WO2024243341A2 - Compounds that re-activate mutant p53 - Google Patents

Abstract

The present disclosure is concerned with compounds that restore p53 activity and methods of using the compounds in the treatment of various disorders related to loss of p53 activity such as, for example, cancer (e.g, a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma)). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

COMPOUNDS THAT RE-ACTIVATE MUTANT P53

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Application No. 63/468,476, filed on May 23, 2023, the contents of which are hereby incorporated by reference in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grant numbers 5R01GM112736 and 5T32CA009035, awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.

BACKGROUND

[0003] Somatic mutations in the TP53 gene occur in nearly every adult malignancy and represent the most commonly occurring genetic defect in tumor genomic sequencing (Rivlin et al. (2011) Genes Cancer. 2:466-74). In the germline, inherited pathogenic variants (PVs) in TP53, characteristic of clinical Li-Fraumeni Syndrome (LFS), are rare. Occurring with an estimated prevalene of ~1/3500-1/5500, these PVs are associated with high risks of early- onset and multiple cancers over a lifetime (de Andrade et al. (2019) Hum Mutat. 40:97-105; Mai et al. (2016) Cancer 20 122:3673-81; Schneider et al. (1993) GeneReviews((R))). In addition to increased risk of colorectal cancer, leukemia, and adrenocortical cancers, LFS greatly increases the risk of breast cancer (up to 54% by age 70), childhood and adult soft- tissue sarcomas (15-22% lifetime risk), and brain tumors (6-19% lifetime risk) (Mai et al. (2016) Cancer 20 122:3673-81). Overall, lifetime risk of any cancer (penetrance) for germline carriers of TP53 pathogenic variants has been estimated to be as high as 90% for women and 70% for men (Rana et al. (2018) J Natl Cancer Inst. 110:863-70). The rate of de novo germline pathogenic variants in TP 53 is estimated to be -10-20% (Gonzalez et al. (2009) J Clin Oncol. 27: 1250-6; Gonzalez et al. (2009) J Med Genet. 46:689-93) “The biological underpinnings of therapeutic resistance in pancreatic cancer” Genes Dev).

[0004] Among LFS families, intensive surveillance is required to detect pre-malignant lesions (e.g., colorectal polyps) and diagnose/prevent invasive cancers at their earliest stages, when curative treatments may be available (Villani et al. (2016) Lancet Oncol 17:1295-305; The National Comprehensive Cancer Network Clinical Practice Guidelines® in Oncology: Li-Fraumeni syndrome (Version 1.2015). ©2015 National Comprehensive Cancer Network, Inc. 2019). LFS individuals are recommended to undergo neurologic exams, whole -body MRI annually, and abdominal ultrasonography every 3-4 months in childhood and adolescence. Adult women are recommended to commence annual mammogram and breast MRI in their 20s (some patients undergo surgical prophylaxis) (e.g., bilateral mastectomy)); and adult men and women are recommended to have annual skin exams and upper and lower endoscopy every 2-5 years starting at age 25 (Frebourg et al. (2020) Eur J Hum Genet. 28: 1379-86).

[0005] Most TP 53 mutations in LFS are missense, and nearly all map to p53’s DNA-binding “core domain” (Malkin (2011) Genes Cancer 2:475-84). Tumors from LFS patients have also lost the WT allele (loss of heterozygosity) in 40-60% of cases (Varley et al. (1997) BrJ Cancer 76:1-14; Shetzer et al. (2014) Cell Death Differ 21: 1419-31). With the exception of one specific Brazilian LFS founder mutation (Giacomazzi et al. (2014) PLoS One 9:e99893), the distribution of germline mutations in LFS closely matches that observed in cancers with somatic TP 53 mutations (Walerych et al. (2012) Carcinogenesis 33:2007-17). While some of these mutations unsurprisingly map to residues in direct contact with DNA, many do not (FIG. 1A). Importantly, the biophysical changes in p53 structure induced by many of these PVs inspires a potential interception strategy. From a thermodynamic standpoint, wild-type p53 is only marginally stable (Bullock et al. (1997) Proc Natl Acad Sci USA 94:14338-42; Butler and Loh (2006) Protein Sci. 15:2457-65). Many of the most frequently occurring deactivating mutations, then, reduce the conformational stability of the core domain such that the protein instead adopts an unfolded (or misfolded) conformation (Bullock et al. (2000) Oncogene 19: 1245-56). This mechanism is supported by the observation that compensatory (“second-site suppressor”) mutations to stabilize p53 (Baroni et al. (2004) Proc Natl Acad Sci USA. 101 :4930-5), or reduce its propensity for aggregation (Xu et al. (2011) Nat Chem Biol. 7:285-95), can rescue loss-of-function associated with these particular deactivating mutations. Together, these observations strongly suggest that a compound with the capacity to re-stabilize p53 may reverse the pathophysiological effects of certain LFS mutations. [0006] The study of diverse cancers with somatic missense mutations in TP53 has revealed three key aspects of p53 activity. First, in light of p53’s strong tumor suppressive role, expression of WT p53 is lost in >93% of these cancers (loss of heterozygosity) (Parikh et al. (2014) J Pathol. 232:522-33). Second, levels of WT p53 in cells are limited based on interactions with the ubiquitin ligase MDM2, which targets it for degradation. In LFS, by contrast, mutant p53’s degradation by MDM2 is disrupted, such that destabilized mutant p53 accumulates in cells (Ashcroft and Vousden (1999) Oncogene 18:7637-43; Yue et al. (2017) J Mol Biol. 429:1595-606). Third, and finally, certain p53 mutants also acquire gain-of- function (GOF) activities that promote chemoresistance, proliferation, invasion, and metastasis (Yue et al. (2017) J Mol Biol. 429: 1595-606; Dittmer et al. (1993) Nat Genet. 4:42-6; Blandino et al. (2018) J Exp Clin Cancer Res. 37:30; Hanel et al. (2013) Cell Death Differ. 20:898-909; Lang et al. (2004) Cell 119:861-72), and LFS individuals heterozygous for these missense mutations (TP53^+/mut) have earlier onset of their first tumor relative to TP53^+/~ indivudals (Hanel et al. (2013) Cell Death Differ. 20:898-909).

[0007] In addition to the TP53 mutations specific to LFS, mutations and deletions in p53 have been found in more than half of human cancers. Some of the most frequently occurring of these missense mutations are localized to the DNA-binding “core domain” of p53, but do not involve surface residues directly responsible for binding DNA. Rather, these mutations reduce the thermodynamic stability of this already marginally-stable protein, leading to loss of function (LOF) due to an insufficient amount of correctly folded p53. Separate from the loss of tumor suppressive function by these mutants, some mutants of p53 also confer oncogenic gain of function (GOF) activities.

[0008] Many groups have sought compounds that restore p53 activities to cells expressing mutant p53, essentially aiming to phenocopy the effect of second-site suppressor mutations. Most commonly, these deployed cell-based phenotypic screens: for example, transfecting a luciferase reporter controlled by a p53 response element into a cell line expressing mutant p53, and then screening for compounds that induce luciferase (Wang et al. (2006) Proc Natl Acad Sci USA 103: 11003-8). Typically, however, this approach has led to compounds that activate the desired transcriptional response through other means, including induction of Hsp40 activity (chetomin) (Hiraki et al. (2015) Chem Biol. 22: 1206-16), inhibition of MDM2-family members (e.g, Nutlin-3) (Vassilev et al. (2004) Science 303:844-8), and modulation of cellular zinc concentration (NSC319726/ZMC1) (Yu et al. (2012) Cancer Cell. 21:614-25; Yu et al. (2014) Oncotarget 5:8879-92). Many of these compounds also retain at least some of their anti-cancer activities in TP 53-nulI cells of independent of TP53 status, implying (at best) that their direct cellular target is not limited to mutant p53 (Wang et al. (2006) Proc Natl Acad Sci USA 103 : 11003-8; Sonnemann et al. (2015) Eur J Cancer 51:841-51). Clearly, the broad and potentially undefined molecular targets of these agents make them unsuitable in the context of prevention/early disease. [0009] Already some novel therapeutics have sought to directly target p53. Among many of the apparent successes in correcting missense mutations in mutant p53, however, mechanistic surprises have emerged. The first compound designed to bind mutant p53, CP-31398 (Foster et al. (1999) Science 286:2507-10), exhibited good pre-clinical efficacy in TP53-mutated cancer; however, some data indicate this compound may be acting as a DNA intercalator rather than via direct p53 targeting (Rippin et al. (2002) Oncogene 21:2119-29; Tanner et al. (2004) J Negat Results Biomed 3:5). PRIMA-1^MET (APR-246) is thought to directly engage and covalently bind to mutant p53 (Bykov et al. (2005) Oncogene 24:3484-91), and in 2020 was FDA-approved for patients with TP 53-mutated hematologic malignancies. However, data from several groups, and clinical trials, indicate that in addition to p53 re- activation, this compound kills tumors in a manner independent of mutant p53 (Rokaeus et al. (2010) Oncogene 29:6442-51; Saha et al. (2013) Mol Cancer Ther, 12:2331-41), possibly through inhibiting MEK kinase (Lu et al. (2016) Oncotarget 7:83017-30), or through some entirely different mechanism. PK11007, like PRIMA-1^MET, forms a covalent adduct to p53 but also acts in both a p53-dependent and p53 -independent manner (Bauer et al. (2016) Proc Natl Acad Sci USA 113:E5271-80; Synnott et al. (2018) Cancer Lett 414:99-106). Most recently, arsenic trioxide (ATO) was reported as another cysteine -reactive refolder of mutant p53 (Chen et al. (2021) Cancer Cell 39:225-39 e8); but here again, ATO has open-ended polypharmacology with previously reported molecular targets including JNK (Kajiguchi et al. (2006) Cancer Sci. 97:540-5; Wu et al. (2014) PLoS One 9:e86445; Huang et al. (2010) Toxicol Appl Pharmacol 244:234-41), PML-RARA (Gumari et al. (2019) Chemotherapy 64:238-47), and more (Miller et a. (2002) Cancer Res 62:3893-903). While some of these may prove to be valuable chemotherapeutic agents, their numerous off-target activities preclude utility for prevent/interception of early disease in LFS individuals.

[0010] At present, there are only three compounds with activity that likely derives solely from direct targeting of p53. The first is SCH529074, which binds to both mutant and WT p53 in a DNA-competitive manner. Acting as a chaperone to help maintain p53’s active conformation, the compound is then displaced by p53’s cognate DNA (Demma et al. (2010) J Biol Chem 285: 10198-212). This compound binds to p53 very weakly, which precludes direct translation to the clinic; a tighter-binding analog would inhibit p53’s DNA-binding capability, which would prove undesirable by phenocopying TP53 loss-of- function. Two other compounds, PhiKan083 and PC 14586, target a shallow surface cleft that is introduced by the Y220C mutation: these two compounds each fill this newly- available pocket. Because this pocket is present only in the folded conformation, and only on the Y220C mutant, these compounds selectively restore WT p53’s activity to this particular mutant (Boeckler et al. (2008) Proc Natl Acad Sci USA 105:10360-5; Liu et al. (2013) Nucleic Acids Res 41:6034- 44; Baud et al. (2018) EurJ Med Chem 152: 101-14; Dumble et al. (2021) Experimental and Molecular Therapeutics p. LB006-LB). However, this approach is also not extensible to the majority of cancer-associated mutations, because most do not produce a new surface pocket (as Y220C does), and only a small fraction of the LFS population harbors this particular mutation.

