Tetracyclic compounds and uses thereof

12122,776

18/316579

May 12, 2023

The present disclosure relates generally to certain tetracyclic compounds, pharmaceutical compositions comprising said compounds, and methods of making said compounds and pharmaceutical compositions. The compounds of the disclosure are useful in treating or preventing human immunodeficiency virus (HIV) infection.

Gilead Sciences, Inc. (Foster City, CA, US)

Gilead Sciences, Inc. (Foster City, CA, US)

1. A compound selected from the group consisting of: [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is selected from the group consisting of: [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included]

3. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: [chemical expression included]

4. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: [chemical expression included] [chemical expression included] [chemical expression included]

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition of claim 5 , further comprising one, two, three, or four additional therapeutic agents.

7. The pharmaceutical composition of claim 6 , wherein the additional therapeutic agent or agents are anti-HIV agents.

8. The pharmaceutical composition of claim 6 , wherein the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

9. The pharmaceutical composition of claim 6 , wherein the additional therapeutic agent or agents comprise a HIV capsid inhibitor.

10. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is for oral or parenteral administration.

11. A kit comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and instructions for use.

12. The kit of claim 5 , further comprising one, two, three, or four additional therapeutic agent or agents.

13. The kit of claim 12 , wherein the additional therapeutic agent or agents are anti-HIV agents.

14. The kit of claim 12 , wherein the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

15. The kit of claim 12 , wherein the additional therapeutic agent or agents comprise a HIV capsid inhibitor.

16. A method of treating an HIV infection in a human having or at risk of having the infection, comprising administering to the human a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 , further comprising administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents.

