WO2025160227A1

WO2025160227A1 - Advantageous compounds for treatment of hpv infection and hpv-induced neoplasia

Info

Publication number: WO2025160227A1
Application number: PCT/US2025/012682
Authority: WO
Inventors: Ankush Argade; Ramakrishna GADIRAJU
Original assignee: Antiva Biosciences Inc
Current assignee: Antiva Biosciences Inc
Priority date: 2024-01-24
Filing date: 2025-01-23
Publication date: 2025-07-31
Anticipated expiration: 2026-07-24

Abstract

The present disclosure relates to acyclic nucleotide phosphonamidates that are useful in treating HPV and related conditions including neoplasia, as well as pharmaceutical compositions and dosage forms thereof.

Description

ADVANTAGEOUS COMPOUNDS FOR

TREATMENT OF HPV INFECTION AND HPV-INDUCED NEOPLASIA

CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63/624,701, filed January 24, 2024, the entire contents of which are entirely incorporated by reference herein.

FIELD OF THE DISCLOSURE

[0002] The present disclosure provides advantageous compounds, compositions, salts, regioisomers stereoisomers, tautomers, dosage forms, and uses thereof to treat a human papilloma virus (HPV) infection or a related disorder such as HPV-induced neoplasia in a host in need thereof.

BACKGROUND

[0003] According to the U.S. Center for Disease Control, there is no direct cure for human papilloma virus (HPV). HPV is so common that most sexually active people have been infected at some point in their lives.

[0004] Papillomaviruses are a group of non-enveloped DNA viruses, which in humans infect keratinocytes of skin and mucous membranes including in the cervical area. HPV infections can cause cellular transformations in the human patient that have not yet progressed to cancer but have reached the stage of neoplasia. Forms of HPV-induced neoplasia include cervical intraepithelial neoplasia (“CIN”), anal intraepithelial neoplasia (“AIN”), perianal intraepithelial neoplasia (“PAIN”), vulvar intraepithelial neoplasia (“VIN”), penile intraepithelial neoplasia (“PIN”), and vaginal intraepithelial neoplasia (“VAIN”). Cancers caused by HPV include cervical, anal, perianal, penile, vaginal, vulvar, and oropharyngeal cancer.

[0005] Thus, HPV can cause viral infection, neoplasia and cancer. Most of the cancer-causing HPV types are from the alpha-7 and alpha-9 species and include types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82. The most common cancer-causing HPV types are 16 and 18. The causal role of HPV in cancer of the cervix has been firmly established biologically and epidemiologically. Persistent infection with high-risk HPV is necessary to promote progression of pre-malignant stages to invasive cancer. Oncogenic HPV types are detected in almost all cervical cancer specimens, with types 16 and 18 accounting for about 70% of cervical cancers and about 50% of high-grade lesions. The majority of venereal warts are caused by the low-risk HPV types 6 and 11.

[0006] The current therapeutic options for HPV and cervical intraepithelial neoplasia are adjunctive only. Commonly used drug therapies include trichloroacetic acid, 5- fluorouracil, imiquimod and podofilox. Imiquimod (Aldara™, Zyclara™) stimulates the immune system to clear the infection through toll-like receptor signaling and causes redness and swelling. Podofilox (Condylox™) destroys tissues by destabilizing microtubules which prevents host cell replication.

[0007] The cervical epithelium is composed of several layers of tissue and is referred to as stratified squamous epithelium. The layers are the superficial cell layer, the intermediate cell layer, the parabasal cell layer and the basal cell layer. It is essential that a topical drug for the treatment of cervical intraepithelial neoplasia is able to penetrate these multiple layers of tissue to adequately reach and treat the transformed cells. This is a formidable task because the cells are tightly bound and without blood vessels.

[0008] Cervical intraepithelial neoplasia is most often treated by observation (the wait and see approach) or by excision or ablation of the cervical transformation zone. Techniques include cryotherapy, laser therapy, loop electrosurgical procedure (LEEP) and cone biopsy. All of these surgical procedures damage the affected areas and can lead to scarring. The most common intervention, LEEP, is effective in 60-90% of cases, however, it can be a painful procedure and may be associated with a significantly increased risk of miscarriage, ectopic pregnancies, and negative psychological outcomes. Despite extensive research, no drug has been approved to replace or combine with these surgical methods.

[0009] Cervical high-grade squamous intraepithelial lesions (cHSIL), sometimes referred to as CIN2 and CIN3, is a disease caused by the abnormal hyperproliferation (dysplasia) of squamous cells in the cervical epithelium (Waxman, A. G., et. al 2012. “Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix”. Obstet Gynecol, 120, 1465-71). Hyperproliferation usually occurs where the simple columnar, endometrial-type epithelium of the endocervix transitions to the stratified squamous epithelium of the ectocervix; this region is referred to as the “transformation zone” (Sellers, J. W. & Sankaranarayanan, R. 2003. An introduction to the anatomy of the uterine cervix. Colposcopy and Treatment of Cervical Intraepithelial Neoplasia: A Beginners' Manual). Cervical HSIL is classified as a pre- cancerous condition because apoptosis is impaired in these hyperproliferating cells, which can lead to the accumulation of genetic alterations that transform the cells into cancer. The probability that the patient’s immune system will be sufficiently activated to clear lesions diminishes over time and is contingent upon a variety of factors including the patient’s immunocompetency, lifestyle (e.g., smoking), and nutritional status (Schiffman, M., et al 2011. “Human papillomavirus testing in the prevention of cervical cancer”. J Natl Cancer Inst, 103, 368-83).

[0010] For women already infected with HPV, there is no approved drug therapy to treat cHSIL and thereby, to prevent the progression of HSIL to cervical cancer.

[0011] Frantz Viral Therapies, LLC is conducting clinical trials to assess the use of artesunate vaginal inserts for the treatment of women with cervical high grade intraepithelial neoplasia (CIN2/3). Artesunate is an artemisinin derivative with cytotoxic activity.

Artesunate is a known WHO-approved anti-malarial agent. The cytotoxic agent is delivered in the trial at a dosage, for example, of 50 to 200 mg for a 5-day cycle on weeks 0, 2 and 4. The artesunate vaginal inserts are self-administered at bedtime with a vaginal applicator, followed by use of a tampon, which is removed in the morning. Artesunate has a cytotoxic effect but is not an anti-viral agent, so does not directly stop the HPV replication. Therefore, artesunate cannot be used to treat patients who have an HPV infection that has not progressed to cervical intraepithelial neoplasia. Also, artesunate has some systemic exposure under these conditions. See generally Trimble, et al., “A first-in-human proof-of-concept trial of intravaginal artesunate to treat cervical intraepithelial neoplasia 2/3 (CIN 2/3)”, Gynecologic Oncology 157 (2020)188-194 as well as U.S. Patents 6,586,464; 8,394,849; 8,940,787 and 7,989,491.

[0012] Cidofovir, a pyrimidine based acyclic phosphonate nucleoside, which has broad spectrum activity against DNA viruses, is recognized as one of the effective treatments for HPV lesions that have not become cancerous. It is a DNA terminator and causes cell death via apoptosis of HPV transformed cells and regression of HPV-induced tumors. Cidofovir has been tested as a topical treatment of CIN2 and CIN3. See Van Pachterbeke, et al., “Topical treatment of CIN 2+ by cidofovir: Results of a phase II, double-blind, prospective, placebo-controlled study”, Gynecologic Oncology 115 (2009) 69-74. Researchers found that cidofovir cannot replace conization but may be used for topical chemotherapy. See also Snoeck, et al, “Cidofovir, a New Approach for the Treatment of Cervix Intraepithelial Neoplasia Grade III (CIN III)” Journal of Medical Virology 60:205- 209 (2000). According to Snoeck, et al., except for two patients, patients had at least partial responses and half had a total response. In the partial responses, the transformed cells persisted in the deep tissues that can lead to neoplasia. [0013] The Regents of the University of California, with Karl Hostetler, et. al, as named inventors, has filed a series of patents on various acyclic nucleotide derivatives to treat papilloma infections, including (i) U.S. Patent Nos. 9,156,867; 9,387,217; 9,629,860; 9,775,852; 10,076,532; 10,076,533; 10,195,222; and 10,449,207 with a priority date of March 15, 2013; (ii) U.S. Patent Nos. 9,493,493; 9,801,884; 10,213,430; 10,702,532;

11,344,555, and PCT WO 2016/044281 with a priority date of September 15, 2014; and (iii) U.S. Patent No. 10,377,782 and 11,014,950 with a priority date of September 15, 2015. [0014] Antiva Biosciences carried out human clinical trials with the acyclic nucleotide phosphonate ABI-1968 to assess its ability to adequately penetrate the various layers of cervical epithelium and release the antiviral agent PMEG (9-(2- phosphonomethyoxy)ethyl)guanine). PMEG is phosphorylated to PMEGpp (PMEG polyphosphate). It was determined that ABI-1968, when used even up to a 3% dose, does not reach 15 ng/mg of tissue concentration for ABI-1968, and thus is not suitable as a topical drug to treat cervical intraepithelial neoplasia. The clinical trials were terminated as not successful.

ABI-1968

[0015] It is thus a formidable challenge to topically dose HPV-infected epithelial stratified tissue in an effective manner that destroys the neoplasia cells in the multiple epithelial layers. The drug must be lipophilic enough to pass through the tissue layers and be metabolized if necessary to the active agent in a sufficient concentration to kill the pathogenic cells.

[0016] One compound of particular interest is ethyl(((2-(2-amino-6-methoxy-9H- purin-9-yl)ethoxy)methyl)(benzyloxy)-phosphoryl)-L-alaninate (called “Compound I” herein, shown below). U.S. Patent Nos. 9,801,884 and 11,344,555 assigned to the Regents of the University of California claim this compound and pharmaceutically acceptable salts generally, as well as methods of using the same for treating a papillomavirus infection.

Compound I is an acyclic nucleotide phosphonamidate that metabolizes to PMEG. Antiva Biosciences is conducting a human clinical trial of a pharmaceutically acceptable salt of Compound I for the treatment of HPV infection and HPV-induced intraepithelial neoplasia.

Compound I

[0017] It is an object of the present disclosure to provide active pharmaceutical compounds, pharmaceutical compositions, and treatments for HPV infection and related conditions such as HPV-induced neoplasia in a host in need thereof, including but not limited to cervical intraepithelial neoplasia (CIN), anal intraepithelial neoplasia (AIN), vulvar intraepithelial neoplasia (VIN), penile intraepithelial neoplasia (PIN), perianal intraepithelial neoplasia (PAIN), and vaginal intraepithelial neoplasia (VAIN).

SUMMARY

[0018] The present disclosure provides active compounds of Formulas I, II, III, IV, V, VI, VII, and Vllla-c and/or a pharmaceutically acceptable salt or cocrystal thereof, optionally in a pharmaceutically acceptable composition for the treatment of HPV infection and related diseases including HPV-induced neoplasia, such as cervical intraepithelial neoplasia, anal intraepithelial neoplasia, perianal intraepithelial neoplasia, penile intraepithelial neoplasia, vulvar intraepithelial neoplasia, and vaginal intraepithelial neoplasia, when administered in an effective amount to a human in need thereof.

[0019] Thus, in certain embodiments, the disclosure relates to compounds of Formula I: or a pharmaceutically acceptable salt or cocrystal thereof, wherein:

[0020] R¹ is selected from C_1-4alkyl-aryl and C_1-4alkyl-heteroaryl either of which can be optionally substituted with 1, 2, 3, 4 or 5 R¹⁴ groups, more typically 1, 2, or 3 R¹⁴ groups, or R¹ is selected from hydrogen, acetylbenzyl, and methoxycarbonylbenzyl;

[0021] R² is selected from hydrogen, C_1-6alkyl, and C_3-6cycloalkyl;

[0022] R³ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1- ₆alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups, more typically 1 or 2 R¹⁵ groups, or R³ is CH₂CO₂NH₂ or (CH₂)2CO₂NH₂;

[0023] R⁴ is selected from hydrogen, deuterium, C_1-6alkyl, halogen, C_1-6haloalkyl, C_1- ₆alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R¹⁶ groups, more typically 1 or 2 R¹⁶ groups;

[0024] or, R¹ and R³, together with the atoms to which they are attached, form a 5, 6, 7, or 8 membered heterocycle, including a bridged heterocycle, optionally substituted with 1 or 2 R¹⁵ groups;

[0025] or, R² and R³, together with the atoms to which they are attached, form a 5, 6, 7, or 8 membered heterocycle, including a bridged heterocycle, optionally substituted with 1 or 2 R¹⁵ groups;

[0026] or, R³ and R⁴, together with the carbon to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl;

[0027] R⁵ is selected at each occurrence from hydrogen, C_1-6alkyl, -OH, -O-C_1-6alkyl, -S-C_1-6alkyl, -NR⁸R⁹, and -NR⁸C(R¹²)2C(O)R⁵⁵ wherein any of the hydrogens on any of the alkyl groups may be substituted with deuterium or halogen, or R⁵ is selected from benzyloxy, naphthalenyloxy, -OCH₂CF3, and benzyl(cyclopropyl)oxy;

[0028] R⁶ is selected from hydrogen, -OH, -O-CH₃, -O-CD3, -O-CD2H, -O-CDH2, - O-CF3, -OCF2H, -OCFH2, -CN, -COOR⁸, -C(O)R⁵, -O-C(O)R⁵, -O-C(O)OR⁸, -O-C_1-6alkyl, - O-C_1-6heteroalkyl (wherein the -O-C_1-6heteroalkyl does not include a directly bonded -O-O- or -O-S-), -O-C_3-6cycloalkyl, -O-C_3-6heterocycle, -NR⁸R⁹, -NR⁸-C(O)OR⁸, -NR⁸-C(O)OR⁸, - NR⁸-C(O)NR⁸R⁹, -NR⁸OR⁸, and -OSi(R¹³)₃;

[0029] R⁷ is selected from hydrogen, deuterium, halogen, -CD3, -CD2H, -CDH2, -CF3, CF2H, -CFH2, -OH, -OCH₃, -O-haloalkyl, -CN, -C(O)R⁵, -C(O)OR⁸, -C(O)NR⁸R⁹, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, -NR⁸R⁹, -NR⁸C(O)OR⁸, -NR⁸C(O)NR⁸R⁹, and -NR⁸C(O)R⁸; [0030] R⁸ and R⁹ are independently selected at each occurrence from hydrogen, C_1- ₆alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_1-4alkyl-aryl, C_1-4alkyl-heteroaryl, C_2-6alkenyl, C2- ₆alkynyl, aryl, heteroaryl, and heterocycle;

[0031] R¹⁰ is independently selected at each occurrence from hydrogen, C_1-6alkyl, C_1- ehaloalkyl, C_3-6cycloalkyl, C_1-4alkyl-aryl, C_1-4alkyl-heteroaryl, aryl, heteroaryl, heterocycle, - OR⁸ and -NR⁸R⁹;

[0032] R¹¹ is independently selected at each occurrence from halogen, -OR⁸, -SR⁸, -

S(O)R¹⁰, -S(O)₂R¹⁰, -NHC(NH)NH₂, -N3, -CN, -C(O)OR8, -C(O)NR8R9, C_2-6alkenyl, C2- ₆alkynyl, -C(S)R¹⁰, and -NR⁸C(O)R¹⁰;

[0033] R¹² is independently selected at each occurrence from hydrogen, C_1-6alkyl, C_1- ehaloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_1-6alkylC(O)R¹⁰, C_1-6alkyl-R¹¹, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R¹⁷ groups, or two R¹² groups, together with the carbon to which they are attached, form a 3-8 member cycloalkyl or heterocyclyl;

[0034] R¹³ is independently selected at each occurrence from C_1-6alkyl, aryl, and C_1- ₆alkyl-aryl;

[0035] R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are independently selected at each occurrence from deuterium, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -SR⁸, C_1- ₆alkylC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -N3, alkenyl, alkynyl, -C(S)R¹⁰, and -NR⁸C(O)R¹⁰;

[0036] R¹⁸ is independently selected at each occurrence from hydrogen, deuterium, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -O-C(O)-R⁵, -C(O)R⁵, -SR⁸, and

-C_1-6alkylC(O)R⁵;

[0037] R⁵⁵ is selected from C_1-6alkyl, -O-C_1-6alkyl, -S-C_1-6alkyl, and -NR⁸R⁹;

[0038] W is selected from -NH₂, -NHR⁸, -NR⁸R⁹, and -NHC(O)R⁵;

[0039] X is selected from N and CR¹²;

[0040] Y is selected from -CH₂-, -CH₂CH₂-, -CH(R¹²)-, -C(R¹²)₂-, -CF2-, -

C(CH₂CH₂)-, and -C(CH₂CH₂)CH₂-;

[0041] z is 0, 1, 2, or 3; and

[0042] Linker is selected from: , wherein the bond from the nitrogen atom in Linker is connected to Y.

[0043] In another embodiment of the disclosure, compounds of Formula la are disclosed: or a pharmaceutically acceptable salt or cocrystal thereof.

[0044] In certain embodiments of Formula la, R¹ is C_1-4alkyl-aryl optionally substituted with 1 or 2 R¹⁴ groups.

[0045] In certain embodiments of Formula la, R¹ is hydrogen or C_1-4alkyl-aryl.

[0046] In certain embodiments of Formula la, R³ is selected from C_1-6alkyl, C_1- ehaloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_1-6alkylC(O)R¹⁰, C_1-6alkyl-R¹¹, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups, typically 1 or 2 R¹⁵ groups and R⁴ is hydrogen.

[0047] In certain embodiments of Formula la, R³ is selected from hydrogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_1-6alkylC(O)R¹⁰, C_1-6alkyl-R¹¹, C_1-6alkyl- aryl, C_1-6alkyl-heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups, typically 1 or 2 R¹⁵ groups and R⁴ is selected from C_1-6alkyl, halogen, and C_1-6haloalkyl.

[0048] In certain embodiments of Formula la, R³ is C_1-6alkyl.

[0049] In certain embodiments, the compound is a compound of Formula II:

Formula II or a pharmaceutically acceptable salt or cocrystal thereof, wherein:

[0050] R³³ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups, and typically 1 or 2 R¹⁵ groups;

[0051] R⁴⁴ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁶ groups, and typically 1 or 2 R¹⁶ groups;

[0052] or R⁴ and R⁴⁴ together with the atoms to which they are attached form a 4, 5, 6, or 7 membered cycloalkyl or heterocyclic ring, including a bridged cycloalkyl or heterocyclic ring;

[0053] or R² and R⁴⁴ together with the atoms to which they are attached, form a 5, 6, or 7 membered heterocyclic ring, including a bridged heterocyclic ring; and

[0054] Linker⁶ is selected from: , d from the nitrogen atom in Linker⁶ is connected to Y; and all other variables are as described for Formula I.

[0055] In another embodiment, compounds of Formula III are disclosed:

Formula III or a pharmaceutically acceptable salt or cocrystal thereof, wherein:

[0056] R⁶⁶ is selected from hydrogen, -OH, -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, -

OCF2H, -OCFH2, -CN, -C(O)R¹⁰, -O-C(O)R¹⁰, -O-C_1-6alkyl, -O-C_3-6cycloalyl, -O-C3- eheterocycle, -NR⁸R⁹, -NR⁸-C(O)OR⁸, -NR⁸-C(O)NR⁸R⁹, and -OSi(R¹³)₃; and [0057] all other variables are as defined for Formula I and Formula II.

[0058] In another embodiment, compounds of Formula IV are disclosed: Formula IV or a pharmaceutically acceptable salt or cocrystal thereof, wherein all variables are as defined for Formula I and Formula II.

[0059] In another embodiment, compounds of Formula V are disclosed:

Formula V or a pharmaceutically acceptable salt or cocrystal thereof, wherein:

[0060] R⁶⁶ is selected from hydrogen, -OH, -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, -

OCF2H, -OCFH2, -CN, -C(O)R¹⁰, -O-C(O)R¹⁰, -O-C(O)OR8, -O-C_1-6alkyl, -O-C_3-6cycloalyl, -O-C_3-6heterocycle, -NR⁸R⁹, -NR⁸-C(O)OR⁸, -NR⁸-C(O)NR⁸R⁹, and -OSi(R¹³)₃;

[0061] Linker⁰ is selected from: , wherein the bond from the nitrogen or oxygen atom in Linker⁰ is connected to Y; and all other variables are as defined for Formula I and III.

[0062] In another embodiment, compounds of Formula VI are disclosed: or a pharmaceutically acceptable salt or cocrystal thereof, wherein:

[0063] Y² is selected from -CH₂-, -CD2-, -CH₂CH₂-, -CH(R¹²)-, -C(R¹²)₂-, -CF2-, -C(CH₂CH₂)CH₂-, -O-, -S-, -OCH₂-, -OCD2-, -OCH₂CH₂-, -OCH(R¹²)-, -OC(R¹²)₂-, -OCF2-, -OC(CH₂CH₂)CH₂-, -SCH₂-, -SCH₂CH₂-, -SCH(R¹²)-, -SC(R¹²)₂-, -SCF2-, - SC(CH₂CH₂)CH₂-, -NR⁸-, -NR⁸CH₂-, -NR⁸CD₂-, -NR⁸CH₂CH₂-, -NR⁸CH(R¹²)-, - NR⁸C(R¹²)2-, - NR⁸CF₂-, and - NR⁸C(CH₂CH₂)CH₂-;

[0064] Linker⁰ is selected from: , wherein either bond may be attached to Y²; and all other variables are as defined herein for Formula I and Formula III.

[0065] In an embodiment, compounds of Formula VII and Formula Vila are disclosed:

Formula Vila or a pharmaceutically acceptable salt or cocrystal thereof; wherein

[0066] Purine is selected from:

[0067] W² is selected from -OH, -O-C_1-6alkyl, -O-C_1-6haloalkyl, -NH₂, -NHR⁸, - NR⁸R⁹, fluoro, chloro, and -C(O)R⁵;

[0068] W³ is selected from R⁶, fluoro, and chloro; and all other variables are as defined herein. [0069] In certain embodiments, W3 is selected from-OH, -NH₂, -NHR⁸, -NR⁸R⁹, fluoro, and chloro.

[0070] In another embodiment, compounds of Formula Villa, Vlllb, and VIIIc are disclosed:

Formula VIIIc or a pharmaceutically acceptable salt thereof; wherein

R⁶⁰ is selected from -OH, -OCD₃, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, and - OCFH2; and all other variables are described herein.

[0071] The compound of the present disclosure has a chiral phosphorus atom which can be in the Rp or Sp stereoconfiguration or a mixture thereof including a racemic mixture. In a non-limiting embodiment, a compound of the present disclosure or a pharmaceutically acceptable salt or cocrystal thereof is a mixture of Rp and Sp stereoisomers. In other embodiments, the amount of Rp by weight is, for example, greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even 85% or more. In other embodiments, the amount of Sp by weight is, for example, greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even 85% or more. In other embodiments, the amount of Rp by weight is, for example, about 90%, 92%, 95%, 98%, or even 99%. In other embodiments, the amount of Sp by weight is, for example, about 90%, 92%, 95%, 98%, or even 99%. In certain embodiments, a compound of the present disclosure or a pharmaceutically acceptable salt or cocrystal thereof is greater than about 90%, 92%, 95%, 98%, or even 99% pure as the Rp stereoisomer. In certain embodiments, a compound of the present disclosure or a pharmaceutically acceptable salt or cocrystal thereof is greater than about 90%, 92%, 95%, 98%, or even 99% pure as an Sp stereoisomer.

[0072] In certain embodiments, R³ and R⁴ are different, resulting in a stereocenter at the carbon to which they are attached. In certain embodiments, the stereocenter corresponds to an S-stereochemistry as assigned by Cahn-Ingold-Prelog rules of priority. In certain embodiments, the stereocenter corresponds to an R-stereochemistry as assigned by Cahn- Ingold-Prelog rules of priority. In certain embodiments, the amount of S-stereoisomer by weight of the chiral center comprising R³ and R⁴ is for example, greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even 85% or more. In certain embodiments, the amount of R-stereoisomer by weight of the chiral center comprising R³ and R⁴ is for example, greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even 85% or more. In certain embodiments, R³ is methyl. An example of a stereocenter at the carbon to which R³ and R⁴ are attached is when R³ corresponds to the side chain of a natural (L-stereoconfiguration) or non-natural (D-stereoconfiguration) amino acid and R⁴ is hydrogen. The stereoconfiguration of the chiral carbon corresponding to the natural amino acid configuration is sometimes selected in the present disclosure. In certain aspects, the amount of S-stereoisomer of the amino acid by weight is for example, greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even 85% or more. In alternative embodiments, the amount of R-stereoisomer of the amino acid by weight is for example greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even 85% or more.

[0073] In certain embodiments, R³³ and R⁴⁴ are different, resulting in a stereocenter at the carbon to which they are attached. In certain embodiments, the stereocenter corresponds to S-stereochemistry of the amino acid. In certain embodiments, the stereocenter corresponds to R-stereochemistry of the amino acid. In certain embodiments, the amount of S-isomer by weight of the chiral center comprising R³³ and R⁴⁴ is for example, greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even 85% or more. In certain embodiments, the amount of R-isomer by weight of the chiral center comprising R³³ and R⁴⁴ is for example, greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even 85% or more. In certain embodiments, the stereocenter is formed when R³³ corresponds to the side chain of a natural (L-stereoconfiguration) or non-natural (D- stereoconfiguration) amino acid and R⁴⁴ is hydrogen.

[0074] In certain embodiments, a compound of Formula I is selected from pharmaceutically acceptable salt or cocrystal thereof.

[0075] In certain embodiments, a compound of Formula la is selected from

pharmaceutically acceptable salt or cocrystal thereof.

[0076] In certain embodiments, a compound of Formula II is selected from

cocrystal thereof.

[0077] In certain embodiments, a compound of Formula III is selected from or a pharmaceutically acceptable salt or cocrystal thereof.

[0078] In certain embodiments, a compound of Formula IV is selected from or a pharmaceutically acceptable salt or cocrystal thereof.

[0079] In certain embodiments, a compound of Formula V is selected from or a pharmaceutically acceptable salt or cocrystal thereof. [0080] In certain embodiments, a compound of Formula VI is selected from or a pharmaceutically acceptable salt or cocrystal thereof.

[0081] In certain embodiments, the present disclosure includes a compound selected

pharmaceutically acceptable salt or cocrystal thereof. [0082] In certain embodiments, the present disclosure includes a compound selected from: pharmaceutically acceptable salt or cocrystal thereof. [0083] In certain embodiments, the present disclosure includes a compound selected from: pharmaceutically acceptable salt or cocrystal thereof.

[0084] In certain embodiments, the present disclosure includes a compound selected from:

pharmaceutically acceptable salt or cocrystal thereof.

[0085] In certain embodiments, the present disclosure includes a compound selected from eutically acceptable salt or cocrystal thereof.

[0086] In certain embodiments, Linker, Linker⁶, Linker⁰, or Linker⁶* as selected, has one or more chiral centers. Each stereocenter in Linker, Linker⁶, Linker⁰, or Linker⁶* can independently be the S- or the R-stereoisomer or a mixture thereof, including but not limited to a racemate, and limited only by any geometric configuration constraints, which are known or should be apparent to those skilled in the art.