[0011] In sum, despite the solid justification for developing drugs that restore p53 activity, currently available agents are fraught with limitations. Accordingly, there remains a need for compounds and compositions that restore p53 activity and methods of making and using same.

SUMMARY

[0012] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compositions for use in restoring p53 activity. Such utility can be useful in, for example, the treatment of cancer (e.g, pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer), the treatment of Li-Fraumeni syndrome (LFS), and the prevention of cancer in a subject having LFS.

[0013] Thus, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH ₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl,

C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] Also disclosed are pharmaceutical compositions comprising an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0015] Also disclosed are methods of restoring p53 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0016] Also disclosed are methods of restoring p53 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure selected from:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0017] Also disclosed are methods of restoring p53 activity in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0018] Also disclosed are methods of restoring p53 activity in a subject, the method comprising administering to the subject an effective amount of a compound having a structure selected from:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0019] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

[0020] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

[0021] Also disclosed are methods of treating Li-Fraumeni syndrome (LFS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

[0022] Also disclosed are methods of treating Li-Fraumeni syndrome (LFS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

[0023] Also disclosed are methods of treating cancer in a subject having Li-Fraumeni syndrome (LFS), the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

[0024] Also disclosed are methods of treating cancer in a subject having Li-Fraumeni syndrome (LFS), the method comprising administering to the subject an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

[0025] Also disclosed are kits comprising a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anticancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

[0026] Also disclosed are kits comprising a compound selected from:

or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anticancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

[0027] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

[0028] The above and other objects, features and advantages of the present invention will become more apparent to those of ordinary skill in the art by describing in detail exemplary embodiments thereof with reference to the accompanying drawings.

[0029] FIG. 1A and FIG. IB show representative data illustrating the unfolding and refolding of mutant p53.

[0030] FIG. 2A and FIG. 2B show representative data illustrating the application of structure -based virtual screening to identify refolders of mutant p53.

[0031] FIG. 3A-D show representative data generated in cell-based assays for p53 refolding.

[0032] FIG. 4 shows representative data illustrating biochemical monitoring of p53 refolding, to drive future optimization.

[0033] FIG. 5 shows a representative schematic illustrating optimization of computation screening hit JO to arrive at compound J3.

[0034] FIG. 6 shows representative data to define rescuable TP53 missense mutations.

[0035] FIG. 7 shows representative data illustrating the rescue of mutant p53 gain-of- function (GOF).

[0036] FIG. 8 shows a representative schematic illustrating a proposed 4NQO treatment regimen for the efficacy study.

[0037] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

[0038] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein. [0039] Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0040] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0041] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.

A. DEFINITIONS

[0042] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like. [0043] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of’ and “consisting essentially of.”

[0044] Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0045] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0046] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound. [0047] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0048] As used herein, “IC50” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an IC50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein. In a further aspect, IC50 refers to the half-maximal (50%) inhibitory concentration (IC) of a substance.

[0049] As used herein, “EC50” is intended to refer to the concentration of a substance (e.g. , a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein. In a further aspect, EC50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response.

[0050] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0051] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0052] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0053] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. [0054] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. [0055] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0056] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0057] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethyl ene9- 10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g. , sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g. , polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0058] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0059] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0060] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14^th edition), the Physicians' Desk Reference (64^th edition), and The Pharmacological Basis of Therapeutics (12^th edition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; anti-cancer and anti-neoplastic agents such as kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HD Ac) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programmed cell death protein 1 (PD-l)/programmed cell death-ligand 1 (PD-L1) mAB, cluster of differentiation 47 (CD47) mAB, toll-like receptor (TLR) agonists and other immune modifiers, cell therapeutics such as chimeric antigen receptor T-cell (CAR-T)/chimeric antigen receptor natural killer (CAR-NK) cells, and proteins such as interferons (IFNs), interleukins (ILs), and mAbs; anti-ALS agents such as entry inhibitors, fusion inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, NCP7 inhibitors, protease inhibitors, and integrase inhibitors; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, antiepileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0061] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0062] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g. , a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0063] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly( orthoesters) and poly( anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0064] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g.. a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0065] In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0066] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0067] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, //-propyl, isopropyl, //-butyl, isobutyl, s- butyl, t-butyl, //-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a Cl alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, Cl -CIO alkyl, and the like up to and including a C1-C24 alkyl.

[0068] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups.

When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0069] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g. , a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0070] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0071] The term “polyalkylene group” as used herein is a group having two or more CH₂ groups linked to one another. The polyalkylene group can be represented by the formula — (CH₂)_a — , where “a” is an integer of from 2 to 500.

[0072] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as — OA¹ where A¹ is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as — OA¹ — OA² or — OA¹ — (OA²)_a — OA³, where “a” is an integer of from 1 to 200 and A¹, A², and A³ are alkyl and/or cycloalkyl groups.

[0073] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as ( A ¹ A²)C=C( A³ A⁴) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0074] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C= C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbomenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0075] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0076] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0077] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0078] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carboncarbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0079] The term “aldehyde” as used herein is represented by the formula — C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C= O. [0080] The terms “amine” or “amino” as used herein are represented by the formula — NA ¹ A², where A¹ and A² can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH₂.

[0081] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0082] The term “dialkylamino” as used herein is represented by the formula — N(-alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N -methylamino group, N-methyl-N -propylamino group, N- ethyl-N-propylamino group and the like. [0083] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH. [0084] The term “ester” as used herein is represented by the formula — OC(O)A¹ or — C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula — (A¹O(O)C-A²-C(O)O)_a — or — (A¹O(O)C-A²-OC(O))_a — , where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0085] The term “ether” as used herein is represented by the formula A 'O A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A¹O-A²O)_a — , where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0086] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0087] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0088] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quatemized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0089] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, A'-mcthylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, bcnzo[<7]oxazolyl, bcnzo[c/]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0090] The terms “heterocycle” or “heterocyclyl” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2, 3 -thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2, 3 -triazole, 1,3,4-triazole, tetrazole, including 1, 2,3,4- tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1 ,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group that has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring. [0091] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2, or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2, or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[l,5-a]pyridinyl, benzo furanyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.

[0092] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0093] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH.

[0094] The term “ketone” as used herein is represented by the formula A¹C(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0095] The term “azide” or “azido” as used herein is represented by the formula — N₃. [0096] The term “nitro” as used herein is represented by the formula — NO₂.

[0097] The term “nitrile” or “cyano” as used herein is represented by the formula — CN. [0098] The term “silyl” as used herein is represented by the formula — S¹A²A³, where A¹, A², and A³ can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0099] The term “sulfo-oxo” as used herein is represented by the formulas — S(O)A¹, — S(O)2A¹, — OS(O)2A¹, or — OS(O)2OA¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A¹S(O)2A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A¹S(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [00100] The term “thiol” as used herein is represented by the formula — SH. [00101] ‘R¹,” “R²,” “R³,” “Rⁿ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R¹ is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group. [00102] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[00103] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[00104] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH₂)o-4R°; -(CH₂)o-40R°; - 0(CH₂)_0-4R°, -0-(CH₂)_0-4 C(0)OR°; -(CH₂)_0-4 CH(OR°)₂; -(CH₂)_0-4 SR°; -(CH₂)_0-4Ph, which may be substituted with R°; -(CH₂)_0-40(CH₂)_0-1Ph which may be substituted with R°; - CH=CHPh, which may be substituted with R°; -(CH₂)o-40(CH₂)o-i-pyridyl which may be substituted with R°; -NO₂; -CN; -N₃; -(CH₂)o-4N(R°)2; -(CH₂)o-4N(R°)C(0)R°; - N(R°)C(S)R°; -(CH₂)_0-4N(R°)C(0)NR°2; -N(R^O)C(S)NR°₂; -(CH₂)_0-4N(R°)C(0)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R^O)C(O)NR^O ₂; -N(R°)N(R°)C(O)OR°; -(CH₂)o-4C(0)R°; - C(S)R°; -(CH₂)O^C(0)OR°; -(CH₂)_0-4 C(0)SR°; -(CH₂)o-4C(0)OSiR°₃; -(CH₂)o-40C(0)R°; -OC(0)(CH₂)_0-4 SR- SC(S)SR°; -(CH₂)_0-4 SC(0)R°; -(CH₂)_0-4 C(0)NR°₂; -C(S)NR^O ₂; - C(S)SR°; -(CH₂)_0-40C(0)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH₂C(O)R^O; - C(NOR°)R°; -(CH₂)_0-4 SSR°; -(CH₂)_0-4 S(0)₂R°; -(CH₂)_0-4 S(0)₂OR⁰; -(CH₂)_0-40S(0)₂R°; - S(O)₂NR°₂; -(CH₂)_0-4 S(0)R°; -N(R^O)S(O)₂NR°2; -N(R^O)S(O)₂R°; -N(OR°)R°; - C(NH)NR°₂; -P(O)₂R^O; -P(O)R^O ₂; -OP(O)R^O ₂; -OP(O)(OR^O)₂; SiR°₃; -(C1-4 straight or branched alkylene)O-N(R°)2; or -(Ci^i straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci- 6 aliphatic, -CH₂Ph , -0(CH₂)_0-1Ph, -CH₂-(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[00105] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH₂)_0-2R^●, -(haloR^●), -(CH₂)_0-2OH, -(CH₂)_0-2OR^●, -(CH₂)_0-2CH(OR^●)2; -O(haloR^●), -CN, -N₃, -(CH₂)_o-2C(0)R^●, -(CH₂)_0-2C(0)OH, -(CH₂)_0-2C(0)OR^●, -(CH₂)_{0- 2}SR^●, -(CH₂)_0-2SH, -(CH₂)O-2NH₂, -(CH₂)_0-2NHR^●, -(CH₂)O-2NR^●2, -NO₂, -SiR^● ₃, -OSiR^● ₃, -C(O)SR^● -(C_1-4 straight or branched alkylene)C(O)OR^●, or -SSR^● wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C_1-4 aliphatic, -CH₂Ph , -0(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[00106] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)₂R*, -NR*. -NOR*. -_O(C(R*2))_2-3O-, or -S(C(R*₂))_2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*₂)_2-3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00107] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR^●), -OH, -OR^●, -O(haloR^●), -CN, -C(O)OH, -C(O)OR^●, -NH₂, -NHR^●, -NR^● ₂, or - NO₂, wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic, -CH₂Ph , -O(CH₂)_0-1Ph, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00108] Suitable substituents on a substitutable nitrogen of an “optionally substituted”

; wherein each

is

independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of

, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00109] Suitable substituents on the aliphatic group of R^♣ are independently halogen, -R^●, -(haloR^●), -OH, -OR^●, -O(haloR^●), -CN, -C(O)OH, -C(O)OR^●, -NH₂, -NHR^●, -NR^● ₂, or -NO₂, wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4 aliphatic, -CH₂Ph, -0(CH₂)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having _0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00110] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[00111] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[00112] The term “organic residue” defines a carbon-containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[00113] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure:

regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e. , substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[00114] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1 -26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, disubstituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[00115] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[00116] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. [00117] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane -polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[00118] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[00119] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[00120] When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g.. (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.

[00121] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[00122] "Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, solvates and combinations thereof The “combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, and solvates. Examples of radioactively labeled forms include compounds labeled with tritium, phosphorous-32, iodine- 129, carbon-11, fluorine- 18, and the like.

[00123] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷0, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon- 14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[00124] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[00125] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[00126] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.

