Pharmacological re-activation of mutant pvhl

Abstract

The present disclosure relates to compounds, pharmaceutical compositions, and methods of using the compounds and compositions to restore activity of von Hippel Lindau tumor suppressor protein (pVHL). Such compounds and compositions can be useful in, for example, the treatment of 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)) and von Hippel-Lindau disease (VHLD). 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

Attorney Docket No. 38235.0016P1PHARMACOLOGICAL RE- ACTIVATION OF MUTANT PVHLCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U. S. Application No. 63 / 721,204, filed on November 15, 2024, the contents of which are incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grant number W81XWH-20-1-0844 awarded by the U. S. Army Medical Research and Development Comand (USAMRDC). The government has certain rights in the invention.REFERENCE TO SEQUENCE LISTING

[0003] The Sequence Listing submitted November 14, 2025 as a text file named “38235.0016P1. xml,” created on November 14, 2024, and having a size of 13,297 kilobytes is hereby incorporated by reference pursuant to 37 C. F. R. § 1.52(e)(5).BACKGROUND

[0004] Biallelic loss of tumor suppressor genes (and their associated protein products) represents a key factor in cancer development and progression (Chemoff J. (2021) Mol Biol Cell. 32:rtl; Lipsick J. (2020) Cold Spring Harb Perspect Biol. 12; Knudson AG, Jr. (1971) Proc Natl Acad Sci U SA. 68: 820-3). Germline or somatic mutations in one such tumor suppressor gene, VHP, lead to development of von Hippel-Lindau Disease (VHLD) and clear cell renal cell carcinoma (ccRCC), respectively (Gossage et al. (2015) Nature Reviews Cancer p. 55-64; Kaelin WG, Jr. (2007) Clin Cancer Res. 13: 680s-4s; Maher et al. (1990) J Med Genet 27(5): 311-4; Latif F (1993) Science 260: 1317-20). Decades of research have revealed that VHL’s protein product, pVHL, serves as an adaptor protein in diverse protein complexes that regulate numerous cellular functions (Gossage et al. (2015) Nature Reviews Cancer p. 55-64; Lai et al. (2011) J Proteome Res. 10: 5175-82; Frew IJ, Krek W. (2008) Sci Signal. 1: pe30).

[0005] Undoubtedly, pVHL / Cul-2 / Elongin B / Elongin C / Rbx-1 represents one of the most vital of these complexes because it forms a key component of the oxygen sensing pathway (Frew IJ, Krek W. (2008) Sci Signal. 1: pe30) and is the most well studied of these protein complexes. This pathway involves all three members of the HIF-a family (HIF-la. HIF-2a, and HlF-3a), collectively referred to as HIF-a (Li M, Kim WY. (2011) J Cell Mol Med. 15:Attorney Docket No. 38235.0016P1187-95). Under normoxic conditions, HIF-a is hydroxylated at one or two specific proline residues. pVHL (as part of the aforementioned complex) then binds to hydroxylated HIF-a with high affinity (Li M, Kim WY. (2011) J Cell Mol Med. 15: 187-95). This complex functions as an E3 ubiquitin ligase to polyubiqui tiny late HIF-a, leading to its degradation (Iwai et al. (1999) Proc Natl Acad Sei USA. 96: 12436-41). Conversely, under hypoxic conditions, HIF-a is not hydroxylated. Because it escapes degradation by this pVHL complex, HIF-a can instead translocate and accumulate in the nucleus, where it forms a heterodimeric transcription factor with constitutively-present HIF-p (Li M, Kim WY. (2011) J Cell Mol Med. 15: 187-95).

[0006] Among the target genes of the HIF transcription factor is vascular endothelial growth factor, VEGF (Ema et al. (1997) Proc Natl Acad Sci U S A. 94: 4273-8). VEGF induces both physiologic and pathologic angiogenesis, with the latter central to cancer pathophysiology (Ferrara N. (2009) Arterioscler Thromb Vase Biol. 29: 789-91) and a hallmark of cancer itself (Hanahan D, Weinberg RA. (2011) Cell 144: 646-74). Another target gene of HIF-a is TWIST, which drives epithelial to mesenchymal transitions (EMT) and thus cancer metastasis (Yang et al. (2008) Nat Cell Biol. 10: 295-305). Additional target genes of HIF-a include erythropoietin (EPO), matrix metalloproteases 2 and 9, and glucose transporter 1 (GLUT1) (Liu et al. (2012) Int J Biochem Mol Biol. 3: 165-78). Aligned with HIF-a's role as an indispensable cancer driver, downregulation of HIF-a (particularly the HIF-2a isoform), prevents tumorigenesis in pVHL-deficient renal carcinoma cells (Kondo et al. (2003) PLoS Biol. 1: E83).

[0007] Clinically, pVHL plays a key role in multiple human pathologies. Germline mutations in the VHL gene cause an autosomal dominant tumor disorder called Von Hippel-Lindau disease (Kaelin WG. Jr. (2007) Clin Cancer Res. 13: 680s-4s). This disorder is characterized by an increased risk of several types of tumors including hemangioblastoma of the central nervous system, renal cell carcinoma, and pheochromocytoma. Somatic mutations in VHL also contribute to cases of sporadic clear cell renal cell carcinoma (Foster et al. (1994) Hum Mol Genet. 3: 2169-73; Shuin et al. (1994) Cancer Res. 54: 2852-5; Brauch et al. (2000) Cancer Res. 60: 1942-8). Characterization of sporadic renal cell carcinoma tumors have found that 46-56% of these included somatic mutations in VHL, with 85% of these showing loss of heterozy gosity (Shuin et al. (1994) Cancer Res. 54: 2852-5). VHL can also be disabled epigenetically through hypermethylation of its promoter, albeit less frequently (Herman et al. ( 1994) Proc Natl Aca d Sci USA. 91: 9700-4).Attorney Docket No. 38235.0016P1

[0008] The clear importance of the pVHL-HIF pathway in driving clear cell renal cell carcinoma (both sporadic and inherited) has made this a longstanding focus for therapeutic intervention (Tamaskar et al. (2011) Clin Adv Hematol Oncol. 9: 101-10). Early efforts focused primarily on inhibiting tumor angiogenesis and cancer cell proliferation by addressing downstream molecular targets. These are exemplified by the use of agents such as sunitinib / sorafenib (inhibitors of receptor tyrosine kinases including VEGFR and PDGFR) and temsirolimus / everolimus (mTOR inhibitors) (Tamaskar et al. (2011) Clin Adv Hematol Oncol. 9: 101-10). Immune checkpoint inhibitors (such as anti-PD-1 nivolumab) have also been approved for the treatment of ccRCC and are currently being investigated in clinical trials as part of a combination therapy based regimen (Ross K, Jones RJ. (2017) Clin Sci (Lond). 131: 2627-42). Most recently, inhibitors have been developed to address HIF-2a directly (PT2385 / PT2977). These promising compounds are currently in ongoing clinical trials (Metelo et al. (2015) Oncotarget. 6: 23036-7; Wallace et al. (2016) Cancer Res. 76: 5491-500; Cho et al. (2016) Nature. 539: 107-11).

[0009] Despite these interventons, there remains a profound unmet medical need for effective pharmacological therapies for clear cell RCC (Atkins and Tannir (2018) Cancer Treat. Rev.70: 127-137; Kim and Zschiedrich (2018) Front. Pediatr. 6: 16). In addition, there remains a need for compounds that directly bind and stabilize folded (mutant) pVHL in cells harboring destabilized mutant pVHL. See. e. g., FIG. 1A and FIG. 1B Likewise, given the central tumor-suppressive role for VHL with respect to cancers such as RCC, there is a need to develop compounds that restore (wild-type) pVHL activity to cells harboring missense mutant pVHL. Thus, there remains a need for compounds and compositions for restoring pVHL activity, and methods of making and using same.SUMMARY

[0010] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds, pharmaceutical compositions, and methods of using the compounds and compositions to restore activity of von Hippel Lindau tumor suppressor protein (pVHL). Such compounds and compositions can be useful in, for example, the treatment of 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,Attorney Docket No. 38235.0016P1myelodysplastic 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)) and von Hippel-Lindau disease (VHLD).

[0011] Thus, disclosed are compounds having a structure represented by a formula:wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein each of R6a, R6b, R6°, R6d, R6e, R6f, R6g. and R6his independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q2, Q4, Q3, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q2, Q4, Q3, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, 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, and Cy3; wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalky l, a 5- to 6-membered heteroaryl, and a 6-membered ar l, 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, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-Attorney Docket No. 38235.0016P1membered aryl and a 5- to 10-membered heteroaryl, 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 hydroxy alky l, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2: wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyd, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl; wherein each of R14a, R14b, R14c, R14d, R14e, R14f, R14g, and R14his independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, provided that when n is 0 and Cy1is:then Ar1is not indole or benzofuran, provided that when n is 0, Cy1is:and Ar1is:Attorney Docket No. 38235.0016P1then each of Q1, Q2, Q2, Q4, Q5, Q6, and Q7is -C(R10)=. provided that when n is 1 and Cy1is:then R1is a C1-C4 alkyl, provided that the compound is not:O. Oor a pharmaceutically acceptable salt thereof.

[0012] Also disclosed are compounds selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0013] Also disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C 1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyd, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] Also disclosed are methods of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:Attorney Docket No.38235.0016P1wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein Cy3is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(R11)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:Attorney Docket No.38235.0016P1wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylammo, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0015] Also disclosed are methods of restoring pVHL activity7in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed by a formula:wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein Cy3is selected from a 3- to 7-memberedAttorney Docket No. 38235.0016P1cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0016] 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 n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein Cy3is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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-C4Attorney Docket No. 38235.0016P1alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R1?is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0017] Also disclosed are methods of treating von Hippel-Lindau disease (VHLD) 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 n is selected from 0 and 1; wherein R1is selected from hydrogen and Cl -C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and CyJ; wherein Cy' is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-. and -N(R")-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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,Attorney Docket No. 38235.0016P1C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0018] Also disclosed are methods of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is selected from hydrogen, halogen,Attorney Docket No.38235.0016P1-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, and Cy3; wherein Cy3is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyd, a 5- to 6-membered heteroaryl, and a 6-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, (C 1-C4)(C1-C4) dialkydamino, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and N(Rn); wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered ary l and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyd, a 3- to 7-membered heterocycloalkyd, a 5- to 6-membered heteroaryl, and a 6-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) dialkydamino, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0019] Also disclosed are kits comprising a compound having a structure represented by a formula:Attorney Docket No.38235.0016P1wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q2, Q4, Q3, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q2, Q4, Q3, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein Cy3is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, (C 1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is substituted with 0, 1, 2, or 3 groups independentlyAttorney Docket No. 38235.0016P1selected 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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, 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.

[0020] Also disclosed are compounds selected from:1. or a pharmaceutically acceptable salt thereof.Attorney Docket No. 38235.0016P1

[0021] Also disclosed are pharmaceutical compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0022] Also disclosed are methods of restoring activity of pVHL in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0023] Also disclosed are methods of restoring activity of pVHL in a subject in need thereof, the method comprising administering to the subject with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0024] 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 disclosed compound or a pharmaceutically acceptable salt thereof.

[0025] Also disclosed are kis comprising a disclosed compound 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.

[0026] 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.Attorney Docket No.38235.0016P1

[0027] Also disclosed are methods of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) 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.

[0028] Also disclosed are methods of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a subject in need thereof, the method comprising contacting the cell with an effective amount of a compound selected from:Attorney Docket No.38235.0016P1Bror a pharmaceutically acceptable salt thereof.

[0029] 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.

[0030] Also disclosed are methods of treating VHLD in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.

[0031] Also disclosed are methods of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound selected from:or a pharmaceutically acceptable salt thereof.