18. The method of claim 17 , wherein the additional therapeutic agent or agents are anti-HIV agents.

19. The method of claim 17 , wherein the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof.

20. The method of claim 17 , wherein the additional therapeutic agent or agents comprise a HIV capsid inhibitor.

3845770 November 1974 Theeuwes et al.
4326525 April 1982 Swanson et al.
4902514 February 1990 Barclay et al.
4992445 February 1991 Lawter et al.
5001139 March 1991 Lawter et al.
5023252 June 1991 Hseih
5616345 April 1997 Geoghegan et al.
9522912 December 2016 Bacon et al.
10087178 October 2018 Miyazaki et al.
10479801 November 2019 Graham
11084832 August 2021 Chu et al.
11492352 November 2022 Ishii et al.
11548902 January 2023 Chu et al.
11613546 March 2023 Chu et al.
11697652 July 2023 Jiang
11884683 January 2024 Yu et al.
11897892 February 2024 Chu et al.
12024528 July 2024 Chu et al.
20090253681 October 2009 Summa et al.
20090270412 October 2009 Hung et al.
20100143301 June 2010 Desai et al.
20130165489 June 2013 Cocklin et al.
20130171214 July 2013 Mundhra et al.
20140221356 August 2014 Jin et al.
20140221378 August 2014 Miyazaki et al.
20140221380 August 2014 Miyazaki et al.
20180155365 June 2018 Graham et al.
20190284208 September 2019 Johns et al.
20190315769 October 2019 Graham et al.
20190322666 October 2019 Yu et al.
20200317689 October 2020 Chu et al.
20210284642 September 2021 Jiang et al.
20220135565 May 2022 Chu et al.
20220267343 August 2022 Chu et al.
20230058677 February 2023 Tomida et al.
20230203061 June 2023 Chu et al.
20230257389 August 2023 Chu et al.
20230339971 October 2023 Chu et al.
20230339972 October 2023 Chu et al.
104995198 October 2015
116390924 July 2023
3938047 January 2022
2006342115 December 2006
200716635 May 2007
202106689 February 2021
202120510 June 2021
WO 2004096286 November 2004
WO 2006015261 February 2006
WO-2006088173 August 2006
WO 2006110157 October 2006
WO-2006116764 November 2006
WO-2007/019098 February 2007
WO-2007049675 May 2007
WO-2007050510 May 2007
WO-2007148780 December 2007
WO-2008010964 January 2008
WO-2008048538 April 2008
WO 2009062285 May 2009
WO-2009088729 July 2009
WO-2009/117540 September 2009
WO-2009154870 December 2009
WO-2010000030 January 2010
WO-2010011812 January 2010
WO-2010011814 January 2010
WO-2010011815 January 2010
WO-2010011816 January 2010
WO-2010011818 January 2010
WO-2010011819 January 2010
WO-2010042391 April 2010
WO-2010068253 June 2010
WO-2010088167 August 2010
WO 2010130034 November 2010
WO-2010147068 December 2010
WO-2011011483 January 2011
WO-2011025683 March 2011
WO-2011045330 April 2011
WO-2011094150 August 2011
WO-2011105590 September 2011
WO-2011121105 October 2011
WO-2011129095 October 2011
WO 2012003497 January 2012
WO 2012003498 January 2012
WO-2012018065 February 2012
WO-2012058173 May 2012
WO-2012078834 June 2012
WO 2012145728 October 2012
WO 2013006738 January 2013
WO 2013006792 January 2013
WO-2013054862 April 2013
WO 2013091096 June 2013
WO 2013159064 October 2013
WO-2014008636 January 2014
WO-2014014933 January 2014
WO-2014028384 February 2014
WO-2014099586 June 2014
WO-2014100323 June 2014
WO-2014/172188 October 2014
WO-2014183532 November 2014
WO-2014200880 December 2014
WO-2015006731 January 2015
WO-2015006733 January 2015
WO-2015039348 March 2015
WO-2015048363 April 2015
WO-2015/095258 June 2015
WO-2015089847 June 2015
WO-2015/196116 December 2015
WO-2016027879 February 2016
WO-2016033009 March 2016
WO-2016/094197 June 2016
WO-2016090545 June 2016
WO-2016094198 June 2016
WO-2016106237 June 2016
WO-2016154527 September 2016
WO-2016161382 October 2016
WO-2016187788 December 2016
WO-2017087256 May 2017
WO-2017087257 May 2017
WO-2017106071 June 2017
WO-2017/116928 July 2017
WO-2017113288 July 2017
WO-2017223280 December 2017
WO-2018102485 June 2018
WO-2018102634 June 2018
WO-2018109786 June 2018
WO-2018140368 August 2018
WO-2019/058393 March 2019
WO-2019160783 August 2019
WO 2019160883 August 2019
WO-2019209667 October 2019
WO-2019223408 November 2019
WO-2019/232216 December 2019
WO-2019230857 December 2019
WO-2019230858 December 2019
WO-2019236396 December 2019
WO-2019244066 December 2019
WO-2020/003093 January 2020
WO-2020086555 April 2020
WO-2020112931 June 2020
WO-2020197991 October 2020
WO-2020221294 November 2020
WO-2020246910 December 2020
WO-2021093846 May 2021
WO-2021/107066 June 2021
WO 2022089562 May 2022
WO 2022159387 July 2022
WO-2022/177840 August 2022