[00127] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, A¹ -unsubstituted, 3-A³ and A¹ -unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possible tautomers.

[00128] It is known that chemical substances form solids that are present in different states of order that are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[00129] In some aspects, a structure of a compound can be represented by a formula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, Rⁿ is understood to represent five independent substituents, R^n(a), R^n(b), R^n(c), R^n(d), R^n(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R^n(a) is halogen, then R^n(b) is not necessarily halogen in that instance.

[00130] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[00131] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[00132] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[00133] It is understood that the compounds and compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

B. COMPOUNDS

[00134] In one aspect, the invention relates to compounds useful in treating disorders associated with loss of p53 activity such as, for example, cancers including, but not limited to, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas). [00135] In one aspect, the compounds of the invention are useful in the treatment of cancer as further described herein.

[00136] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.

1. STRUCTURE

[00137] In one aspect, disclosed are compounds having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[00138] In one aspect, disclosed are compounds selected from:

or a pharmaceutically acceptable salt thereof.

[00139] In one aspect, disclosed are compounds having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

[00140] In one aspect, disclosed are compounds selected from:

or a pharmaceutically acceptable salt thereof.

[00141] In various aspects, the compound has a structure represented by a formula:

wherein n is selected from 0 and 1 , or a pharmaceutically acceptable salt thereof.

[00142] In various aspects, the compound has a structure represented by a formula:

wherein each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl), or a pharmaceutically acceptable salt thereof. [00143] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00144] In various aspects, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

[00145] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00146] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00147] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00148] In various aspects, the compound is:

or a pharmaceutically acceptable salt thereof.

[00149] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00150] In various aspects, the compound is:

or a pharmaceutically acceptable salt thereof.

[00151] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00152] In various aspects, the compound is:

or a pharmaceutically acceptable salt thereof.

[00153] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00154] In various aspects, the compound is:

or a pharmaceutically acceptable salt thereof.

[00155] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00156] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00157] In various aspects, the compound is:

or a pharmaceutically acceptable salt thereof. [00158] In various aspects, the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

[00159] In various aspects, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

[00160] In one aspect, n is selected from 0 and 1. In a further aspect, n is 0. In a still further aspect, n is 1. a. A GROUPS

[00161] In one aspect, A is a structure selected from:

[00162] In various aspects, A is a structure selected from:

[00163] In various aspects, A is a structure selected from:

[00164] In various aspects, A is a structure:

[00165] In various aspects, A is a structure:

[00166] In various aspects, A is a structure selected from:

[00167] In various aspects, A is a structure:

[00168] In various aspects, A is a structure:

[00169] In various aspects, A is a structure selected from:

[00170] In various aspects, A is a structure:

[00171] In various aspects, A is a structure:

b. Q GROUPS

[00172] In one aspect, Q is hydrogen or a structure represented by a formula:

[00173] In various aspects, Q is hydrogen.

[00174] In various aspects, Q is a structure represented by a formula:

c. R¹ GROUPS

[00175] In one aspect, R¹ is selected from hydrogen, C 1 -C4 alkyl, C 1 -C4 alkoxy,

-(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹. In a further aspect, R¹ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH₂OCH₂CH₃, -CH₂OCH₂CH₂CH₃, -CH₂OCH(CH₃)2, -CH₂Ar¹, and -Ar¹. In a still further aspect, R¹ is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH₂OCH₂CH₃, -CH₂Ar¹, and -Ar¹. In yet a further aspect, R¹ is selected from hydrogen, methyl, methoxy, -CH₂OCH₃, -CH₂Ar¹, and -Ar¹. [00176] In various aspects, R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and -(C1-C4 alkyl)O(Cl-C4 alkyl). In a further aspect, R¹ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH₂OCH₂CH₃, -CH₂OCH₂CH₂CH₃, and -CH₂OCH(CH₃)2. In a still further aspect, R¹ is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, -CH₂OCH₃, -CH₂CH₂OCH₃, and -CH₂OCH₂CH₃. In yet a further aspect, R¹ is selected from hydrogen, methyl, methoxy, and -CH₂OCH₃.

[00177] In various aspects, R¹ is selected from C1-C4 alkoxy and -(C1-C4 alkyl)O(Cl-C4 alkyl). In a further aspect, R¹ is selected from isopropyl, methoxy, ethoxy, n- propoxy, isopropoxy, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH₂OCH₂CH₃, -CH₂OCH₂CH₂CH₃, and -CH₂OCH(CH₃)₂. In a still further aspect, R¹ is selected from methoxy, ethoxy, -CH₂OCH₃, -CH₂CH₂OCH₃, and -CH₂OCH₂CH₃. In yet a further aspect, R¹ is selected from methoxy and -CH₂OCH₃.

[00178] In various aspects, R¹ is selected from hydrogen and C 1 -C4 alkyl. In a further aspect, R¹ is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R¹ is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R¹ is selected from hydrogen and ethyl. In an even further aspect, R¹ is selected from hydrogen and methyl.

[00179] In various aspects, R¹ is C 1 -C4 alkyl. In a further aspect, R¹ is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R¹ is selected from methyl and ethyl. In yet a further aspect, R¹ is ethyl. In an even further aspect, R¹ is methyl.

[00180] In various aspects, R¹ is selected from -CH₂Ar¹ and -Ar¹. In a further aspect, R¹ is -CH₂Ar¹. In a still further aspect, R¹ is -Ar¹.

[00181] In various aspects, R¹ is hydrogen. d. R² GROUPS

[00182] In one aspect, R² is selected from hydrogen and C1-C4 alkyl. In a further aspect, R² is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R² is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R² is selected from hydrogen and ethyl. In an even further aspect, R² is selected from hydrogen and methyl.

[00183] In various aspects, R² is C 1 -C4 alkyl. In a further aspect, R² is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R² is selected from methyl and ethyl. In yet a further aspect, R² is ethyl. In an even further aspect, R² is methyl. [00184] In various aspects, R² is hydrogen. e. R^3A, R^3B, R^3C, R^3D, AND R^3E GROUPS

[00185] In one aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, - OH, -NO₂, methyl, ethyl, n -propyl, i-propyl, ethenyl, propenyl, isopropenyl, -CH₂F, -CH₂CI, -CH₂CH₂F, -CH₂CH₂CI, -CH₂CH₂CH₂F, -CH₂CH₂CH₂CI, -CH(CH₃)CH₂F, - CH(CH₃)CH₂C1, -CH₂CN, -CH₂CH₂CN, -CH₂CH₂CH₂CN, -CH(CH₃)CH₂CN, -CH₂OH, - CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH(CH₃)CH₂OH, -OCF₃, -OCH₂CF₃, -OCH₂CH₂CF₃, - OCH(CH₃)CF₃, -OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃, -OCH(CH₃)CH₃, -NHCH₃, - NHCH₂CH₃, -NHCH₂CH₂CH₃, -NHCH(CH₃)CH₃, -N(CH₃)₂, -N(CH₂CH₃)₂, - N(CH₂CH₂CH₃)₂, -N(CH(CH₃)CH₃)₂, -N(CH₃)(CH₂CH₃), -CH₂NH₂, -CH₂CH₂NH₂, - CH₂CH₂CH₂NH₂, and -CH(CH₃)CH₂NH₂. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, methyl, ethyl, ethenyl, -CH₂F, -CH₂C1, -CH₂CH₂F, -CH₂CH₂CI, -CH₂CN -CH₂CH₂CN, -CH₂OH, -CH₂CH₂OH, -OCF₃, -OCH₂CF₃, -OCH₃, -OCH₂CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -N(CH₂CH₃)₂, -N(CH₃)(CH₂CH₃), -CH₂NH₂, and -CH₂CH₂NH₂. In a still further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, - CN, -OH, -NO₂, methyl, -CH₂F, -CH₂C1, -CH₂CN, -CH₂OH, -OCF₃, -OCH₂CF₃, -OCH₃, -NHCH₃, -N(CH₃)₂, and -CH₂NH₂.

[00186] In various aspects, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, - F, -Cl, -NH₂, -CN, -OH, -NO₂, methyl, ethyl, n -propyl, z-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, methyl, ethyl, and ethenyl. In a still further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, - F, -Cl, -NH₂, -CN, -OH, -NO₂, and methyl.

[00187] In various aspects, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, n -propyl, i-propyl, -OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃, and -OCH(CH₃)CH₃. In a still further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, -OCH₃, and -OCH₂CH₃. In yet a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -CN, methyl, and -OCH₃.

[00188] In various aspects, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -CH₂F, -CH₂CI, -CH₂CH₂F, -CH₂CH₂CI, - CH₂CH₂CH₂F, -CH₂CH₂CH₂CI, -CH(CH₃)CH₂F, -CH(CH₃)CH₂C1, -CH₂CN, -CH₂CH₂CN, -CH₂CH₂CH₂CN, and -CH(CH₃)CH₂CN. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -CH₂F, - CH₂CI, -CH₂CH₂F, -CH₂CH₂CI, -CH₂CN, and -CH₂CH₂CN. In a still further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, - OH, -NO₂, -CH₂F, -CH₂CI, and -CH₂CN.

[00189] In various aspects, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -CH₂OH, -CH₂CH₂OH, - CH₂CH₂CH₂OH, -CH(CH₃)CH₂OH, -OCF3, -OCH₂CF3, -OCH₂CH₂CF3, -OCH(CH₃)CF3, - OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃, and -OCH(CH₃)CH₃. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -CH₂OH, -CH₂CH₂OH, -OCF3, -OCH₂CF3, -OCH₃, and -OCH₂CH₃. In a still further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, - F, -Cl, -NH₂, -CN, -OH, -NO₂, -CH₂OH, -OCF3, -OCH₂CF3, and -OCH₃.

[00190] In various aspects, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -NHCH₃, - NHCH₂CH₃, -NHCH₂CH₂CH₃, -NHCH(CH₃)CH₃, -N(CH₃)₂, -N(CH₂CH₃)₂, - N(CH₂CH₂CH₃)₂, -N(CH(CH₃)CH₃)2, -N(CH₃)(CH₂CH₃), -CH₂NH₂, -CH₂CH₂NH₂, - CH₂CH₂CH₂NH₂, and -CH(CH₃)CH₂NH₂. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -NHCH₃, - NHCH₂CH₃, -N(CH₃)₂, -N(CH₂CH₃)₂, -N(CH₃)(CH₂CH₃), -CH₂NH₂, and -CH₂CH₂NH₂. In a still further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -NHCH₃, -N(CH₃)₂, and -CH₂NH₂.

[00191] In various aspects, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R^3a, R^3b, R^3C, R^3d, and R^3e is independently selected from hydrogen, methyl, ethyl, //-propyl, and i- propyl. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen and methyl.

[00192] In various aspects, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen and halogen. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, and -Cl. In a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen and -Cl. In a still further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen and -F.

[00193] In various aspects, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, C 1 -C4 alkyl, and C 1 -C4 alkoxy. In a further aspect, each of R^3a, R^3b, R^3C, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n- propyl, z-propyl, -OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃, and -OCH(CH₃)CH₃. In a still further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, methyl, ethyl, -OCH₃, and -OCH₂CH₃. In yet a further aspect, each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, methyl, -OCH₃.