[0032] Also disclosed are kits comprising compound selected from:Attorney Docket No.38235.0016P1or 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.

[0033] Also disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:R5Cwherein each of R2a, R2b, R2c, R2d, and R3is 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; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyd, 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.

[0034] Also disclosed are methods of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:Attorney Docket No.38235.0016P1wherein each of R2a, R2b, R2c, R2d, and R3is 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; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis 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.

[0035] Also disclosed are methods of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a subject in need thereof, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:R5Cwherein each of R2a, R2b, R2c, R2d, and R3is independently selected from hydrogen, halogen. -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cy anoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5° 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.Attorney Docket No.38235.0016P1

[0036] 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 each of R2a, R2b, R2c, R2d, and R3is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyd, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyd, 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.

[0037] Also disclosed are methods of treating VHLD 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 each of R2a, R2b, R2c, R2d, and R3is 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 C 1 -C4 aminoalkyd; wherein R4is selected from hydrogen and C 1 -C4 alkyd; and wherein each of R5a, R5b, and R5cis 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-Attorney Docket No. 38235.0016P1C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0038] Also disclosed are methods of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein each of R2a, R2b, R2c, R2d, and R3is 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; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkeny l, 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.

[0039] Also disclosed are kits comprising compound having a structure represented by a formula:wherein each of R2a, R2b, R2c, R2d, and R3is independently selected from hydrogen, halogen. -CN. -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl. Cl -C4 hydroxyalkyl, Cl -C4 haloalkoxy. Cl -C4 alkoxy. Cl -C4 alkylamino, (Cl -C4)(C1 -C4) dialkylamino, and C1-C4 aminoalkyl; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis 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, (C 1-Attorney Docket No. 38235.0016P1C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, 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.

[0040] 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:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0041] Also disclosed are methods of treating von Hippel-Lindau disease (VHLD) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.

[0042] Also disclosed are methods of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or 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.Attorney Docket No.38235.0016P1

[0044] 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

[0045] 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.

[0046] FIG. 1A and FIG. 1B show representative data illustrating the ubiquitin proteasomal system pathway of HIF degradation by pVHL (FIG. 1A), and, when pVHL mutated, the progression of the HRE transcription signal (FIG. 1B).

[0047] FIG.2A and FIG.2B show representative NMR data for CP4.29.

[0048] FIG.3A-E show representative schematics for the frequency of VHL missense mutations and their structural distribution (FIG.3A), the refolding of misfolded protein theory (FIG.3B), and for the design of pharmacological pVHL refolders by targeting distinct surface pockets (FIG. 3C-E).

[0049] FIG.4A-K show representative data illustrating evidence of CP4 binding to the pVHL.

[0050] FIG.5A-C show representative data illustrating CP4 stabilizing pVHL in ccRCC cell lines harboring VHL missense mutations (FIG.5A), the accumulation of both pVHL isoforms when cells with different VHL mutations treated with CP4 (FIG. 5B), and CP4 induced stabilization to pVHL when cotreated with CHX (FIG. 5C).

[0051] FIG.6A-I show representative data illustrating: CP4.29 synthesis (FIG. 6A);screening of various CP4 analogues for HIF degradation (FIG. 6B); the degradation of HIF-2a and HIF-l by re-activating mutant pVHL in ccRCC cell lines (FIG. 6C and FIG. 6D); the development of CP4 analogues and their binding sites away from VHL interaction withAttorney Docket No. 38235.0016P1its substrates (FIG. 6E); reduced transcription of HIF target genes (FIG. 6F); generation of isogenic VHL knocked out cell lines (FIG. 6H); and enhanced HIF degradation over time in parent cells treated with CP4.29 and CHX, and not in the VHL- knocked out cells (FIG. 61).

[0052] FIGS. 7A-C show representative on-target inhibition of colony formation and cell migration by different MFH compounds in 769-P cells, not in its isogenic VHL-knocked out cells compared to the HIF-2a inhibitor “Belzutifan" that is known not to have an anti-tumor phenotypic effect on these cells.

[0053] FIG.8A-E show representative data illustrating re-activation of mutant pVHL by CP4.29 attenuating cell survival, colony formation, and migration.

[0054] FIG.9A and FIG.9B show representative data illustrating the VHL mutations most frequently observed in ccRCC.

[0055] FIG. 10A and FIG. 10B show the structures of representative negative and positive control compounds.

[0056] FIG. 11 shows a representative model of compound CP4 bound to the VCBH complex.

[0057] FIG. 12 shows a representative SDS-PAGE illustrating the purity of VCB protein.

[0058] FIG. 13 shows representive data pertaining to the initial STD NMR screen in pools.

[0059] FIG. 14 shows a representive process for identifying hit compounds from pooled STD screen data.

[0060] FIG. 15 shows a representive schematic illustrating the proposed strategy for reactivating mutant pVHL.

[0061] FIG. 16A-C shows representive data illustrating: the results of a CETSA experiment in Caki-1 cells with the wild expression of VHL protein (VHL+ +) (FIG. 16A); the accumulation of pVHL isoforms when renal carcinoma cells with wild and mutant pVHL treated with CP4.29 (FIG. 16B); and CP4 and CP4.29 induced stability’ to pVHL when combined with the protein synthesis inhibitor “CHX”, and the accompanied enhanced degradation of HIF-2a (FIG. 16C).

[0062] FIG. 17 shows representive data illustrating the effect of CP4 treatment compared to vehicle control on HIF-2a protein levels in RCC-MF cells and 786-0 cells.

[0063] FIG. 18 shows representive data illustrating the effect of CP4 co-treatment with 40 pM MG132 on HIF-2a in RCC-MF cells.

[0064] FIG. 19 shows representive results of a CP4.29 derivative screen.

[0065] FIG. 20A and FIG. 20B show representive data pertaining to the affinity chromatography step of purification of N-6xHis-Trx-tagged VCB protein.Attorney Docket No. 38235.0016P1

[0066] FIG.21A and FIG. 21B show representative data pertaining to the affinity chromatography step of untagged VCB protein.

[0067] FIG. 22A and FIG. 22B show representive data pertaining to the initial affinity chromatography step.

[0068] FIG. 23 shows representive data from the initial affinity chromatography step.

[0069] FIG. 24 shows representative Saturation Transfer Difference of compounds in the presence or absence of VCB.

[0070] FIG. 25 shows representive quantification of average STD experiments.

[0071] FIG. 26 shows representive WaterLOGSY spectra of CP4 in the presence or absence of VCB.

[0072] FIG. 27 shows representive quantification of WaterLOGSY experiments.

[0073] FIG. 28 shows representive CPMG spectra of samples in the presence or absence of VCB.

[0074] FIG. 29 shows representive quantification of the CPMG experiments.

[0075] FIG.30 shows a representive model of CP4 bound to pVHL as part of the VCB protein complex.

[0076] FIG.31 shows representive Saturation Transfer Difference of compounds in the presence of VCB or VDI97KCB.

[0077] FIG.32 shows representive quantification of Average STD experiments.

[0078] FIG.33 shows representive WaterLOGSY spectra of CP4 in the presence of VCB or VD197KCB.

[0079] FIG.34 shows representive quantification of WaterLOGSY experiments.

[0080] FIG.35 shows representive data from a CPMG experiment of CP4 in the presence of VCB or VDWTKCB.

[0081] FIG.36 shows representive quantification of the CPMG experiments.

[0082] FIG.37 shows representive structures of compounds CP4 and CP4.29.

[0083] FIG.38 shows representive full STD NMR spectrum for 100 pM CP4 / 100 pM Sitagliptin / 100 pM VH298 / 1% DMSO-d6 in the absence and presence of 7.7 pM VCB protein complex.

[0084] FIG.39 shows representive full WaterLOGSY NMR spectrum for 100 pM CP4 / 100 pM Sitagliptin / 100 pM VH298 / 1% DMSO-d6 in the absence and presence of 7.7 pM VCB protein complex.Attorney Docket No. 38235.0016P1

[0085] FIG.40 shows representive full CPMG NMR spectrum for 100 pM CP4 / 100 pM Sitagliptin / 100 pM VH298 / 1% DMSO-d6 in the absence and presence of 7.7 pM VCB protein complex.

[0086] FIG.41 shows representive full STD NMR spectrum for 100 pM CP4 / 100 pM Sitagliptin / 100 pM VH298Z 1% DMSO-d6 in the presence of 7.7 pM WT VCB protein complex or 7.7 pM VDI97KCB.

[0087] FIG.42 shows representive full WaterLOGSY NMR spectrum for 100 pM CP4 / 100 pM Sitagliptin / 100 pM VH298 / 1% DMSO-d6 in the presence of 7.7 pM WT VCB protein complex or 7.7 pM VDI97KCB.

[0088] FIG.43 shows representive full CPMG NMR spectrum for 100 pM CP4 / 100 pM Sitagliptin / 100 pM VH298 / 1% DMSO-d6 in the presence of 7.7 pM WT VCB protein complex or 7.7 pM VDI97KCB.

[0089] FIG.44 shows representative figures for the reduction in cell survival at different time points by the treatment with increasing concentrations of CP4.29 in RCC4, RCC-MF, 769-P, SLR25. SLR26, and TUHR14TKB cells with S65W, P86S, I180N, N78T, V130D, and L153P mutants of pVHL, respectively.

[0090] FIG.45 shows representative figures for the reduction in cell survival when parent mutant cells were treated with increasing concentrations of CP4.29 cells compared to their isogenic cells with knocked out or silenced VHL.

[0091] FIG.46A-D show representative Western blots and figures for the reduction in HIF-2a levels when RCC4, 769-P, and RCC-MF cells were treated with 5 and 10 pM concentrations of CP4.29 (FIG. 46A), the no reduction in HIF-2 a levels upon the cotreatment with 20 pM MG132 (FIG. 46B), 1 pM MLN4924 (FIG.46C), and 50 pM JNJ42041935 (FIG.46D). and in hypoxia (FIG. 46E).

[0092] FIG.47A and FIG. 47B show the effect of 5 pM CP4.29 on glycolysis and ATP production in RCC4 and RCC4-VHL-KO cells (FIG.47A) and in 769-P and 769-P-VHL-KO cells (FIG. 47B).

[0093] FIG.48A-D show representative Western blots and figures for the reduction in AURKA and ZHX2 levels when RCC4, 769-P, and RCC-MF cells were treated with 5 and 10 pM concentrations of CP4.29 (FIG. 48A) and the no reduction in AURKA and ZHX2 levels upon the cotreatment with 20 pM MG132 (FIG. 48B), 1 pM MLN4924 (FIG. 48C), and 50 pM JNJ42041935 (FIG. 48D).Attorney Docket No.38235.0016P1

[0094] FIG.49 shows representative CP4.29 induced ubiquitination in the eluted HIF2a, AURKA and ZHX2 proteins, when they pulled down with Sepharose A / G beads coated with their antibodies.

[0095] FIG.50 shows representative screening of MFH small molecules for the inhibition of colony formation in RCC-MF and 769-P cells.

[0096] 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

[0097] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0098] 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.

[0099] 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.Attorney Docket No. 38235.0016P1

[0100] 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

[0101] 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, alky ls, or residues, and the like.

[0102] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of’ and “consisting essentially of.”

[0103] 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.

[0104] 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, reflectingAttorney Docket No. 38235.0016P1tolerances, 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] As used herein, the terms “optional” or “optionally” means that the subsequently7described 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.

[0110] 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 orAttorney Docket No. 38235.0016P1rodent. 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.

[0111] 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.).

[0112] 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.

[0113] 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.Attorney Docket No. 38235.0016P1

[0114] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well know n 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.

[0115] 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 variety7of 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.Attorney Docket No. 38235.0016P1

[0116] 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, polyoxyethylene9-10 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-phenoxy ethanol, 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.

[0117] 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.