[0087] For example, as known to the skilled artisan, if Linker, Linker⁶, or Linker⁰ i , the structure includes the stereoisomers geometric configuration constraints.

[0088] In certain embodiments, Linker is selected from

[0090] In certain embodiments, Linker⁰ is selected from

[0091] In certain embodiments, the active anti-HPV agent described herein is provided as a pharmaceutically acceptable salt or cocrystal for use in an effective amount to treat the host in need thereof, such as a human. In certain embodiments, the salt or cocrystal can impart desired properties to the active anti-HPV agent, including, in non-limiting aspects, one or more of advantageous lipophilicity, tissue penetration, and/or bioavailability, controlled release properties, formulation stability, advantageous melting point, favorable morphic form, etc. The salt or cocrystal can be prepared and used in any ratio that achieves the desired results, including but not limited to about 1 : 1 (active moiety to counterion or coformer), 1 :0.5; 1 : 1.5; 1 :2; 1 :2.5, and 1 :3, etc., for any selected counterion/coformer, including any of those listed below with any of the selected active anti-HPV agents described herein.

[0092] For example, an active compound with a nitrogenous base as described herein can be administered as a salt or cocrystal of an organic acid, such as an aliphatic mono- or dicarboxylic acid, a phenyl-substituted alkanoic acid, a hydroxy alkanoic acid, an alkanedioic acid, an aromatic acid, an aliphatic or aromatic sulfonic acid, or the like. The organic salts listed above are as illustrative examples but are not meant to be limiting. Many of the compounds of the disclosure are bases. Accordingly, the reaction of these bases with acids under suitable conditions may be used to generate salts or cocrystals of the disclosure.

[0093] Examples of salts include acetate, propionate, butyrate, fumarate, glyoxylate, caprylate, isobutyrate, oxalate, tosylate, citrate, glycolate, malonate, succinate, valerate, oleate, palmitate, stearate, laurate, suberate, sebacate, fumarate, maleate, lactate, glutarate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenyl acetate, citrate, caproate, adipate, lactate, tartrate, methanesulfonate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate, and isethionate, etc.

[0094] In other embodiments, a salt or cocrystal of a natural or unnatural amino acid can be used. The amino acid can be an alpha (D- or L-), beta, or gamma amino acid. The amino acid may be selected from for example, arginine, histidine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, proline, serine, tyrosine, gluconate, and galacturonate, or the like.

[0095] In another embodiment, a salt or cocrystal of a nitrogenous base can be prepared from an inorganic acid. Inorganic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, borate, iodide, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, and phosphorus.

[0096] In another embodiment, a pharmaceutically acceptable basic salt or cocrystal of an active compound of the present disclosure that has an acidic group (such as a carboxylic acid) contains a cation of an alkali and alkaline earth metal, such as sodium, lithium, potassium, calcium, magnesium or the like, or a non-toxic ammonium, quaternary ammonium, or amine cation such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.

[0097] Salts and/or cocrystals of the compounds disclosed herein may also be hydrates and/or solvates. A hydrate is present when the salt and/or cocrystal also contains water. The hydrate may be stoichiometric (such as a monohydrate) or non-stoichiometric. A solvate is present when the salt and/or cocrystal also contains solvent. The solvate may be stoichiometric (such as a monoethanolate) or non-stoichiometric.

[0098] The present disclosure includes the compounds of Formulas I, II, III, IV, V, VI, VII, Vila, Villa, Vlllb, and VIIIc or pharmaceutically acceptable salts or cocrystals thereof that are active against HPV. The compounds can be used to treat HPV infection, or a disease associated with HPV infection, such as intraepithelial neoplasia, including but not limited to cervical intraepithelial neoplasia, anal intraepithelial neoplasia, vulvar intraepithelial neoplasia, penile intraepithelial neoplasia, perianal intraepithelial, and vaginal intraepithelial neoplasia. Treatment of these conditions may, in some embodiments, prevent the transition of the intraepithelial neoplasia to cancer.

[0099] There are many strains of HPV that may be treated with the compounds disclosed herein, some of which are strongly associated with the development of cancer and are known as high-risk strains. In some embodiments, the compounds of Formulas I, II, III, IV, V, VI, VII, Vila, Villa, Vlllb, and VIIIc can be used to treat the high-risk types of HPV, including HPV- 16 and HPV- 18.

[00100] In exemplary non-limiting embodiments, a method for the treatment of an HPV-induced intraepithelial neoplasia is provided that includes administering an effective amount of one or a combination of the active compounds as described herein in a topical formulation that is sufficient to treat the neoplasia.

[00101] Therefore, the present disclosure includes at least the following features:

(i) A compound of Formula I, II, III, IV, V, VI, VII, Vila, Villa, VIHb, and VIIIc, or a pharmaceutically acceptable salt or cocrystal thereof;

(ii) The compound or a pharmaceutically acceptable salt or cocrystal thereof of (i) in an enantiomerically enriched or enantiomerically pure form;

(iii) The compound or a pharmaceutically acceptable salt or cocrystal thereof of (ii) wherein the phosphorus atom is greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even about 85% or more enantiomerically enriched in the Rp enantiomer;

(iv) The compound or a pharmaceutically acceptable salt or cocrystal thereof of (ii) or (iii) wherein the chiral carbon to which R³ and R⁴ are attached in the active compound is greater than about 50%, or equal to or greater than about 60%, 70%, 75%, 80%, or even about 85% or more enantiomerically enriched as the L-amino acid;

(v) The compound of (i)-(iv) in a pharmaceutically acceptable salt form, wherein the pharmaceutically acceptable salt is selected from a fumarate, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, benzoate, besylate, gluconate, naphthoate, acetate, succinate, lactate, malate, tartrate, citrate, ascorbate, nicotinate, mesylate, and salicylate;

(vi) The compound of (v), wherein the ratio of active moiety to counterion is about 1 :0.5, 1 : 1, 1 : 1.5, 1 :2, 1 :2.5, or 1 :3;

(vii) The compound of (i)-(iv) in a cocrystal form with a coformer; (viii) The compound of (vii), wherein the wherein the ratio of active moiety to coformer is approximately 1 :0.5, 1 : 1, 1 : 1.5, 1 :2, 1 :2.5, or 1 :3;

(ix) Topical pharmaceutical compositions comprising an effective amount of an active compound as described herein, or a pharmaceutically acceptable salt or cocrystal form thereof in a pharmaceutically acceptable composition;

(x) The topical pharmaceutical compositions of (ix) in the form of a tablet;

(xi) The topical pharmaceutical compositions of (ix) in the form of a semi-solid dosage form;

(xii) The topical pharmaceutical compositions of (ix) in the form of a reconstituted powder;

(xiii) The topical pharmaceutical compositions of (ix) in the form of a dry powder dosage form;

(xiv) The topical pharmaceutical compositions of (ix) in the form of a film;

(xv) The topical pharmaceutical compositions of (ix) in the form of a pessary;

(xvi) The topical pharmaceutical compositions of (ix)-(xv) for delivery to the cervix, vagina, vulva, penis, perianal region, and/or anus;

(xvii) A method to treat an HPV-induced infection or an associated condition, including but not limited to intraepithelial neoplasia such as cervical, vaginal, vulvar, perianal, anal or penile, comprising administering to a host in need thereof an effective amount of a compound, morphic form, salt or cocrystal form of any one of the embodiments above, optionally in a pharmaceutical composition, to a host, such as a human, in need thereof;

(xviii) Use of any of the compound, morphic form, salt or cocrystal form of any one of the embodiments above in the manufacture of a medicament for the treatment of HPV infection or an associated condition, including but not limited to intraepithelial neoplasia such as cervical, penile, vulvar, perianal, anal or vaginal, in a host in need thereof;

(xix) Embodiments (i)-(xvi) for use in treating HPV infection or an associated condition, including but not limited to intraepithelial neoplasia, such as cervical, penile, vulvar, perianal, anal or vaginal, in a host in need thereof;

(xx) Any one of above embodiments of (xvii)-(xix), wherein the host is a human. DETAILED DESCRIPTION

[00102] In certain aspects, the disclosure includes a compound of Formula I, II, III, IV, V, VI, VII, Vila, Villa, Vlllb, and VIIIc or a pharmaceutically acceptable salt or cocrystal thereof, optionally in a pharmaceutically acceptable composition. These compounds are active against HPV infection, and therefore can be used to treat HPV infection or a disease or condition related to HPV infection such as HPV-induced neoplasia, including but not limited to cervical intraepithelial neoplasia, perianal intraepithelial neoplasia, penile intraepithelial neoplasia, vulvar intraepithelial neoplasia, anal intraepithelial neoplasia, and vaginal intraepithelial neoplasia.

[00103] The compound, compositions, and dosage forms disclosed herein can also be used to treat conditions related to or occurring as a result of an HPV viral exposure or infection. For example, the active compound can be used to treat precancerous cervical lesions, cervical cancer, rectal cancer, penile cancer, vaginal cancer, or oropharyngeal cancer. [00104] The active compounds and salts and cocrystals thereof, and their compositions, can be used to treat an infection caused by the range of HPV types. Most of the cancer-causing HPV types are from the alpha-7 and alpha-9 species including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82. The most common cancer-causing HPV types are 16 and 18. HPV-16 and HPV-18 are reported to be the cause of 50% of cervical cancers; and 90% of venereal warts are caused by HPV-6 and HPV-11 (World Health Organization, “Cervical Cancer” https://www.who.int/news-room/fact-sheets/detail/cervical- cancer). Infection with one type of genotype does not preclude a later infection with a different genotype.

[00105] In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, Vila, Villa, Vlllb, and VIIIc, or a pharmaceutically acceptable salt or cocrystal thereof, is used to treat HPV-16. In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, Vila, Villa, Vlllb, and VIIIc, or a pharmaceutically acceptable salt or cocrystal thereof, is used to treat HPV-18. In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, Vila, Villa, Vlllb, and VIIIc, or a pharmaceutically acceptable salt or cocrystal thereof, is used to treat a high-risk HPV infection. In certain embodiments, a compound of Formula I, II, III, IV, V, VI, VII, Vila, Villa, Vlllb, and VIIIc, or a pharmaceutically acceptable salt or cocrystal thereof, is used to treat HPV type 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, or 82.

[00106] In certain embodiments, the compound or salt or cocrystal, compositions, or solid dosage forms disclosed herein can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are HPV positive or who have been exposed to HPV.

ENUMERATED EMBODIMENTS

[00107] In certain embodiments, the present disclosure includes at least:

Embodiment 1. A compound of the formula:

Formula IV

Formula Villa

Formula VIIIc or a pharmaceutically acceptable salt or cocrystal thereof, wherein:

[00108] R¹ is selected from C_1-4alkyl-aryl and C_1-4alkyl-heteroaryl either of which can be optionally substituted with 1, 2, 3, 4 or 5 R¹⁴ groups, more typically 1, 2, or 3 R¹⁴ groups, or R¹ is selected from hydrogen, acetylbenzyl, and methoxycarbonylbenzyl;

[00109] R² is selected from hydrogen, C_1-6alkyl, and C_3-6cycloalkyl;

[00110] R³ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1- ₆alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups, more typically 1 or 2 R¹⁵ groups, or R³ is CH₂CO₂NH₂ or (CH₂)2CO₂NH₂;

[00111] R⁴ is selected from hydrogen, deuterium, C_1-6alkyl, halogen, C_1-6haloalkyl, C_1- ₆alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R¹⁶ groups, more typically 1 or 2 R¹⁶ groups;

[00112] or, R¹ and R³, together with the atoms to which they are attached, form a 5, 6, 7, or 8 membered heterocycle, including a bridged heterocycle, optionally substituted with 1 or 2 R¹⁵ groups;

[00113] or, R² and R³, together with the atoms to which they are attached, form a 5, 6, 7, or 8 membered heterocycle, including a bridged heterocycle, optionally substituted with 1 or 2 R¹⁵ groups; [00114] or, R³ and R⁴, together with the carbon to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl;

[00115] R⁵ is selected from hydrogen, C_1-6alkyl, -OH, -O-C_1-6alkyl, -S-C_1-6alkyl, - NR⁸R⁹, and -NR⁸C(R¹²)2C(O)R⁵⁵ wherein any of the hydrogens on any of the alkyl groups may be substituted with deuterium or halogen, or R⁵ is selected from benzyloxy, naphthalenyloxy, -OCH₂CF3, and benzyl(cyclopropyl)oxy;

[00116] R⁶ is selected from hydrogen, -OH, -O-CH₃, -O-CD3, -O-CD2H, -O-CDH2, - O-CF3, -OCF2H, -OCFH2, -CN, -C(O)OR⁸, -C(O)R⁵, -O-C(O)R⁵, -O-C(O)OR⁸, -O-C_1-6alkyl, -O-C_1-6heteroalkyl (wherein the -O-C_1-6heteroalkyl does not include a directly bonded -O-O- or -O-S-), -O-C_3-6cycloalkyl, -O-C_3-6heterocycle, -NR⁸R⁹, -NR⁸-C(O)OR⁸, -NR⁸-C(O)OR⁸, - NR⁸-C(O)NR⁸R⁹, -NR⁸OR⁸, and -OSi(R¹³)₃;

[00117] R⁷ is selected from hydrogen, deuterium, halogen, -CD3, -CD2H, -CDH2, -CF3, CF2H, -CFH2, -OH, -OCH₃, -O-haloalkyl, -CN, -C(O)R⁵, -C(O)OR⁸, -C(O)NR⁸R⁹, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, -NR⁸R⁹, -NR⁸C(O)OR⁸, -NR⁸C(O)OR⁸, -NR⁸C(O)NR⁸R⁹, and - NR⁸C(O)R⁸;

[00118] R⁸ and R⁹ are independently selected at each occurrence from hydrogen, C_1- ₆alkyl, C_1-6haloalkyl, C3-6cycloalkyl, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, C2-₆alkenyl, C2- ₆alkynyl, aryl, heteroaryl, and heterocycle;

[00119] R¹⁰ is independently selected at each occurrence from hydrogen, C_1-6alkyl, C_1- ehaloalkyl, C3-6cycloalkyl, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, aryl, heteroaryl, heterocycle, - OR⁸ and -NR⁸R⁹;

[00120] R¹¹ is independently selected at each occurrence from halogen, -OR⁸, -SR⁸, -

S(O)R¹⁰, -S(O)₂R¹⁰, -NHC(NH)NH₂, -N3, -CN, -C(O)OR⁸, -C(O)NR⁸R⁹, C_2-6alkenyl, C2- ₆alkynyl, -C(S)R¹⁰, and -NR⁸C(O)R¹⁰;

[00121] R¹² is independently selected at each occurrence from hydrogen, C_1-6alkyl, C_1- ehaloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_1-6alkylC(O)R¹⁰, C_1-6alkyl-R¹¹, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, and C3-6cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R¹⁷ groups, or where possible, two R¹² groups, together with the carbon to which they are attached, form a 3-8 member cycloalkyl or heterocyclyl;

[00122] R¹³ is independently selected at each occurrence from C_1-6alkyl, aryl, and C_1- ₆alkyl-aryl;

[00123] R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are independently selected at each occurrence from deuterium, C_1-6alkyl, C3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -SR⁸, C_1- ₆alkylC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -N3, alkenyl, alkynyl, -C(S)R¹⁰, and -NR⁸C(O)R¹⁰; [00124] R¹⁸ is independently selected at each occurrence from hydrogen, deuterium, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -O-C(O)-R⁵, -C(O)R⁵, -SR⁸, and -C_1-6alkylC(O)R⁵;

[00125] R³³ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups, and typically 1 or 2 R¹⁵ groups;

[00126] R⁴⁴ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁶ groups, and typically 1 or 2 R¹⁶ groups;

[00127] or R⁴ and R⁴⁴ together with the atoms to which they are attached form a 4, 5, 6, or 7 membered cycloalkyl or heterocyclic ring, including a bridged cycloalkyl or heterocyclic ring;

[00128] or R² and R⁴⁴ together with the atoms to which they are attached, form a 5, 6, or 7 membered heterocyclic ring, including a bridged heterocyclic ring;

[00129] R⁵⁵ is selected from C_1-6alkyl, -O-C_1-6alkyl, -S-C_1-6alkyl, and -NR⁸R⁹;

[00130] R⁶⁰ is selected from -OH, -OCD₃, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, and

-OCFH2;

[00131] R⁶⁶ is selected from hydrogen, -OH, -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, -

OCF2H, -OCFH2, -CN, -C(O)R¹⁰, -O-C(O)R¹⁰, -O-C_1-6alkyl, -O-C_3-6cycloalyl, -O-C3- eheterocycle, -NR⁸R⁹, -NR⁸-C(O)OR⁸, -NR⁸-C(O)NR⁸R⁹, and -OSi(R¹³)₃;

[00132] W is selected from -NH₂, -NHR⁸, -NR⁸R⁹, and -NHC(O)R⁵;

[00133] W² is selected from -OH, -O-C_1-6alkyl, -O-C_1-6haloalkyl, -NH₂, -NHR⁸, - NR⁸R⁹, fluoro, chloro, and -C(O)R⁵;

[00134] W³ is selected from R⁶, fluoro, and chloro;

[00135] X is selected from N and CR¹²;

[00136] Y is selected from -CH₂-, -CH₂CH₂-, -CH(R¹²)-, -C(R¹²)₂-, -CF2-, -

C(CH₂CH₂)-, and -C(CH₂CH₂)CH₂-;

[00137] Y² is selected from -CH₂-, -CD2-, -CH₂CH₂-, -CH(R¹²)-, -C(R¹²)₂-, -CF2-, -C(CH₂CH₂)CH₂-, -O-, -S-, -OCH₂-, -OCD2-, -OCH₂CH₂-, -OCH(R¹²)-, -OC(R¹²)₂-, -OCF2-, -OC(CH₂CH₂)CH₂-, -SCH₂-, -SCH₂CH₂-, -SCH(R¹²)-, -SC(R¹²)₂-, -SCF2-, - SC(CH₂CH₂)CH₂-, -NR⁸-, -NR⁸CH₂-, -NR⁸CD₂-, -NR⁸CH₂CH₂-, -NR⁸CH(R¹²)-, - NR⁸C(R¹²)2-, - NR⁸CF₂-, and - NR⁸C(CH₂CH₂)CH₂-; z is 0, 1, 2, or 3;

[00138] Purine is selected from: , wherein the bond from the nitrogen atom in Linker is connected to Y;

[00140] Linker⁶ is selected from:

, wherein the bond from the nitrogen atom in Linker⁶ is connected to Y;

[00141] Linker⁰ is selected from: , wherein the bond from the nitrogen or oxygen atom in Linker⁰ is connected to Y; and

[00142] Linker⁶* is selected from:

, wherein either bond may be attached to Y²; or a pharmaceutically acceptable salt or cocrystal thereof.

Embodiment 2. The compound of embodiment 1, wherein R⁷ is selected from hydrogen, C_1-6alkyl, and C_3-6cycloalkyl.

Embodiment 3. The compound or embodiment 1 or 2, wherein R⁷ is selected from hydrogen, methyl, ethyl, isopropyl, and cyclopropyl.

Embodiment 4. The compound of any one of embodiments 1-3, wherein R⁶ is selected from -OH, -O-CH₃, -O-CD3, -O-CF3, -OCF2H, -OCFH2, and -OSi(R¹³)₃.

Embodiment 5. The compound of any one of embodiments 1-4, wherein R⁶ is selected from -OH, -O-CH₃, -O-CD3, -O-CF3, -OCF2H, and -OCFH2.

Embodiment 6. The compound of any one of embodiments 1-5, wherein R⁶ is selected from -OH, -O-CH₃, and -O-CD3.

Embodiment 7. The compound of any one of embodiments 1-3, wherein R⁶⁶ is selected from -OH, -O-CD3, -O-CF3, -OCF2H, -C(O)R¹⁰ (such as -C(O)NR⁸R⁹ or -C(O)OR⁸), -O-C(O)R¹⁰ (such as -O-C(O)NR⁸R⁹), -OCFH2, and -OSi(R¹³)₃.

Embodiment 8. The compound of embodiment 7, wherein R⁶⁶ is selected from -OH, - O-CF3, -OCF2H, -O-CD3, -OCFH2, and -OSi(R¹³)₃.

Embodiment 9. The compound of any one of embodiments 1-8, wherein R¹³ is independently selected at each occurrence from C_1-6alkyl and aryl. Embodiment 10. The compound of any one of embodiments 1-9, wherein at least one R¹³ is C_1-6alkyl.

Embodiment 11. The compound of embodiment 10, wherein the C_1-6alkyl is selected from methyl, ethyl, and isopropyl.

Embodiment 12. The compound of any one of embodiments 1-3 or 9-11, wherein R⁶⁶ is -

OSi(CH₃)3.

Embodiment 13. The compound of any one of embodiments 1-3, wherein the compound is of Formula l

Embodiment 14. The compound of any one of embodiments 1-13, wherein R¹ is C_1- 4alkyl-aryl optionally substituted with 1, 2, or 3 R¹⁴ groups.

Embodiment 15. The compound of embodiment 14, wherein the C_1-4alkyl-aryl is unsubstituted.

Embodiment 16. The compound of any one of embodiments 1-15, wherein R² is hydrogen or C_1-6alkyl.

Embodiment 17. The compound of embodiment 16, wherein R² is hydrogen.

Embodiment 18. The compound of embodiment 16, wherein R² is methyl.

Embodiment 19. The compound of any one of embodiments 1-15, wherein R² is C3- ecycloalkyl

Embodiment 20. The compound of embodiment 19, wherein R² is cyclopropyl.

Embodiment 21. The compound of any one of embodiments 1-20, wherein R³ is selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-

NR⁸R⁹, C_1-6alkylC(O)R¹⁰, C_1-6alkyl-R¹¹, C_1-6alkyl-aryl, and C_1-6alkyl-heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups.

Embodiment 22. The compound of any one of embodiments 1-20, wherein R³ is hydrogen.

Embodiment 23. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl.

Embodiment 24. The compound of any one of embodiments 1-20, wherein R³ is methyl.

Embodiment 25. The compound of any one of embodiments 1-20, wherein R³ is ethyl. Embodiment 26. The compound of any one of embodiments 1-20, wherein R³ is isopropyl.

Embodiment 27. The compound of any one of embodiments 1-20, wherein R³ is CH(CH₃)CH₂CH₃.

Embodiment 28. The compound of any one of embodiments 1-20, wherein R³ is CH₂CH(CH₃)2.

Embodiment 29. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl-OR⁸.

Embodiment 30. The compound of any one of embodiments 1-20, wherein R³ is CH₂OH or CH₂SH.

Embodiment 31. The compound of any one of embodiments 1-20, wherein R³ is CH(CH₃)OH.

Embodiment 32. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl-NR⁸R⁹.

Embodiment 33. The compound of any one of embodiments 1-20, wherein R³ is (CH₂)₄NH₂.

Embodiment 34. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkylC(O)R¹⁰.

Embodiment 35. The compound of any one of embodiments 1-20, wherein R³ is CH₂CO₂H.

Embodiment 36. The compound of any one of embodiments 1-20, wherein R³ is CH₂CO₂NH₂.

Embodiment 37. The compound of any one of embodiments 1-20, wherein R³ is (CH₂)₂CO₂H.

Embodiment 38. The compound of any one of embodiments 1-20, wherein R³ is (CH₂)₂CO₂NH₂.

Embodiment 39. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl-R¹¹.

Embodiment 40. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl-NHC(NH)NH₂.

Embodiment 41. The compound of any one of embodiments 1-20, wherein R³ is (CH₂)₃- NHC(NH)NH₂.

Embodiment 42. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl-aryl. Embodiment 43. The compound of any one of embodiments 1-20, wherein R³ is CH₂- C₆H₅.

Embodiment 44. The compound of any one of embodiments 1-20, wherein R³ is CH₂- C₆H₄-OH.

Embodiment 45. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl-heteroaryl.

Embodiment 46. The compound of any one of embodiments 1-20, wherein R³ is

Embodiment 47. The compound of any one of embodiments 1-20, wherein R³ is

Embodiment 48. The compound of any one of embodiments 1-20, wherein R³ is selected from the group consisting of hydrogen, C_1-6haloalkyl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups.

Embodiment 49. The compound of any one of embodiments 1-20, wherein R³ is CF3.

Embodiment 50. The compound of any one of embodiments 1-20, wherein R³ is cyclopropyl.

Embodiment 51. The compound of any one of embodiments 1-50, wherein R⁴ is hydrogen.

Embodiment 52. The compound of any one of embodiments 1-50, wherein R⁴ is C_1- ₆alkyl.

Embodiment 53. The compound of embodiments 52, wherein R⁴ is methyl.

Embodiment 54. The compound of any one of embodiments 1-15, wherein R² and R³, together with the atoms to which they are attached, form a 5 or 6 membered heterocycle, optionally substituted with 1 or 2 R¹⁵ groups.

Embodiment 55. The compound of embodiment 54, wherein R² and R³ together with the atoms to which they are attached, form a 5-membered ring.

Embodiment 56. The compound of any one of embodiments 1-55, wherein R⁵ is selected from -O-C_1-6alkyl and -NR⁸R⁹.

Embodiment 57. The compound of embodiment 56, wherein R⁵ is -O-C_1-6alkyl.

Embodiment 58. The compound of embodiment 57, wherein R⁵ is -O-CH₂CH₃. Embodiment 59. The compound of embodiment 57, wherein R⁵ is-O-CD₂CD3.

Embodiment 60. The compound of embodiment 57, wherein R⁵ is -O-CH(CH₃)₂.

Embodiment 6E The compound of embodiment 56, wherein R⁵ is -NR⁸R⁹.

Embodiment 62. The compound of embodiment 61, wherein R⁵ is NH₂.

Embodiment 63. The compound of any one of embodiments 1-62, wherein Y is selected from Embodiment 64. The compound of any one of embodiments 1-63, wherein Y is selected from -CH₂-, -CF₂-, and -C(CH₂CH₂)-.

Embodiment 65. The compound of any one of embodiments 1-64, wherein Linker,

Embodiment 66. The compound of any one of embodiments 1-64, wherein Linker,

Embodiment 67. The compound of any one of embodiments 1-64, wherein Linker,

Embodiment 68. The compound of any one of embodiments 1-64, wherein Linker,

Embodiment 69. The compound of any one of embodiments 1-64, wherein Linker,

Embodiment 70. The compound of any one of embodiments 1-64, wherein Linker, Embodiment 71. The compound of any one of embodiments 1-64, wherein Linker,

Embodiment 72. The compound of any one of embodiments 1-64, wherein Linker,

Embodiment 73. The compound of any one of embodiments 1-64, wherein Linker⁶ and

Embodiment 74. The compound of any one of embodiments 1-64, wherein Linker⁰ is

Embodiment 75. The compound of any one of embodiments 1-64, wherein Linker⁰ is

Embodiment 76. The compound of any one of embodiments 1-64, wherein Linker⁰ is

Embodiment 77. The compound of any one of embodiments 1-64, wherein Linker⁰ is

Embodiment 78. The compound of any one of embodiments 1-77, wherein z is 3.