[00194] In various aspects, each of R^3a, R^3b, R^3c, R^3d, and R^3e is hydrogen. f. R^10A, R^10B, R^10C, R^10D, AND R^10E GROUPS

[00195] In one aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, methyl, ethyl, n -propyl, i-propyl, ethenyl, propenyl, isopropenyl, -CH₂F, -CH₂C1, -CH₂CH₂F, -CH₂CH₂C1, -CH₂CH₂CH₂F, - CH₂CH₂CH₂C1, -CH(CH₃)CH₂F, -CH(CH₃)CH₂C1, -CH₂CN, -CH₂CH₂CN, - CH₂CH₂CH₂CN, -CH(CH₃)CH₂CN, -CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH, - CH(CH₃)CH₂OH, -0CF3, -OCH₂CF₃, -OCH₂CH₂CF₃, -OCH(CH₃)CF₃, -0CH₃, - OCH₂CH₃, -OCH₂CH₂CH₃, -OCH(CH₃)CH₃, -NHCH₃, -NHCH₂CH₃, -NHCH₂CH₂CH₃, - NHCH(CH₃)CH₃, -N(CH₃)2, -N(CH₂CH₃)₂, -N(CH₂CH₂CH₃)₂, -N(CH(CH₃)CH₃)₂, - N(CH₃)(CH₂CH₃), -CH₂NH₂, -CH₂CH₂NH₂, -CH₂CH₂CH₂NH₂, -CH(CH₃)CH₂NH₂, -CO₂H, and -CO₂(C1-C4 alkyl). In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, methyl, ethyl, ethenyl, -CH₂F, -CH₂C1, -CH₂CH₂F, -CH₂CH₂C1, -CH₂CN,-CH₂CH₂CN, -CH₂OH, - CH₂CH₂OH, -OCF₃, -OCH₂CF₃, -OCH₃, -OCH₂CH₃, -NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, - N(CH₂CH₃)₂, -N(CH₃)(CH₂CH₃), -CH₂NH₂, -CH₂CH₂NH₂, -CO₂H, and -CO₂(Cl-C4 alkyl). In a still further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, methyl, -CH₂F, -CH₂C1, - CH₂CN, -CH₂OH, -OCF₃, -OCH₂CF₃, -OCH₃, -NHCH₃, -N(CH₃)₂, -CH₂NH₂, -CO₂H, and -CO₂(C1-C4 alkyl).

[00196] In various aspects, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, methyl, ethyl, //-propyl, z-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, methyl, ethyl, and ethenyl. In a still further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, and methyl.

[00197] In various aspects, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, //-propyl, z-propyl, -OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃, and - OCH(CH₃)CH₃. In a still further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, -OCH₃, and -OCH₂CH₃. In yet a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -CN, methyl, and -OCH₃.

[00198] In various aspects, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -CH₂F, -CH₂C1, -CH₂CH₂F, - CH₂CH₂C1, -CH₂CH₂CH₂F, -CH₂CH₂CH₂C1, -CH(CH₃)CH₂F, -CH(CH₃)CH₂C1, -CH₂CN, -CH₂CH₂CN, -CH₂CH₂CH₂CN, and -CH(CH₃)CH₂CN. In a further aspect, each of R^10a, Ri°b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, - OH, -NO₂, -CH₂F, -CH₂CI, -CH₂CH₂F, -CH₂CH₂CI, -CH₂CN, and -CH₂CH₂CN. In a still further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -CH₂F, -CH₂CI, and -CH₂CN.

[00199] In various aspects, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -CH₂OH, - CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH(CH₃)CH₂OH, -OCF3, -OCH₂CF3, -OCH₂CH₂CF3, - OCH(CH₃)CF3, -OCH₃, -OCH₂CH₃, -OCH₂CH₂CH₃, and -OCH(CH₃)CH₃. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, - Cl, -NH₂, -CN, -OH, -NO₂, -CH₂OH, -CH₂CH₂OH, -OCF3, -OCH₂CF3, -OCH₃, and - OCH₂CH₃. In a still further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -CH₂OH, -OCF3, -OCH₂CF3, and -OCH₃.

[00200] In various aspects, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkylamino, (C1-C4)(C1- C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, - NHCH₃, -NHCH₂CH₃, -NHCH₂CH₂CH₃, -NHCH(CH₃)CH₃, -N(CH₃)₂, -N(CH₂CH₃)₂, - N(CH₂CH₂CH₃)₂, -N(CH(CH₃)CH₃)₂, -N(CH₃)(CH₂CH₃), -CH₂NH₂, -CH₂CH₂NH₂, - CH₂CH₂CH₂NH₂, and -CH(CH₃)CH₂NH₂. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is ndependently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, - NHCH₃, -NHCH₂CH₃, -N(CH₃)₂, -N(CH₂CH₃)₂, -N(CH₃)(CH₂CH₃), -CH₂NH₂, and - CH₂CH₂NH₂. In a still further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, -Cl, -NH₂, -CN, -OH, -NO₂, -NHCH₃, -N(CH₃)2, and - CH₂NH₂.

[00201] In various aspects, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R^10a, Ri°b, R^10c, R^10d, and R^10e is independently selected from hydrogen, methyl, ethyl, //-propyl, and z-propyl. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen and methyl.

[00202] In various aspects, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen and halogen. In a further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, -F, and -Cl. In a further aspect, each of R^10a, Ri°b, R^10c, R^10d, and R^10e is independently selected from hydrogen and -Cl. In a still further aspect, each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen and - F.

[00203] In various aspects, at least one of R^10a, R^10b, R^10c, R^10d, and R^10e is hydrogen. In a further aspect, at least two of R^10a, R^10b, R^10c, R^10d, and R^10e is hydrogen. In a still further aspect, at least three of R^10a, R^10b, R^10c, R^10d, and R^10e is hydrogen. In yet a further aspect, at least four of R^10a, R^10b, R^10c, R^10d, and R^10e is hydrogen. In an even further aspect, each of Ri°a, R^10b, R^10c, R^10d, and R^10e is hydrogen. g. AR¹ GROUPS

[00204] In one aspect, Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a further aspect, Ar¹, when present, is a 6-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a still further aspect, Ar¹, when present, is a 6-membered aryl substituted with 0 or 1 group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In yet a further aspect, Ar¹ is a 6-membered aryl monosubstituted with a group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In an even further aspect, Ar¹, when present, is an unsubstituted 6-membered aryl.

[00205] In various aspects, Ar¹ is a 6-membered aryl substituted with 1, 2, or 3 groups selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, and -CO₂(C1-C4 alkyl). In a further aspect, Ar¹ is a 6-membered aryl substituted with 1 or 2 groups selected from halogen, C 1 -C4 alkyl, C1-C4 alkoxy, and -CO₂(C1-C4 alkyl). In a still further aspect, Ar¹ is a 6-membered aryl substituted with 2 groups selected from halogen, C 1 -C4 alkyl, C 1 -C4 alkoxy, and -CO₂(C1-C4 alkyl). In yet a further aspect, Ar¹ is a 6-membered aryl monosubstituted with a group selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, and -CO₂(C1-C4 alkyl).

[00206] In various aspects, Ar¹ is a 6-membered aryl substituted with 1, 2, or 3 groups selected from -F, -Cl, methyl, ethyl, methoxy, ethoxy, -CO₂CH₃, and -CO₂CH₂CH₃. In a further aspect, Ar¹ is a 6-membered aryl substituted with 1 or 2 groups selected from -F, -Cl, methyl, ethyl, methoxy, ethoxy, -CO₂CH₃, and -CO₂CH₂CH₃. In a still further aspect, Ar¹ is a 6-membered aryl substituted with 2 groups selected from -F, -Cl, methyl, ethyl, methoxy, ethoxy, -CO₂CH₃, and -CO₂CH₂CH₃. In yet a further aspect, Ar¹ is a 6-membered aryl monosubstituted with a group selected from -F, -Cl, methyl, ethyl, methoxy, ethoxy, -CO₂CH₃, and -CO₂CH₂CH₃. h. AR² GROUPS

[00207] In one aspect, Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a further aspect, Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1 , or 2 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a still further aspect, Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In yet a further aspect, Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is monosubstituted with 0a group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In an even further aspect, Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted. [00208] In various aspects, Ar² is a 5- to 10-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). Examples of 5- to 10-membered heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine. In a further aspect, Ar² is a 5- to 10-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a still further aspect, Ar² is a 5- to 10-membered heteroaryl substituted with 0 or 1 group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In yet a further aspect, Ar² is a 5- to 10- membered heteroaryl monosubstituted with 0a group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In an even further aspect, Ar² is an unsubstituted 5- to 10-membered heteroaryl.

[00209] In various aspects, Ar² is a pyrimidinyl substituted with 0, 1 , 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a further aspect, Ar² is a pyrimidinyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a still further aspect, Ar² is a pyrimidinyl substituted with 0 or 1 group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In yet a further aspect, Ar² is a pyrimidinyl monosubstituted with 0a group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In an even further aspect, Ar² is an unsubstituted pyrimidinyl.

[00210] In various aspects, Ar² is a pyrazolyl substituted with 0, 1 , 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a further aspect, Ar² is a pyrazolyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a still further aspect, Ar² is a pyrazolyl substituted with 0 or 1 group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In yet a further aspect, Ar² is a pyrazolyl monosubstituted with 0a group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In an even further aspect, Ar² is an unsubstituted pyrazolyl.

[00211] In various aspects, Ar² is a triazo lyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a further aspect, Ar² is a triazo lyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a still further aspect, Ar² is a triazo lyl substituted with 0 or 1 group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In yet a further aspect, Ar² is a triazolyl monosubstituted with 0a group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In an even further aspect, Ar² is an unsubstituted triazolyl.

[00212] In various aspects, Ar² is a 6- to 10-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). Examples of 6- to 10-membered aryls include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar² is a 6- to 10-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a still further aspect, Ar² is a 6- to 10- membered aryl substituted with 0 or 1 group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, Cl- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In yet a further aspect, Ar² is a 6- to 10- membered aryl monosubstituted with 0a group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In an even further aspect, Ar² is an unsubstituted 6- to 10-membered aryl.

[00213] In various aspects, Ar² is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a further aspect, Ar² is a 6-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In a still further aspect, Ar² is a 6-membered aryl substituted with 0 or 1 group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In yet a further aspect, Ar² is a 6-membered aryl monosubstituted with 0a group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl). In an even further aspect, Ar² is an unsubstituted 6-membered aryl.

2. EXAMPLE COMPOUNDS

[00214] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00215] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00216] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00217] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00218] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00219] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00220] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00221] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00222] In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

[00223] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[00224] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[00225] It is understood that pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses. The pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like. C . METHODS OF MAKING A COMPOUND

[00226] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[00227] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Route I, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.

1. ROUTE I

[00228] In one aspect, a disclosed compound can be prepared as shown below.

SCHEME 1A.

[00229] Compounds are represented in generic form, wherein X is a halogen, and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME IB.

[00230] In one aspect, compounds of type 1.10, and similar compounds, can be prepared according to reaction Scheme IB above. Thus, compounds of type 1.8 can be prepared by a coupling reaction between an appropriate sulfonyl halide, e.g., 1.6 as shown above, and an appropriate aniline, e.g., 1.7 as shown above. Appropriate sulfonyl halides and appropriate anilines are commercially available or prepared by methods known to one skilled in the art. The coupling reaction is carried out in the presence of an appropriate solvent, e.g.,

1.4-dioxane as shown above, at an appropriate temperature, e.g. , room temperature, for an appropriate period of time, e.g., 24 hours. Compounds of type 1.9 can be prepared by reduction of an appropriate nitrobenzene, e.g., 1.8 as shown above. The reduction is carried out in the presence of an appropriate reducing agent, e.g., hydrogen gas, and an appropriate catalyst, e.g. , palladium on carbon, in an appropriate solvent, e.g. , ethanol, at an appropriate temperature, e.g., room temperature, for an appropriate period of time, e.g., 24 hours.

