 4-alkenyl derivatives that possess unique anti ment of resistance (Pedersen & Pedersen, Ref 15). A recent viral activity. More particularly, the present invention relates overview of non-nucleoside reverse transcriptase inhibitors: to compounds useful for the treatment of HIV and AIDS. perspectives on novel therapeutic compounds and strategies 25 for the treatment of HIV infection. has appeared (Buckheit, reference 99). A review covering both NRTI and NNRTIs has BACKGROUND ART appeared (De clercq, reference 100). An overview of the current state of the HIV drugs has been published (De clercq, HIV-1 (human immunodeficiency virus-1) infection 30 reference 101) remains a major medical problem, with an estimated 42 mil Several indole derivatives including indole-3-sulfones, lion people infected worldwide at the end of 2002. The num piperazino indoles, pyrazino indoles, and 5H-indolo 3.2-b ber of cases of HIV and AIDS (acquired immunodeficiency 1.5benzothiazepine derivatives have been reported as syndrome) has risen rapidly. In 2002, -5.0 million new infec HIV-1 reverse transciptase inhibitors (Greenlee et al. Ref. 1; tions were reported, and 3.1 million people died from AIDS. 35 Williams etal, Ref.2: Romero etal, Ref.3; Font etal, Ref. 17: Currently available drugs for the treatment of HIV include Romero et al. Ref. 18; Young et al. Ref. 19: Genin et al. Ref. nine nucleoside reverse transcriptase (RT) inhibitors or 20: Silvestri et al. Ref. 21). Indole 2-carboxamides have also approved single pill combinations (Zidovudine or AZT (or been described as inhibitors of cell adhesion and HIV infec RetrovirR), didanosine (or Videx(R), stavudine (or Zerit(R), tion (Boschellietal, U.S. Pat. No. 5,424,329, Ref. 4). 3-sub lamivudine (or 3TC or Epivir R), Zalcitabine (or DDC or 40 HividR), abacavir succinate (or ZiagenR), Tenofovir diso stituted indole natural products (Semicochliodinol A and B, proxil fumarate salt (or Viread(R), Combivir R (contains didemethylasterriquinone and isocochliodinol) were dis -3TC plus AZT), Trizivir R (contains abacavir, lamivudine, closed as inhibitors of HIV-1 protease (Fredenhagen et al. and Zidovudine); three non-nucleoside reverse transcriptase Ref.22). inhibitors: nevirapine (or Viramune(R), delavirdine (or 45 Structurally related aza-indole amide derivatives have been Rescriptor(R) and efavirenz (or SustivaR), and seven pepti disclosed previously (Kato et al. Ref.23; Levacher et al. Ref. domimetic protease inhibitors or approved formulations: 24: Dompe Spa, WO-09504742, Ref. 5(a); SmithKline Bee saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopi cham PLC, WO-0961 1929, Ref. 5(b); Schering Corp., U.S. navir, and Kaletra R (lopinavir and Ritonavir). Each of these Pat. No. 5,023,265, Ref. 5(c)). However, these structures drugs can only transiently restrain viral replication if used 50 differ from those claimed herein in that they are aza-indole alone. However, when used in combination, these drugs have mono-amide rather than unsymmetrical aza-indole piperi a profound effect on viremia and disease progression. In fact, dine 4-alenyl derivatives, and there is no mention of the use of significant reductions in death rates among AIDS patients these compounds for treating viral infections, particularly have been recently documented as a consequence of the wide HIV. Indole and azaindole piperazine containing derivatives spread application of combination therapy. However, despite 55 these impressive results, 30 to 50% of patients ultimately fail have been disclosed in three different PCT and issued U.S. combination drug therapies. Insufficient drug potency, non patent applications (Reference 93-95, 106) Those com compliance, restricted tissue penetration and drug-specific pounds describe oxo acetyl Substituted piperazine amides. limitations within certain cell types (e.g. most nucleoside None of these applications discloses piperidine alkenyl com analogs cannot be phosphorylated in resting cells) may 60 pounds such as described in this invention. The selection of account for the incomplete Suppression of sensitive viruses.