Embodiment 79. The compound of any one of embodiments 1-77, wherein z is 2.

Embodiment 80. The compound of any one of embodiments 1-77, wherein z is 1. Embodiment 81. The compound of any one of embodiments 1-80, wherein R¹⁸ is deuterium, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -SR⁸, and C_1-6alkylC(O)R¹⁰.

Embodiment 82. The compound of any one of embodiments 1-81, wherein R¹⁸ is methyl.

Embodiment 83. The compound of any one of embodiments 1-81, wherein R¹⁸ is fluoro.

Embodiment 84. The compound of embodiments 1-81, wherein R¹⁸ is -OH.

Embodiment 85. The compound of any one of embodiments 1-77, wherein z is 0.

Embodiment 86. The compound of any one of embodiments 1-85, wherein the compound is a pharmaceutically acceptable salt.

[00143] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, and published applications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[00144] The compounds of the present disclosure or a pharmaceutically acceptable salt or cocrystal thereof as described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, regioisomers, and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context.

[00145] The terms “a” and “an” do not denote a limitation of quantity but rather denote the presence of at least one of the referenced item.

[00146] The term “or” means “and/or”.

[00147] Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable.

[00148] All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed. [00149] As used herein, “about” refers to a range that includes up to 10% less than and up to 10% greater than the stated value. For example, “about 100 milligrams” includes all values from 90 milligrams to 110 milligrams.

[00150] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, or its metabolite, that elicits a desired treatment effect. For example, an effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject such as a human being treated.

[00151] The term “pharmaceutical compositions” refers to an active compound described herein and a diluent, excipient, carrier, or vehicle. The term “formulation” is used interchangeably herein with the terms “composition” and “pharmaceutical composition” to mean the same thing.

[00152] A “pharmaceutically acceptable carrier” means a carrier or excipient that is useful in preparing a pharmaceutical composition/combination, that is suitably safe and nontoxic, and that is appropriate for administration to a patient, typically a human.

[00153] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. 11 :942-944 (1972)).

[00154] Attachment points for substituents or chemical groups are shown as terminated

V bonds, for example ^CH3 v or N-^CH3 each depiction equally representing a methyl group. [00155] “Alkyl” is a branched, straight chain, or cyclic saturated aliphatic hydrocarbon group. In certain embodiments, the alkyl contains from 1 to about 6 carbon atoms (C_1-Ce), from 1 to about 5 carbon atoms (C1-C5), from 1 to about 4 carbon atoms (C1-C4), from 1 to 3 carbon atoms (C1-C3), from 1 to 2 carbon atoms (C1-C2) or 1 carbon atom (Ci). In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C_1-Ce. The specified ranges as used herein indicate an alkyl group which is considered to explicitly disclose, as individual species, each member of the range described as a unique species. For example, the term Ci- Ce alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and also a carbocyclic alkyl group of 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C_1-C4alkyl as used herein indicates a straight, branched, or cyclic where possible alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.

[00156] Non-limiting illustrative examples of alkyl include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopentyl, n-hexyl, 2-methylpentane, 3 -methylpentane, 2,2- dimethylbutane, 2, 3 -dimethylbutane, cyclohexyl, and hexyl.

[00157] When a term is used that includes “alk-,” it should be understood that “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkenyl, alkynyl, and haloalkyl can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context.

[00158] “Alkenyl” is a branched, straight chain, or cyclic aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable point along the chain. Nonlimiting illustrative examples are C2-C₆alkenyl, C2-Csalkenyl, C2-C4alkenyl, and C2-C3alkenyl. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Illustrative non-limiting examples of “alkenyl” are vinylcyclopropyl, ethenyl, propenyl, and butenyl.

[00159] “Alkynyl” is a branched, straight chain, or cyclic aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C₆alkynyl or C2-C4alkynyl. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[00160] “Heteroalkyl” is an alkyl or haloalkyl group, wherein a heteroatom is substituted for a carbon atom, for example nitrogen, oxygen, or sulfur, in the alkyl chain, and does not include a directly bonded -O-O- or -O-S-. In some embodiments, the C_1-6heteroalkyl has one, two, three, four, five, or six carbon atoms in the heteroalkyl chain, and also includes at least one heteroatom. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is sulfur. Heteroalkyl groups can be straight chain or branched, wherein the branch point can be at a carbon or nitrogen atom. Nonlimiting examples of heteroalkyl moi eties include -alkyl- O-alkyl, -alkyl-NR⁸-alkyl (wherein R⁸ is as defined elsewhere herein), -alkyl-S-alkyl, -alkyl-O- haloalkyl, ether, thioether, and amide.

[00161] “Haloalkyl” indicates branched, straight chain, or cyclic alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Halogen atoms are selected from fluorine, chlorine, and bromine, typically fluorine and chlorine. Illustrative non-limiting examples of C_1-6haloalkyl include trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, tri chloromethyl, 1 -fluoro- 1 -chloromethyl, 1,1, -difluoroethyl, l,l-difluoro-2, 2, 2-di chloroethyl, 2,2,2-trifluoroethyl, penta-fluoroethyl, hexafluoroisopropyl, fluoropentyl, difluoropentyl, and difluorohexyl.

[00162] “Aryl” indicates an aromatic group containing only carbon in the aromatic ring or rings. In certain embodiments, the aryl group contains 1 or 2 separate or fused rings and is 6 to 12 ring atoms, without heteroatoms as ring members. The term “aryl” includes groups where a saturated or partially unsaturated carbocycle group is fused with an aromatic ring. The term “aryl” also includes groups where a saturated or partially unsaturated heterocycle group is fused with an aromatic ring so long as the attachment point is the aromatic ring. Such compounds may include aryl rings fused to a 4 to 7 or a 5 to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, and S. For example, the rings may be fused to form a 3,4- methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1 -naphthyl and 2-naphthyl. In certain embodiments, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group.

[00163] “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 5 heteroatoms with remaining ring atoms being carbon. In some embodiments, the heteroaryl contains 1, 2, or 3 heteroatoms. In some embodiments, the heteroaryl contains 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, the heteroaryl is a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 3, or in some embodiments, from 1 to 2 heteroatoms selected from N, O, or S, with remaining ring atoms being carbon. In certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 or 6 ring atoms. In some embodiments, bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is, groups containing 8, 9, or 10 ring atoms in which one 5, 6, or 7-member aromatic ring is fused to a second aromatic or nonaromatic ring wherein the point of attachment is the aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl.

[00164] The term “heterocycle” refers to saturated and partially saturated heteroatomcontaining ring radicals, where the heteroatoms may be selected from N, S, and O. The term “heterocycle” includes monocyclic 3-8 membered rings, as well as bicyclic 5-14 membered ring systems (which can include fused, bridged, or spiro, bicyclic ring systems). It does not include rings containing -O-O- or -S-S- portions. Examples of saturated heterocycle groups include saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl); saturated 4 to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[00165] Illustrative non-limiting examples of partially saturated and saturated heterocycle groups include but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3 -dihydro-benzofl, 4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2, 3, 4- tetrahydroisoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 5,6,7-trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, 3,4- dihydro-2H-benzo[l,4]oxazinyl, benzofl, 4]dioxanyl, and dihydrothiazolyl. “Bicyclic heterocycle” includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring. “Bicyclic heterocycle” also includes heterocyclic radicals that are fused or bridged with a carbocycle radical. For example, partially unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indoline, isoindoline, partially unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms.

[00166] Non-limiting examples of bicyclic heterocycles include:

[00167] Unless otherwise drawn or clear from the context, the term “bicyclic heterocycle” includes cis and trans diastereomers. Non-limiting examples of chiral bicyclic heterocycles include:

[00168] In certain embodiments, the term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, and O.

[00169] In certain embodiments, “C_1-6haloalkyl” is a C₁-C₆haloalkyl, C₁-C₅haloalkyl, C_1-C4haloalkyl, C₁-C₃haloalkyl, C_1-C₂haloalkyl, or Cihaloalkyl.

[00170] In certain embodiments, “haloalkyl” has one carbon and one halogen selected from fluorine and chlorine.

[00171] In certain embodiments, “haloalkyl” has one carbon and two halogens selected from fluorine and chlorine.

[00172] In certain embodiments, “haloalkyl” has one carbon and three halogens selected from fluorine and chlorine.

[00173] In certain embodiments, “haloalkyl” has two carbons and one, two, three, four or five halogens selected from fluorine and chlorine.

[00174] In certain embodiments, “haloalkyl” has three carbons and one, two, three, four, or five halogens selected from fluorine and chlorine.

[00175] In certain embodiments, “haloalkyl” has four carbons and one, two, three, four, or five halogens selected from fluorine and chlorine. [00176] In certain embodiments, “haloalkyl” has five carbons and one, two, three, four, or five halogens selected from fluorine and chlorine.

[00177] In certain embodiments, “haloalkyl” has six carbons and one, two, three, four, or five halogens selected from fluorine and chlorine.

[00178] Non-limiting examples of “Cihaloalkyl” include:

[00179] Additional non-limiting examples of “C_1-6haloalkyl” include:

[00180] Additional non-limiting examples of “C_1-6haloalkyl” include:

Cl

> and Cl

[00181] Additional non-limiting examples of “C_1-6haloalkyl” include: Cl Cl

[00182] Illustrative non-limiting examples of “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[00183] Additional non-limiting examples of 5 membered “heteroaryl” groups include:

[00184] In certain embodiments, “heteroaryl” is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[00185] Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include:

[00186] Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole.

[00187] Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

[00188] Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

[00189] Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

[00190] In certain embodiments, “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. [00191] Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. [00192] Additional non-limiting examples of “heteroaryl” groups that are bicyclic include:

[00193] In certain embodiments, “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, or 7 carbon atoms.

[00194] In certain embodiments, “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, or 6 carbon atoms.

[00195] In certain embodiments, “heterocycle” refers to a cyclic ring with two nitrogen atoms and 3, 4, 5, or 6 carbon atoms.

[00196] In certain embodiments, “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, or 5 carbon atoms.

[00197] In certain embodiments, “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, or 5 carbon atoms.

[00198] In certain embodiments, “heterocycle” refers to a cyclic ring with one oxygen, one nitrogen, one phosphorus, and 1, 2, 3, 4, or 5 carbon atoms.

[00199] Non-limiting examples of “heterocycle” include: wherein R¹, R², R⁴, and R⁵ are as defined herein.

[00200] Non-limiting examples of “heterocycle” include azetidine, oxetane, and thietane.

[00201] Additional non-limiting examples of “heterocycle” include pyrrolidine, 3- pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[00202] Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3 -di oxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3 -oxathiolane. [00203] Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-di oxane, morpholine, and thiomorpholine.

[00204] Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocyclic ring.

[00205] For example, group. However, an “aryl” group.

[00206] Non-limiting examples of “heterocycle” also include: :

[00210] Non-limiting examples of “heterocycle” also include: [00211] Additional non-limiting examples of “heterocycle” include:

[00212] Additional non-limiting examples of “heterocycle” include:

[00213] In certain embodiments, “aryl” is a 6-carbon aromatic group (phenyl).

[00214] In certain embodiments, “aryl” is a 10-carbon aromatic group (naphthyl).

[00215] In certain embodiments, “aryl” is a 6-carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring.

[00216] For example, is an “aryl” group. However, is a

“heterocycle” group.

[00217] Illustrative non-limiting examples of “C_1-4alkyl-aryl” include:

[00219] In certain embodiments, “C_1-4alkyl-aryl” refers to a 2-carbon alkyl group substituted with an aryl group. In certain embodiments, “C_1-4alkyl-aryl” refers to a 3-carbon alkyl group substituted with an aryl group.

[00220] Non-limiting examples of “C_1-4alkyl-aryl” include: [00221] In certain embodiments, a compound of Formula I is selected from:

pharmaceutically acceptable salt or cocrystal thereof.

[00222] In certain embodiments, a compound of Formula I is selected from: pharmaceutically acceptable salt or cocrystal thereof.

[00223] In certain embodiments, a compound of Formula I is selected from:

pharmaceutically acceptable salt or cocrystal thereof.

[00224] In certain embodiments, a compound of Formula II is selected from:

pharmaceutically acceptable salt or cocrystal thereof.

[00225] In certain embodiments, a compound of Formula III is selected from pharmaceutically acceptable salt or cocrystal thereof.

[00226] In certain embodiments, a compound of Formula IV is selected from pharmaceutically acceptable salt or cocrystal thereof. [00227] In certain embodiments, a compound of Formula V is selected from pharmaceutically acceptable salt or cocrystal thereof.

[00228] In certain embodiments, the phosphorus atom is greater than about 50%, 60%, 70%, 80%, 85%, 90%, 92%, 95%, 98% or more enantioenriched. In certain embodiments, the phosphorus atom is enriched in the Rp enantiomer. In certain embodiments, the phosphorus atom is greater than about 50% or at least about 60%, 70%, 80%, 85%>, 90%, 92%, 95%, 98% or more enantioenriched as the Rp enantiomer. In certain embodiments, the phosphorus atom is enriched in the Sp enantiomer. In certain embodiments, the phosphorus atom is greater than about 50% or at least about 60%, 70%, 80%, 85%, 90%, 92%, 95%, 98% or more enantioenriched as the Sp enantiomer.

[00229] In certain embodiments, the present disclosure includes a compound selected from:

pharmaceutically acceptable salt or cocrystal thereof.

[00230] In certain embodiments, the present disclosure includes a compound selected

or a pharmaceutically acceptable salt or cocrystal thereof. [00231] In certain embodiments, the present disclosure includes a compound selected from: pharmaceutically acceptable salt or cocrystal thereof. [00232] In certain embodiments, the present disclosure includes a compound selected from: pharmaceutically acceptable salt or cocrystal thereof.

[00233] In certain embodiments, the present disclosure includes a compound selected from:

pharmaceutically acceptable salt or cocrystal thereof.

[00234] In certain embodiments, Linker is selected from

[00235] In certain embodiments, Linker⁶ is selected from

[00236] In certain embodiments, Linker⁰ is selected from [00237] When a substituent is depicted with a floating bond on a bicyclic compound described herein, the substituent can be on either cycle unless excluded by context.

[00238] For example, the formula: pharmaceutically acceptable salt or cocrystal thereof.

[00239] In certain embodiments, R^{ is hydrogen. In certain embodiments, R^{ is -C_1- ₆R.l 1 (for example, - C_1-6-OH and - C_1-6-SH). [00240] In certain embodiments, R’^! is benzyl, R² is hydrogen, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00241] In certain embodiments, R? is benzyl, R² is hydrogen, R¹ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00242] In certain embodiments, R¹ is benzyl, R² is hydrogen, R³ is methyl, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00243] In certain embodiments, R¹ is benzyl, R² is hydrogen, R³ is isopropyl, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00244] In certain embodiments, R¹ is benzyl, R² is methyl, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00245] In certain embodiments, R’¹ is benzyl, R² is methyl, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00246] In certain embodiments, R^{ is benzyl, R² is methyl, R³ is methyl, R⁴ is methyl, and R^; is OCH₂CH₃,

[00247] In certain embodiments, R’^! is benzyl, R² is methyl, R³ is isopropyl, R⁴ is methyl, and R³ is OCH₂CH₃,

[00248] In certain embodiments, R¹ is p-fluorobenzyl, R² is hydrogen, R³ is methyl, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00249] In certain embodiments, R’^! is p-fluorobenzyl, R² is hydrogen, R¹ is hydrogen, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00250] In certain embodiments, R¹ is p-fluorobenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00251] In certain embodiments, R¹ is p-fluorobenzyl, R² is hydrogen, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00252] In certain embodiments, R^! is p-fluorobenzyl, R² is hydrogen, R³ is methyl, R“ is hydrogen, and R’ is OCH₂CH₃.

[00253] In certain embodiments, R¹ is p-fluorobenzyl, R² is methyl, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00254] In certain embodiments, R ^: is p-fluorobenzyl, R² is methyl, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00255] In certain embodiments, R* is p-fluorobenzyl, R² is hydrogen, R³ is CF3, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00256] In certain embodiments, R’^! is p-fluorobenzyl, R² is hydrogen, R ’ is CF3, R⁴ is hydrogen, and R⁵ is OCH₂CH₃ [00257] In certain embodiments, R’^! is p-fluorobenzyl, R² is hydrogen, R¹ is CF3, R⁴ is fluoro, and R³ is OCH₂CH₃.

[00258] In certain embodiments, R¹ is p-methoxybenzyl, R² is hydrogen, R³ is methyl, R⁴ is methyl, and R³ is OCH₂CH₃.

[00259] In certain embodiments, R^! is p-methoxybenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00260] In certain embodiments, R^! is p-methoxybenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00261] In certain embodiments, R¹ is p-methoxybenzyl, R² is hydrogen, R^J is methyl, R⁴ is fluoro, and R³ is OCH₂CH₃.

[00262] In certain embodiments, R ^: is p-methoxybenzyl, R² is hydrogen, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00263] In certain embodiments, R^{ is p-methoxybenzyl, R² is methyl, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00264] In certain embodiments, R’^! is p-methoxybenzyl, R² is methyl, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00265] In certain embodiments, R¹ is p-methoxybenzyl, R² is hydrogen, R³ is CF3, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00266] In certain embodiments, R^! is p-methoxybenzyl, R² is hydrogen, R³ is CF3, R⁴ is hydrogen, and R³ is OCH₂CH₃.

[00267] In certain embodiments, R¹ is p-methoxybenzyl, R² is hydrogen, R³ is CF3, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00268] In certain embodiments, R¹ is benzyl, R² is hydrogen, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₃.

[00269] In certain embodiments, R^! is benzyl, R² is hydrogen, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₃.

[00270] In certain embodiments, R¹ is benzyl, R² is hydrogen, R^J is methyl, R⁴ is methyl, and R⁵ is OCH₃.

[00271] In certain embodiments, R ^: is benzyl, R² is hydrogen, R³ is isopropyl, R⁴ is methyl, and R³ is OCH₃.

[00272] In certain embodiments, R^{ is benzyl, R² is methyl, R³ is methyl, R⁴ is hydrogen, and R³ is OCH₃.

[00273] In certain embodiments, R’^! is benzyl, R² is methyl, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₃. [00274] In certain embodiments, R’^! is benzyl, R² is methyl, R³ is methyl, R⁴ is methyl, and R⁵ is OCH₃.

[00275] In certain embodiments, R¹ is benzyl, R² is methyl, R³ is isopropyl, R⁴ is methyl, and R⁵ is OCH₃.

[00276] In certain embodiments, R¹ is p-fluorobenzyl, R² is hydrogen, R³ is methyl, R⁴ is methyl, and R⁵ is OCH₃.

[00277] In certain embodiments, R¹ is p-fluorobenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen, and R⁵ is OCH₃.

[00278] In certain embodiments, R¹ is p-fluorobenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is fluoro, and R’ is OCH₃.

[00279] In certain embodiments, R ^: is p-fluorobenzyl, R² is hydrogen, R^J is methyl, R⁴ is fluoro, and R⁵ is OCH₃.

[00280] In certain embodiments, R^{ is p-fluorobenzyl, R² is hydrogen, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₃.

[00281] In certain embodiments, R’^! is p-fluorobenzyl, R² is methyl, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₃.

[00282] In certain embodiments, R¹ is p-fluorobenzyl, R² is methyl, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₃.

[00283] In certain embodiments, R’^! is p-fluorobenzyl, R² is hydrogen, R¹ is CF3, R⁴ is methyl, and R⁵ is OCH₃.

[00284] In certain embodiments, R¹ is p-fluorobenzyl, R² is hydrogen, R³ is CF3, R⁴ is hydrogen, and R⁵ is OCH₃.

[00285] In certain embodiments, R¹ is p-fluorobenzyl, R² is hydrogen, R³ is CF3, R⁴ is fluoro, and R⁵ is OCH₃.

[00286] In certain embodiments, R³ is isopropyl and R⁴ is hydrogen.

[00287] In certain embodiments, R³ is n-propyl and R⁴ is hydrogen.

[00288] In certain embodiments, R³ is isobutyl and R⁴ is hydrogen.

[00289] In certain embodiments, R³ is n-butyl and R⁴ is hydrogen.

[00290] In certain embodiments, R^3J is hydrogen, and R⁴⁴ is hydrogen.

[00291] In certain embodiments, R³³ is methyl, and R⁴⁴ is hydrogen.

[00292] In certain embodiments, R³³ is hydrogen, and R⁴⁴ is methyl.

[00293] In certain embodiments, R³³ is methyl, and R⁴⁴ is methyl.

[00294] In certain embodiments, R^3J is hydrogen, and R⁴⁴ is F.

[00295] In certain embodiments, R.^3J is methyl, and R⁴⁴ is F. [00296] In certain embodiments, R’¹ is F, and R⁴⁴ is F.

[00297] In certain embodiments, R^3J is F, and R⁴⁴ is methyl.

[00298] In certain embodiments, R³³ is F, and R⁴⁴ is hydrogen.

[00299] In certain embodiments, R³³ is hydrogen, and R⁴⁴ is CF3.

[00300] In certain embodiments, R³³ is methyl, and R⁴⁴ is CF3.

[00301] In certain embodiments, R^3J is CF3, and R⁴⁴ is CF3.

[00302] In certain embodiments, R³³ is CF3, and R '⁴ is methyl.

[00303] In certain embodiments, R³³ is CF3, and R⁴⁴ is hydrogen.

[00304] In certain embodiments, R³³ is cyclohexyl, and R⁴⁴ is methyl.

[00305] In certain embodiments, R³⁵ is cyclohexyl, and R⁴⁴ is cyclohexyl.

[00306] In certain embodiments, a compound of Formula I is of a formula selected from:

pharmaceutically acceptable salt or cocrystal thereof.

[00308] In certain embodiments, a compound of Formula I is of a formula selected from:

[00309] In certain embodiments, a compound of Formula I is of a formula selected from: pharmaceutically acceptable salt or cocrystal thereof.

[00310] In certain embodiments, a compound of Formula I is selected from: or a pharmaceutically acceptable salt or cocrystal thereof. [00311] In certain embodiments, the compound of Formula II is selected from: pharmaceutically acceptable salt or cocrystal thereof. [00312] In certain embodiments, the compound of Formula II is selected from: pharmaceutically acceptable salt or cocrystal thereof.

[00313] In certain embodiments, the compound of Formula II is selected from:

pharmaceutically acceptable salt or cocrystal thereof.

[00314] In certain embodiments, the compound of Formula II is selected from:

pharmaceutically acceptable salt or cocrystal thereof.

[00315] In certain embodiments, the compound of Formula II is selected from: pharmaceutically acceptable salt or cocrystal thereof.

[00316] In certain embodiments, the compound of Formula III is selected from pharmaceutically acceptable salt or cocrystal thereof.

[00317] In certain embodiments, the compound of Formula III is selected from: pharmaceutically acceptable salt or cocrystal thereof.

[00318] In certain embodiments, the compound of Formula V is selected from: pharmaceutically acceptable salt or cocrystal thereof.

[00319] In certain embodiments, the compound of Formula V is selected from

pharmaceutically acceptable salt or cocrystal thereof.

[00320] In certain embodiments, R¹ is p-acetylbenzyl, R² is hydrogen, R³ is methyl, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00321] In certain embodiments, R’^! is p-acetylbenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00322] In certain embodiments, R^! is p-acetylbenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00323] In certain embodiments, R¹ is p-acetylbenzyl, R^z is hydrogen, R^J is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00324] In certain embodiments, R¹ is p-acetylbenzyl, R² is hydrogen, R³ is methyl, R⁴ is hydrogen, and R’ is OCH₂CH₃. [00325] In certain embodiments, R’^! is p-acetylbenzyl, R² is methyl, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00326] In certain embodiments, R¹ is p-acetylbenzyl, R² is methyl, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00327] In certain embodiments, R^! is p-acetylbenzyl, R² is hydrogen, R³ is CF3, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00328] In certain embodiments, R¹ is p-acetylbenzyl, R² is hydrogen, R³ is CF3, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00329] In certain embodiments, R¹ is p-acetylbenzyl, R² is hydrogen, R^J is CF3, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00330] In certain embodiments, R^: is m-acetylbenzyl, R² is hydrogen, R³ is methyl, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00331] In certain embodiments, R^{ is m-acetylbenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00332] In certain embodiments, R’^! is m-acetylbenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00333] In certain embodiments, R¹ is m-acetylbenzyl, R² is hydrogen, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00334] In certain embodiments, R’^! is m-acetylbenzyl, R² is hydrogen, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00335] In certain embodiments, R¹ is m-acetylbenzyl, R² is methyl, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00336] In certain embodiments, R¹ is m-acetylbenzyl, R² is methyl, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00337] In certain embodiments, R¹ is m-acetylbenzyl, R² is hydrogen, R³ is CF3, R⁴ is methyl, and R’ is OCH₂CH₃.

[00338] In certain embodiments, R¹ is m-acetylbenzyl, R² is hydrogen, R³ is CF3, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00339] In certain embodiments, R¹ is m-acetylbenzyl, R² is hydrogen, R³ is CF3, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00340] In certain embodiments, R* is p-methoxycarbonylbenzyl, R² is hydrogen, R ’ is methyl, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00341] In certain embodiments, R’^! is p-methoxycarbonylbenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen, and R⁵ is OCH₂CH₃. [00342] In certain embodiments, R’^! is p-methoxycarbonylbenzyl, R² is hydrogen, R³ is hydrogen, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00343] In certain embodiments, R¹ is p-methoxycarbonylbenzyl, R² is hydrogen, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00344] In certain embodiments, R^! is p-methoxycarbonylbenzyl, R² is hydrogen, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00345] In certain embodiments, R¹ is p-methoxycarbonylbenzyl, R² is methyl, R³ is methyl, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00346] In certain embodiments, R¹ is p-methoxycarbonylbenzyl, R² is methyl, R³ is methyl, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00347] In certain embodiments, R¹ is p-methoxycarbonylbenzyl, R² is hydrogen, R³ is CF3, R⁴ is methyl, and R⁵ is OCH₂CH₃.

[00348] In certain embodiments, R^{ is p-methoxycarbonylbenzyl, R² is hydrogen, R ’ is CF3, R⁴ is hydrogen, and R⁵ is OCH₂CH₃.

[00349] In certain embodiments, R’^! is p-methoxycarbonylbenzyl, R² is hydrogen, R³ is CF3, R⁴ is fluoro, and R⁵ is OCH₂CH₃.

[00351] In certain embodiments, the compound of the disclosure is selected from:

or a pharmaceutically acceptable salt or cocrystal thereof.

[00352] In certain embodiments, the compound is selected from: cocrystal thereof.

[00353] As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed anti-HPV compound in which the parent compound is modified by making an organic or inorganic, suitably nontoxic, acid or base addition salt thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Salts typically exhibit proton transfer between an acid and a base.