Compounds of type 1.10 can be prepared by cyclization of an appropriate sulphonamide, e.g., 1.9 as shown above. The cyclization is carried out in the presence of an appropriate activating agent, e.g., 1,1 ’ -carbonyldiimidazole (1,1’-CDI), in an appropriate solvent, e.g.,

1.4-dioxane, at an appropriate temperature, e.g., 80 °C, for an appropriate period of time, e.g., 24 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1, 1.2, 1.3, and 1.4), can be substituted in the reaction to provide substituted compounds similar to Formula 1.5.

2. ROUTE II [00231] In one aspect, a disclosed compound can be prepared as shown below.

SCHEME 2A.

2.3

[00232] Compounds are represented in generic form, wherein X is a halogen, and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.

SCHEME 2B.

[00233] In one aspect, compounds of type 2.6, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus, compounds of type 2.6 can be prepared by a coupling reaction between an appropriate benzothiadiazinone, e.g., 2.4 as shown above, and an appropriate haloacetamide, e.g., 2.5 as shown above. Appropriate haloacetamides are commercially available or prepared by methods known to one skilled in the art. The coupling reaction is carried out in the presence of an appropriate base, e.g., sodium carbonate as shown above, in an appropriate solvent, e.g., dimethylformamide (DMF) as shown above. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1 and 2.2), can be substituted in the reaction to provide substituted compounds similar to Formula 2.3.

D. PHARMACEUTICAL COMPOSITIONS

[00234] In one aspect, disclosed are pharmaceutical compositions comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[00235] Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[00236] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00237] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, intravenous, topical, or oral administration.

[00238] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[00239] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[00240] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[00241] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[00242] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[00243] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[00244] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[00245] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[00246] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[00247] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[00248] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[00249] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[00250] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.

[00251] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[00252] In a further aspect, the pharmaceutical composition is used to treat cancer such as, for example, a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).

[00253] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.

E. METHODS OF RESTORING P53 ACTIVITY IN A SUBJECT

[00254] In one aspect, disclosed are methods of restoring p53 activity in a subject, the method comprising the step of administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[00255] Thus, in one aspect, disclosed are methods of restoring p53 activity in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[00256] In one aspect, disclosed are methods of restoring p53 activity in a subject, the method comprising administering to the subject an effective amount of a compound having a structure selected from:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00257] In various aspects, the subject has been diagnosed with a need for treatment of a disorder related to loss of p53 activity prior to the administering step. In a further aspect, the disorder is cancer. In a further aspect, the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In yet a further aspect, the cancer is a solid tumor. In an even further aspect, the cancer is breast cancer.

[00258] In a further aspect, the subject has been diagnosed with a need for restoration of p53 activity prior to the administering step.

[00259] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human.

[00260] In various aspects, the method further comprises the step of identifying a subject in need of treatment of a disorder related to loss of p53 activity prior to the administering step. In a further aspect, the disorder is cancer. In a further aspect, the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In yet a further aspect, the cancer is a solid tumor. In an even further aspect, the cancer is breast cancer.

[00261] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[00262] In a further aspect, the method further comprises the step of administering a therapeutically effective amount of at least one agent associated with the treatment of cancer. In a still further aspect, the at least one agent is a chemotherapeutic agent. In yet a further aspect, the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, and a mTor inhibitor agent. In an even further aspect, the at least one agent is a chemotherapeutic agent or an antineoplastic agent. In a still further aspect, the chemotherapeutic agent or anti-neoplastic agent is selected from kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HD Ac) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programmed cell death protein 1 (PD-l)/programmed cell death-ligand 1 (PD-L1) mAB, cluster of differentiation 47 (CD47) mAB, toll-like receptor (TLR) agonists and other immune modifiers, cell therapeutics such as chimeric antigen receptor T-cell (CAR- T)/chimeric antigen receptor natural killer (CAR-NK) cells, and proteins such as interferons (IFNs), interleukins (ILs), and mAbs.

[00263] In a further aspect, the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

[00264] In a further aspect, the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[00265] In a further aspect, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

[00266] In a further aspect, the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[00267] In a further aspect, the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[00268] In a further aspect, the kinase inhibitor is selected from p38 inhibitors, CDK inhibitors, TNF inhibitors, matrixmetallo proteinase (MMP) inhibitors, COX-2 inhibitors, including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, SOD mimics, and a_v[33 -inhibitors.

[00269] In a further aspect, the PARP inhibitor is selected from iniparib, talazoparib, olaparib, rucapariv, veliparib, CEP 9722, AK 4827, BGB-290 and 3 -aminobenzamide.

[00270] In a further aspect, the epigenetic agent is selected from a histone deacetylase inhibitor and a DNA methylation inhibitor. In a still further aspect, the epigenetic agent is a BET inhibitor. In yet a further aspect, the BET inhibitor is selected from JQ1, 1-BET 151 (GSK1210151A), I-BET 762 (GSK525762), OTX-015, TEN-010 (Tensha therapeutics), CPI- 203, RVX-208 (Resverlogix Corp), LY294002, MK-8628 (Merck/Mitsubishi Tanabe), BMS- 986158 (Bristol-Myers Squibb), INCB54329 (Incyte Pharmaceuticals), ABBV-075 (Abb Vie, also called ABV-075), CPI-0610 (Constellation Pharmaceuticals/Roche), FT-1101 (Forma Therapeutics/Celgene), GS-5829 (Gilead Sciences), and PLX51107 (Daiichi Sankyo).

[00271] In a further aspect, the HD Ac inhibitor is selected from pracinostat and panobinostat.

[00272] In a further aspect, the ribonuclotide reductase inhibitor is selected from fludarabine, cladribine, gemcitabine, tezacitabine, triapine, motexafrn gadolinium, hydroxyurea, gallium maltolate, and gallium nitrate. In a still further aspect, the ribonuclotide reductase inhibitor is an iron chelator.

[00273] In a further aspect, the proteasome inhibitor is selected from lactacystin and bortezomib.

[00274] In a further aspect, the NAE inhibitor is a 1 -substituted methyl sulfamate. In a still further aspect, the NAE inhibitor is MLN4924.

[00275] In a further aspect, the immune checkpoint blockade agent is selected from anti-PD-Ll antibodies, anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-LAG3 antibodies, anti-B7-H3 antibodies, anti-TEVI3 antibodies, antibodies to PD-1, CTLA-4, BTLA, TIM-3, LAG-3, CD 160, TIGIT, LAIR1, and 2B4, antibodies to the corresponding ligands for these receptors including, but not limited to, PD-L1 (for PD-1), PD-L2 (for PD-1), CD80 and CD86 (for CTLA-4), HVEM (for BTLA), Galectin-9 and HMGB1 (for TIM-3), MHC II (for LAG-3), HVEM (for CD 160), CD 155, CD112, and CD113 (for TIGIT), Clq and collagen (for LAIR1), and CD48 (for 2B4). In a still further aspect, the immune checkpoint blockade agent is selected from CTL-4 mAb, PD-1/PD-L1 mAB, and CD47 mAB.

[00276] In a further aspect, the TLR agonist is selected from CRX-527 and OM-174.

[00277] In a further aspect the cell therapeutic is selected from CAR-T cell therapy and

CAR-NK cell therapy.

[00278] In a further aspect, the compound and the agent are administered sequentially. In a still further aspect, the compound and the agent are administered simultaneously.

[00279] In a further aspect, the compound and the agent are co-formulated. In a still further aspect, the compound and the agent are co-packaged.

F. METHODS OF RESTORING P53 ACTIVITY IN A CELL

[00280] In one aspect, disclosed are methods of restoring p53 activity in a cell, the method comprising the step of contacting the cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof. [00281] Thus, in one aspect, disclosed are methods of restoring p53 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[00282] In one aspect, disclosed are methods of restoring p53 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure selected from:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00283] In various aspects, the cell is a cancer cell. In a further aspect, the cell is present in a tissue sample. In a still further aspect, the tissue sample is a malignant tissue sample.

[00284] In various aspects, the cell is human. In a further aspect, the cell has been isolated from a human prior to the administering step. [00285] In various aspects, contacting is via administration to a subject. In a further aspect, the subject has been diagnosed with a need for restoration of p53 activity prior to the administering step. In a still further aspect, the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

G. METHODS OF TREATING CANCER IN A SUBJECT

[00286] In one aspect, disclosed are methods of treating cancer in a subject, the method comprising the step of administering to the subject an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. Examples of cancers include, but are not limited to, a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). [00287] Thus, in one aspect, disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

[00288] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

[00289] In a further aspect, the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

[00290] In a further aspect, the subject has been diagnosed with Li-Fraumeni syndrome (LFS) prior to the administering step.

[00291] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human.

[00292] In various aspects, the method further comprises the step of identifying a subject in need of treatment of cancer. In a further aspect, the cancer is a primary or secondary tumor. In a still further aspect, the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.

[00293] In various aspects, the cancer is selected from a sarcoma, a carcinoma, a head- and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). In yet a further aspect, the cancer osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, an adrenal cortical tumor, stomach cancer, melanoma, Wilms’ tumor, colon cancer, pancreatic cancer, esophageal cancer, lung cancer, and a gonadal germ cell cancer. In a still further aspect, the cancer is selected from pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer. In yet a further aspect, lung cancer is small cell lung carcinoma.

[00294] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[00295] In a further aspect, the cancer is associated with loss of p53 activity. In a still further aspect, the cancer is associated with cells that express a mutant p53. In yet a further aspect, the mutant p53 is a somatic mutation. In an even further aspect, the mutant p53 contains a mutation at an amino acid residue selected from V157F, R175, H179, R213, Y220, M237 G245, R248, R249, R273, and R282. In a still further aspect, the mutant p53 is a mutation associated with LFS. In yet a further aspect, the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R282W, Y220C, V157F, R337H, and R175H. In an even further aspect, the mutant p53 contains a mutation selected from Y220C, V157F, and R175H.

[00296] In a further aspect, administering is oral or parental administration. In a still further aspect, the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

[00297] In a further aspect, the method further comprises administering a therapeutically effective amount of an anti-cancer agent or radiotherapy to the subject. In a still further aspect, the anti-cancer agent or radiotherapy is administered prior to administration of the compound. In yet a further aspect, the anti-cancer agent or radiotherapy is administered subsequent to administration of the compound.

[00298] In a further aspect, the method further comprises the step of administering a therapeutically effective amount of at least one agent associated with the treatment of cancer. In a still further aspect, the at least one agent is a chemotherapeutic agent. In yet a further aspect, the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, and a mTor inhibitor agent. In an even further aspect, the at least one agent is a chemotherapeutic agent or an antineoplastic agent. In a still further aspect, the chemotherapeutic agent or anti-neoplastic agent is selected from kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HD Ac) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programmed cell death protein 1 (PD-l)/programmed cell death-ligand 1 (PD-L1) mAB, cluster of differentiation 47 (CD47) mAB, toll-like receptor (TLR) agonists and other immune modifiers, cell therapeutics such as chimeric antigen receptor T-cell (CAR- T)/chimeric antigen receptor natural killer (CAR-NK) cells, and proteins such as interferons (IFNs), interleukins (ILs), and mAbs.