[0118] As used herein, “instruct! on(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, troubleshooting, 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 anAttorney Docket No. 38235.0016P1electronic 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.

[0119] 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 (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition), 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 maj or 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 deacety lase (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, antiAttorney Docket No. 38235.0016P1epileptics, 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 w ell 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.

[0120] 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.

[0121] 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.Attorney Docket No. 38235.0016P1

[0122] 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.

[0123] 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 ofAttorney Docket No. 38235.0016P1the 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).

[0124] 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.

[0125] 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

[0126] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, / -butyl. / i-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 alky l group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alky l group can be substituted with one or more groups including, but not limited to, alky l, 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 alky l, C1-C8 alkyl, C1-C9 alkyl, Cl -CIO alkyl, and the like up to and including a C1-C24 alkyl.

[0127] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups areAttorney Docket No. 38235.0016P1also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl’7or “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 “monohaloalky 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 “hydroxyalkyd” is used in another, it is not meant to imply that the term “alky l” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0128] 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 cycloalkyd can be referred to as, e.g., an “alkylcycloalkyd.” 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 “cycloalky 1,” and a specific term, such as “alkydcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0129] 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 cycloalkyd 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 heterocycloalkyd group can be substituted or unsubstituted. The cycloalky 1 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.Attorney Docket No. 38235.0016P1

[0130] 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.

[0131] The terms “alkoxy” and “alkoxy!” 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 — OA1where A1is 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— OA2or — OA1— (OA2)a— OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyd and / or cycloalkyl groups.

[0132] 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 (A1A2)C=C(A3A4) 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 alkeny l 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.

[0133] 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, z.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.

[0134] 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 notAttorney Docket No. 38235.0016P1limited 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.

[0135] 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.

[0136] The term '‘aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized n electrons above and below the plane of the molecule, where the 71 clouds contain (4n+2) it 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.

[0137] 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, alkyd, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, —NEE, carboxylic acid, ester, ether, halide, hy droxy, 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 carbon-carbon bond. For example, biary l can be two ary l 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.Attorney Docket No. 38235.0016P1

[0138] 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.

[0139] The terms “amine” or “amino” as used herein are represented by the formula — NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH2.

[0140] 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.

[0141] 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.

[0142] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH.

[0143] The term “ester” as used herein is represented by the formula — OC(O)A1or — C(O)OA’, where A1can 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 A1and A2can 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.

[0144] The term “ether” as used herein is represented by the formula ArOA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cy cloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A1O-A2O)a—, where A1and A2can be, independently, anAttorney Docket No. 38235.0016P1alky l, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of poly ether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0145] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0146] 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.

[0147] The term “heteroalkyl” as used herein refers to an alky l 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 alky l groups.

[0148] 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, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodi oxolyl, 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, benzo[rf]oxazolyl, benzo[<f]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.

[0149] 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,Attorney Docket No. 38235.0016P1but 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, py ridazine, 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, dihydrodiazet l. 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.

[0150] 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[ 1,5 -a] pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl. 1,3-benzodioxolyl. 2,3-dihydro-l,4-benzodioxinyl, 3.4-dihydro-2H-chromenyL lH-pyrazolo[4,3-c]pyridin-3-yl; lH-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0151] 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 aAttorney Docket No. 38235.0016P1nitrogen 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 tetraliydrofur l.

[0152] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH.

[0153] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0154] The term “azide” or “azido” as used herein is represented by the formula — N3.

[0155] The term “nitro” as used herein is represented by the formula — NO2.

[0156] The term “nitrile” or “cyano” as used herein is represented by the formula — CN.

[0157] The term “silyl” as used herein is represented by the formula — SiA3A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0158] The term “sulfo-oxo” as used herein is represented by the formulas — S(O)A', — S(O)2A1, — OS(O)2A1, or — OS(O)2OA1, where A1can 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)2A where A1can 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 A1SfOfiA2. where A1and A2can be, independently, an alky l, cycloalkyl, alkeny l, cycloalkenyl, alky nyl, cy cloalkynyl, aryl, or heteroary l group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0159] The term “thiol” as used herein is represented by the formula — SH.

[0160] “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 R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally beAttorney Docket No. 38235.0016P1substituted 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 (z.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.

[0161] 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).

[0162] 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.

[0163] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o 4R0; -(CH2)o 4OR0; -0(CH2)O-4R°, -0-(CH2)O4C(O)ORO; -(CH2)O 4CH(ORO)2; -(CH2)O4SRO; -(CH2)O4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH 2)0 40(CH2)o -1 -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O-IN(R°)2; -(CH2)o^N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)0. ^N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(Ro)C(0)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)o4C(O)R°; -C(S)R°; -(CH2)O4C(O)ORO; -(CH2)O^C(0)SR°; -(CH2)O4C(O)OSIR°3; -(CH2)O4OC(O)RO; -OC(0)(CH2)O 4SR-, SC(S)SR°; -(CH2)o^SC(0)R°; -(CH2)o^C(0)NR°2; -C(S)NR°2; -C(S)SR°; -(CH2)O 4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°: -Attorney Docket No. 38235.0016P1C(NOR°)R°; -(CH2)O4SSRO; -(CH2)O4S(0)2RO; -(CH2)O4S(0)20RO; -(CH2)O40S(0)2RO; -S(O)2NR°2; -(CH2)O-4S(O)RO; -N(R0)S(0)2NRO2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°3; -(Ci4straight or branched alkylene)O-N(R°)2; or-(Ci^ 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)o iPh, -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.

[0164] 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)o-2OH. -(CH2)0 2OR*. -(CH2)0 2CH(OR*)2;-O(haloR’), -CN, -N3, -(CH2)0 2C(O)R*, -(CH2)0 2C(O)OH, -(CH2)0 2C(O)OR*, -(CH2)02SR‘. (CH2)O 2SH, (CH2)O 2NH2, (CH2)O 2NHR*, (CH2)O 2NR*2, NO2, SiR*3, OSiR*3, -C(O)SR* - (Ci-4straight 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 Ci4aliphatic, -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. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0165] 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 ar l 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, partiallyAttorney Docket No. 38235.0016P1unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0166] 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 C1-4 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.

[0167] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R:. -NR!2, -C(O)Rt -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rf, -S(O)2NR^2, -C(S)NRf2. -C(NH)NR^2, or -NCR^SCO)^; wherein each R: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 RN 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.

[0168] 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 Ci 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.

[0169] 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.

[0170] 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).Attorney Docket No. 38235.0016P1

[0171] 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.

[0172] 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:Oregardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyd) can be further modified (i.e., substituted alky 1) 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.

[0173] “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 anAttorney Docket No. 38235.0016P1alky l, 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.

[0174] 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.

[0175] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as w edges 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.

[0176] 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 inAttorney Docket No. 38235.0016P1different 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.

[0177] 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.

[0178] 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 andAttorney Docket No. 38235.0016P1are. 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.

[0179] 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.

[0180] The compounds according to this disclosure may form prodrugs at hy droxy l 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.

[0181] “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.

[0182] 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 ofAttorney Docket No. 38235.0016P1hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C.15N,180,170.35S,18F and36Cl, 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 as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, z.e.,3H, and carbon-14, z.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, 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.

[0183] 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 cry stallization 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.

[0184] 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. " Cry stal 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.

[0185] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones w ith an a-hydrogen can exist in an equilibrium of the keto form and the enol form.Attorney Docket No. 38235.0016P1O OHH Hketo formamide form imidic acid form

[0186] 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-A3and A1-unsubstituted, 5-A3as shown below.A4A4N-N N-NH HUnless stated to the contrary, the invention includes all such possible tautomers.

[0187] 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.

[0188] In some aspects, a structure of a compound can be represented by a formula:which is understood to be equivalent to a formula:RiXa)y_xL / Rn(b>IRn(eA)^f^Rn<c>Rn(d)wherein n is typically an integer. That is, R” is understood to represent five independent substituents, R”(a), R"(b), R”(c), R"(d), R"(e). By ‘‘independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R"(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0189] 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 suchAttorney Docket No. 38235.0016P1as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N. J.), Strem Chemicals (Newbury- port, 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).

[0190] 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 w ay 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 flow7; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0191] 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. Likew ise, 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. ThisAttorney Docket No. 38235.0016P1concept 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.

[0192] 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

[0193] In one aspect, the invention relates to compounds useful in treating disorders associated with von Hippel Lindau tumor suppressor protein (pVHL) dysfunction 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, liver cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasms (myelomas).

[0194] In one aspect, the compounds of the invention are useful in the treatment of cancer as further described herein.

[0195] 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

[0196] In one aspect, disclosed are compounds having a structure represented by a formula:Attorney Docket No.38235.0016P1wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein each of R6a, R6b, R6°, R6d, R6e, R6f, R6g, and R6his independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, 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, and Cy3; wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-. -S-, and -N(R”)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cy anoalkyd, C1-C4 hydroxyalky 1, C1-C4 haloalkoxy, Cl-Attorney Docket No.38235.0016P1C4 alkoxy, C1-C4 alkylamino. (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl; wherein each of R14a. R14b, R14c, R14d, R14e. R14f, R14g, and R14his independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, provided that when n is 0 and Cy1is:then Ar1is not indole or benzofuran. provided that when n is 0, Cy1is:and Ar1is:then each of Q1, Q2, Q2, Q4, Q5, Q6, and Q7is -C(R10)=, provided that when n is 1 and Cy1is:Attorney Docket No. 38235.0016P1then R1is a C1-C4 alkyl, provided that the compound is not:O 5 Oor a pharmaceutically acceptable salt thereof.

[0197] In one aspect, the compound is selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0199] In one aspect, disclosed are compounds having a structure represented by a formula:wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein Cy3is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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-C4Attorney Docket No.38235.0016P1alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0200] In one aspect, disclosed are compounds selected from:Bror a pharmaceutically acceptable salt thereof.

[0201] In one aspect, disclosed are compounds having a structure represented by a formula:wherein each of R2a, R2b, R2c, R2d, and R3is 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; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5° 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, (C 1-Attorney Docket No. 38235.0016P1C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

[0202] In one aspect, disclosed are compounds selected from:Attorney Docket No. 38235.0016P1Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.

[0203] In various aspects, the compound has a structure represented by a formula:Oor a pharmaceutically acceptable salt thereof.

[0204] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.Attorney Docket No. 38235.0016P1

[0205] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0206] In various aspects, the compound has a structure represented by a formula:Q=Qor a pharmaceutically acceptable salt thereof.

[0207] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0208] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0209] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0210] In various aspects, the compound has a structure represented by a formula:R13OAttorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0211] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0212] In various aspects, the compound is selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0213] In various aspects, the compound is selected from:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0214] In various aspects, the compound is:or a pharmaceutically acceptable salt thereof.

[0215] In various aspects, the compound is selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0216] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof. In a further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0217] In various aspects, the compound is selected from:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0218] or a pharmaceutically acceptable salt thereof.

[0219] In one aspect, n is selected from 0 and 1. In a further aspect, n is 0. In a still further aspect, n is i.Attorney Docket No.38235.0016P1a. Q1, Q2, Q3, Q4, Q5, Q6, AND Q7GROUPS

[0220] In one aspect, Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=.

[0221] In various aspects, each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is -C(R10)=.

[0222] In various aspects, Q1, Q2, Q3, Q4, Q5, Q6, and Q7is -C(R10)= is independently selected from -C(R10)= and -N=, provided that only one of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=. In various aspects, Q1, Q2, Q3, Q4, Q5, Q6, and Q7is -C(R10)= is independently selected from -C(R10)= and -N=, provided that only two of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=. In various aspects, Q1, Q2, Q3, Q4, Q5, Q6, and Q7is -C(R10)= is independently selected from -C(R10)= and -N=, provided that only three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=.b. Z GROUPS

[0223] In one aspect, Z is selected from -O-, -S-, and -N(Rn)-.