[00354] In certain embodiments, the active anti-HPV agent described herein is provided as a pharmaceutically acceptable salt or cocrystal for use in an effective amount to treat the host in need thereof, such as a human. In certain embodiments, the salt or cocrystal can impart desired properties to the active anti-HPV agent, including, in non-limiting aspects, one or more of advantageous lipophilicity, tissue penetration, and/or bioavailability, controlled release properties, formulation stability, advantageous melting point, favorable morphic form, etc. The salt or cocrystal can be prepared and used in any ratio that achieves the desired results, including but not limited to about 1 : 1 (active moiety to counterion or coformer), 1 :0.5; 1 : 1.5; 1 :2; 1 :2.5, and 1 :3, etc., for any selected counterion/coformer, including any of those listed below with any of the selected active anti-HPV agents described herein.

[00355] For example, an active compound with a nitrogenous base as described herein can be administered as a salt or cocrystal of an organic acid, such as an aliphatic mono- or dicarboxylic acid, a phenyl-substituted alkanoic acid, a hydroxy alkanoic acid, an alkanedioic acid, an aromatic acid, an aliphatic or aromatic sulfonic acid, or the like. The organic salts listed above are illustrative examples and are not meant to be limiting. Many of the compounds of the disclosure are bases. Accordingly, the reaction of said bases with acids in suitable conditions may be used to generate salts or cocrystals of the disclosure.

[00356] Examples of salts include acetate, propionate, butyrate, fumarate, glyoxylate, caprylate, isobutyrate, oxalate, tosylate, citrate, glycolate, malonate, succinate, valerate, oleate, palmitate, stearate, laurate, suberate, sebacate, fumarate, maleate, lactate, glutarate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenyl acetate, citrate, caproate, adipate, lactate, tartrate, methanesulfonate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate.

[00357] In other embodiments, a salt or cocrystals of a natural or unnatural amino acid can be used. The amino acid can be an alpha (D- or L-), beta, or gamma amino acid. The amino acid may be for example, arginine, histidine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, proline, serine, tyrosine, gluconate, or galacturonate.

[00358] In another embodiment, a salt or cocrystal of a nitrogenous base can be prepared from an inorganic acid. Inorganic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, borate, iodide, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, or the like.

[00359] In another embodiment, a pharmaceutically acceptable basic salt of an active compound of the present disclosure that has an acidic group such as a carboxylic acid, contains a cation of an alkali and alkaline earth metal, such as sodium, lithium, potassium, calcium, magnesium or the like, or a non-toxic ammonium, quaternary ammonium, or amine cation such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.

[00360] Salts and/or cocrystals of the compounds disclosed herein may also be hydrates and/or solvates. A hydrate is present when the salt and/or cocrystal also contains water. The hydrate may be stoichiometric (such as a monohydrate) or non-stoichiometric. A solvate is present when the salt and/or cocrystal also contains solvent. The solvate may be stoichiometric (such as a monoethanolate) or non-stoichiometric.

[00361] The present disclosure includes but is not limited to compounds, pharmaceutical compositions, and the use of any of the active compounds described herein with desired isotopic substitutions of atoms at amounts above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (²H) and tritium (³H) may be used anywhere in described structures. Alternatively, or in addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used. A preferred isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug. The deuterium can be bound in a location of bond breakage during metabolism (an a-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a P- deuterium kinetic isotope effect). Achillion Pharmaceuticals, Inc. (WO/2014/169278 and WO/2014/169280) describes deuteration of nucleotides to improve their pharmacokinetic or pharmacodynamic, including at the 5-position of the molecule.

[00362] Substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Substitution of deuterium for hydrogen at a site of metabolic break-down can reduce the rate of or eliminate the metabolism at that bond. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including protium (¹H), deuterium (²H) and tritium (³H). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[00363] The term "isotopically-labeled" analog refers to an analog that is a "deuterated analog", a "¹³C-labeled analog," or a "deuterated/¹³C-labeled analog." The term "deuterated analog" means a compound described herein, whereby a H-isotope, i.e., hydrogen/protium (¹H), is substituted with a H-isotope, i.e., deuterium (²H). Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with at least one deuterium. In certain embodiments, the isotope is about 90%, 95%, or 99% or more enriched in an isotope at any location of interest. In some embodiments, it is deuterium that is about 90%, 95%, or 99% isotopically enriched at a desired location. Unless indicated to the contrary, the deuteration is at least about 80% at the selected location. Deuteration of the nucleoside can occur at any replaceable hydrogen that provides the desired results.

[00365] In certain embodiments, R⁵ is selected from -O-CD3, -O-CH₂CD3, -O- CD2CH₃, -0-CD2CF3, -O-CH(CD₃)2, and -O-CD(CD₃)2.

[00366] In certain embodiments, R⁶ is selected from -O-CD3, -O-CD2H, and -O-CDH2. In certain embodiments, R⁶ is selected from -OH, -COOR8, -C(O)R5, -C(O)OR8, -NR⁸R⁹, - NR⁸-C(O)OR⁸, -NR⁸-C(O)OR⁸, -NR⁸-C(O)NR⁸R⁹, and -NR⁸OR⁸. In some embodiments, the -C(O)R⁵ group of R⁶ is selected from -CONR⁸R⁹ and -OC(O)NR⁸R⁹.

[00367] In certain embodiments, R⁷ is selected from deuterium, -CD3, -CH₂CD3, - CD2CH₃, -CD2CF3, -CH(CD₃)₂, and -CD(CD3)2. In certain embodiments, R7 is selected from -OH, -C(O)R⁵-, -C(O)OR⁸, -C(O)NR⁸R⁹, -NR⁸C(O)OR⁸, -NR⁸C(O)NR⁸R⁹, and -NR⁸C(O)R⁸. [00368] In exemplary non-limiting embodiments, a method for the treatment of HPV infection or HPV-induced intraepithelial neoplasia is provided that includes administering an effective amount of one or a combination of the active compounds as described herein or a pharmaceutically acceptable salt or cocrystal thereof, in a topical formulation that is sufficient to treat the neoplasia or the resulting effects thereof, as described further herein.

Types of HPV-induced intraepithelial neoplasia include but are not limited to cervical, vaginal, vulvar, penile, perianal, and anal.

[00369] In an exemplary embodiment, a formulation for the treatment of HPV infection or HPV-induced intraepithelial neoplasia is a dosage form containing from about 0.005 mg to about 50 mg, from about 0.05 mg to about 40 mg, from about 0.1 mg to about 30 mg, from about 0.5 mg to about 20 mg, from about 1 mg to about 20 mg, from about 1 mg to about 15 mg, or from about 1 mg to about 10 mg of any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein. In certain embodiments, a formulation for the treatment of HPV infection or HPV-induced intraepithelial neoplasia is a dosage form that contains from about 0.01 mg to about 10 mg, from about 0.05 to about 5 mg, from about 0.05 to about 0.15 mg, from about 0.15 mg to about 0.45 mg, or from about 0.5 to about 1.5 mg of any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein. In certain embodiments, a formulation for the treatment of HPV infection or HPV-induced intraepithelial neoplasia is a dosage form that contains about or at least 0.005 mg, 0.01 mg, 0.03 mg, 0.05 mg, 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein. The dose strengths in mg used herein refer to the mass of the active compound and do not include the salt or coformer in the molecular mass, and thus the total weight in the dosage form. For example, when a dosage form is said to contain 0.1 mg of a monofumarate salt of a compound of Formula I, the 0.1 mg dose is referring to the amount of compound of Formula I in the dosage form.

[00370] In certain embodiments, a formulation for the treatment of HPV infection or HPV-induced intraepithelial neoplasia is a dosage form containing of from about 0.001 mg to about 20 mg, from about 0.005 to about 10 mg, from about 0.01 mg to about 5 mg, from about 0.03 mg to about 1 mg, or from about 0.05 mg to about 0.3 mg of any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein. In certain embodiments, a formulation for the treatment of HPV infection or HPV-induced intraepithelial neoplasia is a dosage form containing of from about 0.05 mg to about 2 mg. [00371] The term “containing” when used in relation to a composition or dosage form, for example, means “comprising” (i.e., consisting at least in part of). When interpreting statements in this specification and claims which include the term “containing” or “comprising,” it is to be understood that other features that are additional to the features prefaced by this term in each statement or claim may also be present. Related terms such as “comprise” and “comprised” are to be interpreted in a similar manner.

[00372] In certain embodiments, the topical formulation is administered twice a day, once a day, or once every several days a week (such as once every 2 or 3 days), as long as necessary to achieve the desired results. In certain embodiments, the topical formulation is administered on a weekly schedule for one, two, three, four, five, six, or more weeks. In certain aspects, the topical formulation is administered on a schedule of one dosage a week for one, two, three, four, five, or six weeks. In certain aspects, the topical formulation is administered on a schedule of two dosages a week for one, two, three, four, five, or six weeks. In certain aspects, the topical formulation is administered on a schedule of three dosages a week for one, two, three, four, five, or six weeks.

[00373] In certain embodiments, the compound or a pharmaceutically acceptable salt or cocrystal thereof can be administered in one or more therapeutic cycles comprising a treatment cycle and a rest cycle (also known as a treatment break), wherein the treatment cycle comprises administering the compound as described herein, followed by a rest cycle (comprising a period of no treatment) before the next treatment cycle. In certain embodiments, the rest cycle is from about one day to about six months. In certain embodiments, the rest cycle is one, two, three, four, five, six, seven, eight, or more weeks before the next treatment cycle. In certain embodiments, multiple therapeutic cycles are administered, for example one, two, three, four, five, or six therapeutic cycles.

[00374] Dosage forms which do not adhere well to the target site may be dislodged, interfering with treatment. Dosage forms have been discovered that adhere to the target site and dissolve rapidly in low fluid volumes. Adhesion to the target site also prevents exposure to healthy tissues, which may limit toxicity and side effects. Dosage forms which soften, break down, and/or disintegrate quickly in low fluid volumes are advantageous to cause a rapid release of the active compound to the target tissue. Dosage forms that disintegrate in, for example, less than about 50 pL, less than about 100 pL, less than about 125 pL, less than about 150 pL, less than about 175 pL, less than about 200 pL, less than about 250 pL, less than about 500 pL, less than about 1 mL, or less than about 2 mL fluid facilitate drug penetration into the target site.

[00375] In certain embodiments, the dosage form is a gel. In certain embodiments, the dosage form is a cream. In certain embodiments, the dosage form is a tablet. In certain embodiments, the dosage form disintegrates in about one to about ten seconds. In certain embodiments, the dosage form disintegrates in about ten seconds to about one minute. In certain embodiments, the dosage form disintegrates in about one minute to about one hour. In certain embodiments, the dosage form disintegrates in about one hour to about six hours.

[00376] The physical dimensions of the dosage form can impact the effectiveness of the dosage form. A tablet that is thinner provides a greater surface area to volume ratio and may degrade quicker and cover the target area better. In certain embodiments, the dosage form is less than about 6, 5, 4, 3, or 2 millimeters thick in its smallest dimension. In certain embodiments, the dosage form is less than 3 millimeters thick in its smallest dimension. [00377] In some embodiments, the formulation of the dosage form may be important for adequate administration of the active agent into the intraepithelial tissue. The formulation,

I l l for example, can be prepared for use as a tablet, a reconstituted powder, a dry powder, a semi solid dosage form, a film, or a pessary (i.e., a vaginal suppository).

[00378] Some embodiments disclosed herein include the use of an effective amount of any of the active compounds described herein, or a pharmaceutically acceptable salt or cocrystal thereof, in the manufacture of a medicament for ameliorating or treating a human papillomavirus infection, wherein the human papillomavirus infection can be ameliorated or treated by inhibiting viral replication by inhibiting the synthesis of viral DNA. Other embodiments disclosed herein include the use of an effective amount of any of the active compounds described herein, or a pharmaceutically acceptable salt or cocrystal thereof, for ameliorating or treating a human papillomavirus infection, wherein the human papillomavirus infection can be ameliorated or treated by inhibiting viral replication by inhibiting the synthesis of viral DNA.

[00379] Certain nonlimiting embodiments disclosed herein include a method for ameliorating or treating a human papillomavirus infection comprising contacting a cell infected with the human papillomavirus in a subject with an effective amount of any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof, wherein the infection is ameliorated or treated by inhibiting the synthesis of viral DNA. Still other embodiments disclosed herein include a method for ameliorating or treating a human papillomavirus infection comprising administering to a subject infected with the human papillomavirus an effective amount of any of the active compounds described herein, wherein the human papillomavirus infection can be ameliorated or treated by inhibiting viral replication by inhibiting the synthesis of viral DNA. Some embodiments disclosed herein relate to any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof, for use in ameliorating or treating a human papillomavirus infection, wherein the human papillomavirus infection can be ameliorated or treated by inhibiting viral replication by inhibiting the synthesis of viral DNA.

[00380] In some embodiments, the human papillomavirus can be a low-risk human papillomavirus, including those described herein. In some embodiments, the human papillomavirus can be HPV-6. In some embodiments, the human papillomavirus can be HPV-11. In some embodiments, the human papillomavirus can be a high-risk human papillomavirus (hrHPV), such as those described herein. For example, the high-risk human papillomavirus can be selected from HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73, and HPV-82. In some embodiments, the human papillomavirus can be HPV-16. In some embodiments, the human papillomavirus can be HPV-18. In some embodiments, the human papillomavirus can be one or more of the following high-risk types: HPV-31, HPV-33, HPV-35, HPV-39, HPV- 45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59, HPV-68, HPV-73, and HPV-82. As described herein, the presence of an HPV infection can be detected using the Papanicolaou test (Pap smear) and/or DNA probe testing (for example, HPV DNA probe testing for one or more high-risk HPV types). Therefore, in some embodiments, an effective amount of any of the active compounds described herein, or a pharmaceutically acceptable salt or cocrystal thereof, can be provided to a subject diagnosed with an HPV infection, for example a high- risk HPV infection, by a DNA test. In some embodiments, an effective amount of any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be provided to a subject diagnosed with an HPV infection, or a disease associated with HPV infection, as identified by a Papanicolaou test.

[00381] In certain embodiments, an effective amount of any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof may be provided to a subject with a Papanicolaou test result that does not indicate the disease has progressed to cervical cancer. The Bethesda system is a standardized scoring system for reporting pap smear test results and assigns a grade of 1-3 based on severity. Grade 1 CIN (CIN 1) indicates mild dysplasia. Grades 2 and 3 CIN (CIN 2, CIN 3) are more serious and typically require intervention. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used to treat CIN 1 (Grade 1 cervical intraepithelial neoplasia). In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used to treat CIN 2 (Grade 2 cervical intraepithelial neoplasia). In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used to treat CIN 3 (Grade 3 cervical intraepithelial neoplasia).

[00382] In certain embodiments, a pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used in the manufacture of a medicament for the treatment of CIN 1 (Grade 1 cervical intraepithelial neoplasia). In certain embodiments, a pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used in the manufacture of a medicament for the treatment of CIN 2 (Grade 2 cervical intraepithelial neoplasia). In certain embodiments, a pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used in the manufacture of a medicament for the treatment of CIN 3 (Grade 3 cervical intraepithelial neoplasia).

[00383] In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof, optionally in a pharmaceutically acceptable carrier, are used to treat a condition selected from the group consisting of atypical squamous cells of undetermined significance (ASC-US), atypical glandular cells (AGC), low- grade squamous intraepithelial lesions (LSIL), atypical squamous cells (cannot exclude high grade squamous intraepithelial lesion) (ASC-H), high grade squamous intraepithelial lesions (HSIL), adenocarcinoma in situ (AIS), and cervical cancer (e.g. squamous cell carcinoma or adenocarcinoma).

[00384] In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used in the manufacture of a medicament for the treatment of anal intraepithelial neoplasia. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used in the manufacture of a medicament for the treatment of perianal intraepithelial neoplasia. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used in the manufacture of a medicament for the treatment of vulvar intraepithelial neoplasia. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used in the manufacture of a medicament for the treatment of penile intraepithelial neoplasia. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used in the manufacture of a medicament for the treatment of vaginal intraepithelial neoplasia.

[00385] In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used to treat anal intraepithelial neoplasia. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used to treat perianal intraepithelial neoplasia. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used to treat vulvar intraepithelial neoplasia. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used to treat penile intraepithelial neoplasia. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof are used to treat vaginal intraepithelial neoplasia. [00386] In certain embodiments, the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used to ameliorate and/or treat an infection caused by one or more types of human papillomaviruses. For example, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used to ameliorate and/or treat an infection of HPV-16 and/or HPV-18. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used to treat a high-risk HPV infection. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used to treat a related disease or condition occurring as a result of a high-risk HPV infection. In some embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used to ameliorate and/or treat an infection comprising both high-risk and low-risk HPV.

[00387] In certain embodiments, the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used in the manufacture of a medicament for use to ameliorate and/or treat an infection caused by one or more types of human papillomaviruses. For example, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used in the manufacture of a medicament for use to ameliorate and/or treat an infection of HPV-16 and/or HPV-18. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used in the manufacture of a medicament for use to treat a high-risk HPV infection. In certain embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used in the manufacture of a medicament for use to treat a related disease or condition occurring as a result of a high-risk HPV infection. In some embodiments, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used in the manufacture of a medicament for use to ameliorate and/or treat an infection comprising both high-risk and low-risk HPV.

[00388] In certain embodiments, a pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof can be used to treat conditions related to or occurring as a result of exposure to or an infection of HPV. In certain embodiments, a pharmaceutical composition comprising an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is used to treat precancerous cervical lesions. In certain embodiments, a pharmaceutical composition comprising an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is used to treat cervical intraepithelial neoplasia. In certain embodiments, a pharmaceutical composition comprising an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is used to treat vaginal and/or anal intraepithelial neoplasia. In certain embodiments, a pharmaceutical composition comprising an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is used to treat cervical cancer. In certain embodiments, a pharmaceutical composition comprising an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is used to treat rectal cancer. In certain embodiments, a pharmaceutical composition comprising an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is used to treat penile cancer. In certain embodiments, a pharmaceutical composition comprising an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is used to treat vaginal cancer. In certain embodiments, a pharmaceutical composition comprising an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is used to treat oropharyngeal cancer.

[00389] It may be advantageous for the dosage form to be easily applied to the target site. Direct application to the target site can prevent systemic exposure and toxicity. To place the dosage form on the target site, the dosage form may be applied with an applicator. In certain embodiments, the dosage form is applied with a vaginal applicator. In certain embodiments, the dosage form is applied without an applicator. In certain embodiments, additional fluid (such as a lubricant) is delivered along with the dosage form, applied to the dosage form, or applied to the target site or surrounding tissues.

[00390] In certain embodiments, a lubricating fluid is administered in combination with the dosage form to enhance the coverage of the cervix, vagina, vulva, anus, perianal region, or penis. In certain embodiments, water is used as the fluid administered with the dosage form. In certain embodiments, a lubricating glycerol- or hydroxyethylcellulose-based, water soluble fluid is used in combination with the dosage form. In certain embodiments, the dosage form is administered without additional fluid.

[00391] In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 5 milliliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 4 milliliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 3 milliliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 2 milliliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 1 milliliter of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 0.75 milliliter of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 0.5 milliliter of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 0.25 milliliter of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 0.2 milliliter of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 0.15 milliliter of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 0.125 milliliter of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in less than about 0.1 milliliter of fluid.

[00392] In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in from about 10 microliters to about 100 microliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in from about 75 microliters to about 250 microliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in from about 200 microliters to about 500 microliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in from about 400 microliters to about 750 microliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in from about 700 microliters to about 1,000 microliters of fluid.

[00393] In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in from about 1 milliliter to about 2 milliliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in from about 2 milliliters to about 3 milliliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in from about 3 milliliters to about 4 milliliters of fluid. In certain embodiments, the dosage form will soften, disintegrate, and/or dissolve in from about 4 milliliters to about 5 milliliters of fluid.

[00394] In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered for at least 1, 2, 3, 4, 5, or 6 consecutive or nonconsecutive days.

[00395] In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered once a week. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered once a week for up to 12 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered once a week for up to 10 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered once a week for up to 8 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered once a week for up to 6 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered once a week for up to 4 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered once a week for up to 2 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered once a week for up to 1 week.

[00396] In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered twice a week. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered twice a week for up to 12 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered twice a week for up to 10 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered twice a week for up to 8 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered twice a week for up to 6 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered twice a week for up to 4 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered twice a week for up to 2 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered twice a week for up to 1 week.

[00397] In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered three times a week. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered three times a week for up to 12 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered three times a week for up to 10 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered three times a week for up to 8 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered three times a week for up to 6 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered three times a week for up to 4 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered three times a week for up to 2 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered three times a week for up to 1 week.

[00398] In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered daily. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered daily for up to 12 weeks or indefinitely as instructed by a healthcare provider. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered daily for up to 10 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered daily for up to 8 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered daily for up to 6 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered daily for up to 4 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered daily for up to 2 weeks. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof is administered daily for up to 1 week. [00399] In certain embodiments, from about 0.05 mg to about 1.0 mg of an active compound described herein is administered daily for one, two, three, four, five, six, or more weeks, as instructed by a healthcare provider. In certain embodiments, from about 0.05 mg to about 0.3 mg of an active compound described herein is administered daily for one, two, three, four, five, six, or more weeks, as instructed by a healthcare provider.

[00400] In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof may be administered three, four, five, or six times a week. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof may be administered once per day. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof may be administered twice per day. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof may be administered three, four, or more times per day. In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof may be administered daily.

[00401] In certain embodiments, the compound or a pharmaceutically acceptable salt or cocrystal thereof can be administered in one or more therapeutic cycles comprising a treatment cycle and a rest cycle, wherein the treatment cycle comprises administering the compound as described herein, followed by a rest cycle (comprising a period of no treatment) before the next treatment cycle. In certain embodiments, the rest cycle is from about one day to about six months. In certain embodiments, the rest cycle is one, two, three, four, five, six, seven, eight, or more weeks before the next treatment cycle. In certain embodiments, multiple therapeutic cycles are administered, for example one, two, three, four, five, or six therapeutic cycles.

[00402] As described above, a number of compounds have been investigated for the treatment of HPV-induced neoplasia, however none has been approved yet. For non-limiting examples of investigated approaches, see Ahn W.S., et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur. J. Cancer Prev. 2003;12:383-390; Ashrafian L,et al. Double-blind randomized placebo-controlled multicenter clinical trial (phase Ila) on diindolymethane’s efficacy and safety in the treatment of CIN: implications for cervical cancer prevention. EPMA J. 2015;6:doi: 10.1186/s 13167- 13015-10048-13169; Bossens M., et al. Safety and tolerance of cidofovir as a 2% gel for local application in high-grade cervical intraepithelial neoplasia: A phase 1 investigation. Int. J Clin. Pharmacol . 2018;56: 134-141 ; Chen F.P. Efficacy of imiquimod 5% cream for persistent human papillomavirus in genital intraepithelial neoplasm. Taiwanese J. Obstetrics Gynecol. 2013;52(4):475-478; Choo Y., et al. Intravaginal application of leukocyte interferon gel in the treatment of cervical intraepithelial neoplasia (ON) Arch Gynecol. 1985;237:51- 54; de Witte C.J et al. Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review. Gynecol. Oncol. 2015;139:377-384; Desravines N, et al. Low dose 5 -fluorouracil intravaginal therapy for the treatment of cervical intraepithelial neoplasia 2/3: A case series. J. Gynecol. Surg. 2020;36; DiSilvestro P.A., et al. Treatment of cervical intraepithelial neoplasia levels 2 and 3 with adapalene, a retinoid-related molecule. J. Low Genit Tract. Dis. 2001,5:33-37; Graham V,, et al. Phase II trial of beta-all-transretinoic acid for cervical intraepithelial neoplasia via a collagen sponge and cervical cap. West. J. Med. 1986; 145: 192— 195; Grimm C., et al. Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial. Obstet. Gynecol. 2012; 120(1 ): 152- 159; Hampson L., et al. A single-arm, proof-of-concept trial of lopimune (lopinavir/ritonavir) as treatment for HPV- related pre-invasive cervical disease. PLoS ONE. 2016;! 1; Heim C.W. et al. Retinoids for preventing the progression of cervical intra-epithelial neoplasia. Cochrane Systematic Review. 2013, Hubert P., et al. Local applications of GM-CSF induce the recruitment of immune cells in cervical low-grade squamous intraepithelial lesions. Am. J. Reprod. Immunol. 2010;64: 126-136; Koeneman MM, et al. Topical Imiquimod treatment of highgrade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial. BMC Cancer. 20I6:doi: 10.1 186/sl 2885-12016-12187- 12883; Krause S., et. al. Interferon and cervical dysplasia: CIN III treated with local interferon application. Colposcopy Gynecologic Laser Surgery . 1987;3: 195-198; Krebs H.B., et al. Chronic ulcerations following topical therapy with 5 -fluorouracil for vaginal human papillomavirus- associated lesions. Obstet. Gynecol. 1991 ;78(2):205— 208; Laccetta G. et al. Effect of the treatment with beta-glucan in women with cervical cytologic report of atypical squamous cells of undetermined significance (ASCUS) and low-grade intraepithelial lesions (L-SIL) Minerva Ginecol. 2015;67: l 13-120; Meyskens F.L., et al. A phase I trial of beta-all- transretinoic acid delivered via a collagen sponge and a cervical cap for mild or moderate intraepithelial cervical neoplasia. J. Natl Cancer Inst. 1983;71 :921-925; Niwa K., et al. Topical vidarabine of 5 -fluoruracil treatment against persistent HPV in genital (pre)cancerous lesions. Oncol Reports . 2003; 10: 1437-1441; Pachman DR, et al. Randomized clinical trial of imiquimod: an adjunct to treating cervical dysplasia. Am. J. Obstet. Gynecol. 2012;206(l):42 e41-47; Rahangdale L et al. Topical 5 -fluorouracil for treatment of Cervical Intraepithelial Neoplasia 2: a randomized controlled trial. Am. J. Obstet. Gynecol. 2014;2I0:el-e8, Schneider A., et al. Efficacy trial of topically administered Interferon gamma-lbeta gel in comparison to laser treatment in cervical intraepithelial neoplasia. Arch. Gynecol Obsle. 1995;256:75-83; Silman F.H., et al. 5-fluorouracil/chemosurgery for intraepithelial neoplasia of the lower genital tract. Obstet. Gynecol. 1981;58:356-360; Snoeck R., Noel J.C., Muller C., Clercq De, Bossens M. Cidofovir, a new approach for the treatment of cervix intraepithelial neoplasia III (CIN III) J. Med. Virol. 2000;60:205-209; Stentella P., Biamonti A., Carraro C. Efficacy of carboxymethyl beta-glucan in cervical intraepithelial neoplasia: a retrospective, case-control study. Minerva Ginecol. 2017;69:425-430; Suh-Burgmann E., Sivret J., Duska L.R., Del Carmen M., Seiden M.V. Long-term administration of intravaginal dehydroepiandrosterone on regression of low-grade cervical dysplasia - a pilot study. Gynecol. Obstet. Invest. 2003;55:25-31, Valencia M.H., Pacheco A.C., Quijano T.H., Giron A.V., Lopez C.V. Clinical response to glycyrrhizinic acid in genital infection due to human papillomavirus and low-grade squamous intraepithelial lesion. Clin. Pract. 2011 l(e93); van de Sande A., Koeneman M., Gerestein C., Kruse A., van Kemenade F ., van Beekhuizen H. Topical Imiquimod treatment of residual or recurrent cervical intraepithelial neoplasia (TOPIC-2 trial): a study protocol for a randomized controlled trial. BMC Cancer. 2018;18:4510-4517; and Van Pachterbeke C., Bucella D., Rozenberg S. Topical treatment of CIN 2+ by cidofovir: Results of a phase II, double-blind, prospective, placebo-controlled study. Gynecol One. 2009; 1 15:69-74.