[00299] In a further aspect, the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

[00300] In a further aspect, the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[00301] In a further aspect, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

[00302] In a further aspect, the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof. [00303] In a further aspect, the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. [00304] In a further aspect, the kinase inhibitor is selected from p38 inhibitors, CDK inhibitors, TNF inhibitors, matrixmetallo proteinase (MMP) inhibitors, COX-2 inhibitors, including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, SOD mimics, and α_vβ3 -inhibitors.

[00305] In a further aspect, the PARP inhibitor is selected from iniparib, talazoparib, olaparib, rucapariv, veliparib, CEP 9722, AK 4827, BGB-290 and 3 -aminobenzamide.

[00306] In a further aspect, the epigenetic agent is selected from a histone deacetylase inhibitor and a DNA methylation inhibitor. In a still further aspect, the epigenetic agent is a BET inhibitor. In yet a further aspect, the BET inhibitor is selected from JQ1, 1-BET 151 (GSK1210151A), I-BET 762 (GSK525762), OTX-015, TEN-010 (Tensha therapeutics), CPI- 203, RVX-208 (Resverlogix Corp), LY294002, MK-8628 (Merck/Mitsubishi Tanabe), BMS- 986158 (Bristol-Myers Squibb), INCB54329 (Incyte Pharmaceuticals), ABBV-075 (Abb Vie, also called ABV-075), CPI-0610 (Constellation Pharmaceuticals/Roche), FT-1101 (Forma Therapeutics/Celgene), GS-5829 (Gilead Sciences), and PLX51107 (Daiichi Sankyo).

[00307] In a further aspect, the HD Ac inhibitor is selected from pracinostat and panobinostat.

[00308] In a further aspect, the ribonuclotide reductase inhibitor is selected from fludarabine, cladribine, gemcitabine, tezacitabine, triapine, motexafrn gadolinium, hydroxyurea, gallium maltolate, and gallium nitrate. In a still further aspect, the ribonuclotide reductase inhibitor is an iron chelator.

[00309] In a further aspect, the proteasome inhibitor is selected from lactacystin and bortezomib.

[00310] In a further aspect, the NAE inhibitor is a 1 -substituted methyl sulfamate. In a still further aspect, the NAE inhibitor is MLN4924.

[00311] In a further aspect, the immune checkpoint blockade agent is selected from anti-PD-Ll antibodies, anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-LAG3 antibodies, anti-B7-H3 antibodies, anti-TEVI3 antibodies, antibodies to PD-1, CTLA-4, BTLA, TIM-3, LAG-3, CD 160, TIGIT, LAIR1, and 2B4, antibodies to the corresponding ligands for these receptors including, but not limited to, PD-L1 (for PD-1), PD-L2 (for PD-1), CD80 and CD86 (for CTLA-4), HVEM (for BTLA), Galectin-9 and HMGB1 (for TIM-3), MHC II (for LAG-3), HVEM (for CD 160), CD 155, CD112, and CD113 (for TIGIT), Clq and collagen (for LAIR1), and CD48 (for 2B4). In a still further aspect, the immune checkpoint blockade agent is selected from CTL-4 mAb, PD-1/PD-L1 mAB, and CD47 mAB.

[00312] In a further aspect, the TLR agonist is selected from CRX-527 and OM-174. [00313] In a further aspect, the cell therapeutic is selected from CAR-T cell therapy and CAR-NK cell therapy.

[00314] In a further aspect, the compound and the agent are administered sequentially. In a still further aspect, the compound and the agent are administered simultaneously.

[00315] In a further aspect, the compound and the agent are co-formulated. In a still further aspect, the compound and the agent are co-packaged.

H. METHODS OF TREATING LI-FRAUMENI SYNDROME IN A SUBJECT

[00316] In one aspect, disclosed are methods of treating Li-Fraumeni syndrome (LFS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

[00317] In one aspect, disclosed are methods of treating Li-Fraumeni syndrome (LFS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

[00318] In various aspects, the effective amount is a therapeutically effective amount. In a further aspect, the effective amount is a prophylactically effective amount.

[00319] In various aspects, the subject is a mammal. In a further aspect, the mammal is a human.

[00320] In various aspects, the subject has been diagnosed with a need for treatment of cancer prior to the administering step. In a further aspect, the cancer is selected from osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, an adrenal cortical tumor, stomach cancer, melanoma, Wilms’ tumor, colon cancer, pancreatic cancer, esophageal cancer, lung cancer, and a gonadal germ cell cancer. In a still further aspect, the subject has not been diagnosed with a need for treatment of cancer prior to the administering step.

[00321] In various aspects, the subject has been diagnosed with LFS prior to the administering step. In a further aspect, the method further comprises the step of identifying a subject in need of treatment of LFS. In a still further aspect, LFS is associated with loss of p53 activity. In yet a further aspect, the LFS is associated with cells that express a mutant p53. In an even further aspect, the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R282W, Y220C, V157F, R337H, and R175H. [00322] In various aspects, administering is oral or parental administration. In a further aspect, the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

I. METHODS OF TREATING CANCER IN A SUBJECT HAVING LI-FRAUMENI SYNDROME

[00323] In one aspect, disclosed are methods of treating cancer in a subject having Li- Fraumeni syndrome (LFS), the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

[00324] In one aspect, disclosed are methods of treating cancer in a subject having Li- Fraumeni syndrome (LFS), the method comprising administering to the subject an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

[00325] In a further aspect, the subject has not yet been diagnosed as having cancer.

[00326] In a further aspect, the subject has been diagnosed with a need for prevention of cancer prior to the administering step.

[00327] In a further aspect, the subject has been diagnosed with Li-Fraumeni syndrome (LFS) prior to the administering step.

[00328] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human.

[00329] In various aspects, the method further comprises the step of identifying a subject in need of cancer treatment (i.e., a subject having LFS who has not yet been diagnosed as having cancer). In a further aspect, the subject is at risk for developing cancer such as, for example, a primary or secondary tumor. In a still further aspect, subject is at risk for developing a primary or secondary tumor within their brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.

[00330] In various aspects, the subject is at risk for developing a cancer selected from a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, nonsmall cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). In yet a further aspect, the subject is at risk for developing a cancer selected from osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, an adrenal cortical tumor, stomach cancer, melanoma, Wilms’ tumor, colon cancer, pancreatic cancer, esophageal cancer, lung cancer, and a gonadal germ cell cancer. In a still further aspect, the subject is at risk for developing a cancer selected from pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer. In yet a further aspect, lung cancer is small cell lung carcinoma.

[00331] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[00332] In a further aspect, the cancer is associated with loss of p53 activity. In a still further aspect, the cancer is associated with cells that express a mutant p53. In yet a further aspect, the mutant p53 is a somatic mutation. In an even further aspect, the mutant p53 contains a mutation at an amino acid residue selected from V157, R175, H179, R213, Y220, M237 G245, R248, R249, R273, and R282. In a still further aspect, the mutant p53 is a mutation associated with LFS. In yet a further aspect, the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R248Q, R248W, R273H, R282W, Y220C, V157F, R337H, and R175H. In an even further aspect, the mutant p53 contains a mutation selected from Y220C, V157F, and R175H.

[00333] In a further aspect, administering is oral or parental administration. In a still further aspect, the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

J. ADDITIONAL METHODS OF U SING THE COMPOUNDS

[00334] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders related to restoration of p53 activity, and, in particular, cancer.

[00335] Examples of cancers for which the compounds and compositions can be useful in treating, include, but are not limited to, a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).

[00336] To treat or control the disorder, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of cancer.

[00337] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of cancer.

[00338] The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.

1. USE OF COMPOUNDS

[00339] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for the treatment of cancer in a subject.

[00340] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[00341] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.

[00342] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[00343] In various aspects, the use relates to a treatment of cancer in a subject. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the cancer is pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, or ovarian cancer.

[00344] In a further aspect, the use relates to the manufacture of a medicament for the treatment of cancer in a subject.

[00345] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a mammal.

2. MANUFACTURE OF A MEDICAMENT

[00346] In one aspect, the invention relates to a method for the manufacture of a medicament for treating cancer in a subject having the disorder, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[00347] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of cancer. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time-frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.

[00348] The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 0.05 mg/kg and about 100 mg/kg of body weight for mice, and more preferably between 0.05 mg/kg and about 50 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[00349] The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

[00350] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.

3. KITS

[00351] In one aspect, the invention relates to kits comprising an effective amount of a disclosed compound, and one or more selected from: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

[00352] Thus, in one aspect, disclosed are kits comprising a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and Cl- C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anticancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

[00353] In one aspect, disclosed are kits comprising a compound selected from:

or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anticancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer. [00354] In a further aspect, the cancer is selected from a sarcoma, a carcinoma, a head- and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma). In a still further aspect, the cancer is selected from osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, an adrenal cortical tumor, stomach cancer, melanoma, Wilms’ tumor, colon cancer, pancreatic cancer, esophageal cancer, lung cancer, and a gonadal germ cell cancer. In yet a further aspect, the cancer is selected from pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer. In a still further raspect, lung cancer is small cell lung carcinoma.

[00355] In a further aspect, the cancer is associated with loss of p53 activity. In a still further aspect, the cancer is associated with cells that express a mutant p53. In yet a further aspect, the mutant p53 is a somatic mutation. In an even further aspect, the mutant p53 contains a mutation at an amino acid residue selected from V157F, R175, H179, R213, Y220, M237 G245, R248, R249, R273, and R282. In a still further aspect, the mutant p53 is a mutation associated with LFS. In yet a further aspect, the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R282W, Y220C, V157F, R337H, and R175H. In an even further aspect, the mutant p53 contains a mutation selected from Y220C, V157F, and R175H.

[00356] In a further aspect, the anti-cancer agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a DNA damage-inducing agent, and a mTor inhibitor agent.

[00357] In a further aspect, the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

[00358] In a further aspect, the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof. [00359] In a further aspect, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

[00360] In a further aspect, the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[00361] In a further aspect, the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[00362] In a further aspect, the DNA damage-inducing agent is selected from doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, oxaliplatin, or ionizing radiation.

[00363] In a further aspect, the compound and the anti-cancer agent are co-formulated. In a further aspect, the compound and the anti-cancer agent are co-packaged.

[00364] The kits can also comprise compounds and/or products co-packaged, coformulated, and/or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient.

[00365] It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.

[00366] The foregoing description illustrates and describes the disclosure.

Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments. [00367] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls.

K. EXAMPLES

[00368] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[00369] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way.

1. IDENTIFICATION OF BROAD-SPECTRUM RE -FOLDERS OF MUTANT P53

[00370] Compounds were identified that bind to a “non-functional” surface of folded p53 that is present irrespective of which mutation leads to loss of conformational stability. The underlying hypothesis is that such compounds would bind to WT p53 as well, but would not induce a phenotype. Since WT p53 is already fully folded in cells, these compounds will not affect its conformation or activity. Though the thermodynamic stability of WT p53 may be enhanced, this is not expected to affect cellular p53 concentration since active p53 is degraded via MDM2/MDMX in a carefully-regulated manner (Vogelstein et al. (2000) Nature 408:307-10), and the disclosed compounds do not interfere with the MDM2/MDMX binding interface.