[0224] In various aspects, Z is selected from -O- and -N(Rn)-. In various aspects, Z is selected from -O- and -S-. In various aspects, Z is selected from -S- and -N(Rn)-. In various aspects, Z is -O-. In various aspects, Z is -S-. In various aspects, Z is -N(Rn)-.c. R1GROUPS

[0225] In one aspect, R1is selected from hydrogen and C1-C4 alkyl. In a further aspect, R1is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R1is selected from hydrogen, methyl, and ethyl. In a still further aspect, R1is selected from hydrogen and methyl.

[0226] In various aspects, R1is C1-C4 alkyl. In a further aspect, R1is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R1is selected from methyl and ethyl. In yet a further aspect, R1is ethyl. In an even further aspect, R1is methyl.

[0227] In various aspects, R1is hydrogen.d. R2A, R2B, R2C, AND R2DGROUPS

[0228] In one aspect, each of R2a, R2b, R2c, and R2dis 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 R2a, R2b, R2C, and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH,Attorney Docket No. 38235.0016P1-N02, methyl, ethyl, n-propyl, z-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 R2a, R2b, R2c, and R2dindependently 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 R2a, R2b, R2c, and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -CH2F. -CH2C1, -CH2CN, -CH2OH, -OCF3, -OCH2CF3, -OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0229] In various aspects, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, / z-propyl, z-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each of R2a, R2b, R2c. and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, and ethenyl. In a still further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, -F, -Cl, - NH2, -CN, -OH. -NO2, and methyl.

[0230] In various aspects, each of R2a. R2b, R2c, and R2dis independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, each of R2a, R2b, R2C, and R2dis independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, / z-propyl, z-propyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a still further aspect, each of R2a. R2b, R2c, and R2dis independently selected from hydrogen, -F, -CL -CN, methyl, ethyl, -OCH3, and -OCH2CH3. In yet a further aspect, each of R2a, R2b, R2C, and R2dis independently selected from hydrogen, -F, -Cl, -CN, methyl, and -OCH3.

[0231] In various aspects, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, halogen, -CN. -NH2, -OH, -NO2, C1-C4 haloalky 1, and C1-C4 cyanoalkyl. In a further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2C1, -CH2CH2CH2F,Attorney Docket No. 38235.0016P1-CH2CH2CH2CI. -CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN. -CH2CH2CN, -CH2CH2CH2CN. and -CH(CH3)CH2CN. In a further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CN, and -CH2CH2CN. In a still further aspect, each of R2a, R2b, R2C, and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F. -CH2CI, and -CH2CN.

[0232] In various aspects, each of R2a, R2b, R2c, and R2dis 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 R2a, R2b, R2c, and R2dis 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 R2a, R2b, R2C, and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, -CH2CH2OH, -OCF3. -OCH2CF3, -OCH3, and -OCH2CH3. In a still further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, -OCF3, -OCH2CF3, and -OCH3.

[0233] In various aspects, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alky lamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R2a, R2b, R2c, and R2dis 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 R2a, R2b, R2c, and R2dis 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 R2a, R2b, R2c, and R2dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -NHCH3, -N(CH3)2, and -CH2NH2.

[0234] In various aspects, each of R2a. R2b, R2c, and R2dis independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, methyl, ethyl, n-propyl, and z-propyl. In a further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen and methyl.Attorney Docket No. 38235.0016P1

[0235] In various aspects, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen and halogen. In a further aspect, each of R2a, R2b. R2c, and R2dis independently selected from hydrogen, -F, and -Cl. In a further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen and -Cl. In a still further aspect, each of R2a, R2b, R2C, and R2dis independently selected from hydrogen and -F.

[0236] In various aspects, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, halogen, C1-C4 alkyd, and C1-C4 alkoxy. In afurther aspect, each of R2a, R2bR2Canc| j^2d -sinc]epenc]ent]y selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, / -propyl, OCH3, OCH2CH3, OCH2CH2CH3, and OCH(CH3)CH3. In a still further aspect, each of R2a, R2b, R2c, and R2dis independently selected from hydrogen, -F, -Cl, methyl, ethyl. -OCH3, and -OCH2CH3. In yet a further aspect, each of R2a. R2b, R2c, and R2dis independently selected from hydrogen, -F, methyl, -OCH3.

[0237] In various aspects, each of R2a, R2b, R2c, and R2dis hydrogen.e. R3GROUPS

[0238] In one aspect, R3is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, C2-C4 alkenyl, C1-C4 haloalk 1, 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. R3is selected from hydrogen, -F, -CL -NH2, -CN, -OH, -NO2, methyl, ethyl, / 7-propyl, z-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, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl. -CH2F, -CH2CI. -CH2CH2F, -CH2CH2CI, -CH2CN,-CH2CH2CN, -CH2OH, -CH2CH2OH, -0CF3, -OCH2CF3, -OCHs, -OCH2CH3, -NHCHs, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In a still further aspect, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -CH2F, -CH2C1, -CH2CN, -CH2OH, -OCF3, -OCH2CF3. -OCH3, -NHCH3. -N(CH3)2, and-CH2NH2.Attorney Docket No. 38235.0016P1

[0239] In various aspects, R' is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, rz-propyl, z-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, and ethenyl. In a still further aspect, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, and methyl.

[0240] In various aspects, R3is selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, R3is selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, n-propyl, z-propyl, OCH3, OCH2CH3, OCH2CH2CH3, and OCH(CH3)CH3. In a still further aspect, R3is selected from hydrogen, -F, -Cl, -CN. methyl, ethyl, -OCH3, and -OCH2CH3. In yet a further aspect, R3is selected from hydrogen, -F, -Cl, -CN, methyl, and -OCH3

[0241] In various aspects, R3is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 haloalky 1, and C1-C4 cyanoalkyl. In a further aspect, R3is selected from hydrogen, -F, -Cl. -NH2, -CN, -OH, -NO2, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2C1, -CH2CH2CH2F, -CH2CH2CH2C1, -CH(CH3)CH2F, -CH(CH3)CH2CL -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, and -CH(CH3)CH2CN. In a further aspect, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2C1, -CH2CN, and -CH2CH2CN. In a still further aspect, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2. -CH2F, -CH2C1. and -CH2CN.

[0242] In various aspects, R3is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, R3is 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, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, -CH2CH2OH, -OCF3, -OCH2CF3, -OCH3, and -OCH2CH3. In a still further aspect, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, -OCF3, -OCH2CF3, and -OCH3.

[0243] In various aspects, R3is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, R3is 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, -CH2CH2CH2NH;!, and -CH(CH3)CH2NH2. In a further aspect, R3is selected from hydrogen.Attorney Docket No. 38235.0016P1-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, R3is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -NHCH3, -N(CH3)2, and -CH2NH2.

[0244] In various aspects, R3is selected from hydrogen and C1-C4 alkyl. In a further aspect, R3is selected from hydrogen, methyl, ethyl, n-propyl, and / -propyl. In a further aspect, R3is selected from hydrogen, methyl, and ethyl. In a still further aspect, R3is selected from hydrogen and methyl.

[0245] In various aspects, R3is selected from hydrogen and halogen. In a further aspect, R3is selected from hydrogen, -F, and -Cl. In a further aspect, R3is selected from hydrogen and -Cl. In a still further aspect, R3is selected from hydrogen and -F.

[0246] In various aspects, R3is selected from hydrogen, halogen. C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, R3is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, / -propyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a still further aspect, R3is selected from hydrogen, -F, -Cl, methyl, ethyl, -OCH3, and -OCH2CH3. In yet a further aspect, R3is selected from hydrogen, -F, methyl, -OCH3.

[0247] In various aspects, R3is selected from hydrogen, halogen, and C1-C4 alkyl. In a further aspect, R3is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, / / -propyl, and / -propyl. In a still further aspect, R3is selected from hydrogen, -F, -Cl, methyl, and ethyl. In yet a further aspect, R3is selected from hydrogen. -F. and methyl.

[0248] In various aspects, R3is hydrogen.f. R4GROUPS

[0249] In one aspect. R4is selected from hydrogen and C1-C4 alkyl. In a further aspect, R4is selected from hydrogen, methyl, ethyl, n-propyl. and isopropyl. In a still further aspect, R4is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R4is selected from hydrogen and ethyl. In an even further aspect, R4is selected from hydrogen and methyl.

[0250] In various aspects, R4is C1-C4 alkyl. In a further aspect, R4is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R4is selected from methyl and ethyl. In yet a further aspect, R4is ethyl. In an even further aspect, R4is methyl.

[0251] In various aspects, R4is hydrogen.Attorney Docket No.38235.0016P1g. R5A, R5B, AND R5CGROUPS

[0252] In one aspect, each of R5a, R5b, and R5° 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 R5a, R5b, and R5° is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, n-propyl, z-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 R5a, R5b, and R5cindependently 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, and -CH2CH2NH2. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -CH2F, -CH2C1, -CH2CN, -CH2OH, -OCF3, -OCH2CF3, -OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0253] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2. methyl, ethyl, / z-propyl. z-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, and ethenyl. In a still further aspect, each of R5a, R5b, and R5Cis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, and methyl.

[0254] In various aspects, each of R5a. R5b, and R5cis independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 alkoxy. In afurther aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, zz-propyl, z-propyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a still furtherAttorney Docket No. 38235.0016P1aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, -OCH3, and -OCH2CH3. In yet a further aspect, each of R5a, R5b, and R5° is independently selected from hydrogen, -F, -Cl, -CN, methyl, and -OCH3.

[0255] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R5a. R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2. -CN. -OH. -NO2. -CH2F. -CH2CI. -CH2CH2F. -CH2CH2CL -CH2CH2CH2F. -CH2CH2CH2CI, -CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, and -CH(CH3)CH2CN. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CN. and -CH2CH2CN. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F, -CH2CI, and -CH2CN.

[0256] In various aspects, each of R5a, R5b, and R5cis 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 R5a, R5b, and R5cis 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 R5a. R5b, and R5Cis independently selected from hydrogen, -F, -Cl. -NH2, -CN, -OH. -NO2, -CH2OH. -CH2CH2OH, -OCF3, -OCH2CF3, -OCH3, and -OCH2CH3. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, -OCF3, -OCH2CF3, and -OCH3.

[0257] In various aspects, each of R5a. R5b, and R5° 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 R5a, R5b, and R5cis 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(CHs)CH2NH2. In a further aspect, each of R5a, R5b, and R5cis 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 R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -NHCH3, -N(CH3)2, and -CH2NH2.Attorney Docket No. 38235.0016P1

[0258] In various aspects, each of R5a, R5b, and R5° is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R5a. R5b, and R5° is independently selected from hydrogen, methyl, ethyl, w-propyl. and z-propyl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen and methyl.

[0259] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen and halogen. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, and -Cl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen and -Cl. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen and -F.

[0260] In various aspects, each of R5a. R5b, and R5cis independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, each of R5a, R5b, and R5Cis independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, w-propyl. z-propyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a still further aspect, each of R5a, R5b, and R5° is independently selected from hydrogen, -F, -Cl. methyl, ethyl, -OCH3, and -OCH2CH3. In yet a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, methyl, -OCH3.

[0261] In various aspects, each of R5a, R5b, and R5cis hydrogen.

[0262] In various aspects, R5ais halogen. In a further aspect, R5ais selected from -F, -Cl, and -Br. In a still further aspect, R5ais selected from -F and -Cl. In yet a further aspect, R5ais -F.

[0263] In various aspects, R5bis C1-C4 alkyl. In a further aspect, R5bis selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspsect, R5bis selected from methyl and ethyl. In yet a further aspect, R5bis ethyl.