Thenin-Houssier et al. Antimicrobial Agents and Chemotherapy 2016, 60, 2195-2208 (Year: 2016). cited by examiner
2020) “Product Monograph Including Patient Medication Information” ViiV Healthcare ULC, 51 pages. cited by applicant
Benn, P. et al. (2021) “Long-Acting Cabotegravir + Rilpivirine in Older Adults: Pooled Phase 3 Week 48 Results” CROI 2021, Science Spotlight, 1-11. cited by applicant
Bowers, G. et al. (2016) “Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans” Xenobiotica, 46(2):147-162. cited by applicant
Brooks, K. et al. (2019) “Integrase Inhibitors: After 10 Years of Experience, Is the Best Yet to Come?” Pharmacotherapy, 1-23. cited by applicant
Burns, J. et al. (2020) “No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV” AIDS, 34:109-114. cited by applicant
Castellino, S. et al. (2013) “Metabolism, Excretion, and Mass Balance of the HIV-1 Integrase Inhibitor Dolutegravir in Humans” 57(8):3536-3546. cited by applicant
Cook, N. et al. (2019) “Structural basis of second-generation HIV Integrase inhibitor action and viral resistance” Science, 1-9. cited by applicant
Correll, C. et al. (2021) “Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview” CNS Drugs, 35: 39-59. cited by applicant
Cottura, N. (2021) “In-Silico Prediction of Long-Acting Cabotegravir PK in Liver Impaired Patients” CROI 2021, Science Spotlight, 6 pages. cited by applicant
Flexner, C. (2020) “Novel Approaches to HIV Treatment and Prevention using Long Acting Drug Delivery” Johns Hopkins University, Division of Clinical Pharmacology, 45 pages. cited by applicant
Friedman, E. et al. (2016) “A Single Monotherapy Dose of MK-8591, a Novel NRTI, Suppresses HIV for 10 Days” CROI 2016, Poster, Abstract #437LB. cited by applicant
Gallant, J. et al. (2017) “Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults” J Acquir Immune Defic Syndr, 75(1):61-66. cited by applicant
Grobler, J. et al. (2019) “MK-8591 Potency and PK Provide High Inhibitory Quotients at Low Doses QD and QW” CROI 2019, Poster, Abstract #481. cited by applicant
Groseclose, M. et al. (2019) “Intramuscular and subcutaneous drug depot characterization of a long-acting abotegravir nanoformulation by MALDI IMS” International Journal of Mass Spectometry, 437:92-98. cited by applicant
Han, K. et al. (2021) “Cabotegravir Population Pharmacokinetic (PPK) Simulation to Inform Q2M Strategies Following Dosing Interruptions” CROI 2021, Science Spotlight, 9 pages. cited by applicant
Hill, L. et al. (2018) “Profile of bictegravir/emtricitabine/tenofovir alafenamide fixed dose combination and its potential in the treatment of HIV-1 infection: evidence to date” HIV/AIDS—Research and Palliative Care, 10:203-213. cited by applicant
Hughes, D. (2019) “Review of Synthetic Routes and Final Forms of Integrase Inhibitors Dolutegravir, Cabotegravir, and Bictegravir” Organic Process Research & Development, 23:716-729. cited by applicant
Intl. Search Report and Written Opinion dated May 4, 2021 for Intl. Appl. No. PCT/US2021/019179. cited by applicant
Jaeger, H. et al. (2021) “Week 96 Efficacy and Safety of Long-Acting Cabotegravir + Rilpivirine Every 2 Months: Atlas-2M” CROI 2021, Science Spotlight, 1-9. cited by applicant
Jiskoot, W. (2020) “Long-actinginjectables& implantables: immunogenicityconcerns” Third Long-Acting Injectables & Implantables Conference, 32 pages. cited by applicant
Jogiraju, V. (2021) “Pharmacokinetics of Lenacapavir, an HIV-1 Capsid Inhibitor, in Hepatic Impairment” CROI 2021, Science Spotlight, 6 pages. cited by applicant
Johns, B. et al. (2013) “Carbamoyl Pyridone HIV?1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)” J. Med. Chem., 56:5901-5916. cited by applicant
Jucker, B. et al. (2021) “Multiparametric magnetic resonance imaging to characterize cabotegravir long-acting formulation depot kinetics in healthy adult volunteers” Br J Clin Pharmacol., 1-12. cited by applicant