[00371] The development of compounds with the p53 refolding properties described above was enabled by computational approaches for sampling cryptic pockets on protein surfaces (Johnson et al. (2013) PLoS Comput Biol 9:el002951; Johnson et al. (2015) PLoS Comput Biol ll:el004081). Enabled by this approach, a hitherto unexplored surface site was identified on p53 that forms a highly druggable pocket, and which was used as the basis for virtual screening. The ensuing computational hits provided each of the desired activities except potency, which is being address through the medicinal chemistry optimization described herein. Importantly, these compounds exhibit distinct advantages that stem from their unique mechanism of action: it has already been found that a given compound can refold many different p53 mutants in cells, without affecting activity in cells that harbor WT p53. Moreover, by refolding mutant p53, these compounds can also revert the GOF phenotypes of these mutants. a. FINDING A DRUGGABLE SITE ON THE SURFACE OF P53

[00372] The existence of a suitable binding pocket is often used to assess the “druggability” of a particular region on the protein surface (Brown et al. (2006) ChemMedChem 1:70-2; An et al. (2004) Genome Inform 15:31-41; Sugaya et al. (2007) BMC Pharmacol 7: 10; Keller et al. (2006) Curr Opin Chem Biol 10:357-61; Perot et al. (2010) Drug Discov Today 15:656-67; Schmidtke et al. (2010) J Med Chem 53:5858-67; Hajduk et al. (2005) J Med Chem 48:2518-25). Whereas an unbound crystal structure may be used to look for a pre-formed pocket, many protein targets require a “pocket-opening” conformational change to enable ligand binding (Wells et al. (2007) Nature 450: 1001-9). An algorithm that detects and quantifies the volume of pockets on protein structures was implemented into the Rosetta macromolecular modeling suite. Rather than simply apply this approach to static crystal structures, though, this tool was used to explore protein fluctuations that lead to conformations containing surface pockets suitable for small molecule binding. Accordingly, the implementation uses the computed pocket volume as a term in the Rosetta energy function (Leaver-Fay et al. (2011) Methods Enzymol 487:545-74), alongside the canonical energetic determinants of protein structure such as packing, hydrogen bonding, and solvation. This allows for standard simulations to be carried out in which the protein structure is allowed to vary, but inclusion of this extra biasing term in the energy function leads to simultaneous optimization of both “pocket score” and the traditional energy terms. This new approach allows for natural protein fluctuations to be sampled in a highly efficient manner, identifying low-energy structural changes in the protein that reveal cryptic surface pockets. Further, the benchmark experiments have shown that the presence of low-energy pocketcontaining conformations is indeed a signature of druggable surface sites, and that analogous pockets are not formed at non-druggable sites elsewhere on the protein surface (Johnson et al. (2013) PLoS Comput Biol 9:e 1002951 ; Johnson et al. (2015) PLoS Comput Biol ll:el004081).

[00373] This approach was applied to p53’s core domain, starting from the crystal structure of the WT protein in complex with DNA, and it was found that a single dominant site emerged from the simulations (FIG. 2A). The potentially-druggable region of p53’s surface that was identified is not responsible for interacting with any of p53’s known or predicted binding partners (Tunebag et al. (2009) Mol Biosyst 5:1770-8), so it is not expected that compounds binding here will disrupt or interfere with the activity of WT p53. Because DNA was included in the simulations, it is also not expected that the conformational changes needed for the compounds to bind will disrupt p53’s DNA-binding activity. b. SCREENING FOR COMPOUNDS THAT FIT THIS SITE

[00374] To identify small-molecules that would complement the cryptic pocket from the simulations, a method called “DARC” (Docking Approach using Ray-Casting) was developed (Gowthaman et al. (2016) J Med Chem 59:4152-70; Gowthaman et al. (2015) PLoS 10:e0131612). Briefly, this approach entails casting a set of rays from the protein center of mass to a series of points mapping out a surface pocket, thus building up a description of the topography of the protein surface as viewed from the protein interior. Since a small molecule bound to this site should have a complementary topography, the same set of rays was then cast towards the candidate ligand. If the ligand is indeed complementary to the protein surface, the intersection distance of each ray with the ligand should closely match the distance at which the ray reaches the protein surface. In benchmark studies, it was found that DARC could identify known active ligands hidden among sets of “decoy” compounds, with discriminative power similar or better to other popular docking programs (Gowthaman et al. (2016) J Med Chem 59:4152-70).

[00375] By adapting the code to run on graphics processing units (GPUs), we achieved a dramatic speedup was achieved (Gowthaman et al. (2015) PLoS 10:e0131612; Khar et al. (2013) PLoS One 8:e70661) that enabled for very large compound libraries to be screened. The screening pipeline was concluded by carrying out a detailed energy minimization of the resulting complex in Rosetta using a custom energy function, and then these complexes were re-ranked to identify the most promising compounds to be carried forward (Bazzoli et al. (2015) PLoS One 10:e0140359; Bazzoli et al. (2017) J Comput Chem 38:1321-31).

[00376] Using the newly-identified pocket on the surface of p53, DARC was used to screen a set of ~9 million commercially available compounds from the ZINC database (Sterling et al. (2015) J Chem Inf Model 55:2324-37). The (virtual) compound library set was assembled by filtering for compounds with molecular weight less than 450 Da, estimated octanol/ water partition coefficient (xlogP) less than 4.5, and less than 8 rotatable bonds. Finally, the adaptation of the detailed Rosetta energy function (Bazzoli et al. (2015) PLoS One 10:e0140359; Bazzoli et al. (2017) J Comput Chem 38:1321-31) was used to minimize and re -rank the top scoring 10,000 compounds from each screen. The 36 top-scoring compounds, including the three shown in FIG. 2B, were purchased.

[00377] In the time since the initial screen, the chemical vendor Enamine has released a new library of 19 billion “make-on-demand” compounds (Lyu et al. (2019) Nature 566:224-9). The computational screening methods have also been improved by incorporating machine learning to determine which hits should be pursued (Adeshina et al. (2020) Proc Natl Acad Sci USA 117: 18477-88). This new approach was used to screen the Enamine library against other targets, and in a first pilot experiment against an enzyme target, identified a completely new inhibitor with Ki = 175 nM (Adeshina et al. (2020) Proc Natl Acad Sci USA 117:18477-88).

[00378] A complete listing of the compounds evaluated is shown in Table 1 below.

TABLE 1.

c. CELLULAR CHARACTERIZATION OF P53 REFOLDERS

[00379] With the goal of evaluating the toxicity and cell permeability of these compounds, and of determining their efficacy in a true cellular environment rather than optimizing for biochemical activity alone, the effect of these compounds on cell viability was tested, using cancer cell lines with varied TP53 status. Compound JO (as well as TO and AO) dramatically reduced viability in cell lines that harbor destabilized mutant p53, but not TP53- WT or TP 53-null cell lines (FIG. 3A). It was later confirmed through additional characterization that the difference in sensitivity to JO does indeed derive from refolding of p53; however, it was also recognized that JO harbored structural liabilities that could confound its characterization and lead to potentially toxic off-target interactions. As such, computational scaffold hopping was used to identify a “cleaner” starting point for the studies, which was dubbed J3.

[00380] As a first test for refolding mutant p53 in cells, cells were transfect with a plasmid encoding a luciferase reporter gene under control of a p53 response element (el- Deiry et al. (1993) Cell 75:817-25). For this assay it was opted to use the BxPC-3 (pancreatic adenocarcinoma) cell line, which harbors the destabilized TP53 mutant Y220C. It was found that treatment with J3 leads to increased luciferase activity (FIG. 3B), consistent with the intention that it would restore the wild-type fold to the Y220C mutant, and thus restore its activity. A scrambled version of the p53 -response element was used as a negative control, and it was found that J3 had no effect.

[00381 ] Extending the strategy of probing for refolding using p53- induced expression, qRT-PCR was next used to monitor the effect of J3 on several endogenous p53 target genes. These assays were carried out in cancer cell lines that each harbor a specific p53 mutant of interest. In cells harboring a destabilized p53 mutant (Y220C, R175H, and V157F), it was found that treatment with J3 increases both p21 and PUMA mRNA (FIG. 3C): as in the luciferase reporter assay, this implies that J3 “re-activates” mutant p53 in these cells. Encouragingly, treatment with the designed compounds did not significantly increase p53 activity in cells harboring WT p53 (or that lack p53 entirely). This was interpreted as evidence that the J3 mechanism of action is likely as intended, since activity of the (already fully folded) WT p53 core domain is not activated any further. Lending support to the interpretation that refolded p53 was driving expression of these genes, chromatin immunoprecipitation (ChIP) also confirmed that J3 recruits mutant p53 to the p21 and PUMA promoter sites.

[00382] As a further, direct probe of p53 refolding, a we 11- validated pair of antibodies, PAb240 and PAbl620 (Wang et al. (2001) Oncogene 20:2318-24), were used. PAb240 binds a linear epitope that is buried in the core of natively-folded p53, making this epitope accessible only when the protein is unfolded/misfolded. In contrast, PAb 1620 recognizes a conformational epitope that is presented only in natively-folded p53. This assay was initially applied to cells expressing p53 Y220C (FIG. 3D). Prior to treatment with J3, extensive staining was observed with PAb240 but not PAb 1620, implying that most of the protein is not folded correctly. Upon treatment with J3, however, there is a complete reversal: PAbl620 staining, but not PAb240, is now observed. Together, these results provide direct evidence that J3 shifts the population of p53 Y220C from an unfolded/misfolded species to the folded state; meanwhile, the increased transcription of established p53 target genes confirms that this conformation is indeed active. These two antibodies have also been used to stain CAL-33 and H₂087 cells (expressing TP53 R175H and V157F, respectively), and the same shift was observed upon treatment with J3. d. BIOCHEMICAL CHARACTERIZATION OF P53 REFOLDERS

[00383] To validate the interaction between J3 and the p53 core domain, the WT human p53 core domain was expressed and affinity-purified in E coli, along with three destabilized p53 mutants (Y220C, R175H, and V157F). The interaction of the agents was probed with these constructs using a series of biophysical methods, including STD-NMR. These approaches gratifyingly confirmed the interaction, and spurred the development of a direct biochemical assay for p53 refolding that could be used to identify improved analogs. [00384] The assay monitors binding of purified p53 (core domain) to FITC-labeled 30- mer oligonucleotides comprising a p53 recognition site. Binding of p53 to the DNA slows tumbling of the dye, which is readily detectable via fluorescence polarization (FP). In comparison to WT p53, it was found that destabilized mutant p53 binds to DNA less well: presumably because much of the mutant p53 is unfolded. Addition of the refolding agents enhances the interaction of mutant p53 for its cognate DNA (FIG. 4), in agreement with the corpus of observations from cellular assays. Importantly, these compounds show no impact on WT p53: this allows for potential mechanisms by which false positives may arise (e.g., compounds that alter DNA structure) to be ruled out. It was found that the same agent can refold multiple different destabilized mutants, consistent with the intended mechanism of action. e. EARLY OPTIMIZATION OF P53 REFOLDERS

[00385] As described earlier, the studies leading to these p53 refolders derive from computational screens that identified JO. Though not shown, this compound does have activity in each of the assays presented above. However, this structure raised “alerts” by virtue of having a Michael acceptor, and a tautomeric form of a quinone methide. The former can be problematic by forming covalent adducts to cysteine residues on other proteins, and the latter is a well-known redox cycler that causes promiscuous binding or unanticipated toxicities (Baell et al. (2010) J Med Chem 53:2719-40; Rana et al. (2013) MedChemComm

4).

[00386] It was therefore sought to employ computational “scaffold hopping” methods for identifying simpler cores that maintain JO’s activity. The active conformation of JO from the structural model was used as a template for further ligand-based (pharmacophore) screening with the ROCS software (Rush et al. (2005) J Med Chem 48:1489-95), and the compound J3 was identified to mimic the 3D arrangement of JO’s interactions with p53 (FIG.