[0264] In various aspects, R5cis hydrogen.h. R6A, R6B, R6c, R6D, R6E, R6F, R6G, AND R6HGROUPS

[0265] In one aspect, each of R6a, R6b. R6°, R6d, R6e. R6f, R6g, and R6his independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6his independently selected from hydrogen, -F, -Cl, methyl, ethyl, n-propyl, z-propyl, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2CL -CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH3)CH2F, -CH(CH3)CH2C1, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -Atorney Docket No. 38235.0016P1N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, and -N(CH3)(CH2CH3). In a further aspect, each of R6a, R6b, R6°, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen, -F, -Cl, methyl, ethyl, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2C1, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, and -N(CH3)(CH2CH3. In a still further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6his independently selected from hydrogen, -F, -Cl, methyl, -CH2F, -CH2C1, -OCH3, -NHCH3, and -N(CH3)2.

[0266] In various aspects, each of R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R61’ is independently selected from hydrogen, halogen, and C1-C4 alkyl. In a further aspect, each of R6a, R6b, R6C, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen, -F, -Cl, methyl, ethyl, n-propyl, and / -propyl. In a further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6his independently selected from hydrogen. -F. -Cl, methyl, and ethyl. In a still further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6gand R6bis independently selected from hydrogen, -F, -Cl, and methyl.

[0267] In various aspects, each of R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6his independently selected from hydrogen, halogen. C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen, -F, -Cl, methyl, ethyl, n-propyl, / -propyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a still further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen, -F, -Cl. methyl, ethyl, -OCH3, and -OCH2CH3. In yet a further aspect, each of R6a. R6b, R6c, R6d. R6e, R6f, R6gand R611is independently selected from hydrogen, -F, -Cl, methyl, and -OCH3.

[0268] In various aspects, each of R6a, R6b, R6°, R6d, R6e, R6f, R6gand R6bis independently selected from hydrogen, halogen, and C1-C4 haloalkyl. In a further aspect, each of R6a, R6b, R6°. R6d, R6e, R6f. R6gand R6his independently selected from hydrogen. -F. -Cl, -CH2F, -CH2CL -CH2CH2F, -CH2CH2C1, -CH2CH2CH2F, -CH2CH2CH2C1, -CH(CH3)CH2F, and -CH(CH3)CH2C1. In a further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6gand R6his independently selected from hy drogen, -F, -Cl, -CH2F, -CH2C1, -CH2CH2F, and -CH2CH2C1. In a still further aspect, each of R6a. R6b, R6°, R6d. R6e, R6f, R6gand R6his independently selected from hydrogen, -F, -Cl, -CH2F, and -CH2C1.

[0269] In various aspects, each of R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6bis independently selected from hydrogen, halogen, and C1-C4 alkoxy. In a further aspect, each of R6a, R6b, R6C, R6d, R6e, R6f, R6gand R6bis independently selected from hydrogen, -F, -Cl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a further aspect, each of R6a, R6b, R6c. R6d. R6C. R6*. R6gand R6bis independently selected from hydrogen, -F, -Cl, -OCH3,Attorney Docket No. 38235.0016P1and -OCH2CH3. In a still further aspect, each of R6a, R6b. R6c, R6d, R6e, R6f, R6g, and R6his independently selected from hydrogen, -F, -Cl, and -OCH3.

[0270] In various aspects, each of R6a, R6b, R6c, R6d, R6e, R6f, Rfig. and R6his independently selected from hydrogen, halogen, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen, -F, -Cl, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2. and -N(CH3)(CH2CH3). In a further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen, -F, -Cl, -NHCH3, -NHCH2CH3, -N(CHs)2, - N(CH2CH3)2, and -N(CH3)(CH2CH3). In a still further aspect, each of R6a, R6b, R6°, R6d. R6e, R6fj^6g anj j^6h jsindepencientiy selected from hydrogen, -F, -Cl, -NHCH3. and -N(CHs)2.

[0271] In various aspects, each of R6a, R6b, R6c, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R6a, R6b, R6C, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen, methyl, ethyl, n-propyl, and z-propyl. In a further aspect, each of R6a, R6b. R6°, R6d, R6e. R6f, R6g, and R6his independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R6a, R6b. R6C. R6d. R6C. R® R6= and R6his independently selected from hydrogen and methyl.

[0272] In various aspects, each of R6a, R6b, R6c, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen and halogen. In a further aspect, each of R6a, R6b. R6c, R6d, R6e, R6f. R6g. and R6his independently selected from hydrogen. -F. and -Cl. In a further aspect, each of R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6his independently selected from hydrogen and -Cl. In a still further aspect, each of R6a, R6b, R6°, R6d, R6e, R6f, R6gand R6his independently selected from hydrogen and -F.

[0273] In various aspects, each of R6a. R6b, R6c, R6d. R6e, R6f, R6gand R611is hydrogen.i. R10GROUPS

[0274] In one aspect, R10, when present, is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalky 1, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and Cy3. In a further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methy l, ethyl, n-propyl, / -propyl, ethenyl, propenyl, isopropenyl, -CH2F. -CH2C1, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F. -CH2CH2CH2CI, -CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN, -CH2CH2CN. -CH2CH2CH2CN, -CH(CH )CH2CN, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -Attorney Docket No. 38235.0016P1CH(CH3)CH2OH, -0CF3, -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, -CH(CH3)CH2NH2, and Cy3. In a further aspect, R10, when present, is 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, -CH2CH2NH2, and Cy3. In a still further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, - CN, -OH, -NO2. methyl, -CH2F, -CH2C1, -CH2CN, -CH2OH, -OCF3, -OCH2CF3, -OCH3, -NHCH3, -N(CH3)2. -CH2NH2. and Cy3.

[0275] In various aspects, R10, when present, is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, and Cy3. In a further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, n-propyl, / -propyl, ethenyl, propenyl, isopropenyl, and Cy3. In a further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, and Cy3. In a still further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, and Cy3.

[0276] In various aspects, R10, when present, is selected from hydrogen, halogen, -CN. C1-C4 alkyl. C1-C4 alkoxy, and Cy3. In a further aspect. R10, when present, is selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, n-propyl, / -propyl, -OCH3, -OCH2CH5, -OCH2CH2CH3, -OCH(CH3)CH3, and Cy3. In a still further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, -OCH3, -OCH2CH3, and Cy3. In yet a further aspect, R10. when present, is selected from hydrogen, -F, -Cl. -CN. methyl, -OCH3, and Cy3.

[0277] In various aspects, R10, when present, is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 haloalkyl, C1-C4 cyanoalkyl, and Cy3. In a further aspect, R10, when present, is 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, Cy3. In a further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CN, -CH2CH2CN, and Cy3. In a still further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F, -CH2CI, -CH2CN, and Cy3.Attorney Docket No. 38235.0016P1

[0278] In various aspects, R10, when present, is selected from hydrogen, halogen, -CN. -NH2, -OH, -NO2, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, and Cy3. In a further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(CH3)CH2OH, -0CF3, -OCH2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, and Cy3. In a further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH. -NO2, -CH2OH. -CH2CH2OH, -OCF3. -OCH2CF3, -OCH3. -OCH2CH3, and Cy3. In a still further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, NO2, CH2OH, OCF3, -OCH2CF3, OCH3, and Cy3.

[0279] In various aspects, R10, when present, is selected from hydrogen, halogen, -CN. -NH2, -OH, -NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. C1-C4 aminoalkyl, and Cy3. In a further aspect, R10, when present, is 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, -CH(CH3)CH2NH2. and Cy3. In a further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and Cy3. In a still further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -NH2. -CN. -OH, -NO2, -NHCH3, -N(CH3)2, -CH2NH2, and Cy3.

[0280] In various aspects, R10. when present, is selected from hydrogen, C1-C4 alkyl, and Cy3. In a further aspect, R10, when present, is selected from hydrogen, methyl, ethyl, n-propyl, z-propyl, and Cy3. In a further aspect, R10, when present, is selected from hydrogen, methyl, ethyl, and Cy3. In a still further aspect, R10, when present, is selected from hydrogen, methyl, and Cy3.

[0281] In various aspects, R10, when present, is selected from hydrogen and halogen. In a further aspect, R10, when present, is selected from hydrogen, -F, and -Cl. In a further aspect, R10, when present, is selected from hydrogen and -Cl. In a still further aspect, R10, when present, is selected from hydrogen and -F.

[0282] In various aspects, R10, when present, is selected from hydrogen, halogen, Cl-C4 alkyl, C1-C4 alkoxy, and Cy3. In a further aspect, R10, when present, is selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, zz-propyl, z-propyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, and Cy3. In a still further aspect, R10. when present, is selected from hydrogen, -F. -Cl, methyl, ethyl. -OCH3, -OCH2CH3, and Cy3. In yet a further aspect, R10, when present, is selected from hydrogen, -F, methyl, -OCH3, and Cy3.Attorney Docket No. 38235.0016P1

[0283] In various aspects, R10, when present, is hydrogen.

[0284] In various aspects, R10. when present, is Cy3j. R11GROUPS

[0285] In one aspect, R11is selected from hydrogen and C1-C4 alkyl. In a further aspect, R11is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R11is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R11is selected from hydrogen and ethyl. In an even further aspect, R11is selected from hydrogen and methyl.

[0286] In various aspects, R11is C1-C4 alkyl. In a further aspect. R11is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R11is selected from methyl and ethyl. In yet a further aspect, R11is ethyl. In an even further aspect, R11is methyl.

[0287] In various aspects, R11is hydrogen.k. R12GROUPS

[0288] In one aspect, R12is selected from hydrogen, C1-C4 alkyl, and Cy2. In a further aspect, R12is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and Cy2. In a still further aspect, R12is selected from hydrogen, methyl, ethyl, and Cy2. In a still further aspect, R12is selected from hydrogen, methyl, and Cy2.

[0289] In various aspects, R12is selected from C1-C4 alkyl and Cy2. In a further aspect, R12is selected from methyl, ethyl, n-propyl, isopropyl, and Cy2. In a still further aspect, R12is selected from methyl, ethyl, and Cy2. In yet a further aspect, R12is selected from methyl and Cy2.

[0290] In various aspects, R12is C1-C4 alkyl. In a further aspect, R12is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R12is selected from methyl and ethyl. In yet a further aspect, R12is ethyl. In an even further aspect, R12is methyl.

[0291] In various aspects, R12is hydrogen.

[0292] In various aspects, R12is Cy2.l. R13GROUPS

[0293] In one aspect. R13is selected from hydrogen and C1-C4 alkyl. In a further aspect, R13is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R13is selected from hydrogen, methyl, and ethyl. In a still further aspect, R13is selected from hydrogen and methyl.Attorney Docket No. 38235.0016P1

[0294] In various aspects, R13is C1-C4 alkyl. In a further aspect, R13is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R13is selected from methyl and ethyl. In yet a further aspect, R13is ethyl. In an even further aspect, R13is methyl.

[0295] In various aspects, R13is hydrogen.m. R14A, R14B, R14c, R14D, R14E, R14F, R14G, AND R14HGROUPS

[0296] In one aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14g. and R14his independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, each of R14a, R14b, R14C, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, methyl, ethyl, zz-propyl, z-propyl, -CH2F, -CH2CI. -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH3)CH2F, -CH(CH3)CH2C1, -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, and -N(CH3)(CH2CH3). In a further aspect, each of R14a. R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, methyl, ethyl, / z-propyl. z-propyl, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2C1, -CH2CH2CH2F, -CH2CH2CH2C1, -CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, -CH(CH3)CH2CN, -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, and -N(CH3)(CH2CH3). In a further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14hindependently selected from hydrogen, -F, -Cl, methyl, ethyl, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2CI, -CH2CN,-CH2CH2CN, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2. and -N(CH3)(CH2CH3). In a still further aspect, each of R14a. R14b. R14c, R14d, R14e, R14f. R14gand R14his independently selected from hydrogen, -F, -Cl, methyl, -CH2F, -CH2C1, -CH2CN, -OCF3, -OCH2CF3, -OCH3, -NHCH3, and -N(CH3)2.