Kalicharan, R. et al. (2017) “New Insights Into Drug Absorption From Oil Depots” University Medical Center Utrecht, Utrecht, the Netherlands, Thesis, 152 pages. cited by applicant
Kalicharan, R. et al. (2016) “Fundamental understanding of drug absorption from a parenteral oil depot” European Journal of Pharmaceutical Sciences, 83: 19-27. cited by applicant
Kandala, B. et al. (2021) “Model-informed dose selection for Islatravir/MK-8507 oral once-weekly phase 2B study” CROI 2021, Science Spotlight, 6 pages. cited by applicant
Kandel, C. et al. (2015) “Dolutegravir—a review of the pharmacology, efficacy, and safety in the treatment of HIV” Drug Design, Development and Therapy, 9:3547-3555. cited by applicant
Kinvig, H. (2021) “In-Silico Prediction of Monthly Bictegravir Microneedle Array Patches” CROI 2021, Science Spotlight, 6 pages. cited by applicant
Klooster, G. et al. (2010) “Pharmacokinetics and Disposition of Rilpivirine (TMC278) Nanosuspension as a Long-Acting Injectable Antiretroviral Formulation” Antimicrobial Agents and Chemotherapy, 54(5): 2042-2050. cited by applicant
Lalezari, J. et al. (2009) “Potent Antiviral Activity of S/GSK1349572, A Next Generation Integrase Inhibitor (INI), in INI-Naïve HIV-1-Infected Patients: ING111521 Protocol” IAS 2009, 5th Conference on HIV Pathogenesis, Abstract TUAB105, 15 pages. cited by applicant
Landovitz, R. et al. (2018) “Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial” PLoS Med, 15(11):1-22. cited by applicant
Le Hingrat, Q. et al. (2018) “A New Mechanism of Resistance of Human Immunodeficiency Virus Type 2 to Integrase Inhibitors: A 5-Amino-Acid Insertion in the Integrase C-Terminal Domain” Clinical Infectious Diseases, 1-11. cited by applicant
Liu, S. et al. (2019) “Mechanistic Assessment of Extrahepatic Contributions to Glucuronidation of Integrase Strand Transfer Inhibitors” Drug Metabolism and Disposition, 47(5) 535-544. cited by applicant
Martin, C. et al. (2021) “Bictegravir and Cabotegravir: In Vitro Phenotypic Susceptibility of HIV-1 Nongroup M” CROI 2021, Science Spotlight, 1-6. cited by applicant
McMillan, J. et al. (2019) “Pharmacokinetic testing of a first generation cabotegravir prodrug in rhesus macaques” AIDS, 33(3):585-588. cited by applicant
Muller, R. et al. (2011) “State of the art of nanocrystals—Special features, production, nanotoxicology aspects and intracellular delivery” European Journal of Pharmaceuticals and Biopharmaceutics, 78:1-9. cited by applicant
Neary, M. (2021) “In Vitro / In Vivo Development of Long Acting Biodegradable Emtricitabine Implants” CROI 2021, Science Spotlight, 6 pages. cited by applicant
Office Action dated Feb. 11, 2022 for ROC (Taiwan) Application No. 110106560. cited by applicant
Orkin, C. et al. (2020) “Long-Acting Cabotegravir + Rilpivirine for HIV Treatment: Flair Week 96 Results” Conference on Retroviruses and Opportunistic Infections, Poster 0482, 1 page. cited by applicant
Passos, D. et al. (2020) “Structural basis for strand transfer inhibitor binding to HIV intasomes” Science, 1-9. cited by applicant
Passos, D. et al. (2020) Supplementary Materials for “Structural basis for strand transfer inhibitor binding to HIV intasomes” Science, Supplementary Text, 38 pages. cited by applicant
Provisional Application as filed on Apr. 6, 2022 for U.S. Appl. No. 63/328,061. cited by applicant
Raheem, I. et al. (2015) “Discovery of 2?Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV?1 Integrase Strand Transfer Inhibitors” J. Med. Chem., 58:8154-8165. cited by applicant
Rahnfeld, L. et al. (2020) “Injectable Lipid-Based Depot Formulations: Where Do We Stand?” Pharmaceutics 12(0567):1-28. cited by applicant
Rossenu, S. et al. (2021) “Population PK Modeling of Every 2 Months IM RPV LA for Managing Dosing Interruptions in HIV-1 Patients” CROI 2021, Science Spotlight, 1-7. cited by applicant