[00403] In an aspect of the disclosure, pharmaceutical compositions according to the present disclosure comprise an anti-HPV effective amount of any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, and/or in combination or alternation with at least one other active compound. The dose strengths in mg used herein refer to the mass of the active compound and do not include the salt or coformer in the molecular mass, and thus the total mass in the dosage form. For example, when a dosage form is said to contain 0.1 mg of a monofumarate salt of a compound of Formula I, the 0.1 mg dose is referring to the amount of compound of Formula I in the dosage form.

[00404] In certain embodiments, the disclosure includes a solid dosage form of an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof in a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is administered directly to the cervix, vagina, vulva, perianal region, anus, or penis. In certain embodiments, the dosage forms adhere to the cervix, vagina, vulva, perianal region, anus, or penis.

[00405] In an aspect of the disclosure, pharmaceutical compositions according to the present disclosure comprise an anti-HPV effective amount of an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, further optionally in combination with at least one other antineoplastic agent or antiviral agent, such as an anti- HPV agent. In certain embodiments, the pharmaceutical composition includes an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof in combination with a second antiviral drug. In certain embodiments, the pharmaceutical composition comprising an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof in combination with an anticancer drug. [00406] The disclosure includes pharmaceutical compositions comprising an effective amount to treat an HPV infection of any of the active compounds described herein of the present disclosure or a pharmaceutically acceptable salt or cocrystal thereof, in a pharmaceutically acceptable carrier or excipient. In an alternative embodiment, the disclosure includes pharmaceutical compositions comprising an effective amount of an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof, in a pharmaceutically acceptable carrier or excipient, to prevent an HPV infection.

[00407] An active compound or a pharmaceutically acceptable salt or cocrystal thereof described herein can be formulated in a mixture with a pharmaceutically acceptable carrier. To treat HPV infection, it may be preferable to administer the pharmaceutical composition directly to the cervix, vagina, vulva, perianal region, anus, or penis.

[00408] In certain pharmaceutical dosage forms, the prodrug form of the compounds, especially including acylated (acetylated or other), and ether (alkyl and related) derivatives, phosphate esters, thiophosphonamidates, phosphonamidates, and various salt forms of the present compounds, may be used to achieve the desired effect.

[00409] The amount of any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof included within the therapeutically active formulation according to the present disclosure is an effective amount to achieve a desired outcome according to the present disclosure. In some embodiments, the desired outcome is treating the HPV infection, reducing the likelihood of a HPV infection, or the inhibition, reduction, and/or abolition of HPV or its secondary effects, including disease states, conditions, and/or complications which occur secondary to HPV infection.

[00410] In some embodiments, to treat, prevent or delay the onset of these infections and/or to reduce the likelihood of an HPV virus infection, or a secondary disease state, condition or complication of HPV, a dosage form containing any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein are administered in an amount ranging from about 0.001 milligrams to about 100 milligrams. In certain embodiments, the solid dosage form comprises from about 0.001 milligrams to about 0.005 milligrams, from about 0.005 milligrams to about 0.01 milligram, from about 0.01 milligram to about 0.03 milligram, from about 0.03 milligrams to about 0.25 milligrams, from about 0.20 milligrams to about 0.5 milligrams, from about 0.4 milligrams to about 1 milligram, from about 0.75 milligram to about 3 milligrams, from about 1 milligram to about 10 milligrams, from about or 5 milligrams to about 20 milligrams. In certain embodiments, the solid dosage form comprises at least about 0.001, 0.003, 0.005 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3, 4, 5, 10, 20, 30, 40, or 50 milligrams or more of any of the active compounds described herein. As noted earlier, the dose strengths in mg used herein refer to the mass of the active compound and do not include the salt or coformer in the molecular mass, and thus the total weight in the dosage form.

[00411] In certain embodiments, to treat or delay the onset of these infections and/or to reduce the likelihood of an HPV virus infection, or a secondary disease state, condition or complication of HPV, a dosage form containing any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein are administered in an amount ranging from about 0.001 to about 20 mg, from about 0.005 to about 10 mg, from about 0.01 mg to about 5 mg, from about 0.03 mg to about 1 mg, or from about 0.05 mg to about 0.3 mg. The dosage can be administered 1, 2, 3, or more times a week, up to daily administration, typically in a dose ranging between 0.05 and 0.3 mg of an active compound described herein. In certain embodiments, a formulation for the treatment of HPV infection or HPV-induced intraepithelial neoplasia is a dosage form containing of from about 0.05 mg to about 2 mg.

[00412] In certain embodiments, to treat an infection of HPV (including a high-risk strain of HPV), a dosage form containing any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein are administered in an amount ranging from about 0.001 to about 20 mg, from about 0.005 to about 10 mg, from about 0.01 mg to about 5 mg, from about 0.03 mg to about 1 mg, or from about 0.05 mg to about 0.3 mg. The dosage for treating HPV (including a high-risk strain of HPV) can be administered 1, 2, 3, or more times a week, up to daily administration, in a dose ranging, for example, between 0.05 and 0.3 mg of an active compound described herein.

[00413] In certain embodiments, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof may be administered in a gel. In certain embodiments, the gel contains from about 0.001% to about 10%, from about 0.01% to about 10%, from about 0.05% to about 5%, from about 0.1 to about 3% from about 0.1 to about 2% of an active compound described herein (weight/weight). In certain embodiments, the gel contains from about 0.001% to about 0.05% of an active compound described herein. In certain embodiments, the gel contains from about 0.01% to about 0.5% of an active compound described herein. In certain embodiments, the gel contains from about 0.1% to about 5% of an active compound described herein. [00414] In a certain non-limiting embodiments, any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein is administered topically. More generally, an active compound described herein or a pharmaceutically acceptable salt or cocrystal thereof can be administered in any form, for example, in a tablet, capsule, suspension, liquid, emulsion, implant, particle, sphere, cream, ointment, suppository, pessary, transdermal form, gel, mucosal, and the like. The dosage form may also be a bilayer tablet, for example, in which the full dose of active compound is released in one direction (for example towards the target tissue).

[00415] In certain embodiments, a formulation for the treatment of intraepithelial neoplasia is a dosage form containing of from about 0.001 to about 20 mg, from about 0.005 to about 10 mg, from about 0.01 mg to about 5 mg, from about 0.03 mg to about 1 mg, from about 0.05 mg to about 0.3 mg, from about 0.03 mg to about 0.07 mg, from about 0.05 mg to about 0.15 mg, or from about 0.15 mg to about 0.45 mg of a compound or a pharmaceutically acceptable salt or cocrystal thereof described herein.

[00416] In certain embodiments, a formula for the treatment of intraepithelial neoplasia is a dosage form containing from about 0.001 milligrams to about 0.005 milligrams, from about 0.005 milligrams to about 0.01 milligram, from about 0.01 milligram to about 0.03 milligram, from about 0.03 milligrams to about 0.25 milligrams, from about 0.20 milligrams to about 0.5 milligrams, from about 0.4 milligrams to about 1 milligram, from about 0.75 milligram to about 3 milligrams, from about 1 milligram to about 10 milligrams, or from about or 5 milligrams to about 20 milligrams. In certain embodiments, a formulation for the treatment of intraepithelial neoplasia is a dosage form contains about or at least 0.005 mg, 0.01 mg, 0.03 mg, 0.05 mg, 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45mg or 50 mg of a compound or a pharmaceutically acceptable salt or cocrystal thereof described herein.

[00417] In some embodiments, the physical dimensions of the dosage form can impact the effectiveness of the dosage form. A tablet that is thinner provides a greater surface area to volume ratio and may degrade quicker and cover the target area better. In certain embodiments, the dosage form is less than 3 millimeters thick in its smallest dimension. [00418] In some embodiments, the formulation of the dosage form is important for adequate administration of the active agent into the intraepithelial tissue. The formulation, for example, can be prepared for use as a tablet, a reconstituted powder, a dry powder, a semi solid dosage form, a film, or a pessary (i.e., a vaginal suppository). [00419] In some embodiments, the tablet formulation should display the properties of mucoadhesion and substantivity and include excipients that have solubilizing, erosiongenerating (for disintegration), porosity (for water uptake), and viscosity enhancing (to keep the drug at the target site) properties.

[00420] Examples of excipients that may cause rapid disintegration of a solid dosage form to cover the cervix, anal, penile, perianal, vulvar, or vaginal areas include, but are not limited to mannitol, microcrystalline cellulose, lactose, sucrose, calcium phosphate, sodium phosphate, sodium bicarbonate, citric acid, maleic acid, adipic acid, or fumaric acid. Examples of excipients that can enhance disintegration and coverage of the affected area include but are not limited to sodium starch glycollate, pregelatinized starch, crospovidone, and croscarmellose sodium. Mucoadhesive excipients that may be useful in the present disclosure include but are not limited to microcrystalline cellulose, polycarbophil, hydroxymethyl cellulose, hypromellose, hydroxypropyl cellulose, and PVP.

[00421] In certain embodiments, the dosage form can soften, disintegrate, and/or release the drug in low fluid volumes. In certain embodiments, the dosage form softens and begins to release the drug immediately. In certain embodiments, the dosage form softens and begins to release the drug gradually. In certain embodiments, the dosage form softens and begins to release the drug within about one hour. In certain embodiments, the dosage form softens and begins to release the drug within about two hours. The dosage form may be prepared to maximize surface area, facilitating disintegration.

[00422] In certain embodiments, the dosage form is an oval tablet. In certain embodiments, the dosage form is a caplet. In certain embodiments, the dosage form is a tablet such as a round tablet. In certain embodiments, the tablet width is the largest dimension, and the tablet thickness is the smaller dimension.

[00423] In certain embodiments, the dosage form (such as a tablet) is twice as wide as it is thick. In certain embodiments, the dosage form is three times as wide as it is thick. In certain embodiments, the dosage form is four or more times as wide as it is thick. In certain embodiments, the dosage form is from about 0.1 mm thick to about 5 mm thick. In certain embodiments, the dosage form is from about 1 mm to about 2 mm thick. In certain embodiments, the dosage form is from about 2 mm to about 3 mm thick. In certain embodiments, the dosage form is from about 3 mm to about 4 mm thick. In certain embodiments, the dosage form is from about 4 mm to about 5 mm thick. In certain embodiments, the dosage form is from about 5 mm to about 15 mm thick. [00424] In certain embodiments, the dosage form (such as a tablet) is less than about 5 grams. In certain embodiments, the dosage form is from about 0.05 gram to about 0.15 gram. In certain embodiments, the dosage form is from about 0.1 gram to about 1 gram. In certain embodiments, the dosage from about 0.75 grams to about 2 grams. In certain embodiments, the dosage form is from about 1 gram to about 5 grams.

[00425] In certain embodiments, the dose form (such as a tablet) is not easily removed, dislodged, or moved from the target site. These desirable properties may be achieved by inclusion of a mucoadhesive polymer into the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises a mucoadhesive polymer or mucoadhesive excipient. Nonlimiting examples of mucoadhesive polymers and excipients include: hypromellose, lectin, thiolated polymers (e.g. chitosan-iminothiolane, poly(acrylic acid)-cysteine, poly(acrylic acid)-homocysteine, chitosan-thioglycolic acid, chitosanthioethylamidine, alginate- cysteine, poly(methacrylic acid)-cysteine and sodium carboxymethylcellulose-cysteine), polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidinone, polyacrylic acid (Carbopol®), polyheroxyethyl methacrylate, chitosan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, sodium carboxymethyl cellulose, aminated com starch, cellulose derivatives, poly (acrylic acid) polymers, poly (hydroxyethyl methylacrylate), poly (ethylene oxide), poly (vinyl pyrrolidone), poly (vinyl alcohol), tragacanth, sodium alginate, karaya gum, guar gum, xanthan gum, soluble starch, gelatin, pectin, chitosan, methyl cellulose, hyaluronic acid, hydroxy propyl methylcellulose, hydroxy propyl cellulose, gellan gum, carrageenan, cationic hydroxyethyl celluloses, hydrogel, dihydroxyphenylalanine, and alginate-polyethylene glycol acrylate. In certain embodiments, the pharmaceutical composition comprises from about 0% to about 10% mucoadhesive polymer excipients selected from the list consisting of carbomer, polyethylene glycol, crospovidone, polycarbophil, hypromellose, and hydroxyethyl cellulose. [00426] Percentage ranges of excipients and other components of the pharmaceutical composition are given as a percent by weight, unless otherwise specified.

[00427] In certain embodiments, the pharmaceutical composition comprises from at least about 0.1% to about 90%, about 92%, about 93%, about 95%, about 98%, about 97%, about 98%, or about 99% of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises from about 0.1% to about 1% of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises from about 0.5% to about 5% of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises from about 1% to about 10% of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises from about 5% to about 20% of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises from about 10% to about 50% of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises from about 20% to about 75% of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises from about 50% to about 90% of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises from about 75% to about 99% of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises at least about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 % of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises no more than about 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 % of a mucoadhesive polymer(s). In certain embodiments, the pharmaceutical composition comprises about 0% mucoadhesive polymer(s). In this instance, the adhesion to the target site may be achieved by use of other pharmaceutically acceptable excipients.

[00428] To prepare the pharmaceutical compositions according to the present disclosure, a therapeutically effective amount of any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof according to the present disclosure may be admixed with a pharmaceutically acceptable carrier to produce a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., topical, oral, or parenteral. In preparing pharmaceutical compositions in topical dosage form, any of the usual pharmaceutical media may be used. Thus, for liquid or semi-solid topical preparations such as gels, creams, ointments, suspensions, elixirs, and solutions, suitable carriers and additives including water, glycols, oils, alcohols, preservatives, and the like may be used. In certain embodiments, the pharmaceutical composition comprises propylene glycol. In certain embodiments, the pharmaceutical composition comprises carboxypolymethylene. In certain embodiments, the pharmaceutical composition comprises ethylenediaminetetraacetic acid (EDTA). In certain embodiments, the pharmaceutical composition comprises sorbic acid. In certain embodiments, the pharmaceutical composition comprises carbomer. In certain embodiments, the pharmaceutical composition comprises hydroxyethyl cellulose. In certain embodiments, the pharmaceutical composition comprises polyethylene glycol.

[00429] For solid topical preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose, and related carriers, diluents, granulating agents, lubricants, binders, mucoadhesive polymer, disintegrating agents, and the like may be used. If desired, the tablets or capsules may be coated for sustained release by standard techniques. The use of these dosage forms may significantly enhance the bioavailability of the compounds in the patient.

[00430] In certain embodiments, the pharmaceutical composition comprises mannitol. In certain embodiments, the pharmaceutical composition comprises magnesium stearate. In certain embodiments, the pharmaceutical composition comprises microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises polycarbophil. In certain embodiments, the pharmaceutical composition comprises polyethylene oxide. In certain embodiments, the pharmaceutical composition comprises colloidal silicon dioxide. In certain embodiments, the pharmaceutical composition comprises povidone. In certain embodiments, the pharmaceutical composition comprises isopropyl alcohol. In certain embodiments, the pharmaceutical composition comprises sodium starch glycolate. In certain embodiments, the pharmaceutical composition comprises croscarmellose sodium. In certain embodiments, the pharmaceutical composition comprises crospovidone. In certain embodiments, the pharmaceutical composition comprises hydroxypropylmethylcellulose. In certain embodiments, the pharmaceutical composition comprises lactose.

[00431] In certain embodiments, a powder pharmaceutical composition comprises one or more excipient selected from the group consisting of xanthan gum, microcrystalline cellulose, polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, povidone, mannitol, colloidal silicon dioxide, sodium benzoate, sodium starch glycolate, sodium lauryl sulfate, poloxamer 407, polyoxypropylenepolyoxyethylene copolymers, and the like.

[00432] In certain embodiments, the pharmaceutical composition comprising an effective amount of a salt (such as a fumarate salt) of any of the active compounds described herein, further comprises a pharmaceutically acceptable excipient selected from the list consisting of Acacia, agar, alginic acid, ascorbyl palmitate, bentonite, benzoic acid, butylated hydroxyanisole, butylated hydroxytoluene, butylene glycol, calcium acetate, calcium hydroxide, canola oil, carob bean gum, carrageenan, castor oil, cellulose, corn starch, disodium edetate, erythorbic acid, ethyl lactate, ethylcellulose, glycerin, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactic acid, lauric acid, lecithin, linoleic acid, medium chain triglycerides, methyl paraben, methylcellulose, microcrystalline cellulose, microcrystalline wax, myristic acid, oleic acid, palmitic acid, peanut oil, pectin, phosphoric acid, polycarbophil, potassium alginate, propionic acid, propyl gallate, propyl paraben, propylene glycol, propylene glycol alginate, silicon dioxide, simethicone, sodium alginate, sodium benzoate, sodium bicarbonate, sodium carboxymethylcellulose, sodium chloride, sodium citrate, sodium lactate, sodium lauryl sulfate, sodium metabi sulfate, sodium phosphate, sodium sulfite, sodium thiosulfate, sorbic acid, stearic acid, talc, tapioca starch, tartaric acid, thymol, urea, vitamin E polyethylene succinate, beeswax, xanthan gum, and zinc acetate. [00433] In certain embodiments, the pharmaceutical composition comprises pharmaceutically acceptable excipients for use as a pessary. In certain embodiments, the pharmaceutical composition comprising any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein further comprises up to about 99.9% of a pessary excipient selected from the group consisting of hard fat, PEG, macrogols, cocoa butter, and glycerol. Non limiting examples of hard fat include Ovucire® (mono-, di- and triglyceride esters of fatty acids (Cio to Cis), the triester fraction being predominant and ethoxylated fatty alcohols), Witepsol® (glycerol esters of vegetable saturated fatty acids, such as lauric acid), and Supposi-base™ (a blend of saturated polyglycolysed glycerides). [00434] In certain embodiments, the pharmaceutical composition comprising an effective amount of any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein further comprises a pharmaceutically acceptable excipient that enhances the penetration, disintegration, film forming, and/or controlled release properties of the composition.

[00435] In certain embodiment, the pharmaceutical composition comprising any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein further comprises a penetration enhancing excipient. In certain embodiments, the penetration enhancing excipient is selected from the group consisting of oleic acid, eucalyptol, Caprylol, Labrafil, Labrasol, Lauroglycol, diethylene glycol monomethyl ether (Transcutol), propylene glycol, sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, poloxamer (231, 182, 184), Tween 20, 40, 60, 80, fatty acids and fatty acid esters, isostearic acid, glycerin, and chitosan. In certain embodiments, the pharmaceutical composition comprising a salt (such as a fumarate salt) of an active compound described herein contains from about 0% to about 20% of a penetration enhancing excipient(s) selected from the group consisting of cetyl alcohol, propylene glycol, transcutol P, oleic acid, isopropyl myristate, propylene glycol dicaprylate, glyceryl monooleate, propylene glycol monocaprylate, PEG-8 bees wax, cetyl alcohol, stearic acid, cetyl palmitate, and cetosteryl alcohol. In certain embodiments, the pharmaceutical composition comprises from about 0% to about 25% of a penetration enhancing excipient(s) selected from the list consisting of stearyl alcohol, polysorbate 80, sodium lauryl sulfate, mono and diglycerides, sorbitan monostearate, glyceryl isostearate, polyoxyl 15 hydroxystearate, polyoxyl 40 hydrogenated castor oil, octyl dodecanol, and soybean lecithin.

[00436] In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises a film forming excipient. In certain embodiments, the pharmaceutical composition comprising from about 0% to about 99% of a film forming excipient(s) selected from the group consisting of hypromellose, polyethylene glycol, polymethacrylates, microcrystalline cellulose, guar gum, xanthan gum, and polyvinylpyrrolidone.

[00437] In certain embodiments, the pharmaceutical composition comprising any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein further comprises an excipient which allows for controlled release of the active compound. In certain embodiments, the controlled release pharmaceutical composition comprises ethylcellulose, hypromellose, microcrystalline wax, polycarbophil, and/or beeswax.

[00438] In certain embodiments, the pharmaceutical composition comprising any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein further comprises a disintegration enhancing excipient. In certain embodiments, the disintegration enhancing excipient is selected from the group consisting of cellulose, guar gum, crospovidone, polyplasdone, soy polysaccharides, calcium silicate, gelatin, cation exchange resins, bentonite, citrus pulp, alginic acid, calcium alginate, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, croscarmellose, solka floc, corn starch, sodium starch glycolate (Explotab, Primojel), glycine, hydroxypropyl starch, and starch 1500. In certain embodiments, the pharmaceutical composition comprises up to about 99% of a disintegration enhancing excipient(s) such as mannitol and/or microcrystalline cellulose. In certain embodiments, the pharmaceutical composition comprises from about 0% to about 70% of a disintegration enhancing excipient(s) selected from the list consisting of lactose, sucrose, and calcium phosphate. In certain embodiments, the pharmaceutical composition comprises from about 0% to about 50% of a disintegration enhancing excipient(s) selected from the list consisting of sodium bicarbonate, citric acid, maleic acid, adipic acid, and fumaric acid. In certain embodiments, the pharmaceutical composition comprises from about 0% to about 20% of a disintegration enhancing excipient(s) selected from the list consisting of sodium starch glycollate, pregelatinized starch, crospovidone, and croscarmellose sodium.

[00439] In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 70% mannitol, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70%. In certain embodiments, the pharmaceutical composition comprising a salt (such as a fumarate salt) of an active compound described herein further comprises from about 0% to about 70% lactose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 20%, about 30% about 40%, about 50%, about 60%, or about 70%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 70% sucrose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 70% microcrystalline cellulose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 20% sodium starch glycolate, including but not limited to any amount that achieves the desired results, for example up to about 1%, about 2%, about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, or about 20%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 20% pregelatinized starch, including but not limited to any amount that achieves the desired results, for example up to about 1%, about 2%, about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, or about 20%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 20% crospovidone, including but not limited to any amount that achieves the desired results, for example up to about 1%, about 2%, about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, or about 20%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 20% croscarmellose sodium, including but not limited to any amount that achieves the desired results, for example up to about 1%, about 2%, about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, or about 20%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 50% xanthan gum, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 50% polycarbophil, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 50% polyethylene oxide, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof comprises from about 0% to about 50% hydroxyethylmethyl cellulose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 50% hydroxy ethyl cellulose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 50% hypromellose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 50% hydroxypropyl cellulose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 50% PVP, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In certain embodiments, the pharmaceutical composition comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises from about 0% to about 50% microcrystalline cellulose, including but not limited to any amount that achieves the desired results, for example up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%.

[00440] In some embodiments according to the present disclosure, any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof and the compositions described are used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV.

[00441] In certain embodiments, a tablet used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV comprising any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein further comprises about 250 mg of microcrystalline cellulose, about 20 mg of crospovidone, about 5 mg of magnesium stearate, about 5 mg of silicon dioxide, about 5 mg of polyethylene oxide, and about 100 mg of mannitol. In certain embodiments, a tablet used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV further comprises about 155 mg microcrystalline cellulose, about 1.75 mg of magnesium stearate, and about 17.5 mg of mannitol.

[00442] In certain embodiments, a semi-solid formulation used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV comprising any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein further comprises about 15 mg of carbomer, about 50 mg of propylene glycol, about 10 mg of sorbic acid, about 5 mg of EDTA, and about 920 mg of water. In certain embodiments, a semi-solid formulation used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV comprising any of the active compounds described herein or a pharmaceutically acceptable salt or cocrystal thereof further comprises about 20 mg of carbomer; about 70 mg of mineral oil; about 80 mg of a mixture of polyoxyl 6 stearate Type I, ethylene glycol stearates, and polyoxyl 32 stearate type 1; about 5 mg parabens; about 60 mg propylene glycol; about 5 mg EDTA; and about 760 mg water.

[00443] In certain embodiments, a dry powder for reconstitution is used to treat, prevent, or delay an HPV infection or a secondary disease state, condition, or complication of HPV comprising any of the active compounds or a pharmaceutically acceptable salt or cocrystal thereof described herein further comprises about 15.5 mg xanthan gum, about 19.8 mg mannitol, about 5 mg silicon dioxide, and about 0.5 mg sodium benzoate.

[00444] The treatments described herein for intraepithelial neoplasia can be combined with conventional approaches such as, but not limited to, excision or ablation of the transformed zone. Techniques include cryotherapy, laser therapy, loop electrosurgical procedure (LEEP), and cone biopsy. All of these surgical procedures damage the affected areas and can lead to scarring. The most common intervention for cervical intraepithelial neoplasia, LEEP, is effective in 60-90% of cases, however, it may be associated with a significantly increased risk of miscarriage, ectopic pregnancies, and negative psychological outcomes. In certain embodiments, the treatments described herein are used to lessen, ameliorate or substitute for the use of these conventional practices.

[00445] In certain embodiments, the treatments described herein can be used in combination with a surgical technique. In certain embodiments, a patient in need thereof can receive surgery before, during, and/or after administration of an effective amount of a compound or a pharmaceutically acceptable salt or cocrystal thereof described herein. In certain embodiments, the surgical procedure can be an excision of the target and/or diseased tissue, including but not limited to loop electrosurgical excision procedure (LEEP), large loop excision of the transformation zone (LLETZ), knife conization, cold knife conization, knife cone biopsy, or laser conization. In certain embodiments, the surgical procedure can be ablation, including but not limited to laser ablation or cryoablation.