[0297] In various aspects, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, halogen. -CN, and C1-C4 alkyl. In a further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14g. and R14his independently selected from hydrogen, -F, -Cl, methyl, ethyl, / z-propyl. and z-propyl. In a further aspect, each of R14a, R14b, R14c. R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, methyl, and ethyl. In a still further aspect, each of R14a. R14b, R14c, R14d, R14e. R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, and methyl.Attorney Docket No. 38235.0016P1

[0298] In various aspects, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, halogen. C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, methyl, ethyl, n-propyl, z-propyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a still further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, methyl, ethyl, -OCH3, and -OCH2CH3. In yet a further aspect, each of R14a, R14b, R14c, R14d, R14e. R14f, R14g. and R141’ is independently selected from hydrogen, -F, -Cl, methyl, and -OCH3.

[0299] In various aspects, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, halogen, and C1-C4 haloalkyl. In a further aspect, each of R14a, R14b, R14c, R14d. R14e. R14f, R14g, and R14his independently selected from hydrogen, -F, -Cl, -CH2F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH3)CH2F, and -CH(CH3)CH2C1. In a further aspect, each of R14a, R14b, R14c. R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, -CH2F, -CH2CI, -CH2CH2F, and -CH2CH2CI. In a still further aspect, each of R14a, R14b. R14c, R14d, R14e. R14f. R14gand R14his independently selected from hydrogen, -F, -Cl, -CH2F, and -CH2Cl

[0300] In various aspects, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, halogen, and C1-C4 alkoxy. In a further aspect, each of R14a. R14b. R14c, R14d, R14e, R14f. R14g, and R14his independently selected from hydrogen, -F, -Cl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, -OCH3, and -OCH2CH3. In a still further aspect, each of R14a, R14b, R14c. R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, -OCF3, -OCH2CF3. and -OCH3.In various aspects, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, halogen, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, and - N(CH3)(CH2CH3). In a further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, -NHCH3, -NHCH2CH3, -N(CH3)2, -Attorney Docket No. 38235.0016P1N(CH2CH3)2, and -N(CH3)(CH2CH3). In a still further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, -Cl, -NHCH3. and - N(CH3)2.

[0301] In various aspects, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R14a, R14b, R14c, R14d, R14e. R14f, R14gand R14his independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen and methyl.

[0302] In various aspects, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen and halogen. In a further aspect, each of R14a, R14b, Ri4“, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, -F, and -Cl. In a further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f. R14g, and R14his independently selected from hydrogen and -Cl. In a still further aspect, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen and -F.

[0303] In various aspects, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his independently selected from hydrogen, halogen. C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, each of R14a, R14b, R14c, R14d. R14e, R14f, R14g. and R14his independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, i-propyl, -OCH3, -OCH2CH3, - OCH2CH2CH3, and -OCH(CH3)CH3. In a still further aspect, each of R14a, R14b, R14c, R14d,Ri4e 4f RI 4g anc| 4h -sjndependently selected from hydrogen, -F, -Cl, methyl, ethyl, - OCH3, and -OCH2CH3. In yet a further aspect, each of R14a, R14b, R14c, R14d. R14e, R14f, R14gand R14his independently selected from hydrogen, -F, methyl, -OCH3.

[0304] In various aspects, each of R14a, R14b, R14c, R14d, R14e, R14f, R14gand R14his hydrogen.n. AR1GROUPS

[0305] In one aspect, Ar1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1

[0306] In various aspects, Ar1is a structure represented by a formula selected from:

[0307] In various aspects, Ar1is a structure represented by a formula:

[0308] In various aspects, Ar1is a structure represented by a formula selected from:R10iand K KIn a further aspect, each occurrence of R10is independently selected from hydrogen, halogen, C1-C4 alkyl. C1-C4 alkoxy, and Cy3.

[0309] In various aspects. Ar1is a structure represented by a formula:X M

[0310] In various aspects, Ar1is a structure represented by a formula:In a further aspect, each occurrence of R10is independently selected from hydrogen, halogen, and C1-C4 alkyl.

[0311] In various aspects, Ar1is a structure represented by a formula:H NClClAttorney Docket No. 38235.0016P1

[0312] In various aspects, Ar1is a structure represented by a formula selected from:In a further aspect, each occurrence of R10is independently selected from hydrogen, halogen, and C1-C4 alkyl.

[0313] In various aspects, Ar1is a structure represented by a formula:Ar2^ / Qt \H IQ23--Q4Q3

[0314] In various aspects, Ar1is a structure represented by a formula:R10

[0315] In various aspects, Ar1is a structure represented by a formula:

[0316] In various aspects, Ar1is a structure represented by a formula:o. AR2GROUPS

[0317] In one aspect, Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, (C 1-C4)(C 1 -C4) dialkylamino, and C 1 -C4 aminoalkyl. In a further aspect, Ar2is selected from a 5- to 10-membered heteroaryl and a 6-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 hydroxy alky 1, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In aAttorney Docket No. 38235.0016P1still further aspect, Ar2is selected from a 5- to 10-membered heteroaryl and a 6-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, Cl-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar2is selected from a 5- to 10-membered heteroaryl and a 6-membered aryl, and is 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, and C1-C4 aminoalkyl. In an even further aspect, Ar2is selected from a 5- to 10-membered heteroaryl and a 6-membered aryl, and is unsubstituted.

[0318] In various aspects, Ar2is 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 hydroxy alkyd, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Aris 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, and C1-C4 aminoalky l. In a still further aspect, Ar2is 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. CI-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalky l. In yet a further aspect, Ar2is a 6-membered ary 1 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, and C1-C4 aminoalkyl. In an even further aspect, Ar2is an unsubstituted 6-membered aryl.

[0319] In various aspects, Ar2is 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, and C1-C4 aminoalkyl. 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, Ar2is a 5- to 10-membered heteroaryl substituted with 0, 1, or 2 groups independentlyAttorney Docket No.38235.0016P1selected 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, and C1-C4 aminoalkyl. In a still further aspect, Ar2is 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, and C1-C4 aminoalkyl. In yet a further aspect. Ar2is a 5- to 10-membered heteroaryl 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, Cl-C4 haloalkoxy. C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect. Ar2is an unsubstituted 5- to 10-membered heteroaryl.

[0320] In various aspects, Ar2is 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 hydroxyalky l, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino. (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect. Ar2is 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, (Cl-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar2is 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, Cl-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar2is a pyrimidinyl 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) dialkydamino, and C1-C4 aminoalkyl. In an even further aspect, Ar2is an unsubstituted pyrimidinyl.

[0321] In various aspects, Ar2is 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, and C1-C4 aminoalky. In a further aspect, Ar2is a pyrazolyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, CI-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl-Attorney Docket No. 38235.0016P1C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Artis 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, and C1-C4 aminoalkyl. In yet a further aspect, Ar2is a pyrazolyl monosubstituted with a 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, and C1-C4 aminoalkyl. In an even further aspect, Ar2is an unsubstituted pyrazolyl.

[0322] In various aspects, Ar2is a triazolyl 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, and C1-C4 aminoalkyl. In a further aspect, Ar2is a triazolyl 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, (C 1-C4)(CI-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar2is a triazolyl 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, and CI-C4 aminoalkyl. In yet a further aspect, Ar2is a triazolyl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, 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, and C1-C4 aminoalkyl. In an even further aspect, Artis an unsubstituted triazolyl.p. CY1

[0323] In one aspect. Cy1is a structure represented by a formula selected from:and

[0324] In various aspects, Cy1is a structure represented by a formula:Attorney Docket No. 38235.0016P1

[0325] In various aspects, Cy1is a structure represented by a formula selected from:

[0326] In various aspects, Cy1is a structure represented by a formula:

[0327] In various aspects, Cy1is a structure represented by a formula:

[0328] In various aspects, Cy1is a structure represented by a formula:

[0329] In various aspects, Cy1is a structure represented by a formula:q. CY2

[0330] In one aspect, Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl. In a further aspect. Cy2is selected from a 3- to 7-membered cycloalkyl. a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is substituted with 0, 1, or 2 groups independently selected fromAttorney Docket No. 38235.0016P1halogen, -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. In a still further aspect, Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, Cl-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is monosubstituted with a 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, and C1-C4 aminoalkyl. In an even further aspect, Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is unsubstituted.

[0331] In various aspects, Cy2is selected from a 3- to 7-membered cycloalkyl and a 3- to 7-membered heterocycloalkyl, 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, and C1-C4 aminoalkyl. In a further aspect, Cy2is selected from a 3- to 7-membered cycloalkyl and a 3- to 7-membered heterocycloalkyl, 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, and C1-C4 aminoalkyl. In a still further aspect, Cy2is selected from a 3- to 7-membered cycloalkyl and a 3- to 7-membered heterocycloalkyl, 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, and C1-C4 aminoalkyl. In yet a further aspect, Cy2is selected from a 3- to 7-membered cycloalkyl and a 3- to 7-membered heterocycloalkyl, and is 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, and C1-C4Attorney Docket No.38235.0016P1aminoalkyl. In an even further aspect. Cy2is selected from a 3- to 7-membered cycloalkyl and a 3- to 7-membered heterocycloalkyl, and is unsubstituted.

[0332] In various aspects, Cy2is a 3- to 7-membered cycloalkyl 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, and C1-C4 aminoalkyl. Examples of 3- to 7-membered cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2,2]pentanyl, andnorbomyl. In a further aspect, Cy2is a 3- to 7-membered cycloalkyl 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, and C1-C4 aminoalkyl. In a still further aspect, Cy2is a 3- to 7-membered cycloalkyl 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, (Cl-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Cy2is a 3- to 7-membered cycloalkyd 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, and C1-C4 aminoalkyl. In an even further aspect, Cy2is an unsubstituted 3- to 7-membered cycloalkyd.

[0333] In various aspects, Cy2is a 3- to 7-membered heterocycloalkyl substituted with 0, 1. 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH. -NO2, Cl-C4 alkyd. 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. Examples of 3- to 7-membered heterocycloalkyls include, but are not limited to, tetrahydrofuran, tetrahydro thiophene, pyrrolidine, thiazolidine, oxazolidine, imidazolidine, tetrahydropyran, tetrahydrothiopyran, piperazine, piperidine, and morpholine. In a further aspect, Cy2is a 3- to 7-membered heterocycloalkyl 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, and C1-C4 aminoalkyl. In a still further aspect, Cy2is a 3- to 7-membered heterocycloalkyl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, C2-C4 alkenyl, C1-C4 haloalkyl, Cl-Attorney Docket No. 38235.0016P1C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect. Cy2is a 3- to 7-membered heterocycloalkyl 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, and C1-C4 aminoalkyl. In an even further aspect, Cy2is an unsubstituted 3- to 7-membered heterocycloalkyl.

[0334] In various aspects, Cy2is selected from a 5- to 6-membered heteroaryl and a 6-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, (C 1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Cy2is selected from a 5- to 6-membered heteroaryl and a 6-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, and C1-C4 aminoalkyl. In a still further aspect, Cy2is selected from a 5- to 6-membered heteroaryl and a 6-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, and C1-C4 aminoalkyl. In yet a further aspect, Cy2is selected from a 5- to 6-membered heteroaryl and a 6-membered aryl, and is 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, and C1-C4 aminoalkyl. In an even further aspect, Cy2is selected from a 5- to 6-membered heteroary 1 and a 6-membered an 1, and is unsubstituted.

