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WO 2017/048727 Al 23 March 2017 (23.03.2017) P O P C T

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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/048727 Al 23 March 2017 (23.03.2017) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/519 (2006.01) A61P 31/18 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/US20 16/05 1545 KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 13 September 2016 (13.09.201 6) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/218,858 15 September 2015 (15.09.2015) US kind of regional protection available): ARIPO (BW, GH, 62/382,550 1 September 2016 (01.09.2016) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: GILEAD SCIENCES, INC. [US/US]; 333 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Lakeside Drive, Foster City, CA 94404 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: GELEZIUNAS, Romas; C/o Gilead Sciences, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Inc., 333 Lakeside Drive, Foster City, CA 94404 (US). GW, KM, ML, MR, NE, SN, TD, TG). HESSELGESSER, Joseph, E.; C/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404 (US). KAUR, Declarations under Rule 4.17 : Jasmine; C/o Gilead Sciences, Inc., 333 Lakeside Drive, — as to applicant's entitlement to apply for and be granted a Foster City, CA 94404 (US). MURRY, Jeffrey, Patrick; patent (Rule 4.1 7(H)) C/o Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404 (US). SLOAN, Derek, Dean; 291 1 San Juan — as to the applicant's entitlement to claim the priority of the Blvd., Belmont, CA 94002 (US). earlier application (Rule 4.1 7(in)) (74) Agents: POLSTER, Philip, B. et al; Gilead Sciences, Published: Inc., 333 Lakeside Drive, Foster City, CA 94404 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: MODULATORS OF TOLL-LIKE RECPTORS FOR THE TREATMENT OF HIV (57) Abstract: Provided are methods, uses, pharmaceutical regimens, pharmaceutical compositions, and kits comprising modulators of TLR8 and pharmaceutically acceptable salts thereof, useful in treating H V infections. MODULATORS OF TOLL-LIKE RECEPTORS FOR THE TREATMENT OF HIV CROSS REFERENCES TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Nos. 62/382,550, filed September 1, 201 6 , and 62/21 8,858, filed September 15 , 201 5 , each of which is incorporated herein in its entirety for all purposes. FIELD This application relates generally to compounds and pharmaceutical compositions which selectively modulate toll-like receptors (such as TLR8) and methods of using such compounds in the treatment of Human Immunodeficiency Virus (H IV) infections. BACKGROUND The innate immune system provides the body with a first line defense against invading pathogens. In an innate immune response, an invading pathogen is recognized by a germline-encoded receptor, the activation of which initiates a signaling cascade that, among other functions, leads to the induction of cytokine expression and stimulation of multiple immune cell subsets. Innate immune system receptors have broad specificity, recognizing molecular structures that are highly conserved among different pathogens. One family of these receptors is known as Toll-like receptors (TLRs) , due to their homology with receptors that were first identified and named in Drosophila, and are present in cells such as macrophages, dendritic cells, and epithelial cells. The toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and activation of innate immunity. Toll-like receptor 8 (TLR8) is predominantly expressed by myeloid immune cells and activation of this receptor stimulates a broad immunological response. Agonists of TLR8 activate myeloid dendritic cells, monocytes, natural killer (NK) cells, leading to the production of proinflammatory cytokines and chemokines, such as interleukin- 18 (IL-1 8) , interleukin- 12 (IL- 12), tumor necrosis factor-alpha (TNF-a), and interferon-gamma (IFN-γ ) . Such agonists also promote the increased expression of co-stimulatory molecules on CD8+ cells, major histocompatibility complex molecules (MAIT, NK cells), and chemokine receptors. Collectively, activation of these innate and adaptive immune responses induces an immune response and regulation of these processes may provide a therapeutic benefit in various conditions involving autoimmunity, inflammation, allergy, asthma, graft rejection, graft versus host disease (GvHD) , infection, cancer, and immunodeficiency Around the world more than thirty million people are infected by the HIV virus. Numerous drugs and combination therapies have been developed for the treatment of HIV infections in humans. While combination antiretroviral therapies (cART) and highly active antiretroviral therapies (HAART) have been able to reduce HIV viral activation, often below 50 copies of HIV RNA/ml of plasma, no therapy has provided elimination of HIV infected cells which are not actively replicating HIV, commonly referred to as a patient's latent reservoir of HIV. "Kick and kill" strategies have been proposed for reservoir reduction and/or elim ination. Compounds with "kick" activity have the potential to reverse latency and increase HIV protein expression in infected cells, making them more susceptible to immune-mediated killing. Compounds with "kill" activity have the potential to enhance killing of HIV-infected cells, e.g. by enhancing immune effector cell function. Prospects for Treatment of Latent HIV, Barton et al. , Clin. Pharm. & Therap., Vol. 93, Issue 1, pp. 46-56; Neutralizing the HIV Reservoir, Marsden et al. , Cell, 158, August 28, 201 4 , pp.971 -972; HIV-1 Latency: An Update of Molecular Mechanisms and Therapeutic Strategies, Battistini et al. , Viruses 201 4 , 6 , 17 15-1 758; and Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy, Cillo et al. , PNAS, May 13 201 4 , Vol. 111, No. 19 , pp. 7078-7083. There remains a need for new agents and therapies capable of assisting in the activation of the latent HIV-infected cells to enhance the activity of antiretroviral therapies and immune responses. SUMMARY Provided herein are methods of treatment, regimens, pharmaceutical formulations, and kits which may be useful in treating HIV infections in a human, wherein each of the methods of treatment, regimens, pharmaceutical formulations, and kits comprise the use of a TLR8 modulating compound, including for example a compound of Formula (J) or (I) , or a pharmaceutically acceptable salt thereof: wherein: X is N or CR 0 ; R is selected from the group consisting of hydrogen, halogen, Chalky!, CN, -NR aRb, is optionally substituted with 1 to 5 R20 groups; R2 is selected from the group consisting of hydrogen, halogen, Chalky!, CN, -NR aRb, is optionally substituted with 1 to 5 R20 groups; 3 a b R is selected from the group consisting of hydrogen, halogen, C1-6alkyl, CN, -NR R , a a 20 -S(0) 1-2 R , and OR , wherein C alky! is optionally substituted with 1 to 5 R groups; 4 R is C1-12 alkyl which is optionally substituted with 1 to 5 substituents independently selected from halogen, -ORa, -NR aRb, CN, -C(0)R a, -C(0)OR a, -C(0)NR aRb, - a b a b a b a b a a OC(0)NR R , -NR C(0)R , -NR C(0)NR -NR C(0)OR , -SR , - S 2 , - a b a b S(0) 2NR R , -NR S(0) 2R , C^haloalkyl, C3. cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, C . 0 aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein each C3. cycloalkyl, 3 to 6 membered heterocyclyl, C . 0 aryl, and 5 to 10 membered heteroaryl is optionally substituted with 1 to 5 R2 groups; 0 a b a a R is selected from hydrogen, halogen, C1-6alkyl, CN, -NR R , -S(0) 1-2R , and OR , 20 wherein C1-6alkyl is optionally substituted with 1 to 5 R groups each R20 is independently selected from the group consisting of halogen, Ci. a b a ehaloalkyl, CN, -NR R , S(0)i -2R , and OR ; 2 each R is independently selected from the group consisting of halogen, C1-6alkyl, Ci. a b a ehaloalkyl, CN, -NR R , S(0)i -2R , and OR ; each Ra and Rb are independently selected from the group consisting of hydrogen and C1-6alkyl; wherein each C1-6alkyl is optionally substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, amino, 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and C1-6 haloalkyl; 2 3 4 provided that when X is N, R is CI, R is H and R is H then R is not CH2CH2OMe or CH2CH2S0 2Me.
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    Background Paper 6.7 Human Immunodeficiency Virus (HIV)/ Acquired Immune Deficiency Syndromes (AIDS)