Rudd, D. et al. (2020) “Modeling-Supported Islatravir Dose Selection for Phase 3” CROI 2020, Poster, Abstract #462. cited by applicant
Scarsi, K. et al. (2020) “HIV-1 Integrase Inhibitors: A Comparative Review of Efficacy and Safety” Drugs, 80(16):1649-1676. cited by applicant
Shaik, J. et al. (2019) “A Phase 1 Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Patients With Hepatic Impairment and Healthy Matched Controls” Clinical Pharmacology in Drug Development, 00(0):1-10. cited by applicant
Shi, Y. et al. (2021) “A review of existing strategies for designing longacting parenteral formulations: Focus on underlying mechanisms, and future perspectives” Acta Pharmaceutica Sinica B, 11(8): 2396-2415. cited by applicant
Spreen, W. et al. (2013) “Pharmacokinetics, Safety, and Monotherapy Antiviral Activity of GSK1265744, an HIV Integrase Strand Transfer Inhibitor” HIV Clinical Trials, 14(5):192-203. cited by applicant
Spreen, W. et al. (2014) “GSK1265744 Pharmacokinetics in Plasma and Tissue After Single-Dose Long-Acting Injectable Administration in Healthy Subjects” J Acquir Immune Defic Syndr, 67(5):481-486. cited by applicant
Trezza, C. et al. (2015) “Formulation and pharmacology of long-acting cabotegravir” Current Opinion—HIV and AIDS, 10(4):239-245. cited by applicant
Walji, A. et al. (2015) “Discovery of MK-8970: An Acetal Carbonate Prodrug of Raltegravir with Enhanced Colonic Absorption” ChemMedChem, 10:245-252. cited by applicant
Weller, S. et al. (2014) “Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment” Eur J Clin Pharmacol 70:29-35. cited by applicant
Wilkinson, J. et al. (2022) “Lipid based intramuscular long-acting injectables: Current state of the art” European Journal of Pharmaceutical Sciences, 178(106253): 1-20. cited by applicant
Yoshinaga, T. et al. (2015) “Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection” 59(1):397-406. cited by applicant
Yoshinaga, T. et al. (2018) “Novel secondary mutations C56S and G149A confer resistance to HIV-1 integrase strand transfer inhibitors” Antiviral Research, 152:1-9. cited by applicant
Zhang, W. et al. (2018) “Accumulation of Multiple Mutations In Vivo Confers Cross-Resistance to New and Existing Integrase Inhibitors” The Journal of Infectious Diseases, 218:1773-1776. cited by applicant
Opposition, by opponent Laboratorios Legrand S.A., dated Dec. 14, 2022 for Colombian Application No. NC2022-0011947. cited by applicant
First Examination Report dated Mar. 16, 2023 for Australian Patent Application No. 2021225809. cited by applicant
Akiyama, T. et al. (2013) “Discovery of Novel HIV Integrase Inhibitors Part 2. Selection and Evaluation of an Azabicyclic Carbamoyl Pyridone as a Pre-clinical Candidate”, 245th ACS National Meeting and Exposition, Poster MEDI 403. cited by applicant
Andersson, V. et al. (2016) “Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability”, J Med Chem, 59(14):6658-6670. cited by applicant
Anonymous (2013) “Thomson Reuters Drug News: Results from phase III trials of dolutegravir presented”, Thomson Reuters. Retrieved from the Internet Jul. 5, 2013 . cited by applicant
Bari, H. (2010) “A Prolonged Release Parenteral Drug Delivery System—An Overview”, Int J Pharm Sci Rev Res, 3(1):1-11. cited by applicant
Bocedi, A. et al. (2004) “Binding of Anti-HIV Drugs to Human Serum Albumin”, IUBMB Life, 56(10):609-614. cited by applicant
Brinson, C. et al. (2013) “Dolutegravir Treatment Response and Safety by Key Subgroups in Treatment Naive HIV Infected Individuals”, 20th CROI, Poster 554. cited by applicant
Cottrell, M. et al. (2013) “Clinical Pharmacokinetic, Pharmacodynamic and Drug-Interaction Profile of the Integrase Inhibitor Dolutegravir”, Clin Pharmacokinet, 52(11):981-994. cited by applicant