[0335] In various aspects, Cy2is a 5- to 6-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, and C1-C4 aminoalkyl. Examples of 5- to 6-membered heteroaryls include, but are not limited to, furan, triazole, benzoimidazole, oxazole, oxadiazole, pyridine, and pyrazine. In a further aspect, Cy2is a 5- to 6-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4Attorney Docket No. 38235.0016P1haloalkyl, 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 still further aspect, Cy2is a 5- to 6-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, and C1-C4 aminoalkyl. In yet a further aspect, Cy2is a 5- to 6-membered heteroaryl 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, Cl-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Cy2is an unsubstituted a 5- to 6-membered heteroaryl.

[0336] In various aspects, Cy2is 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 hydroxy alkyd, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Cy2is 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, (Cl-C4)(C1-C4) dialkylamino, and C1-C4 aminoalk d. In a still further aspect, Cy2is a pyrimidinyl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, CI-C4 alkyd. C2-C4 alkenyl. CI-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, Cl-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Cy2is a pyrimidinyl 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, and C1-C4 aminoalkyl. In an even further aspect, Cy2is an unsubstituted pyrimidinyl.

[0337] In various aspects, Cy2is 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, and C1-C4 aminoalky. In a further aspect, Cy2is 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, (C 1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy2is a pyrazolylAttorney Docket No. 38235.0016P1substituted 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, and C1-C4 aminoalkyl. In yet a further aspect, Cy2is a pyrazolyl monosubstituted with a 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, and C1-C4 aminoalkyl. In an even further aspect, Cy2is an unsubstituted pyrazolyl.

[0338] In various aspects, Cy2is triazolyl 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, and C1-C4 aminoalkyl. In a further aspect, Cy2is triazolyl 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, (Cl-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy2is triazolyl substituted with 0 or 1 group selected from halogen, -CN, -NHz, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cy anoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Cy2is triazolyl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alky 1, C2-C4 alkenyl, C1-C4 haloalkyl, Cl-C4 cyanoalkyd, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialk damino, and C1-C4 aminoalkyl. In an even further aspect, Cy2is an unsubstituted triazolyl.

[0339] In various aspects, Cy2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, 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, and C1-C4 aminoalkyl. In a further aspect, Cy2is 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, and C1-C4 aminoalky l. In a still further aspect, Cy2is a 6-membered aryl substituted with 0 or I group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4Attorney Docket No. 38235.0016P1hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect. Cy2is 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, and C1-C4 aminoalkyl. In an even further aspect. Cy2is an unsubstituted 6-membered aryl.r. CY3

[0340] In one aspect, each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, Cl-C4 cyanoalkyd, 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 occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyd, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroary 1, and a 6-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. (C 1-C4)(C1 -C4) dialkydamino, and Cl -C4 aminoalkyl. In yet a further aspect, each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyd, a 3- to 7-membered heterocycloalky l, a 5- to 6-membered heteroaryl, and a 6-membered ary 4, and is 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) dialkydamino, and C1-C4 aminoalkyl. In an even further aspect, each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyd, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is unsubstituted.Attorney Docket No. 38235.0016P1

[0341] In various aspects, each occurrence of Cy3is independently selected from a 3-to 7-membered cycloalkyl and a 3- to 7-membered heterocycloalkyl, 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 cyanoalkyd, C1-C4 hydroxyalky 1, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alky lamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl and a 3- to 7-membered heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently7selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalky7!, 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 still further aspect, each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl and a 3- to 7-membered heterocycloalkyl, 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 hydroxyalky l, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl and a 3- to 7-membered heterocycloalkyl, and is 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)(CI-C4) dialkylamino, and CI-C4 aminoalkyl. In an even further aspect, each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalky7! and a 3- to 7-membered heterocycloalkyl, and is unsubstituted.

[0342] In various aspects, each occurrence of Cy3is a 3- to 7-membered cycloalkyl 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, and C1-C4 aminoalky l. Examples of 3- to 7-membered cy cloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyd. cyclohexyl, spiro [2,2] pentanyl, and norbomyl. In a further aspect, each occurrence of Cy3is a 3- to 7-membered cycloalkyl substituted with 0, 1, or 2 groups independently7selected 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, and C1-C4 aminoalkyl. In a still further aspect, each occurrence of Cy3is a 3-to 7-membered cycloalkyl substituted with 0 or 1 group selected from halogen, -CN, -NH2,Attorney Docket No. 38235.0016P1-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 yet a further aspect, each occurrence of Cy3is a 3-to 7-membered cycloalkyl 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, and C1-C4 aminoalkyl. In an even further aspect, each occurrence of Cy3is an unsubstituted 3- to 7-membered cycloalkyl.

[0343] In various aspects, each occurrence of Cy3is a 3- to 7-membered heterocycloalkyl 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, and C1-C4 aminoalkyl. Examples of 3- to 7-membered heterocycloalkyls include, but are not limited to, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, thiazolidine, oxazolidine, imidazolidine, tetrahydropyran, tetrahydrothiopyran, piperazine, piperidine, and morpholine. In a further aspect, each occurrence of Cy3is a 3- to 7-membered heterocycloalkyl 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, and C1-C4 aminoalkyl. In a still further aspect, each occurrence of Cy3is a 3-to 7-membered heterocycloalkyl 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, and C1-C4 aminoalkyl. In yet a further aspect, each occurrence of Cy3is a 3-to 7-membered heterocycloalkyl 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, and C1-C4 aminoalkyl. In an even further aspect, each occurrence of Cy3is an unsubstituted 3- to 7-membered heterocycloalkyl.

[0344] In various aspects, each occurrence of Cy3is independently selected from a 5-to 6-membered heteroaryl and a 6-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, and C1-C4 aminoalkyl. In a furtherAttorney Docket No. 38235.0016P1aspect, each occurrence of Cy3is independently selected from a 5- to 6-membered heteroaryl and a 6-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, (Cl-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each occurrence of Cy3is independently selected from a 5- to 6-membered heteroaryl and a 6-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 hydroxyalky 1, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, each occurrence of Cy3is independently selected from a 5- to 6-membered heteroaryl and a 6-membered aryl, and is 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 alk damino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each occurrence of Cy3is independently selected from a 5- to 6-membered heteroaryl and a 6-membered aryl, and is unsubstituted.

[0345] In various aspects, each occurrence of Cy3is a 5- to 6-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 cyanoalkyd, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of 5- to 6-membered heteroaryls include, but are not limited to, furan, triazole, benzoimidazole, oxazole, oxadiazole, pyridine, and pyrazine. In a further aspect, each occurrence of Cy3is a 5- to 6-membered heteroary! 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, and C1-C4 aminoalkyl. In a still further aspect, each occurrence of Cy3is a 5-to 6-membered heteroary! 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, and C1-C4 aminoalkyl. In yet a further aspect, each occurrence of Cy3is a 5-to 6-membered heteroary 1 monosubstituted with a group selected from halogen, -CN, -NH2. -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, CI-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)Attorney Docket No. 38235.0016P1dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each occurrence of Cy3is an unsubstituted a 5- to 6-membered heteroaryl.

[0346] In various aspects, each occurrence of Cy3is 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, and C1-C4 aminoalkyl. In a further aspect, each occurrence of Cy3is 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, and C1-C4 aminoalkyl. In a still further aspect, each occurrence of Cy3is 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, and C1-C4 aminoalkyl. In yet a further aspect, each occurrence of Cy3is a pyrimidinyl 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, and C1-C4 aminoalkyl. In an even further aspect, each occurrence of Cy3is an unsubstituted pyrimidinyl.

[0347] In various aspects, each occurrence of Cy3is 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, and C1-C4 aminoalky. In a further aspect, each occurrence of Cy3is 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 hydroxy alkyd, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each occurrence of Cy3is 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 hydroxyalky 1, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialky lamino, and C1-C4 aminoalky l. In yet a further aspect, each occurrence of Cy3is a pyrazolyl 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)Attorney Docket No. 38235.0016P1dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each occurrence of Cy3is an unsubstituted pyrazolyl.

[0348] In various aspects, each occurrence of Cy3is triazolyl 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, and C1-C4 aminoalkyl. In a further aspect, each occurrence of Cy3is triazolyl 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 hydroxy alkyd, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino. (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy3is triazolyl 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, and C1-C4 aminoalkyl. In yet a further aspect, each occurrence of Cy3is triazolyl monosubstituted with a group selected from halogen, -CN, -NH2. -OH. -NO2, Cl-C4 alkyd, 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) dialkydamino, and C1-C4 aminoalky 1. In an even further aspect, each occurrence of Cy3is an unsubstituted triazolyl.

[0349] In various aspects, each occurrence of Cy3is a 6-membered aryl substituted with 0. 1. 2, or 3 groups independently selected from halogen, -CN, -NH2. -OH. -NO2, CI-04 alkyd, 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 occurrence of Cy3is 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 hydroxyalky 1, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each occurrence of Cy3is 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 hydroxy alky 1, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalky 1. In yet a further aspect, each occurrence of Cy3is a 6-membered ary 1 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-C4Attorney Docket No. 38235.0016P1alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, each occurrence of Cy3is an unsubstituted 6-membered aryl.2. EXAMPLE COMPOUNDS

[0350] In one aspect, a compound can be present as:or a pharmaceutically acceptable salt thereof.

[0351] In one aspect, a compound can be present as:Attorney Docket No.38235.0016P1Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.

[0352] In one aspect, a compound can be present as:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0353] In one aspect, a compound can be present as:Attorney Docket No.38235.0016P1Bror a pharmaceutically acceptable salt thereof.

[0354] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[0355] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[0356] 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

[0357] 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 clarity7, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0358] 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 Routes I and II, as described and exemplified below. The following examples are provided so that the invention might be more fully7understood, are illustrative only, and should not be construed as limiting.1. ROUTE I

[0359] In one aspect, the disclosed compounds can be prepared as show n below7.Attorney Docket No. 38235.0016P1SCHEME 1A.R1Ar’fV0” "o1.11.3

[0360] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME IB.HATU, DiPEA DMF, rt, 24h1.4

[0361] In one aspect, compounds of type 1.6, and similar compounds, can be prepared according to Scheme IB above. Thus, compounds of type 1.6 can be prepared by coupling an appropriate carboxylic acid derivative, e.g., 1.4 as shown above, using an appropriate amine, e.g., 1.5 as shown above. Appropriate carboxylic acid derivatives and appropriate amines 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 coupling agent, e.g, hexafluorophosphate azabenzotriazole tetramethyl uroniuman (HATU), and an appropriate base, e.g., diisopropylethyl amine (DIPEA), for an appropriate period of time, e.g., 24 hours, in an appropriate solvent system, e.g., dimethyl formamide (DMF). and at an appropriate reaction temperature, e.g., room temperature. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compoundssimilar in structure to the specific reactants above (compounds similar to compounds of type 1.1 and 1.2), can be substituted in the reaction to provide substituted compounds similar to Formula 1.3.2. ROUTE 2

[0362] In one aspect, the disclosed compounds can be prepared as shown below.Attorney Docket No. 38235.0016P1 SCHEME 2A.

[0363] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME 2B.HATU, DIPEA DMF, rt, 24h

[0364] In one aspect, compounds of type 2.6, and similar compounds, can be prepared according to Scheme 2B above. Thus, compounds of ty pe 2.6 can be prepared by coupling an appropriate carboxylic acid derivative, e.g., 2.4 as shown above, and an appropriate amine, e.g., 2.5 as shown above. Appropriate carboxylic acids and appropriate amines 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 coupling agent, e.g., hexafluorophosphate azabenzotriazole tetramethyl uroniuman (HATU), and an appropriate base, e.g., diisopropylethyl amine (DIPEA), for an appropriate period of time, e.g.. 24 hours, in an appropriate solvent system, e.g., dimethyl formamide (DMF), and at an appropriate reaction temperature, e.g., room temperature. As can be appreciated by one skilled in the art,Attorney Docket No. 38235.0016P1the 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

[0365] In one aspect, disclosed are pharmaceutical compositions comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0366] Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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,Attorney Docket No. 38235.0016P1C1-C4 alkylamino. (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Z is selected from -O-. -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered ar l, 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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0367] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0368] Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0369] Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:wherein each of R2a, R2b, R2c, R2d, and R3is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyd, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyd, 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.