[00446] In some embodiments, the efficacy of a drug against an HPV infection may be prolonged, augmented, or restored by administering the compound in combination or alternation with another, and perhaps even two or three other, antiviral compounds that induce a different mutation or act through a different pathway from that of the principal drug. Alternatively, the pharmacokinetic, biodistribution, half-life, or other parameter of the drug can be altered by such combination therapy (which may include alternation therapy if considered concerted). Furthermore, since HPV is associated with several types of cancer, combination therapy with anticancer therapeutics can in some embodiments provide better outcomes for patients. Since the compounds disclosed herein and pharmaceutically acceptable salts and cocrystals thereof are DNA polymerase inhibitors, it may be useful to administer the compound or salt or cocrystal thereof to a host in need thereof in combination with, for example: a) a protease inhibitor; b) another DNA polymerase inhibitor; c) an inhibitor of E6 or E6AP such as MEDI0457, luteolin, CAF-24, or gossypetin; d) an inhibitor of E7; e) an inhibitor of El or E2, including inhibitors of the E1-E2 protein interaction; f) L2 lipopeptides; g) an inhibitor or degrader of LI or L2; h) an HD AC inhibitor such as vorinostat; i) degraders of tetraspanins such as CD9, CD63, or CD151; j) immunotherapeutics such as T-cell therapies (including adoptive T-cell therapies) and checkpoint inhibitors; k) anti-proliferative drugs; l) a therapeutic vaccine; m) a prophylactic vaccine; n) trichloroacetic acid; o) salicylic acid; p) imiquimod; q) podofilox; r) Gardasil® 9; s) Gardasil® 4; t) Cervarix; u) VGX-3100; v) GGX-188E; and/or w) ADXS11-001. ADDITIONAL EMBODIMENTS

Embodiment 1. A compound of the formula:

Formula IV

Formula Villa

Formula VIIIc wherein:

[00447] R¹ is selected from C_1-4alkyl-aryl, and C_1-4alkyl-heteroaryl either of which can be optionally substituted with 1, 2, 3 R¹⁴ groups, or R¹ is selected from hydrogen, acetylbenzyl, and methoxycarbonylbenzyl;

[00448] R² is selected from hydrogen, C_1-6alkyl, and C_3-6cycloalkyl;

[00449] R³ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1- ₆alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups, or R³ is CH₂CO₂NH₂ or (CH₂)2CO₂NH₂;

[00450] R⁴ is selected from hydrogen, deuterium, C_1-6alkyl, halogen, C_1-6haloalkyl, C_1- ₆alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R¹⁶ groups;

[00451] or, R¹ and R³, together with the atoms to which they are attached, form a 5, 6, 7, or 8 membered heterocycle, including a bridged heterocycle, optionally substituted with 1 or 2 R¹⁵ groups;

[00452] or, R² and R³, together with the atoms to which they are attached, form a 5, 6, 7, or 8 membered heterocycle, including a bridged heterocycle, optionally substituted with 1 or 2 R¹⁵ groups; [00453] or, R³ and R⁴, together with the carbon to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl;

[00454] R⁵ is selected from hydrogen, C_1-6alkyl, -OH, -O-C_1-6alkyl, -S-C_1-6alkyl, - NR⁸R⁹, and -NR⁸C(R¹²)2C(O)R⁵⁵ wherein any of the hydrogens on any of the alkyl groups may be substituted with deuterium or R⁵ is selected from benzyloxy, naphthalenyloxy, - OCH₂CF3, and benzyl(cyclopropyl)oxy;

[00455] R⁶ is selected from hydrogen, -OH, -O-CH₃, -O-CD3, -O-CD2H, -O-CDH2, - O-CF3, -OCF2H, -OCFH2, -CN, -COOR⁸, -C(O)R⁵, -O-C(O)R⁵, -OC(O)OR⁸, -O-C_1-6alkyl, - O-C_1-6heteroalkyl, -O-C3-6cycloalkyl, -O-C_3-6heterocycle, -NR⁸R⁹, -NR⁸-C(O)OR⁸, -NR⁸- C(O)OR⁸, -NR⁸-C(O)NR⁸R⁹, -NR⁸OR⁸, and -OSi(R¹³)₃;

[00456] R⁷ is selected from hydrogen, deuterium, halogen, -CD3, -CD2H, -CDH2, -CF3, CF2H, -CFH2, -OH, -OCH₃, -O-haloalkyl, -CN, -C(O)R⁵, -C(O)OR⁸, -C(O)NR⁸R⁹, C_1-6alkyl, C_1-6haloalkyl, C_3-6cycloalkyl, -NR⁸R⁹, -NR⁸C(O)OR⁸, -NR⁸C(O)NR⁸R⁹, and -NR⁸C(O)R⁸;

[00457] R⁸ and R⁹ are independently selected at each occurrence from hydrogen, C_1- ₆alkyl, C_1-6haloalkyl, C3-6cycloalkyl, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, C2-₆alkenyl, C2- ₆alkynyl, aryl, heteroaryl, and heterocycle;

[00458] R¹⁰ is independently selected at each occurrence from hydrogen, C_1-6alkyl, C_1- ehaloalkyl, C3-6cycloalkyl, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, aryl, heteroaryl, heterocycle, - OR⁸ and -NR⁸R⁹;

[00459] R¹¹ is independently selected at each occurrence from halogen, -OR⁸, -SR⁸, -

[00460] R¹² is independently selected at each occurrence from hydrogen, C_1-6alkyl, C_1- ehaloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_1-6alkylC(O)R¹⁰, C_1-6alkyl-R¹¹, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, and C3-6cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R¹⁷ groups, or where possible, two R¹² groups, together with the carbon to which they are attached, form a 3-8 member cycloalkyl or heterocyclyl;

[00461] R¹³ is independently selected at each occurrence from C_1-6alkyl, aryl, and C_1- ₆alkyl-aryl;

[00462] R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are independently selected at each occurrence from deuterium, C_1-6alkyl, C3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -SR⁸, C_1- ₆alkylC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -N3, alkenyl, alkynyl, -C(S)R¹⁰, and -NR⁸C(O)R¹⁰; [00463] R¹⁸ is independently selected at each occurrence from hydrogen, deuterium, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -O-C(O)-R⁵, -C(O)R⁵, -SR⁸, and -C_1-6alkylC(O)R⁵;

[00464] R³³ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1 or 2 R¹⁵ groups; [00465] R⁴⁴ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1 or 2 R¹⁶ groups; [00466] or R⁴ and R⁴⁴ together with the atoms to which they are attached form a 4, 5, 6, or 7 membered cycloalkyl or heterocyclic ring, including a bridged cycloalkyl or heterocyclic ring;

[00467] or R² and R⁴⁴ together with the atoms to which they are attached, form a 5, 6, or 7 membered heterocyclic ring, including a bridged heterocyclic ring;

[00468] R⁵⁵ is selected from C_1-6alkyl, -O-C_1-6alkyl, -S-C_1-6alkyl, and -NR⁸R⁹;

[00469] R⁶⁰ is selected from -OH, -OCD₃, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, and

-OCFH2;

[00470] R⁶⁶ is selected from hydrogen, -OH, -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, -

[00471] W is selected from -NH₂, -NHR⁸, -NR⁸R⁹, and -NHC(O)R⁵;

[00472] W² is selected from -OH, -O-C_1-6alkyl, -O-C_1-6haloalkyl, -NH₂, -NHR⁸, - NR⁸R⁹, fluoro, chloro, and -C(O)R⁵;

[00473] W³ is selected from R⁶, fluoro, and chloro;

[00474] X is selected from N and CR¹²;

[00475] Y is selected from -CH₂-, -CH₂CH₂-, -CH(R¹²)-, -C(R¹²)₂-, -CF2-, -

C(CH₂CH₂)-, and -C(CH₂CH₂)CH₂-;

[00476] Y² is selected from -CH₂-, -CD2-, -CH₂CH₂-, -CH(R¹²)-, -C(R¹²)₂-, -CF2-, -C(CH₂CH₂)CH₂-, -O-, -S-, -OCH₂-, -OCD2-, -OCH₂CH₂-, -OCH(R¹²)-, -OC(R¹²)₂-, -OCF2-, -OC(CH₂CH₂)CH₂-, -SCH₂-, -SCH₂CH₂-, -SCH(R¹²)-, -SC(R¹²)₂-, -SCF2-, - SC(CH₂CH₂)CH₂-, -NR⁸-, -NR⁸CH₂-, -NR⁸CD₂-, -NR⁸CH₂CH₂-, -NR⁸CH(R¹²)-, - NR⁸C(R¹²)2-, - NR⁸CF₂-, and - NR⁸C(CH₂CH₂)CH₂-; z is 0, 1, 2, or 3; [00477] Purine is selected from: , wherein the bond from the nitrogen atom in Linker is connected to Y;

[00479] Linker⁶ is selected from: , wherein the bond from the nitrogen atom in Linker⁰ is connected to Y;

[00480] Linker⁰ is selected from: , wherein the bond from the nitrogen or oxygen atom in Linker⁰ is connected to Y; and

[00481] Linker⁰ is selected from:

Embodiment 3. The compound of embodiment 1 or 2, wherein R⁷ is selected from hydrogen, methyl, ethyl, isopropyl, and cyclopropyl.

Embodiment 4. The compound of any one of embodiments 1-3, wherein R⁶ is selected from hydrogen, -O-CH₃, -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, -OCFH2, - O-C_1-6alkyl, -O-C_1-6heteroalkyl, -O-C3-6cycloalkyl, -O-C_3-6heterocycle, and - OSi(R¹³)₃.

Embodiment 5. The compound of any one of embodiments 1-3, wherein R⁶ is selected from -O-CH₃, -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, and -OCFH2.

Embodiment 6. The compound of any one of embodiments 1-3, wherein R⁶ is -O-CH₃ or -O-CD3.

Embodiment 7. The compound of any one of embodiments 1-3, wherein R⁶⁶ is selected from -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, -OCFH2, and -OSi(R¹³)₃.

Embodiment 8. The compound of any one of embodiments 1-3, wherein R⁶⁶ is selected from -O-CF3, -OCF2H, -O-CD3, -O-CD2H, -O-CDH2, and -OCFH2.

Embodiment 12. The compound of any one of embodiments 1-3, 7, or 9-11, wherein R⁶⁶ is -OSi(CH₃)3.

Embodiment 17. The compound of embodiment 16, wherein R² is hydrogen.

Embodiment 18. The compound of embodiment 16, wherein R² is methyl.

Embodiment 20. The compound of embodiment 19, wherein R² is cyclopropyl.

Embodiment 24. The compound of embodiment 23, wherein R³ is methyl.

Embodiment 25. The compound of embodiment 23, wherein R³ is ethyl. Embodiment 26. The compound of embodiment 23, wherein R³ is isopropyl.

Embodiment 27. The compound of embodiment 23, wherein R³ is CH(CH₃)CH₂CH₃.

Embodiment 28. The compound of embodiment 23, wherein R³ is CEECE^CEE)?.

Embodiment 29. The compound of any one of embodiments 1-21, wherein R³ is C_1- ₆alkyl-OR⁸.

Embodiment 30. The compound of embodiment 29, wherein R³ is CH₂OH.

Embodiment 31. The compound of embodiment 29, wherein R³ is CH(CH₃)OH.

Embodiment 32. The compound of any one of embodiments 1-21, wherein R³ is C_1- ₆alkyl-NR⁸R⁹.

Embodiment 33. The compound of embodiment 32, wherein R³ is (CEb^NEb.

Embodiment 37. The compound of any one of embodiments 1-20, wherein R³ is (CH₂)2CO₂H.

Embodiment 38. The compound of any one of embodiments 1-20, wherein R³ is (CH₂)2CO₂NH₂.

Embodiment 39. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl-R¹¹

Embodiment 40. The compound of embodiment 39, wherein R³ is C_1-6alkyl- NHC(NH)NH₂.

Embodiment 41. The compound of embodiment 39, wherein R³ is (CH₂)3- NHC(NH)NH₂.

Embodiment 42. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl-aryl optionally substituted with 1, 2, 3, or 4 R¹⁵ groups.

Embodiment 43. The compound of embodiment 42, wherein R³ is CEb-CeEE.

Embodiment 44. The compound of embodiment 42, wherein R³ is CH₂-C6H4-OH.

Embodiment 45. The compound of any one of embodiments 1-20, wherein R³ is C_1- ₆alkyl-heteroaryl. Embodiment 46. The compound of embodiment 45, wherein R³ is

Embodiment 47. The compound of embodiment 45, wherein

Embodiment 49. The compound of embodiment 48, wherein R³ is CF3.

Embodiment 50. The compound of embodiment 48, wherein R³ is cyclopropyl.

Embodiment 53. The compound of embodiment 52, wherein R⁴ is methyl.

Embodiment 57. The compound of any one of embodiments 1-55, wherein R⁵ is -O-C_1- ₆alkyl.

Embodiment 58. The compound of any one of embodiments 1-55, wherein R⁵ is -O- CH₂CH₃.

Embodiment 59. The compound of any one of embodiments 1-55, wherein R⁵ is-O- CD2CD3.

Embodiment 60. The compound of any one of embodiments 1-55, wherein R⁵ is -O- CH(CH₃)₂.

Embodiment 61. The compound of any one of embodiments 1-55, wherein R⁵ is - NR⁸R⁹.

Embodiment 62. The compound of embodiment 61, wherein R⁵ is NH₂. Embodiment 63. The compound of any one of embodiments 1-62, wherein Y is selected from -CH₂-, -CH(R¹²)-, -C(R¹²)₂- -CF2-, and -C(CH₂CH₂)-.

Embodiment 64. The compound of any one of embodiments 1-63, wherein Y is selected from -CH₂-, -CF2-, and -C(CH₂CH₂)-.

Embodiment 65. The compound of any one of embodiments 1-64, wherein Linker,

Linker⁶ and Linker⁰ are

Embodiment 66. The compound of any one of embodiments 1-64, wherein Linker,

Linker⁶ and Linker⁰ are

Embodiment 67. The compound of any one of embodiments 1-64, wherein Linker,

Linker⁶ and Linker⁰ are

Embodiment 68. The compound of any one of embodiments 1-64, wherein Linker,

Linker⁶ and Linker⁰ are

Embodiment 69. The compound of any one of embodiments 1-64, wherein Linker,

Linker⁶ and Linker⁰ are

Embodiment 70. The compound of any one of embodiments 1-64, wherein Linker,

Linker⁶ and Linker⁰ are .

Embodiment 71. The compound of any one of embodiments 1-64, wherein Linker,

Linker⁶ and Linker⁰ are Embodiment 72. The compound of any one of embodiments 1-64, wherein Linker,

Linker⁶ and Linker⁰ are

Linker⁰ are .

Embodiment 74. The compound of any one of embodiments 1-64, wherein Linker⁰ are

Embodiment 75. The compound of any one of embodiments 1-64, wherein Linker⁰ are

Embodiment 76. The compound of any one of embodiments 1-64, wherein Linker⁰ are

Embodiment 77. The compound of any one of embodiments 1-64, wherein Linker⁰ are

Embodiment 78. The compound of any one of embodiments 1-77, wherein z is 3.

Embodiment 79. The compound of any one of embodiments 1-77, wherein z is 2.

Embodiment 80. The compound of any one of embodiments 1-77, wherein z is 1.

Embodiment 81. The compound of any one of embodiments 1-80, wherein R¹⁸ is deuterium, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -SR⁸, and C_1-6alkylC(O)R¹⁰.

Embodiment 83. The compound of any one of embodiments 1-81, wherein R¹⁸ is fluoro. Embodiment 84. The compound of any one of embodiments 1-81, wherein R¹⁸ is -OH.

Embodiment 85. The compound of any one of embodiments 1-77, wherein z is 0.

Embodiment 87. A pharmaceutical composition comprising a compound of any one of embodiments 1-86, or a pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier.

Embodiment 88. The pharmaceutical composition of embodiment 87, wherein the pharmaceutical composition is suitable for topical administration.

Embodiment 89. The pharmaceutical composition of embodiment 87 or 88, in the form of a tablet.

Embodiment 90. The pharmaceutical composition of embodiment 87 or 88, in the form of a semi-solid dosage form.

Embodiment 91. The pharmaceutical composition of embodiment 87 or 88, in the form of a reconstituted powder.

Embodiment 92. The pharmaceutical composition of embodiment 87 or 88, in the form of a dry powder dosage form.

Embodiment 93. The pharmaceutical composition of embodiment 87 or 88, in the form of a film.

Embodiment 94. The pharmaceutical composition of embodiment 87 or 88, in the form of a pessary.

Embodiment 95. The pharmaceutical composition of any one of embodiments 87-94, for delivery to the cervix, vagina, vulva, penis, perianal region, or anus.

Embodiment 96. A method to treat an HPV-induced infection or an associated condition comprising administering to a host in need thereof an effective amount of a compound of any one of embodiments 1-86, or a pharmaceutically acceptable salt or cocrystal thereof, optionally in a pharmaceutical composition, to a human in need thereof.

Embodiment 97. The method of embodiment 96, wherein the HPV-induced infection or associated condition is an intraepithelial neoplasia.

Embodiment 98. The method of embodiment 97, wherein the intraepithelial neoplasia is cervical intraepithelial neoplasia.

Embodiment 99. The method of embodiment 97, wherein the intraepithelial neoplasia is penile intraepithelial neoplasia. Embodiment 100. The method of embodiment 97, wherein the intraepithelial neoplasia is vulvar intraepithelial neoplasia.

Embodiment 101. The method of embodiment 97, wherein the intraepithelial neoplasia is perianal intraepithelial neoplasia.

Embodiment 102. The method of embodiment 97, wherein the intraepithelial neoplasia is anal intraepithelial neoplasia.

Embodiment 103. The method of embodiment 97, wherein the intraepithelial neoplasia is vaginal intraepithelial neoplasia.

EXAMPLES

Example 1: General Synthesis of Compounds of the Present Disclosure

[00482] All of the examples provided below are non-limiting illustrative examples of processes of manufacture. Other processes and reagents can be used to make the described compounds that are known to the skilled artisan.

R⁶ or R⁶⁶

[00483] The R⁶ or R⁶⁶ group can be positioned on the purine ring according to one of the following exemplary syntheses, starting from 2-aminopurine or 2-amino-6-chloropurine or as otherwise known in the art. The bond to the N⁹ position on the purine ring (shown as a terminated bond in the schemes below) may be hydrogen, Linker, Linker⁶, Linker⁰, or Linker¹⁹. If Linker, Linker⁶, Linker⁰, or Linker¹⁹ is attached to the purine before the R⁶ or R⁶⁶ group is attached, suitable protecting groups for nitrogen or oxygen atoms in the linker group may be used.

[00484] The purine base can be coupled to the linker, for example, through alkylation, Mitsunobu reaction, or decarboxylative cross coupling. Example reaction schemes for the base to linker coupling as shown in the scheme below, where LG represents a leaving group and PG represents a protecting group:

Example 1 A. Alkylation of Linker

[00485] The following non-limiting examples of reagents and reaction conditions for attaching the purine base to Linker may also be used for attaching a purine base to LinkerB, LinkerC, and LinkerD to make a compound which has a Linker⁶, Linker⁰, or Linker⁰. Other reaction conditions will be known to those of skill in the art. [00486] Purine 1 is coupled to Linker phosphorus ester 2 through displacement of a leaving group (LG), for example an alkyl chloride, bromide, mesylate, tosylate, or brosylate. In certain embodiments, the displacement is carried out in a polar aprotic solvent such as DMF or DMSO in the presence of a base, for example a carbonate base such as cesium carbonate. Other reaction conditions will be known to those of skill in the art. In certain embodiments, Step 1 may lead to two products (regioisomers) via N-7 and N-9 alkylation. These can be separated by, for example, silica gel chromatography.

[00487] To a solution of compound 3 in DCM is then added a Lewis acid such as trimethylsilyl bromide to form compound 4. Compound 4 is then coupled to amino acid 6 and alcohol 7 with aldithriol-2, an amine base such as triethylamine, and triphenyl phosphine.

[00488] In certain embodiments, when R³ or R⁴ contain a nucleophile such as an amine or alcohol, the nucleophile can be protected with a suitable protecting group to lessen the generation of side products. Suitable protecting groups for amines include but are not limited to tertbutoxycarbonyl (Boc), carboxybenzyl (Cbz), and benzyl (Bn). Suitable protecting groups for alcohols include silyl protecting groups (e.g. trimethylsilyl, triisopropylsilyl, tertbutyldimethylsilyl, tertbutyldiphenylsilyl), benzyl (Bn), benzoyl (Bz), pivalic ester (Piv), methoxymethyl (MOM), and allyl ether. Additional protecting groups are described by Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc.

[00489] In alternative embodiments, 2-amino-6-chloropurine can be used in Step 1, and then the R⁶ or R⁶⁶ group can be installed as Step 2A (shown below). For example, if R⁶ is -O-CH₃, the corresponding alcohol (methanol) can displace the chloride via nucleophilic aromatic substitution in the presence of a base. [00490] If R⁶ is -O-CF3, the trifluoromethoxy group can be installed by reacting the guanine base with a trifluoromethylating reagent such as Togni’s reagent (Step 2B, shown below). Other reaction conditions will be known to those of skill in the art.

[00491] If R⁶ is -O-CF2H, the difluoromethoxy group can be installed by reacting the guanine base with a difluromethyl carbene source, for example diethyl P-

(bromodifluoromethyl)phosphonate (Step 2C, shown below). Other reaction conditions will be known to those of skill in the art.

[00492] If R⁶ is -O-Si(CH₃)3, the trimethyl silyl group can be installed by reacting the guanine base the corresponding silyl chloride (Step 2D, shown below):

[00493] Additional examples of silyl chlorides include but are not limited to triethylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, and tertbutyldiphenylsilyl chloride. Example IB. Linker attachment through photochemical coupling

[00494] In certain non-limiting embodiments, compounds of the present disclosure are synthesized according to the scheme below. Reaction conditions other than those shown will be known to those of skill in the art.

Step 1 : Decarboxylative coupling of purine and linker

[00495] Purine 1 is coupled to carboxylic acid-functionalized Linker 2 through a decarboxylative coupling reaction. Decarb oxy lative N-alkylation reaction procedures are described in, for example, Li, P. et al. “The Direct Decarboxylative N-Alkylation of Azoles, Sulfonamides, Ureas, and Carbamates with Carboxylic Acids via Photoredox Catalysis”, Org. Lett. 2021, 23, 9563-9568; Sheng, T. et al. “Electrochemical Decarboxylative N-Alkylation of Heterocycles” Org. Lett. 2020, 22, 7549-7598; and Dow, N. et al. “A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides” Cell Che nr 7, 1827-1842. In certain embodiments, the amine of 2 is protected by a protecting group, for example Boc or Cbz. In alternative embodiments, when the linker is Linker⁰, then the oxygen of Linker⁰ is protected by a protecting group, for example benzyl.

Step 2: Deprotection of linker protecting group

[00496] After coupling 1 and 2, the amine protecting group is deprotected (Step 2). Deprotection conditions vary according to the protecting group used. For example, if the protecting group is Cbz, hydrogenolysis can be used to deprotect the amine. Hydrogenolysis can be performed using hydrogen gas (H2) and a catalyst, typically palladium, iridium, or rhodium on carbon. Alternatively, hydrogenolysis can be performed by transfer hydrogenation with a solid source of hydrogen (e.g. ammonium formate), and a catalyst such as palladium (additional transfer hydrogenation conditions can be found in, for example, Wang, D. et al “The Golden Age of Transfer Hydrogenation”, Chem. Rev. 2015, 115, 13, 621-6686). Additional deprotection conditions for protecting groups can be found in Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc.

Step 3: Coupling of Phosphonate Ester

[00497] After deprotection of the Linker amine (for Linker, Linker⁶ or Linker⁰) or alcohol (Linker⁰), the phosphonate benzyl ester is attached via displacement of a leaving group (LG). Leaving groups include chloride, bromide, mesylate, tosylate, and brosylate (as described above). This reaction is preferably carried out in the presence of a base, such as sodium carbonate or potassium carbonate in an aprotic solvent such as acetonitrile.

Step 4: Deprotection of Phosphonate Ester

[00498] Deprotection of the phosphonate benzyl ester groups can be performed via hydrogenolysis as described in Step 2.

Step 5: Preparation of Phosphonoamidate

[00499] Formation of the phosphonamidate 10 from phosphonate 6, amine 8, and alcohol 9 is performed using a diaryldisulfide (for example Aldrithiol™-2) and triphenylphosphine. In alternative non-limiting embodiments, the phosphonamidate is synthesized using dehydrative coupling reagents including but not limited to hydroxybenzotriazole (HOBt), Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU), 157enzotriazole-l-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N’ -di cyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), (l-Cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), and tripropylphosphonic anhydride (T3P®).

[00500] In some instances, to prepare phosphonamidite 10 wherein the R¹ and R³ of compound 10, together with the atoms to which they are attached, form a five-membered ring, amine 8 contains the following groups: R² is hydrogen, R³ is -CH₂OH, R⁴ is hydrogen, and R⁵ is -OCH₂CH₃.

Example 1C. Attachment of Linker through Mitsunobu reaction

Step 1 : Mitsunobu Coupling of Purine and Linker

[00501] In certain embodiments, purine 1 is coupled to alcohol-functionalized Linker 2 through a Mitsunobu coupling reaction. Coupling of 1 and 2 via Mitsunobu reaction may be advantageous when the Linker, Linker⁶, Linker⁰, or Linker⁶* is readily prepared with an alcohol group. The Mitsunobu reaction may be advantageous for coupling 1 and 2 when 2 is a bicyclic heterocycle. Mitsunobu reaction can be performed using an azodi carb oxy late and triphenylphosphine. Azodicarboxylates which may be used include but are not limited to di ethylazodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD), and 1,1’- (azodicarbonyl)dipiperidine (ADDP). The reaction is typically performed in tetrahydrofuran at reduced temperature, for example 0°C. Order of reagent addition may influence the amount of product formed. In some embodiments, the purine, the alcohol, and triphenylphosphine are dissolved in a solvent such as tetrahydrofuran, followed by dropwise addition of the azodicarboxylate as a solution in tetrahydrofuran. In some embodiments, the azodicarboxylate and triphenylphosphine are dissolved, the mixture stirred, then the alcohol and acid are added. In alternative non-limiting embodiments, the solvent is toluene. Other Mitsunobu reaction conditions will be known to those of skill in the art.

[00502] Some Linker⁰ groups contain an ether linkage to Y. In these embodiments, a monoprotected diol is used in the Mitsunobu reaction of Step 1. The unprotected alcohol becomes bound to the purine base in Step 1. After deprotection, the second alcohol is r ^/ attached to Y in Step 3. For example, when Linker is °~-Y , a non-limiting

'’ V'A ,^Bn L / °' exemplary monoprotected diol used in Step 1 is °"Y

[00503] In certain embodiments, the amine of 2 is protected by a protecting group, for example Boc or Cbz. In certain embodiments, one alcohol of a diol Linker⁶ or Linker⁰ is protected by a protecting group, for example benzyl.

[00504] To synthesize compounds of Formula VI, the Mitsunobu conditions described herein can be used to attach the purine base to Linker⁰. In certain embodiments, Linker⁰- Y²- P(O)(OEt)2 is used when forming the bond between the purine base and Linker⁰ (shown in the scheme below). Step 2: Deprotection of Linker Protecting Group

[00505] After coupling 1 and 2, the amine or alcohol protecting group is deprotected (Step 2). Deprotection conditions vary according to the protecting group used. For example, if the protecting group is Boc, acid can be used to deprotect the amine. Common acids for deprotecting Boc groups include but are not limited to trifluoroacetic acid and hydrochloric acid.

[00506] If the protecting group is benzyl, hydrogenolysis can be used to deprotect the amine. Hydrogenolysis can be performed using hydrogen gas (H2) and a catalyst, typically palladium, iridium, or rhodium on carbon. Additional deprotection conditions for protecting groups can be found in Greene and Wuts in Protective Groups in Organic Synthesis (1991) New York, John Wiley and Sons, Inc.

Step 3-5: Coupling of Phosphonate Ester and Preparation of Phosphonamidate [00507] Steps 3-5 can be carried out as in Example IB, above.