Curley, P. et al. (2019) “Long-Acting Emtricitabine Prodrugs Provide Protection From HIV Infection In Vivo”, 2019 CROI, Poster 2262. cited by applicant
Del Mar Gutierrez, M. et al. (2014) “Drug safety profile of integrase strand transfer inhibitors”, Expert Opin Drug Saf, 13(4):431-445. cited by applicant
Dicker, I. et al. (2011) “Simple and Accurate In Vitro Method for Predicting Serum Protein Binding of HIV Integrase Strand Transfer Inhibitors”, HIV-1 Integrase: Mechanism and Inhibitor Design, First Edition. cited by applicant
EFSA (European Food Safety Authority), (2005) “Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the Tolerable Upper Intake Level of Potassium”, EFSA Journal 2005, 3(3):193, 19 pp. cited by applicant
Gelé, T. et al. (2020) “Characteristics of Dolutegravir and Bictegravir Plasma Protein Binding: a First Approach for the Study of Pharmacologic Sanctuaries”, Antimicrob Agents Chemother, 64(11):e00895-20. cited by applicant
Grobler, J. et al. (2016) “Efficacy of once-weekly MK-8591 in SIV infected rhesus macaques”, Merck & Co., Inc., 7th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. cited by applicant
Günthard, H. et al. (2016) “Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel”, JAMA, 316(2):191-210. cited by applicant
Gurevich, K. (2013) “Effect of blood protein concentrations on drug-dosing regimes: practical guidance”, Theor Biol Med Model, 10:20. cited by applicant
Hare, S. et al. (2011) “Structural and Functional Analyses of the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572)”, Mol Pharmacol, 80(4):565-572. cited by applicant
Hurt, C. et al. (2013) “Characterization of Resistance to Integrase Strand Transfer Inhibitors among Clinical Specimens in the United States, 2009-2012”, 20th CROI, Poster 591. cited by applicant
Johns, B. et al. (2010) “The Discovery of S/GSK1349572: A Once Daily Next Generation Integrase Inhibitor with a Superior Resistance Profile”, 17th CROI. cited by applicant
Kochansky, C. et al. (2008) “Impact of pH on Plasma Protein Binding in Equilibrium Dialysis”, Mol Pharm, 5(3):438-448. cited by applicant
Kulkarni, T. et al. (2019) “Prodrugs extend the half life and potency of Cabotegravir”, CROI, Poster 489. cited by applicant
Kulkarni, T. et al. (2020) “A Year-Long Extended Release Nanoformulated Cabotegravir Prodrug”, Nat Mater, 19(8):910-920. cited by applicant
Landovitz, R. et al. (2020) “Cabotegravir Is Not Associated With Weight Gain in Human Immunodeficiency Virus-uninfected Individuals in HPTN 077”, Clin Infect Dis, 70(2):319-322. cited by applicant
Letendre, S. et al. (2013) “Distribution and Antiviral Activity in Cerebrospinal Fluid (CSF) of the Integrase Inhibitor, Dolutegravir (DTG): ING116070 Week 16 Results”, 20th CROI, Poster 178LB. cited by applicant
Markowitz, M. (2017) “Weekly Oral MK-8591 Protects Male Rhesus Macaques against Repeated Low Dose Intrarectal Challenge with SHIV109CP3”, 9th IAS Conference on HIV Science (IAS 2017), PowerPoint Presentation. cited by applicant
Matthews, R. et al. (2017) “Single doses as low as 0.5 mg of the novel NRTTI MK-8591 suppress HIV for at least seven days”, IAS 2017: Conference on HIV Pathogenesis, Poster. cited by applicant
McElnay, J. & D'Arcy, P. (1983) “Protein Binding Displacement Interactions and their Clinical Importance”, Drugs, 25(5):495-513. cited by applicant
Menéndez-Arias, L. & Alvarez, M. (2014) “Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection”, Antiviral Res, 102:70-86. cited by applicant
Métifiot, M. et al. (2013) “HIV Integrase Inhibitors: 20-Year Landmark and Challenges”, Adv Pharmacol, 67:75-105. cited by applicant
Min, S. et al. (2011) “Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults” AIDS 25(14):1737-1745. cited by applicant
Mullokandov, E. et al. (2014) “Protein Binding Drug-Drug Interaction between Warfarin and Tizoxanide in Human Plasma”, Austin J Pharmacol Ther, 2(7):id1038. cited by applicant