5). Gratifyingly, J3 indeed mimicked the activity of JO.

2. BIOLOGICAL EVALUATION OF EXEMPLARY COMPOUNDS

[00387] The exemplary compounds shown in Table 1 above were evaluated for their ability to rescue p53 activity as described herein. The results of these analyses are shown in Table 2 below.

[00388] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition comprising an effective amount of a compound having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(Cl- C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C 1 -C4 haloalkyl, C 1 -C4 cyanoalkyl, C 1 -C4 hydroxyalkyl, C 1 -C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and C 1 -C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1, wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and -(C1-C4 alkyl)O(Cl-C4 alkyl).

3. The pharmaceutical composition of claim 1, wherein R¹ is selected from -CH₂Ar¹ and

4. The pharmaceutical composition of claim 3, wherein Ar¹ is a 6-membered aryl monosubstituted with a group selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl).

5. The pharmaceutical composition of claim 3, wherein Ar¹ is a 6-membered aryl substituted with 1 or 2 groups selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, and -CO₂(C1-C4 alkyl).

6. The pharmaceutical composition of claim 3, wherein Ar¹ is a 6-membered aryl substituted with 1 or 2 groups selected from -F, -Cl, methyl, ethyl, methoxy, ethoxy, -CO₂CH₃, and -CO₂CH₂CH₃.

7. The pharmaceutical composition of claim 3, wherein Ar¹ is an unsubstituted 6- membered aryl.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein R² is hydrogen.

9. The pharmaceutical composition of any one of claims 1 to 7, wherein R² is C1-C4 alkyl.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy.

11. The pharmaceutical composition of any one of claims 1 to 9, wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, -F, -Cl, methyl, ethyl, methoxy, and ethoxy.

12. The pharmaceutical composition of any one of claims 1 to 9, wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is hydrogen.

13. The pharmaceutical composition of claim 1, wherein the compound has a structure represented by a formula:

wherein n is selected from 0 and 1 , or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 13, wherein the compound has a structure represented by a formula:

wherein each of R^10a, R^10b, R^10c, R^10d, and R^10e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C 1 -C4 alkyl), or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 14, wherein at least two of R^10a, R^10b, R^10c, R^10d, and R^10e is hydrogen.

16. The pharmaceutical composition of claim 14, wherein at least three of R^10a, R^10b, R^10c, R^10d, and R^10e is hydrogen.

17. The pharmaceutical composition of claim 14, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A method of restoring p53 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(Cl- C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C 1 -C4 haloalkyl, C 1 -C4 cyanoalkyl, C 1 -C4 hydroxyalkyl, C 1 -C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and C 1 -C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

21. The method of claim 20, wherein the cell is a cancer cell.

22. The method of claim 20, wherein the cell is present in a tissue sample.

23. The method of claim 22, wherein the tissue sample is a malignant tissue sample.

24. The method of claim 20, wherein the cell is human.

25. The method of claim 20, wherein the cell has been isolated from a human prior to the contacting step.

26. The method of claim 20, wherein contacting is via administration to a subject.

27. The method of claim 26, wherein the subject has been diagnosed with a need for restoration of p53 activity prior to the administering step.

28. The method of claim 26, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

29. A method of restoring p53 activity in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure selected from:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30. A method of restoring p53 activity in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(Cl- C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C 1 -C4 haloalkyl, C 1 -C4 cyanoalkyl, C 1 -C4 hydroxyalkyl, C 1 -C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein R² is selected from hydrogen and C 1 -C4 alkyl; and wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein the subject is a mammal.

32. The method of claim 30, wherein the subject is a human.

33. The method of any one of claims 30 to 32, wherein the subject has been diagnosed with a need for restoration of p53 activity prior to the administering step.

34. The method of any one of claims 30 to 32, wherein the subject has been diagnosed with a need for treatment of a disorder related to loss of p53 activity prior to the administering step.

35. The method of claim 34, wherein the disorder is cancer.

36. A method of restoring p53 activity in a subject, the method comprising administering to the subject an effective amount of a compound having a structure selected from:

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

37. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C 1 -C4 alkyl); wherein R² is selected from hydrogen and C 1 -C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1 , 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

38. The method of claim 37, wherein A is a structure selected from:

39. The method of claim 37, wherein A is a structure selected from:

40. The method of claim 37, wherein A is a structure:

41. The method of claim 37, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

42. The method of claim 37, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

43. The method of claim 37, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

44. The method of claim 43, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

45. The method of claim 37, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

46. The method of claim 45, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

47. The method of claim 37, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

48. The method of claim 47, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

49. The method of claim 37, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

50. The method of claim 49, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

51. The method of claim 37, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

52. The method of claim 37, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

53. The method of claim 52, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

54. The method of claim 37, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

55. The method of claim 54, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

56. The method of claim 37, wherein the effective amount is a therapeutically effective amount.

57. The method of claim 37, wherein the effective amount is a prophylactically effective amount.

58. The method of claim 37, wherein the subject is a mammal.

59. The method of claim 58, wherein the mammal is a human.

60. The method of claim 37, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

61. The method of claim 37, wherein the subject has been diagnosed with Li-Fraumeni syndrome (LFS) prior to the administering step.

62. The method of claim 37, further comprising the step of identifying a subject in need of treatment of cancer.

63. The method of claim 37, wherein the cancer is a primary or secondary tumor.

64. The method of claim 63, wherein the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.

65. The method of claim 37, wherein the cancer is selected from a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).

66. The method of claim 37, wherein the cancer is selected from osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, an adrenal cortical tumor, stomach cancer, melanoma, Wilms’ tumor, colon cancer, pancreatic cancer, esophageal cancer, lung cancer, and a gonadal germ cell cancer.

67. The method of claim 37, wherein the cancer is selected from pancreatic cancer, head- and-neck cancer, lung cancer, breast cancer, and ovarian cancer.

68. The method of claim 67, wherein lung cancer is small cell lung carcinoma.

69. The method of claim 37, wherein the cancer is associated with loss of p53 activity.

70. The method of claim 37, wherein the cancer is associated with cells that express a mutant p53.

71. The method of claim 70, wherein the mutant p53 is a somatic mutation.

72. The method of claim 71, wherein the mutant p53 contains a mutation at an amino acid residue selected from V157F, R175, H179, R213, Y220, M237 G245, R248, R249, R273, and R282.

73. The method of claim 70, wherein the mutant p53 is a mutation associated with LFS.

74. The method of claim 73, wherein the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R282W, Y220C, V157F, R337H, R273H, R248W, R248Q, and R175H.

75. The method of claim 70, wherein the mutant p53 contains a mutation selected from Y220C, V157F, and R175H.

76. The method of claim 37, wherein administering is oral or parental administration.

77. The method of claim 76, wherein the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

78. The method of claim 37, further comprising administering a therapeutically effective amount of an anti-cancer agent or radiotherapy to the subject.

79. The method of claim 78, wherein the anti-cancer agent or radiotherapy is administered prior to administration of the compound.

80. The method of claim 78, wherein the anti-cancer agent or radiotherapy is administered subsequent to administration of the compound.

81. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

82. A method of treating Li-Fraumeni syndrome (LFS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), - CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently lelected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C 1 -C4 alkyl); wherein R² is selected from hydrogen and C 1 -C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1 , 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

83. The method of claim 82, wherein A is a structure selected from:

84. The method of claim 82, wherein A is a structure selected from:

85. The method of claim 82, wherein A is a structure:

86. The method of claim 82, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

87. The method of claim 82, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

88. The method of claim 82, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

89. The method of claim 88, wherein the compound is:

or a pharmaceutically acceptable salt thereof.

90. The method of claim 82, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

91. The method of claim 90, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

92. The method of claim 82, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

93. The method of claim 92, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

94. The method of claim 82, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

95. The method of claim 94, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

96. The method of claim 82, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

97. The method of claim 82, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

98. The method of claim 97, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

99. The method of claim 82, wherein the compound has a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

100. The method of claim 99, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

101. The method of claim 82, wherein the effective amount is a therapeutically effective amount.

102. The method of claim 82, wherein the effective amount is a prophylactically effective amount.

103. The method of claim 82, wherein the subject is a mammal.

104. The method of claim 103, wherein the mammal is a human.

105. The method of claim 82, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

106. The method of claim 105, wherein the cancer is selected from osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, an adrenal cortical tumor, stomach cancer, melanoma, Wilms’ tumor, colon cancer, pancreatic cancer, esophageal cancer, lung cancer, and a gonadal germ cell cancer.

107. The method of claim 82, wherein the subject has not been diagnosed with a need for treatment of cancer prior to the administering step.

108. The method of claim 82, wherein the subject has been diagnosed with LFS prior to the administering step.

109. The method of claim 82, further comprising the step of identifying a subject in need of treatment of LFS.

110. The method of claim 82, wherein LFS is associated with loss of p53 activity.

111. The method of claim 82, wherein the LFS is associated with cells that express a mutant p53.

112. The method of claim 111, wherein the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R282W, Y220C, V157F, R337H, and R175H.

113. The method of claim 82, wherein administering is oral or parental administration.

114. The method of claim 113, wherein the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

115. A method of treating Li-Fraumeni syndrome (LFS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

116. A method of treating cancer in a subject having Li-Fraumeni syndrome (LFS), the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C 1 -C4 alkyl); wherein R² is selected from hydrogen and C 1 -C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1 , 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof.

117. A method of treating cancer in a subject having Li-Fraumeni syndrome (LFS), the method comprising administering to the subject an effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

118. A kit comprising a compound having a structure represented by a formula:

wherein A is a structure selected from:

wherein R¹ is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)O(C 1 -C4 alkyl), -CH₂Ar¹, and -Ar¹; wherein Ar¹, when present, is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C 1 -C4 alkyl); wherein R² is selected from hydrogen and C 1 -C4 alkyl; wherein Ar² is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is substituted with 0, 1 , 2, or 3 groups independently selected from halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO₂H, and -CO₂(C1-C4 alkyl); wherein Q is hydrogen or a structure represented by a formula:

wherein each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from hydrogen, halogen, -CN, -NH₂, -OH, -NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that when Q is hydrogen, then A is:

or a pharmaceutically acceptable salt thereof, and one or more selected from:

(a) an anti-cancer agent;

(b) instructions for administering the compound in connection with treating cancer; and

(c) instructions for treating cancer.

119. The kit of claim 118, wherein the anti-cancer agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a DNA damage -inducing agent, and a mTor inhibitor agent.

120. The kit of claim 119, wherein the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

121. The kit of claim 119, wherein the antimetabolite agent is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

122. The kit of claim 119, wherein the alkylating agent is selected from carbop latin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

123. The kit of claim 119, wherein the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

124. The kit of claim 119, wherein the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt thereof.

125. The kit of claim 119, wherein the DNA damage-inducing agent is selected from doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, oxaliplatin, or ionizing radiation.

126. The kit of any one of claims 118 to 125, wherein the compound and the anti-cancer agent are co-packaged.

127. The kit of any one of claims 118 to 125, wherein the compound and the anti-cancer agent are co-formulated.

128. A kit comprising a compound selected from:

or a pharmaceutically acceptable salt thereof, and one or more selected from:

(a) an anti-cancer agent;

(b) instructions for administering the compound in connection with treating cancer; and

(c) instructions for treating cancer.