Example 2: Preparation of a mixture of (7?, 7?)- and (5,7?)-ethyl (((3-(2-amino-6-methoxy- 9H-purin-9-yl)piperidin-l-yl)methyl)(benzyloxy)phosphoryl)alaninate

Step 1 : Coupling of Purine Base to Linker Phosphate Ester

[00508] A dry reaction container is charged with 2-amino-6-chloropurine 1 (50 g, 0.296 mol, 1 equiv.), CS2CO3 (96.37 g, 0.296 mol, 1 equiv.) and DMF (250 mL) under N2 atmosphere at room temperature. To this at room temperature and under stirring is added diethyl ((3-chloropiperidin-l-yl)methyl)phosphonate 2 (74.85 g, 0.325 mol, 1.1 equiv.) in a drop-wise manner. The reaction is stirred at 40-50°C for 0.5 to 1.5 hours, heated to 60-70°C and stirred for 0.5-1.5 hours, and then stirred at 75 to 85°C for 18-24 h. After bringing the reaction temperature to 20-30°C, the reaction mixture is filtered and the resulting cake is washed with DMF (100 mL x 2). The combined filtrate is concentrated to a half volume below 70°C, diluted with n-heptane (250 mL) and again concentrated to a half volume below 75°C. The resulting solution is poured into DCM (1 L), stirred at 20 to 30°C for 20-40 min., then aqueous 10% Na2SO4 solution (-100 mL) is added. The resulting bi-phasic solution is stirred for 20-40 minutes then filtered through diatomite and the wet cake is washed with DCM (-100 mL). From the filtrate, the aqueous phase is separated and the organic phase is again washed with aqueous 10% Na2SO4 solution (-100 mL). The combined aqueous phases are extracted with DCM (200-300 mL), the organic phases are combined and are concentrated. The resulting crude product 3 is then purified by silica gel column chromatography using DCM to 1% MeOH in DCM. The fractions containing products are combined and the solvent is evaporated below 40°C. The solid product 3 is treated with the repeated dilution with MTBE and concentration (up to 1/3 ^rd volume). The resulting slurry is then diluted with MTBE (400-500 mL) and agitated at 40-50°C for 4-6 h and at 15-25°C for 8-15 h. The suspension is filtered and washed with MTBE and dried at 35-40°C for 15-20 h to afford the desired product, diethyl ((4-(2-amino-6-chloro-9H-purin-9-yl)piperidin-l- yl)methyl)phosphonate 3.

Step 2: Preparation of diethyl ((4-(2-amino-6-chloro-9H-purin-9-yl)piperidin-l- yl)methyl)phosphonic acid (4)

[00509] A dry reaction container containing DCM under N2 atmosphere is charged with diethyl ((3-(2-amino-6-chloro-9H-purin-9-yl)piperidin-l-yl)methyl)phosphonate 3 followed by 2,6-lutidine (5 equiv.) and the temperature is adjusted to 0-5°C. To this is added TMSBr (4.0 equiv.) in a drop-wise manner and stirred further for 0.5-1 h at 0-5°C and 15-20 h at 20-25°C. After adjusting the reaction temperature at 0-5°C, aqueous IN NaOH is added drop wise. After maintaining the temperature at 20-30°C for 1-2 h, the aqueous alkaline layer is separated and repeatedly washed with MTBE. An aqueous solution is acidified with a drop-wise addition of aqueous 2N HC1 to pH= 6-7 at 15-25°C and charged with MeOH (10 Vol.). This resulting methanolic solution is further acidified with a drop-wise addition of aqueous 2N HC1 to pH= 3-4 at 35-45°C. After addition of seeds of compound 4, the methanolic acidic solution is stirred at 35-45°C for 3-5 h and acidified furthermore using a drop-wise addition of aqueous 2N HC1 to pH= 1.5-2.5 and is stirred for 11-20 h at 15-20°C. The resulting solid is isolated by filtration, and is washed with MeOH and dried at 45-55°C for 20-30 h to yield the desired product ((4-(2-amino-6-chloro-9H-purin-9-yl)piperidin-l- yl)methyl)phosphonic acid. The use of seeds herein are optional. In addition, the seeds themselves may be made by following the steps set forth herein, absent the addition of seeds.

Step 3: Preparation of ((4-(2-amino-6-methoxy-9H-purin-9-yl)piperidin-l- yl)methyl)phosphonic acid (5)

[00510] To a flask containing MeOH is charged ((4-(2-amino-6-chloro-9H-purin-9- yl)piperidin-l-yl)methyl)phosphonic acid 4 at 20-30°C, and stirred for 10-30 min. To this solution is added a 30 wt% NaOMe solution in MeOH (10 equiv.) in a drop-wise manner and then is stirred at 50-60°C for 15-24 h. The reaction is maintained at 20-30°C for 20-40 min and then filtered. The filtrate is then acidified at 20-30°C by a drop-wise addition of cone. HC1 to adjust pH= 6-7 and concentrated below 40°C to one third of the volume. The temperature of the concentrated solution is raised to 35-45°C and acidified to adjust the pH= 3-4 by means of a drop-wise addition of cone. HC1. The resulting acidic solution is charged with the seeds of compound 5, and stirred at 35-45°C for 1.5-2.5 h. At this temperature, the addition of cone. HC1 to adjust the pH= 2-3 is done in a drop-wise rate, stirred for 3-5 h, cooled to -3°C to 3°C range and stirred for 8-15 h. The resulting solid is filtered, washed with MeOH and n-heptane. The resulting cake is dried at 50-60°C for 16-24 h under vacuum to afford the desired product, ((4-(2-amino-6-methoxy-9H-purin-9-yl)piperidin-l- yl)methyl)phosphonic acid 5. The use of seeds herein are optional. In addition, the seeds themselves may be made by following the steps set forth herein, absent the addition of seeds.

Step 4a: Preparation of a mixture of (RS)- and CS'.M-ethyl (((3-(2-amino-6-methoxy-9H- purin-9-yl)piperidin- 1 -yl)methyl)(benzyloxy)phosphoryl)alaninate (8) [00511] To a solution of ((4-(2-amino-6-methoxy-9H-purin-9-yl)piperidin-l- yl)methyl)phosphonic acid 5 in DCM (560 mL) at 20-30°C under stirring is charged amino acid hydrogen chloride salt 6 (1 equiv.), alcohol 7 (5 equiv.) and TEA (12 equiv.), and the solution is stirred for 10-30 min. To this is added a solution prepared from PF13P (6 equiv.) and 2,2’ -dithiopyridine (Aldrithiol-2) (6 equiv.) in DCM (320 mL) at 20-30°C over 60 min. The resulting reaction mixture is stirred at 35-45°C for 15-20 h and is then concentrated to remove 3/4^th of solvent under vacuum below 40°C. To the resulting residue is added MeOH, distilled water, toluene and n-heptane and is then stirred at 20-30°C for 0.5-1 h. After allowing the reaction mixture to stand for 0.5 to 1 h at 20-30°C, the organic phase is separated and the aqueous phase is extracted several more times with a mixture of toluene and n-heptane to remove maximum amount of remaining reagents and by-products. The remaining aqueous phase is then extracted with DCM (2 x 400 mL) and upon concentration of DCM under vacuum below 40°C, the crude product is purified by silica gel column chromatography with DCM to 2% MeOH in DCM as a mobile phase. The eluting fractions containing product are combined and solvent is removed under vacuum below 40°C to give the desired product as a mixture of diastereoisomers, namely, (R,S)- and (5,5)-ethyl (((4-(2- amino-6-methoxy-9H-purin-9-yl)piperidin-l-yl)methyl)(benzyloxy)phosphoryl)alaninate 8.

Step 4b: Preparation of a mixture of (RRY and -ethyl (((3-(2-amino-6-methoxy-9H- purin-9-yl)piperidin-l-yl)methyl)(benzyloxy)phosphoryl)alaninate

[00512] To synthesize the (R,R) and (S,R) mixture, the procedure of Step 4a can be performed substituting D-alanine ethyl ester ((R)-ethyl 2-aminopropionate hydrogen chloride salt) for the L-alanine ethyl ester (fS')-ethyl 2-aminopropionate hydrogen chloride salt). Example 3: Synthesis of isopropyl ((l-(((R)-3-(2-amino-6-methoxy-9H-purin-9- yl)piperidin-l-yl)methyl)cyclopropyl)(benzyloxy)phosphoryl)-L-alaninate

Step 1. Preparation of benzyl 3 -(2-amino-6-methoxy-9H-purin-9-yl)piperidine-l -carboxylate

[00513] To an oven dried vial is added l-((benzyloxy)carbonyl)piperidine-3- carboxylic acid 2, 3-oxo-2-tosyl-2,3-dihydro-lH-lX3-benzo[d][l,2]iodazol-l-yl acetate (1 equiv.) and [Ru(dtbbpy)3](PFe)2 (0.025 equiv.). The vial is then charged with DCE and HFIP (2/1) and 2-amino-6-methoxypurine 1 (3.00 equiv.). The vial is sealed with a screw neck cap and PTFE septum. Following this, the reaction mixture is sparged with nitrogen gas with slow stirring (100 rpm) for 10 minutes. After the vial is sealed with parafilm, it is placed 2 cm in front of two PR 160 blue Kessil lamps with a fan cooling. The reaction mixture is stirred and irradiated for 20 hours. Upon completion, the reaction mixture is concentrated under reduced pressure and the residue is purified by flash column chromatography on silica gel to afford benzyl 3 -(2-amino-6-methoxy-9H-purin-9-yl)piperidine-l -carboxylate (3).

Step 2: Isolation of benzyl (R)-3-(2-amino-6-methoxy-9H-purin-9-yl)piperidine-l- carboxylate

[00514] Separation of the R- and S-enantiomer of 3 is performed by chiral chromatography, for example chiral supercritical fluid chromatography. Conditions for purification by supercritical fluid chromatography or other chiral chromatographic purification techniques will be known to those of skill in the art.

[00515] Non-limiting exemplary conditions for purification by supercritical fluid chromatography are set forth below:

Column: ChiralPak AD, 250x30mm I.D., 10pm;

Mobile phases: A: CO₂ and B: Ethanol (0.1% NH3H2O);

Gradient: B 45% isocratic;

Flow rate: 200 mL /min;

Wavelength: 310 nm;

[00516] Additional non-limiting examples of chiral stationary phases which may be used include Chiralpak AS, Chiralcel OG, and Chiralcel OJ.

Step 3, Preparation of (R)-6-methoxy-9-(piperidin-3-yl)-9H-purin-2-amine

[00517] (R)-3-(2-amino-6-methoxy-9H-purin-9-yl)piperidine-l -carboxylate 3a is dissolved in 1 : 1 ethyl acetate: methanol with stirring. Next, palladium on carbon is added and the reaction container is sealed. The atmosphere in the reaction container is then exchanged with hydrogen and the reaction stirred overnight. The reaction is then filtered and the filtrate concentrated to provide (R)-6-methoxy-9-(piperi din-3 -yl)-9H-purin-2-amine 4 used in the next step.

Step 4a. Preparation of dibenzyl (R)-(l-((3-(2-amino-6-methoxy-9H-purin-9-yl)piperidin-l- yl)methyl)cyclopropyl)phosphonate

[00518] (R)-6-methoxy-9-(piperidin-3-yl)-9H-purin-2-amine 4 is dissolved in dry acetonitrile, and potassium carbonate is then added. Next, dibenzyl (1- (chloromethyl)cyclopropyl)phosphonate (which can be prepared as shown below in Step 4b) is added to the mixture and the reaction stirred overnight. The reaction mixture is then concentrated and purified by chromatography to provide dibenzyl (R)-(l-((3-(2-amino-6- methoxy-9H-purin-9-yl)piperidin-l-yl)methyl)cyclopropyl)phosphonate 5.

Step 4b. Preparation of dibenzyl (l-(chloromethyl)cyclopropyl)phosphonate

[00519] Dibenzyl (l-(chloromethyl)cyclopropyl)phosphonate can be synthesized from commercial starting materials according to the scheme described above. Ethyl 2- (bis(benzyloxy)phosphoryl)acetate is first reacted with a base and dibromoethane to form ethyl l-(bis(benzyloxy)phosphoryl)cyclopropane-l-carboxylate. Next, the ester is hydrolyzed using LiOH in tetrahydrofuran. The resulting carboxylic acid is reduced using borane- dimethylsulfide to form dibenzyl (l-(hydroxymethyl)cyclopropyl)phosphonate. The alcohol functional group can be converted into many different leaving groups (LG), for example the chloride or bromide (using the Appel reaction conditions shown, substituting CBn for CCL if the alkyl bromide is the LG), or the mesylate, tosylate, or brosylate (using mesyl, tosyl, or brosyl chloride in DCM with triethylamine).

Step 5, Preparation of (R)-(l-((3-(2-amino-6-methoxy-9H-purin-9-yl)piperidin-l-yl)methyl) cyclopropyDphosphonic acid

[00520] Dibenzyl (R)-( 1 -((3 -(2-amino-6-methoxy-9H-purin-9-yl)piperidin- 1 - yl)methyl)cyclopropyl)phosphonate 5 is then dissolved in 1 : 1 ethyl acetate: methanol with stirring. Next, palladium on carbon is added and the reaction container is sealed. The atmosphere in the reaction container is then exchanged with hydrogen and the reaction stirred overnight. The reaction is then filtered and the filtrate concentrated to provide (R)-(l-((3-(2- amino-6-methoxy-9H-purin-9-yl)piperidin-l-yl)methyl)cyclopropyl)phosphonic acid 6 used in the next step.

Step 6, Preparation of isopropyl ((l-(((R)-3-(2-amino-6-methoxy-9H-purin-9-yl)piperidin-l- yl)methyl)cyclopropyl)(benzyloxy)phosphoryl)-L-alaninate mixture of R_P and S_P isomers

[00521] To a solution of (R)-(l-((3-(2-amino-6-methoxy-9H-purin-9-yl)piperidin-l- yl)methyl)cyclopropyl)phosphonic acid 6 in DCM at 20-30°C under stirring is charged isopropyl L-alaninate hydrogen chloride salt 8 (1 equiv.), benzyl alcohol 9 (5 equiv.) and TEA (12 equiv.), and the solution is stirred for 10-30 min. To this is added a solution prepared from PF13P (6 equiv.) and 2,2’ -dithiopyridine (Aldrithiol™-2) (6 equiv.) in DCM. The resulting reaction mixture is stirred at 35-45°C for 15-20 h and is then concentrated to remove 3/4^th of solvent under vacuum below 40°C. To the resulting residue is added MeOH, distilled water, toluene and n-heptane and is then stirred at 20-30°C for 0.5-1 h. After allowing the reaction mixture to stand for 0.5 to 1 h at 20-30°C, the organic phase is separated, and the aqueous phase is extracted with a mixture of toluene and n-heptane. The remaining aqueous phase is then extracted with DCM three times and the organic layers dried and concentrated under vacuum below 40°C. The crude product is purified by silica gel column chromatography, for example with DCM to 2% MeOH in DCM as a mobile phase. The eluting fractions containing product are combined and solvent is removed under vacuum below 40°C to give the desired product as a mixture of stereoisomers, namely, (R,R,S)- and (R, S, S)- i sopropyl (( 1 -(((R)-3 -(2-amino-6-methoxy-9H-purin-9-yl)piperidin- 1 - yl)methyl)cyclopropyl)(benzyloxy)phosphoryl)-L-alaninate 10. Example 4. Synthesis of ethyl (((6-(2-amino-6-methoxy-9H-purin-9-yl)-2- azabicyclo[2.2.2]octan-2-yl)methyl)(benzyloxy)phosphoryl)alaninate Step la. Preparation of tert-butyl 6-(2-amino-6-methoxy-9H-purin-9-yl)-2- azabicvclo[2.2.21octane-2-carboxylate ep

[00522] To a solution of 2-amino-6-methoxypurine in dry THF is added tert-butyl 6- hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate (1.2 eqivalents) and triphenylphosphine (1.5 equivalents). The solution is cooled to 0°C, and then a solution of diethylazodicarboxylate (1.2 equivalents) in THF is added dropwise. The reaction is stirred overnight and is then concentrated. The residue is optionally triturated with methyl tert-butyl ether to facilitate removal of triphenylphosphine oxide, filtered, and concentrated. The resulting residue is then purified by chromatography to provide tert-butyl 6-(2-amino-6- methoxy-9H-purin-9-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate 2.

Step lb. Isolation of Stereoisomers of tert-butyl 6-(2-amino-6-methoxy-9H-Durin-9-yl)-2- azabicyclor2.2.21octane-2-carboxylate

[00523] Tert-butyl 6-(2-amino-6-methoxy-9H-purin-9-yl)-2-azabicyclo[2.2.2]octane-

2-carboxylate is optionally purified into the individual stereoisomers. The individual isomer(s) can be carried through the following steps. Step 2, Preparation of 9-(2-azabicvclo[2.2.21octan-6-yl)-6-methoxy-9H-purin-2-amine

[00524] To a solution of tert-butyl 6-(2-amino-6-methoxy-9H-purin-9-yl)-2- azabicyclo[2.2.2]octane-2-carboxylate 2 in dichloromethane is added excess trifluoroacetic acid. The reaction is stirred at room temperature until complete. The solution is then extracted with aqueous sodium bicarbonate, and then concentrated. The concentrated residue is purified by chromatography, yielding 9-(2-azabicyclo[2.2.2]octan-6-yl)-6-methoxy-9H-purin-2-amine 3.

Step 3, Preparation of dibenzyl ((6-(2-amino-6-methoxy-9H-purin-9-yl)-2- azabicyclor2.2.21octan-2-yl)methyl)phosphonate

[00525] To a reaction vessel, 9-(2-azabicyclo[2.2.2]octan-6-yl)-6-methoxy-9H-purin- 2-amine 3 is charged, then dry acetonitrile and potassium carbonate are added. Next, dibenzyl (chloromethyl)phosphonate is added to the mixture and the reaction stirred overnight. The reaction mixture is then concentrated and purified by chromatography to provide dibenzyl ((6-(2-amino-6-methoxy-9H-purin-9-yl)-2-azabicyclo[2.2.2]octan-2-yl)methyl)phosphonate 4 Step 4, Preparation of ((6-(2-amino-6-methoxy-9H-purin-9-yl)-2-azabicvclo[2.2.21octan-2- yl)methyl)phosphonic acid

[00526] To a solution of dibenzyl ((6-(2-amino-6-methoxy-9H-purin-9-yl)-2- azabicyclo[2.2.2]octan-2-yl)methyl)phosphonate 4 in 1 : 1 ethanokethyl acetate is added 5% palladium on carbon. The suspension is stirred and the atmosphere in the reaction vessel is exchanged with hydrogen. The reaction is stirred under hydrogen overnight, and then the suspension is filtered. The filtrate is concentrated and optionally purified by silica chromatography to give compound 5.

Step 5, Preparation of ethyl (((6-(2-amino-6-methoxy-9H-purin-9-yl)-2- azabicvclor2.2.21octan-2-yl)methyl)(benzyloxy)phosphoryl)-L-alaninate

Step 5

[00527] To a solution of ((6-(2-amino-6-methoxy-9H-purin-9-yl)-2- azabicyclo[2.2.2]octan-2-yl)methyl)phosphonic acid 5 in DCM at 20-30°C under stirring is charged ethyl L-alaninate hydrogen chloride salt 6 (1 equiv.), benzyl alcohol 7 (5 equiv.) and TEA (12 equiv.), and the solution is stirred for 10-30 min. To this is added a solution prepared from PhsP (6 equiv.) and 2,2’ -dithiopyridine (Aldrithiol™-2) (6 equiv.) in DCM. The resulting reaction mixture is stirred at 35-45°C for 15-20 h and is then concentrated to remove 3/4^th of solvent under vacuum below 40°C. To the resulting residue is added MeOH, distilled water, toluene and n-heptane and is then stirred at 20-30°C for 0.5-1 h. After allowing the reaction mixture to stand for 0.5 to 1 h at 20-30°C, the organic phase is separated, and the aqueous phase is extracted with a mixture of toluene and n-heptane. The remaining aqueous phase is then extracted with DCM three times and the organic layers dried and concentrated under vacuum below 40°C. The crude product is purified by silica gel column chromatography, for example with DCM to 2% MeOH in DCM as a mobile phase. The eluting fractions containing product are combined and solvent is removed under vacuum below 40°C to give the desired product ethyl (((6-(2-amino-6-methoxy-9H-purin-9-yl)-2- azabicyclo[2.2.2]octan-2-yl)methyl)(benzyloxy)phosphoryl)-L-alaninate 8 as a mixture of stereoisomers.

Example 5: Chiral Separation of (R,S)- and (5,5)-Isomers

H C-

Step la: Chiral Separation of (KM-Compound I and (AM-Compound I

[00528] The diastereoisomeric mixture of isomers is subjected to a chiral chromatography separation under SFC separation conditions as shown below to separate and obtain the (R,S)- and (S,S)- isomers. Other chiral purification conditions will be known to those of skill in the art.

Exemplary SFC Conditions:

Column: ChiralPak AD, 250x30mm I.D., 10pm;

Mobile phases: A: CO₂ and B: Ethanol (0.1% NH3H2O);

Gradient: B 45% isocratic; Flow rate: 200 mL /min;

Wavelength: 310 nm;

Cycle time: ~6 min;

Back pressure: 100 bar;

Injection amount: ~lg.

[00529] In certain nonlimiting embodiments, the stereoisomers are separated using HPLC or SFC with achiral or chiral stationary phases. Non limiting examples of chiral stationary phases which may be used include Chiralpak AS, Chiralcel OG, and Chiralcel OJ.

[00530] In alternative non limiting embodiments, the individual isomers can be synthesized asymmetrically. For nonlimiting examples of asymmetric synthesis of phosphonamidates see Numan, A et al. “Asymmetric Synthesis of Stereogenic Phosphorus P(V) Centers Using Chiral Nucleophilic Catalysis”, Molecules 2021, 26, 3661 and Ambrosi, A. et al. “Synthesis of Rovafovir Etalafenamide (Part III): Evolution of the Synthetic Process to the Phosphonamidate Fragment” 2021, Org. Process Res. Dev. 25, 5, 1247-1262.

Step lb: Chiral Separation of (7?, AO-Compound II and (A', AO-Compound II

[00531] Separation of (A,A)-Compound II and (5,A)-Compound II can be performed using same techniques for the (R,S) and (5,5) mixture as described above. Example 6. Non-limiting examples of preparation of semisolid formulations

[00532] A topical cream formulation can be prepared, for example, by emulsifying an oil phase and an aqueous phase along with an active pharmaceutical ingredient. In a nonlimiting embodiment, the oil phase of the cream is prepared by mixing light mineral oil, propylparaben and Tefose® 63. Next, the aqueous phase of the cream is prepared by mixing water, EDTA, methylparaben, and Carbopol®974P. The oil and water phases are then emulsified. To the emulsified mixture is added the active pharmaceutical ingredient and propylene glycol. The mixture is pH adjusted and then filled into tubes.

[00533] A topical gel formulation can be prepared, for example, by mixing an aqueous gel carrier with an active pharmaceutical ingredient. In a non-limiting embodiment, the aqueous phase of the topical gel is prepared by mixing water, EDTA, methylparaben (or sorbic acid) and Carbopol®974P. The active pharmaceutical ingredient and propylene glycol is added to this solution, mixed and pH adjusted, then is filled into tubes.

[00534] In certain nonlimiting embodiments, from about 0.001% w/w to about 10% w/w active pharmaceutical ingredient is added to the semisolid formulation. For example, from about 0.0025% w/w to about 2.5% w/w, such as about 0.003%, 0.01%, 0.03%, 0.1%, 0.3% or 1%.

Example 7. Illustrative Preparation of Tablet Dosage Forms

[00535] A nonlimiting example of the preparation of cervical tablets (also known as vaginal tablets or vaginal inserts) is provided below. The dose strengths in mg used herein refer to the weight mass of the active pho sphonami date compound and do not include the salt or coformer in the molecular mass, and thus the total weight in the dosage form. Two or more of the excipients are combined, blended, and screened to make the excipient blend. Then the active pharmaceutical ingredient is screened and added to a portion of the excipient blend. The resulting mixture is then blended and then more excipient blend is added. The mixture is thus gradually diluted with the excipient blend, with thorough mixing after each addition of excipient blend. Once the excipient blend has been used up, the magnesium stearate is added and the mixture blended once more. The mixture is then compressed into tablets and packaged. Table 1. Batch Formula for a Vaginal Tablet, 0.3 mg for batch size of 1.0 Kg

Individual tablet weight: 175 mg

Vaginal Tablet Dosage Form, 0.3 mg

[00536] An illustrative non-limiting example of a process to prepare the vaginal tablet of a compound described herein is provided below.

Dispensing

1. Weigh the materials as per the batch manufacturing formula and dispense in separate poly bags.

Screening

1. All excipients can be sieved through a screen.

Blending of Active and Screening

1. The screened excipients can be blended: microcrystalline cellulose and mannitol in a diffusion blender.

2. Take 49.5 grams of the excipients blend and add 2.12 grams of a pharmaceutically acceptable salt of a compound of Formula I, II, III, IV, V, VI, VII, Vila, Villa, Vlllb, or VIIIc

3. The active and the excipients can be blended, and screen to remove chunks

4. To this blend add 148.5 grams of the excipients blend

5. Blend the active blend and the excipients and screen to remove chunks 6. To this blend add 247.5 grams of the excipients blend

7. Blend the active blend and the excipients and screen to remove chunks

8. To this blend add the remaining 495 grams of the excipients blend

9. Blend the active blend and the excipients and screen to remove chunks

Final Blending

10. Add magnesium stearate to the diffusion blender and mix the contents.

11. Discharge and reconcile blend.

Compression

1. Compress the blend on a rotary tablet press using appropriate tooling (punches and die), to target weight. Check friability and disintegration at the beginning of the compression run, and check periodically for individual tablet weights, thickness and hardness.

Packaging

1. Package bulk tablets into double lined re-closable clear PE bags with desiccants between the bags and further into an aluminum foil pouch with desiccant and heat sealed.

Example 8. Illustrative excipients for a tablet formulation

[00537] A tablet formulation is selected to display the properties of mucoadhesion and substantivity and include excipients that have solubilizing, erosion-generating (for disintegration), porosity (for water uptake), and viscosity enhancing (to keep the drug at the target site) properties. Examples of excipients that will cause rapid disintegration to cover the cervix, anal or vaginal areas include, but are not limited to mannitol, microcrystalline cellulose, lactose, sucrose, calcium phosphate, sodium phosphate, sodium bicarbonate, citric acid, maleic acid, adipic acid or fumaric acid. Examples of excipients that can enhance disintegration and coverage of the affected area include but are not limited to sodium starch glycollate, pregelatinized starch, crospovidone and croscarmellose sodium. Mucoadhesive excipients that are useful in the present disclosure include but are not limited to microcrystalline cellulose, polycarbophil, hydroxymethyl cellulose, hypromellose, hydroxypropyl cellulose, and PVP. [00538] The table below lists combinations of excipients which may have the desired properties for a tablet formulation. A tablet formulation comprises the active pharmaceutical ingredient and microcrystalline cellulose and may contain mannitol. In certain non-limiting embodiments, the tablet formulation comprises one or more excipients selected from the rapid disintegrant category (left column of Table 2). In certain non-limiting embodiments, the tablet formulation comprises one or more excipients selected from the disintegration enhancement category (middle column of Table 2). In certain non-limiting embodiments, the tablet formulation comprises one or more excipients selected from the mucoadhesive excipient category (right column of Table 2).