Nair, V. et al. (2014) “Pharmacokinetics and Dose-range Finding Toxicity of a Novel anti-HIV Active Integrase Inhibitor”, Antiviral Res, 108:25-29. cited by applicant
Nair, V. et al. (2014) “Pharmacokinetics and Dose-range Finding Toxicity of a Novel anti-HIV Active Integrase Inhibitor” Supplementary Materials. cited by applicant
Orkin, C. et al. (2019) “Long-Acting Cabotegravir + Rilpivirine for HIV Maintenance: Flair Week 48 Results”, CROI 2019, PowerPoint Presentation. cited by applicant
Park, B. et al. (2001) “Metabolism of Fluorine-Containing Drugs” Annu. Rev. Pharmacol. Toxicol. 41:443-470. cited by applicant
Podany, A. et al. (2017) “Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors”, Clin Pharmacokinet, 56(1):25-40. cited by applicant
Pozniak, A. et al. (2013) “Dolutegravir (DTG) Versus Raltegravir (RAL) in ART-Experienced, Integrase-Naive Subjects: 24-Week Interim Results From Sailing (ING111762)”, 20th CROI. cited by applicant
Quashie, P. et al. (2013) “Evolution of HIV integrase resistance mutations”, Curr Opin Infect Dis, 26(1):43-49. cited by applicant
Raffi, F. et al. (2013) “Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study”, Lancet, 381(9868):735-743. cited by applicant
Rajoli, R. et al. (2019) “In Silico Simulation Of Long-Acting Tenofovir Alafenamide Subcutaneous Implant”, CROI 2019, Poster 487. cited by applicant
Rautio, J. et al. (2018), “The expanding role of prodrugs in contemporary drug design and development”, Nat Rev Drug Discov, 17(8):559-587. cited by applicant
Reese, M. et al. (2013) “In Vitro Investigations into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor” Drug Metab Dispos 41:353-361. cited by applicant
Rhodes, M. et al. (2012) “Assessing a Theoretical Risk of Dolutegravir-Induced Developmental Immunotoxicity in Juvenile Rats”, Toxicol Sci, 130(1):70-81. cited by applicant
Roberts, J. et al. (2013) “The Clinical Relevance of Plasma Protein Binding Changes”, Clin Pharmacokinet, 52(1):1-8. cited by applicant
Song, I. et al. (2013) “Dolutegravir Has No Effect on the Pharmacokinetics of Methadone or Oral Contraceptives With Norgestimate and Ethinyl Estradiol”, 20th CROI. cited by applicant
Taoada, Y. et al. (2013) “Discovery of Novel HIV Integrase Inhibitors Part 1. Molecular Design and SAR of Azabicyclic Carbamoyl Pyridone Inhibitors”, 245th ACS National Meeting and Exposition, Poster MEDI 402. cited by applicant
Tian, H. et al. (2018) “Effects of Plasma Albumin on the Pharmacokinetics of Esomeprazole in ICU Patients”, Biomed Res Int, 2018:6374374. cited by applicant
Van Der Galiën, R. et al. (2019) “Pharmacokinetics of HIV-Integrase Inhibitors During Pregnancy: Mechanisms, Clinical Implications and Knowledge Gaps”, Clin Pharmacokinet, 58(3):309-323. cited by applicant
Wang, Y. C. et al. (2002) “Switch in asymmetric induction sense in cycloadditions using camphor-based nitroso dienophiles”, Tetrahedron: Asymmetry, 13(7):691-695. cited by applicant
Weaving, G. et al. (2016) “Age and sex variation in serum albumin concentration: an observational study”, Ann Clin Biochem, 53(1):106-111. cited by applicant
Wolkowicz, U. et al. (2014) “Structural Basis of Mos1 Transposase Inhibition by the Anti-retroviral Drug Raltegravir”, ACS Chem Biol, 9(3):743-751. cited by applicant
Wu, J. et al. (2012) “Implications of Plasma Protein Binding for Pharmacokinetics and Pharmacodynamics of the γ-Secretase Inhibitor RO4929097”, Clin Cancer Res, 18(7):2066-2079. cited by applicant
Zhao, X. et al. (2014) “4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-Containing Compounds Having High Potency against Raltegravir-Resistant Integrase Mutants of HIV-1”, J Med Chem, 57(12):5190-5202. cited by applicant
Williams, D. & Lemke, T. (2002), Foye's Principles of Medicinal Chemistry, 5th Ed., pp. 59-63. cited by applicant
Non-Final Office Action dated Jul. 13, 2022 for U.S. Appl. No. 17/182,559. cited by applicant