    Priority Medicines for Europe and the World "A Public Health Approach to Innovation" Update on 2004 Background Paper Written by Warren Kaplan Background Paper 6.7 Human Immunodeficiency Virus (HIV)/ Acquired Immune Deficiency Syndromes (AIDS) By Warren Kaplan, Ph.D., JD, MPH 15 February 2013 Update on 2004 Background Paper, BP 6.7 HIV/AIDS Table of Contents What is new since 2004? ..................................................................................................................................... 4 1. Introduction ................................................................................................................................................. 7 2. What are the Epidemiological Trends for Europe and the World? ................................................... 7 2.1 Western and Central Europe ............................................................................................................. 7 2.2 Eastern Europe .................................................................................................................................... 9 2.2 The World (including Europe) ........................................................................................................ 11 3. What is the Control Strategy? Is There an Effective Package of Control Methods Assembled into a “Control Strategy” for Most Epidemiological Settings?................................................................. 13 3.1 Is there a pharmaceutical ‘gap’? ....................................................................................................
  • Dedication to Kyoichi A. Watanabe

    Dedication to Kyoichi A. Watanabe

    Heterocycl. Commun. 2015; 21(5): 245–248 Guest Editorial Dedication to Kyoichi A. Watanabe DOI 10.1515/hc-2015-0206 synthesize a 2-fluoro-2-deoxy-D-arabinose derivative from D-glucose [9]. This issue of Heterocyclic Communications is dedicated The above arabinose was key in synthesis of F- ara- to Kyoichi A. ‘Kyo’ Watanabe (1935–2015), formerly of the nucleosides that have anti-viral activity [10–13], anti-cancer Memorial Sloan Kettering Cancer Center (MSKCC), Codon activity [14–16] and are commercially available today. Impor- Pharmaceuticals and Pharmasset, Inc. Kyo earned his PhD tant examples of these nucleosides include 1-(2′-deoxy-2′- in the Mizuno lab at Hokkaido University. He was a member fluoro-1-β-D-arabinofuranosyl)-5-methyluracil (FMAU) and of the American Chemical Society, the Polish Academy 1-(2-deoxy-2-fluoro-1-β-D-arabinofuranosyl)-5-iodouracil of Sciences and a founding member of the International (FIAU, fialuridine). FMAU advanced to clinical trials for Society of Nucleosides, Nucleotides and Nucleic Acids cancer [17] and a radiolabeled FMAU has been used as an (IS3NA). As the head of the Organic Chemistry Laboratory imaging agent [18]. FIAU reached clinical trials for hepatitis at MSKCC and Vice President for Research and Develop- B but was withdrawn due to safety concerns [19]. However, ment at Pharmasset he was an eminent organic chemist the most notable example is probably 2′-F-ara-C. Radiola- who trained and influenced the careers of numerous sci- beled versions are used in positron emission tomography entists. Kyo’s impact has been recognized in five interna- imaging and for in vivo prediction of clinical response to tional awards, the most notable and recent being the Marie gemcitabine [20].