Table 2. Excipients for Tablets (Percentages are given in a weight/weight %)

Example 9. Illustrative excipients for a reconstitution powder or dry powder formulation

[00539] A reconstitution powder or dry powder formulation may improve the shelf stability of a pharmaceutical agent or formulation. In certain nonlimiting embodiments, the dry powder formulation may be mixed with saline, propylene glycol or other aqueous carrier shortly before it is administered, minimizing the time for degradation. In certain nonlimiting embodiments, the dry powder formulation is mixed with an oil, cream, or other nonaqueous carrier shortly before it is administered.

[00540] In certain embodiments, the reconstitution powder or dry powder formulation rapidly covers the infected or diseased tissue in the cervix, vulva, vagina, perianal region, penis or anus. Excipients which enhance the rapid coverage of the cervix, vulva, vagina, perianal region, penis or anus include but are not limited to mannitol, lactose, sucrose, calcium phosphate, and microcrystalline cellulose. In certain embodiments, the excipient for rapid coverage of the cervix, vulva, vagina, perianal region, penis or anus is mannitol.

[00541] In certain embodiments, the reconstitution powder or dry powder formulation has good coverage of the cervix, vulva, vagina, perianal region, penis or anus. Nonlimiting examples of excipients which enhance the coverage of the cervix, vulva, vagina, perianal region, penis or anus include sodium starch glycollate, pregelatinized starch, crospovidone, and croscarmellose sodium.

[00542] In certain embodiments, the reconstitution powder or dry powder formulation contains mucoadhesive properties once it has been reconstituted. This prevents smearing of the dosage form or otherwise exposing healthy tissues to the active pharmaceutical ingredient. Excipients which improve the mucoadhesive properties of the reconstituted powder or dry powder formulation include but are not limited to xanthan gum, polycarbophil, polyethylene oxide, hydroxyethylmethyl cellulose, hydroxyethyl cellulose, hypromellose, hydroxypropyl cellulose, PVP, and microcrystalline cellulose. In certain embodiments, the excipient which improves mucoadhesion is xanthan gum.

[00543] The table below lists combinations of excipients which have the desired properties for a reconstitution powder or dry powder formulation. A dry powder or reconstitution powder formulation comprises the active pharmaceutical ingredient and may contain mannitol and/or xanthan gum. In certain non-limiting embodiments, the dry powder or reconstitution powder formulation comprises one or more excipients selected from the rapid coverage category (left column of Table 3). In certain non-limiting embodiments, the dry powder or reconstitution powder formulation comprises one or more excipients selected from the coverage enhancement category (middle column of Table 3). In certain non-limiting embodiments, the dry powder or reconstitution powder formulation comprises one or more excipients selected from the mucoadhesive excipient category (right column of Table 3).

Table 3. Excipients for Reconstitution Powders of Dry Powder Dosage Forms

(Percentages are given in a weight/weight %) Example 10. Illustrative excipients for a semisolid formulation

[00544] Semisolid formulations are selected to display the properties of mucoadhesion and assist in the drug penetration into the tissue. Semisolid formulations may include excipients that have solubilizing, lipophilic (to assist in solubilizing lipophilic compound), penetration enhancing (for higher activity), and mucoadhesive (to keep the drug at the target site) properties.

[00545] In certain embodiments, the semisolid formulation is mucoadhesive. Excipients which contribute to the mucoadhesive properties include but are not limited to carbomer, polyethylene glycol, crospovidone, polycarbophil, hypromellose, and hyroxyethyl cellulose.

[00546] In certain embodiments, the semisolid formulation enhances the penetration and/or solubility of the active pharmaceutical ingredient. Excipients which enhance the penetration and/or solubility of the active pharmaceutical ingredient include but are not limited to polyoxyl 6 stearate type I, ethylene glycol stearate, polyoxyl 32 stearate type I, and propylene glycol.

[00547] The table below lists combinations of excipients which have the desired properties for a semisolid formulation. In certain embodiments, a semisolid formulation comprises the active pharmaceutical ingredient and one or more excipients from each column of Table 4. In certain non-limiting embodiments, the semisolid formulation comprises one or more excipients selected from the mucoadhesive polymer category (left column of Table 4). In certain non-limiting embodiments, the tablet formulation comprises one or more excipients selected from the solubility and penetration enhancers category (second column of Table 4). In certain non-limiting embodiments, the semisolid formulation comprises one or more excipients selected from the lipophilic solubilizer category (third column of Table 4). In certain non-limiting embodiments, the semisolid formulation comprises one or more excipients selected from the penetration enhancer category (right column of Table 4).

Table 4. Excipients for semisolid dosage forms

(Percentages are given in a weight/weight %)

Example 11. Illustrative excipients for pessary and film forming formulations

[00548] Pessary and film forming formulations are selected to be solid at room temperature but soften to release the active pharmaceutical ingredient at body temperature. This allows for easy handling and storage of the formulation as well as achieving desired tissue coverage at the cervix, vulva, vagina, perianal region, penis or anus. In a non-limiting embodiment of a film forming formulation, one or more excipients from the left column of Table 5 provide the desired properties. In a non-limiting embodiment of a pessary formulation, one or more excipients from the right column of Table 5 provide the desired properties.

Table 5. Excipients for films and pessaries (Percentages are given in a weight/weight %)

Example 12. Illustrative tablet formulations

[00549] In certain non-limiting embodiments, the formulation for a tablet dosage form comprises the ingredients in Table 6. In certain non-limiting embodiments, the formulation for a tablet dosage form comprises the ingredients in Table 7. An illustrative process for combining these ingredients into a tablet dosage form can be found in Example 8. When the active pharmaceutical ingredient is in the form of a salt or coformer, the doses noted below (0.05 mg to 5 mg) refer to the mass of the corresponding free compound. For example, one would include 0.124 mg of a monofumarate of a compound of Formula I to provide a dose of 0.1 mg of said compound of Formula I.

Table 6. Example Tablet Formulation

Table 7. Example Tablet Formulation

Example 13. Illustrative semisolid formulations

[00550] In certain non-limiting embodiments, the formulation for a gel semisolid dosage form comprises the ingredients in Table 8. In certain non-limiting embodiments, the formulation for a cream semisolid dosage form comprises the ingredients in Table 9. An illustrative process for combining these ingredients into a cream or gel dosage form can be found in Example 10. As noted above, for all types of formulations, when the active pharmaceutical ingredient is in the form of a salt or coformer, the doses in a formulation (e.g., 0.025 mg to 25 mg) refer to the mass of the corresponding free compound.

Table 8. Example semisolid formulation (gel) Table 9. Example semisolid formulation (cream)

Example 14. Illustrative film forming formulation

[00551] A film dosage form can be prepared by solvent casting or hot melt extrusion. To prepare the film dosage form, for example, the active pharmaceutical ingredient is dissolved into a solution of the excipients and water. This solution is then optionally deaerated and cast into a thin film and dried in an oven. The film dosage form can also be prepared by hot melt extrusion. In certain embodiments, the active pharmaceutical ingredient is mixed with the excipient(s) in a hopper. The components are then mixed, grinded and kneaded into a homogeneous mixture. The mixture is heated until it flows and is extruded through a die onto a roller where it is cooled. In certain embodiments, the ingredients for a film dosage form can be found in Table 10. As noted above, for all types of formulations, when the active pharmaceutical ingredient is in the form of a salt or coformer, the doses in a formulation (e.g., 0.025 mg to 25 mg) refer to the mass of the corresponding free compound. Table 10. Example formulation of a film

Example 15. Illustrative dry powder or reconstitution powder formulation

[00552] In certain non-limiting embodiments, the dry powder or reconstitution powder formulation comprises the ingredients listed in Table 11. These ingredients can be mixed in a suitable apparatus, for example, a V blender, and then portioned into sterile vials for reconstitution. As noted above, for all types of formulations, when the active pharmaceutical ingredient is in the form of a salt or coformer, the doses in a formulation (e.g., 0.025 mg to 25 mg) refer to the mass of the corresponding free compound.

Table 11. Example formulation of a dry powder or powder for reconstitution

Example 16. Illustrative pessary formulation

[00553] In certain non-limiting embodiments, the pessary formulation comprises the ingredients listed in Table 12 or Table 13. The pessary dosage form can be prepared, for example, by mixing the active pharmaceutical ingredient with the excipient. In one nonlimiting embodiment, the excipient is heated in a mixing apparatus while stirring until it has softened or melted, then the active pharmaceutical ingredient is added portionwise. The temperature, stirring speed, and rate of addition are controlled to ensure an even distribution of active pharmaceutical ingredient. The mixture is then mixed until homogeneous and placed into pessary or suppository molds to solidify. As noted above, for all types of formulations, when the active pharmaceutical ingredient is in the form of a salt or coformer, the doses in a formulation (e.g., 0.025 mg to 25 mg) refer to the mass of the corresponding free compound.

Table 12. Example formulation for a pessary

Table 13. Example formulation for a pessary

Example 17. In-vitro cytotoxicity testing

Compounds:

[00554] A compound of Formula I, II, III, IV, V, VI, VII, Vila, Villa, Vlllb, or VIIIc is solubilized at 40 mM in DMSO and stored at -20°C. The test compounds are evaluated using a high test concentration of 50 pM. Serial half-logarithmic dilutions are performed for the in vitro cytotoxicity assays. Tamoxifen citrate can be purchased from Sigma- Aldrich (St. Louis, MO). Tamoxifen citrate is solubilized in DMSO at 40 mM and is used as a positive control compound at a high test concentration of 100 pM for the cytotoxicity assays.

In Vitro Cytotoxicity Evaluations:

[00555] Cells listed in Table 14 are enumerated by Trypan Blue Dye exclusion method and are seeded in the interior wells of a 96 well flat bottom microtiter plate at 100 pL/well. Proliferating cells are incubated overnight at 37°C/5% CO₂ to allow the cells to adhere to the plates at approximately 70% confluency. Tissue culture medium is removed and replaced with 100 pL/well of fresh medium. One-hundred microliters (100 pL) of each compound at six concentrations is transferred to the 96-well plate containing the cells in triplicate. Table 14 lists the cell line, type of cell, source of cell stock, base tissue culture medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 U/mL penicillin and 100 pg/mL streptomycin, and microtiter plate seeding density.

Table 14:

Cytotoxicity XTT :

[00556] Following incubation at 37°C in a 5% CO₂ incubator for five days, the test plates are stained with the tetrazolium dye XTT (2,3-bis(2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide). XTT-tetrazolium is metabolized by the mitochondrial enzymes of metabolically active cells to a soluble formazan product. XTT solution is prepared daily as a stock of 1 mg/ml in RPM11640. Phenazine methosulfate (PMS) solution is prepared at 0.15 mg/ml in PBS and stored in the dark at -20°C. XTT/PMS stock is prepared immediately before use by adding 40 pL of PMS per ml of XTT solution. Fifty microliters of XTT/PMS are added to each well of the plate and the plate is reincubated for 4 hours at 37°C. Plates are sealed with adhesive plate sealers and shaken gently or inverted several times to mix the soluble formazan product and the plate is read spectrophotometricallyat 450/650 nm with a Molecular Devices Vmax plate reader.

Data Analysis and Evaluation:

[00557] Microsoft Excel 2010 is used to analyze and graph the raw data. CCso (50% reduction in cell viability) values are tabulated and provided. Raw data for cytotoxicity with a graphic representation of the data can be provided in a printout summarizing the compound effect on cell viability.

[00558] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[00559] Although the foregoing disclosure has been described in some detail by way of illustration and example for the purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teaching of this disclosure that certain changes and modifications may be made thereto without departing from the spirit or scope of the disclosure as defined in the embodiments and/or claims.

Claims

1. A compound of the formula: Formula V

Formula Villa

Formula Vlllb

Formula VIIIc wherein:

R¹ is selected from C_1-4alkyl-aryl and C_1-4alkyl-heteroaryl either of which can be optionally substituted with 1, 2, 3 R¹⁴ groups, or R¹ is selected from hydrogen, acetylbenzyl, and methoxy carbonylbenzyl;

R² is selected from hydrogen, C_1-6alkyl, and C_3-6cycloalkyl;

R³ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl- OR⁸, C_1-6alkyl-NR⁸R⁹, Co-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl-heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups, or R³ is CH₂CO₂NH₂ or (CH₂)2CO₂NH₂;

R⁴ is selected from hydrogen, deuterium, C_1-6alkyl, halogen, C_1-6haloalkyl, C_1-6alkyl- OR⁸, C_1-6alkyl-NR⁸R⁹, Co-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl-heteroaryl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R¹⁶ groups; or, R¹ and R³, together with the atoms to which they are attached, form a 5, 6, 7, or 8 membered heterocycle, including a bridged heterocycle, optionally substituted with 1 or 2 R¹⁵ groups; or, R² and R³, together with the atoms to which they are attached, form a 5, 6, 7, or 8 membered heterocycle, including a bridged heterocycle, optionally substituted with 1 or 2 R¹⁵ groups; or, R³ and R⁴, together with the carbon to which they are attached, form a 3-8 membered cycloalkyl or heterocyclyl;

R⁵ is selected from hydrogen, C_1-6alkyl, -OH, -O-C_1-6alkyl, -S-C_1-6alkyl, -NR⁸R⁹, and -NR⁸C(R¹²)2C(O)R⁵⁵ wherein any of the hydrogens on any of the alkyl groups may be substituted with deuterium or halogen, or R⁵ is selected from benzyloxy, naphthalenyloxy, - OCH₂CF3, and benzyl(cyclopropyl)oxy; R⁶ is selected from hydrogen, -OH, -O-CH₃, -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, - OCF2H, -OCFH2, -CN, -COOR⁸, -C(O)R⁵, -O-C(O)R⁵, -O-C(O)OR⁸, -O-C_1-6alkyl, -O-C_1- eheteroalkyl, -O-C3-6cycloalkyl, -O-C_3-6heterocycle, -NR⁸R⁹, -NR⁸-C(O)OR⁸, -NR⁸-C(O)OR⁸, -NR⁸-C(O)NR⁸R⁹, -NR⁸OR⁸, and -OSi(R¹³)₃;

R⁷ is selected from hydrogen, deuterium, halogen, -CD3, -CD2H, -CDH2, -CF3, CF2H, -CFH2, -OH, -OCH₃, -O-haloalkyl, -CN, -C(O)R⁵, -COOR⁸, -CONR⁸R⁹, C_1-6alkyl, C_1- ehaloalkyl, C_3-6cycloalkyl, -NR⁸R⁹, -NR⁸C(O)OR⁸, -NR⁸C(O)NR⁸R⁹, and -NR⁸COR⁸;

R⁸ and R⁹ are independently selected at each occurrence from hydrogen, C_1-6alkyl, C_1-6haloalkyl, C3-6cycloalkyl, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, C2-₆alkenyl, C2-₆alkynyl, aryl, heteroaryl, and heterocycle;

R¹⁰ is independently selected at each occurrence from hydrogen, C_1-6alkyl, C_1- ehaloalkyl, C3-6cycloalkyl, C_1-6alkyl-aryl, C_1-6alkyl-heteroaryl, aryl, heteroaryl, heterocycle, - OR⁸ and -NR⁸R⁹;

R¹¹ is independently selected at each occurrence from halogen, -OR⁸, -SR⁸, -S(O)R¹⁰, -S(O)₂R¹⁰, -NHC(NH)NH₂, -N3, -CN, -C(O)OR⁸, -C(O)NR⁸R⁹, C_2-6alkenyl, C₂-6alkynyl, - C(S)R¹⁰, and -NR⁸C(O)R¹⁰;

R¹² is independently selected at each occurrence from hydrogen, C_1-6alkyl, C_1- ehaloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_1-6alkylC(O)R¹⁰, C_1-6alkyl-R¹¹, C_1-6alkyl-aryl, C_1-6alkyl- heteroaryl, and C3-6cycloalkyl, each of which is optionally substituted with 1, 2, or 3 R¹⁷ groups, or where possible, two R¹² groups, together with the carbon to which they are attached, form a 3-8 member cycloalkyl or heterocyclyl;

R¹³ is independently selected at each occurrence from C_1-6alkyl, aryl, and C_1-6alkyl- aryl;

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are independently selected at each occurrence from deuterium, C_1-6alkyl, C3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -SR⁸, C_1-6alkylC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -N3, alkenyl, alkynyl, -C(S)R¹⁰, and -NR⁸C(O)R¹⁰;

R¹⁸ is independently selected at each occurrence from hydrogen, deuterium, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -O-C(O)-R⁵, -C(O)R⁵, -SR⁸, and -C_1-6alkylC(O)R⁵;

R³³ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl- OR⁸, C_1-6alkyl-NR⁸R⁹, Co-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl-heteroaryl, and C3-6cycloalkyl, each of which is optionally substituted with 1 or 2 R¹⁵ groups; R⁴⁴ is selected from hydrogen, deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_0-6alkylC(0)R¹⁰, C_1-6alkyl-R¹¹, C_0-6alkyl-aryl, C_0-6alkyl- heteroaryl, and C3-6cycloalkyl, each of which is optionally substituted with 1 or 2 R¹⁶ groups; or R⁴ and R⁴⁴ together with the atoms to which they are attached form a 4, 5, 6, or 7 membered cycloalkyl or heterocyclic ring, including a bridged cycloalkyl or heterocyclic ring; or R² and R⁴⁴ together with the atoms to which they are attached, form a 5, 6, or 7 membered heterocyclic ring, including a bridged heterocyclic ring;

R⁵⁵ is selected from C_1-6alkyl, -O-C_1-6alkyl, -S-C_1-6alkyl, and -NR⁸R⁹;

R⁶⁰ is selected from -OH, -OCD₃, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, and -

OCFH2;

R⁶⁶ is selected from hydrogen, -OH, -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, - OCFH2, -CN, -C(O)R¹⁰, -O-C(O)R¹⁰, -O-C_1-6alkyl, -O-C_3-6cycloalyl, -O-C_3-6heterocycle, - NR⁸R⁹, -NR⁸-C(O)OR⁸, -NR⁸-C(O)NR⁸R⁹, and -OSi(R¹³)₃;

W is selected from -NH₂, -NHR⁸, -NR⁸R⁹, and -NHC(O)R⁵;

W² is selected from -OH, -O-C_1-6alkyl, -O-C_1-6haloalkyl, -NH₂, -NHR⁸, -NR⁸R⁹, fluoro, chloro, and -C(O)R⁵;

W³ is selected from R⁶, fluoro, and chloro;

X is selected from N and CR¹²;

Y is selected from -CH₂-, -CH₂CH₂-, -CH(R¹²)-, -C(R¹²)₂-, -CF2-, -C(CH₂CH₂)-, and -

C(CH₂CH₂)CH₂-;

Y² is selected from -CH₂-, -CD2-, -CH₂CH₂-, -CH(R¹²)-, -C(R¹²)₂- -CF2-, -C(CH₂CH₂)CH₂-, -O-, -S-, -OCH₂-, -OCD2-, -OCH₂CH₂-, -OCH(R¹²)-, -OC(R¹²)₂-, -OCF2-, -OCH(CH₂CH₃)CH₂-, -SCH₂-, -SCH₂CH₂-, -SCH(R¹²)-, -SC(R¹²)₂-, -SCF2-, - SC(CH₂CH₂)CH₂-, -NR⁸-, -NR⁸CH₂-, -NR⁸CD₂-, -NR⁸CH₂CH₂-, -NR⁸CH(R¹²)-, - NR⁸C(R¹²)2-, - NR⁸CF₂-, and - NR⁸C(CH₂CH₂)CH₂-; z is 0, 1, 2, or 3;

Purine is selected from: , wherein the bond from the nitrogen atom in Linker is connected to Y;

Linker⁶ is selected from: , wherein the bond from the nitrogen atom in Linker⁶ is connected to Y;

Linker⁰ is selected from: , wherein the bond from the nitrogen or oxygen atom in Linker⁰ is connected to Y; and

Linker⁶* is selected from:

2. The compound of claim 1, wherein R⁷ is selected from hydrogen, C_1-6alkyl, and C_3-6cycloalkyl, or wherein R⁷ is selected from hydrogen, methyl, ethyl, isopropyl, and cyclopropyl.

3. The compound of claim 1 or 2, wherein R⁶ is selected from hydrogen, -O-CH₃, -O- CD3, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, -OCFH2, -O-C_1-6alkyl, -O-C_1- eheteroalkyl, -O-C3-6cycloalkyl, -O-C_3-6heterocycle, and -OSi(R¹³)3, or wherein R⁶ is selected from -O-CH₃, -O-CD3, -O-CD2H, -O-CDH2, -O-CF3, -OCF2H, and - OCFH2, or wherein R⁶ is -O-CH₃ or -O-CD3.

4. The compound of claim 1 or 2, wherein R⁶⁶ is selected from -O-CD3, -O-CD2H, -O- CDH2, -O-CF3, -OCF2H, -OCFH2, and -OSi(R¹³)₃ or R⁶⁶ is selected from -O-CF3, - OCF2H, -O-CD3, -O-CD2H, -O-CDH2, and -OCFH2.

5. The compound of any one of claims 1-4, wherein R¹³ is independently selected at each occurrence from C_1-6alkyl and aryl, or wherein at least one R¹³ is C_1-6alkyl, or wherein at least one R¹³ is selected from methyl, ethyl, and isopropyl.

6. The compound of any one of claims 1-, 2, or 5, wherein R⁶⁶ is -OSi(CH₃)3.

7. The compound of any one of claims 1-2, wherein the compound is of Formula la

8. The compound of any one of claims 1-7, wherein R¹ is C_1-4alkyl-aryl substituted with 1, 2, or 3 R¹⁴ groups, or wherein R¹ is unsubstituted C_1-4alkyl-aryl.

9. The compound of any one of claims 1-8, wherein R² is hydrogen or C_1-6alkyl or wherein R² is hydrogen or wherein R² is methyl or wherein R² is C_3-6cycloalkyl or wherein R² is cyclopropyl.

10. The compound of any one of claims 1-9, wherein R³ is selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkyl-OR⁸, C_1-6alkyl-NR⁸R⁹, C_1- ₆alkylC(O)R¹⁰, C_1-6alkyl-R¹¹, C_1-6alkyl-aryl, and C_1-6alkyl-heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups, or wherein R³ is hydrogen, or wherein R³ is C_1-6alkyl.

11. The compound of any one of claims 1-9, wherein R³ is selected from methyl, ethyl, isopropyl, CH(CH₃)CH₂CH₃, and CH₂CH(CH₃)2.

12. The compound of any one of claims 1-9, wherein R³ is C_1-6alkyl-OR⁸.

13. The compound of any one of claims 1-9, wherein R³ is CH₂OH or CH(CH₃)OH.

14. The compound of any one of claims 1-9, wherein R³ is C_1-6alkyl-NR⁸R⁹.

15. The compound of any one of claims 1-9, wherein R³ is (CH₂)4NH₂.

16. The compound of any one of claims 1-9, wherein R³ is C_1-6alkylC(O)R¹⁰.

17. The compound of any one of claims 1-9, wherein R³ is selected from CH₂CO₂H,

CH₂CO₂NH₂, (CH₂)₂CO₂H, and (CH₂)₂CO₂NH₂.

18. The compound of any one of claims 1-9, wherein R³ is C_1-6alkyl-R¹¹.

19. The compound of any one of claims 1-9, wherein R³ is C_1-6alkyl-NHC(NH)NH₂ or

(CH₂)3-NHC(NH)NH₂.

20. The compound of any one of claims 1-9, wherein R³ is C_1-6alkyl-aryl.

21. The compound of any one of claims 1-9, wherein R³ is CTfc-CeHs or Cfb-CeFU-OH.

22. The compound of any one of claims 1-9, wherein R³ is C_1-6alkyl-heteroaryl.

23. The compound of any one of claims 1-9, wherein

24. The compound of any one of claims 1-9, wherein R³ is selected from the group consisting of hydrogen, C_1-6haloalkyl, and C_3-6cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 R¹⁵ groups or wherein R³ is CF3 or wherein R³ is cyclopropyl.

25. The compound of any one of claims 1-24, wherein R⁴ is hydrogen or wherein R⁴ is C_1-6alkyl or wherein R⁴ is methyl.

26. The compound of any one of claims 1-8, wherein R² and R³, together with the atoms to which they are attached, form a 5 or 6 membered heterocycle, optionally substituted with 1 or 2 R¹⁵ groups or wherein R² and R³ together with the atoms to which they are attached, form a 5-membered ring.

27. The compound of any one of claims 1-26, wherein R⁵ is selected from -O-C_1-6alkyl and -NR⁸R⁹ or wherein R⁵ is -O-C_1-6alkyl or wherein R⁵ is -O-CH₂CH₃ or wherein R⁵ is-O-CD2CD3 or wherein R⁵ is -O-CH(CH₃)2 or wherein R⁵ is -NR⁸R⁹ or wherein R⁵ is NH₂.

28. The compound of any one of claims 1-27, wherein Y is selected from -CH₂-, r wherein Y is selected from -CH₂-, -CF2-, and -C(CH₂CH₂)-.

29. The compound of any one of claims 1-28, wherein Linker, Linker⁶ and Linker⁰ are

30. The compound of any one of claims 1-28, wherein Linker⁶ and Linker⁰ are selected

31. The compound of any one of claims 1-30, wherein z is 0, 1, 2, or 3.

32. The compound of any one of claims 1-31, wherein R¹⁸ is deuterium, C_1-6alkyl, C_3-6cycloalkyl, C_1-6haloalkyl, halogen, -OR⁸, -NR⁸R⁹, -SR⁸, and C_1-6alkylC(O)R¹⁰.

33. The compound of any one of claims 1-31, wherein R¹⁸ is chosen from methyl, fluoro, or -OH.

34. The compound of any one of claims 1-33, wherein the compound is a pharmaceutically acceptable salt.

35. A pharmaceutical composition comprising a compound of any one of claims 1-34, or a pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is optionally suitable for topical administration.

36. The pharmaceutical composition of claim 35, in the form of a tablet, a semi-solid dosage form, a reconstituted powder, a dry powder dosage form, a film, or a pessary.

37. The pharmaceutical composition of claim 35 or 36, for delivery to the cervix, vagina, vulva, penis, perianal region, or anus.

38. A method to treat an HPV-induced infection or an associated condition comprising administering to a host in need thereof an effective amount of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt or cocrystal thereof, optionally in a pharmaceutical composition.

39. The method of claim 38, wherein the HPV-induced infection or associated condition is a neoplasia selected from an intraepithelial neoplasia, cervical intraepithelial neoplasia, penile intraepithelial neoplasia, vulvar intraepithelial neoplasia, perianal intraepithelial neoplasia, anal intraepithelial neoplasia, and vaginal intraepithelial neoplasia.