Notice of Allowance dated Nov. 2, 2022 for U.S. Appl. No. 17/182,559. cited by applicant
Notice of Allowance dated Feb. 15, 2023 for U.S. Appl. No. 17/182,559. cited by applicant
Corrected Notice of Allowability dated Jun. 7, 2023 for U.S. Appl. No. 17/182,559. cited by applicant
Intl. Preliminary Report on Patentability dated Sep. 9, 2022 for Intl. Appl. No. PCT/US2021/019179. cited by applicant
Office Action dated Aug. 8, 2023 for Japanese Appl. No. 2022-550787. cited by applicant
Ivashchenko et al., “Synthesis, biological evaluation and in silico modeling of novel integrase strand transfer inhibitors (INSTIs),” European Journal of Medicinal Chemistry, Mar. 1, 2020, 189:112064. cited by applicant
Patani et al., “Bioisoterism: A Rational Approach in Drug Design,” Chem Rev., Dec. 1996, 8:3147-3176. cited by applicant
Office Action in Chinese Appln. No. 202180016403.3, dated Jan. 2, 2024, 13 pages (with English translation). cited by applicant
Office Action in Dominican Republic Appln. No. P2022-0171, dated Mar. 5, 2024, 16 pages (with English Translation). cited by applicant
clinicalinfo.hiv.gov [online], “Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV,” Dec. 18, 2019, retrieved on Feb. 19, 2020, retrieved from URL, 379 pages. cited by applicant
Foster, “Deuterium isotope effects in studies of drug metabolism”, Trends Pharmacol. Sci., 1984, 5(12):524-527. cited by applicant
Fulmali et al., “Phosphate moiety in FDA-approved pharmaceutical salts and prodrugs,” Drug Dev. Res., Jun. 2, 2022, 83(5):1059-1074. cited by applicant
Hurt et al., “Resistance to HIV Integrase Strand Transfer Inhibitors Among Clinical Specimens in the United States, 2009-2012,” Clinical Infectious Diseases, Feb. 2014, 58:423-431. cited by applicant
Levine et al., “Trimethyl lock: A trigger for molecular release in chemistry, biology, and pharmacology,” Chem. Sci., Jan. 2012, 3(8):2412-2420. cited by applicant
Palella et al., “Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection, HIV Outpatient Study Investigators,” N. Engl. J Med., Mar. 1998, 338(13):853-860. cited by applicant
Randolph et al., “Prodrug Strategies to Improve the Solubility of the HCV NS5A Inhibitor Pibrentasvir (ABT-530),” J. Med. Chem., Sep. 3, 2020, 63:11034-11044. cited by applicant
Richman, “HIV chemotherapy,” Nature, Apr. 2001, 410(6831):995-1001 (abstract only). cited by applicant
Tang et al., “HIV-1 antiretroviral resistance: scientific principles and clinical applications,” Drugs, Jun. 2012, 72(9):e1-25. cited by applicant
Tantra et al., “Phosphate Prodrugs: An Approach to Improve the Bioavailability of Clinically Approved Drugs,” Curr. Med. Chem., Mar. 21, 2023, 31(3):336-357. cited by applicant
Thierry et al., “Different Pathways Leading to Integrase Inhibitors Resistance,” Front. Microbiol., Jan. 11, 2017, 7:2165, 13 pages. cited by applicant
Voight et al., “Desymmetrization of pibrentasvir for efficient prodrug synthesis,” Chem. Sci., Jun. 29, 2021, 12(29):10076-10082. cited by applicant
Notice of Acceptance in Australian Appln. No. 2021225809, mailed Aug. 11, 2023, 3 pages. cited by applicant
Office Action in Canadian Appln. No. 3166480, mailed on Sep. 14, 2023, 4 pages. cited by applicant
Office Action in Eurasian Appln. No. 202292356, mailed on Nov. 11, 2023, 6 pages (with English translation). cited by applicant
Office Action in Japanese Appl. No. 2022-550787, mailed on Nov. 20, 2023, 6 pages (with English translation). cited by applicant
Office Action in Canadian Appln. No. 3166480, dated Jun. 12, 2024, 2 pages. cited by applicant
Office Action in Chilean Appln. No. 202202300, dated May 30, 2024, 30 pages (with English translation). cited by applicant
Office Action in Eurasian Appln. No. 202292356, mailed on Jun. 5, 2024, 5 pages (with English translation). cited by applicant

edspgr.12122776