[0370] In various aspects, disclosed are pharmaceutical compositions comprising an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0371] In various aspects, disclosed are pharmaceutical compositions comprising an effective amount where the compound is:

[0372] In various aspects, disclosed are pharmaceutical compositions comprising an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0373] In various aspects, disclosed are pharmaceutical compositions comprising an effective amount of a compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0374] In various aspects, disclosed are pharmaceutical compositions comprising an effective amount of a compound wherein the compound is selected from:Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.Attorney Docket No. 38235.0016P1

[0375] In various aspects, disclosed are pharmaceutical compositions comprising an effective amount of a compound wherein the compound is

[0376] 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.

[0377] 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 know n and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0378] 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.Attorney Docket No. 38235.0016P1topical, 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.

[0379] 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.

[0380] 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.

[0381] 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.

[0382] 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.

[0383] 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 additionalAttorney Docket No. 38235.0016P1therapeutic 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.

[0384] 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, hydroxypropyl cellulose.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.

[0385] 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.

[0386] 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.

[0387] 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 usedAttorney Docket No.38235.0016P1in 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.

[0388] 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.

[0389] 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.

[0390] 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.

[0391] 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).

[0392] 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 ACTIVITY OF PVHL IN A CELL

[0393] In one aspect, disclosed are methods of restoring activity’ of von Hippel Lindau tumor suppressor protein (pVHL) in a cell, 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.

[0394] Thus, in one aspect, disclosed are methods of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a cell, the method comprising the step ofAttorney Docket No. 38235.0016P1administering to the subject an effective amount of a compound having a structure represented by a formula:wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein each occurrence of Cy3is independently7selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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) dialkydamino, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(R”)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, 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)Attorney Docket No.38235.0016P1dialkylamino, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0395] In one aspect, are methods of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a cell, the method comprising administering to the cell an effective amount of a compound having a structure selected from:Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.

[0396] In one aspect, are methods of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a cell, the method comprising administering to the cell an effective amount of a compound having a structure selected from:or a pharmaceutically acceptable salt thereof.

[0397] In one aspect, are methods of restoring activity of pVHL in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:Attorney Docket No. 38235.0016P1,2bI\r NR2dwherein each of R2a, R2b, R2c, R2d, and R3is 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; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis 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.

[0398] In various aspects, the cell is a cancer cell.

[0399] In a various aspects, the cell is present in a tissue sample. In a still further aspect, the tissue sample is a malignant tissue sample.

[0400] In various aspects, the cell is human.

[0401] In a various aspects, the cell has been isolated from a human prior to the administering step.

[0402] 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 pVHL 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.F. METHODS OF RESTORING PVHL ACTIVITY IN A SUBJECT IN NEED THEREOF

[0403] In one aspect, disclosed are methods of restoring pVHL activity in a subject in need thereof, the method comprising the step of contacting the subject with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[0404] Thus, in one aspect, disclosed are methods of restoring pVHL activity 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:Attorney Docket No.38235.0016P1

[0405] wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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) dialky lamino, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, 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; wherein Cy1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylammo, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0406] In one aspect, disclosed are methods of restoring pVHL activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.

[0407] Also disclosed are are methods of restoring pVHL activity 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.

[0408] Also disclosed are methods of restoring pVHL activity 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:Attorney Docket No.38235.0016P1,2bI\r NR2dwherein each of R2a, R2b, R2c, R2d, and R3is 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; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis 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.

[0409] In various aspect, the subject is a mammal.

[0410] In a various aspects, the subject is a human.

[0411] In various aspects, the subject has been diagnosed with a need for restoration of pVHL activity prior to the administering step.

[0412] In various aspects, the subject has been diagnosed with a need for treatment of a disorder related to loss of pVHL activity prior to the administering step. In a further aspect, the disorder is cancer. In a yet further aspect, the cancer is clear cell renal cell carcinoma (ccRCC).G. METHODS OF TRE TING CANCER IN A SUBJECT

[0413] 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).Attorney Docket No.38235.0016P1

[0414] 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 n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(R”)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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)Attorney Docket No.38235.0016P1dialkylamino, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0415] 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:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0416] 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 selectedBror a pharmaceutically acceptable salt thereof.

[0417] 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:Attorney Docket No. 38235.0016P1wherein each of R2a, R2b, R2c, R2d, and R3is 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; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis 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

[0418] 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:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1andCl 0or a pharmaceutically acceptable salt thereof.

[0419] In various aspects, the effective amount is a therapeutically effective amount.

[0420] In various aspects, the effective amount is a prophylactically effective amount.

[0421] In various aspects, the subject is a mammal. In a further aspect, the mammal is a human.

[0422] In various aspects, the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

[0423] In various aspects, the subject has been diagnosed with von Hippel-Lindau disease (VHLD) prior to the administering step.

[0424] In various aspects, the cancer is a primary or secondary tumor. In a 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.

[0425] 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).

[0426] In various aspects, the cancer is renal cell carcinoma.

[0427] In various aspects, the cancer is associated with loss of pVHL activity.

[0428] In various aspects, the cancer is associated with cells that express a mutant pVHL. In yet a further aspect, the mutant pVHL is a genetic mutation. In yet a further aspect, the mutant pVHL is a somatic mutation. In an even further aspect, the mutant pVHL contains a mutation at an amino acid residue at a position selected from 111, 89, 80, 162, 151, 86, 78, 115, 88, 65, 117, 109, 110, 158, 155, 166, 184, 153, and 163. In a still further aspect, the mutant pVHL contains a mutation at an amino acid residue at a position selected from 86, 78, 65, and 153. In yet a further aspect, the mutant pVHL contains a mutation selected from P86S, L89H, and S65W.Attorney Docket No. 38235.0016P1

[0429] In various aspects, administering is oral or parental administration. In a further aspect, the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

[0430] In various aspects, the method further comprises administering a therapeutically effective amount of an anti-cancer agent or radiotherapy to the subject. In a 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.

[0431] 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 deacety lase (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.

[0432] 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.

[0433] In a further aspect, the antimetabolite agent is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine.Attorney Docket No. 38235.0016P1nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0434] 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.

[0435] 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.

[0436] In a further aspect, the mTor inhibitor agent is selected from everolimus, sirolimus. and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0437] 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 av(33 -inhibitors.

[0438] In a further aspect, the PARP inhibitor is selected from iniparib, talazoparib, olaparib, rucapariv, veliparib, CEP 9722, AK 4827, BGB-290 and 3 -aminobenzamide.

[0439] 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 (GSK12I0I51A), 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).

[0440] In a further aspect, the HD Ac inhibitor is selected from pracinostat and panobinostat.

[0441] In a further aspect, the ribonuclotide reductase inhibitor is selected from fludarabine, cladribine, gemcitabine, tezacitabine, triapine, motexafm gadolinium, hydroxyurea, gallium maltolate, and gallium nitrate. In a still further aspect, the ribonuclotide reductase inhibitor is an iron chelator.

[0442] In a further aspect, the proteasome inhibitor is selected from lactacystin and bortezomib.Attorney Docket No. 38235.0016P1

[0443] In a further aspect, the NAE inhibitor is a 1 -substituted methyl sulfamate. In a still further aspect, the NAE inhibitor is MLN4924.

[0444] 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, CD160, 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 CD160), CD155, 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.

[0445] In a further aspect, the TLR agonist is selected from CRX-527 and OM-174.

[0446] In a further aspect, the cell therapeutic is selected from CAR-T cell therapy and CAR-NK cell therapy.

[0447] 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.[0044S] 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 VON HIPPEL-LINDAU DISEASE (VHLD) IN A SUBJECT

[0449] In one aspect, disclosed are methods of treating von Hippel-Lindau disease (VHLD) 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 n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-. -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:R13Nand wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is substituted wi th 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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.Attorney Docket No. 38235.0016P1

[0450] In one aspect, disclosed are methods of treating VHLD 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.

[0451] In one aspect, disclosed are methods of treating VHLD in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.

[0452] In one aspect, disclosed are methods of treating VHLD 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:R5Cwherein each of R2a, R2b, R2c, R2d, and R3is 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; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5° 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.

[0453] In one aspect, disclosed are methods of treating von Hippel-Lindau disease (VHLD) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof

[0454] In various aspects, the effective amount is a therapeutically effective amount.

[0455] In various aspects, the effective amount is a prophylactically effective amount.

[0456] In various aspects, the subject is a mammal. In a further aspect, the mammal is a human.

[0457] In various aspects, the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

[0458] In various aspects, the cancer is renal cell carcinoma.

[0459] In various aspects, the subject has been diagnosed with VHLD prior to the administering step.

[0460] In various aspects, the method further comprising the step of identifying a subject in need of treatment of VHLD.

[0461] In various aspects, VHLD is associated with loss of pVHL activity.

[0462] In various aspects, the VHLD is associated with cells that express a mutant pVHL. In an even further aspect, the mutant pVHL contains a mutation selected from P86S, L89H, and S65W.Attorney Docket No. 38235.0016P1

[0463] 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

[0464] In one aspect, disclosed are methods of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q2, Q4, Q3, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q2, Q4, Q3, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, (CI-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and Cy3; wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyd, a 5- to 6-membered heteroaryl, and a 6-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 alky lamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Z is selected from -O-, -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl,Attorney Docket No. 38235.0016P1and 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2: wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyd, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0465] In one aspect, disclosed are methods of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of aAttorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

[0466] In one aspect, disclosed are methods of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound selected from:or a pharmaceutically acceptable salt thereof.Attorney Docket No.38235.0016P1

[0467] In one aspect, disclosed are methods of treating cancer in a subject having VHLD. the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein each of R2a, R2b, R2c, R2d, and R3is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyd, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyd, 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.

[0468] In one aspect, disclosed are methods of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1andCl 0or a pharmaceutically acceptable salt thereofJ. ADDITIONAL METHODS OF USING THE COMPOUNDS

[0469] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders related to restoration of pVHL activity, and, in particular, in treating or controlling cancer and VHLD. 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).

[0470] 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 or for treatment of VHLD.

[0471] 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 treatAttorney Docket No. 38235.0016P1an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of cancer or prevention of VHLD.

[0472] 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

[0473] 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. In a still further aspect, a use relates to the manufacture of a medicament for the treatment of VHLD in a subject.

[0474] 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.

[0475] 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.

[0476] 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.Attorney Docket No. 38235.0016P1

[0477] 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 renal cell carcinoma.

[0478] In various aspects, the use relates to a treatment of VHLD in a subject. In one aspect, the use is characterized in that the subject is a human.

[0479] In a further aspect, the use relates to the manufacture of a medicament for the treatment of cancer in a subject.

[0480] In a further aspect, the use relates to the manufacture of a medicament for the treatment of VHLD in a subject.

[0481] 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 cancer or VHLD in a mammal.2. MANUFACTURE OF A MEDICAMENT

[0482] 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. In a further aspect, the invention relates to a method for the manufacture of a medicament for treating VHLD 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.

[0483] 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.

[0484] 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, andAttorney Docket No. 38235.0016P1more 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.

[0485] 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.

[0486] 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

[0487] 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.

[0488] Thus, in one aspect, disclosed are kits comprising compound having a structure represented by a formula:wherein n is selected from 0 and 1; wherein R1is selected from hydrogen and C1-C4 alkyl; wherein Ar1is a structure represented by a formula selected from:Attorney Docket No.38235.0016P1andwherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=; wherein each occurrence of R10, when present, is 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, and Cy3; wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl; wherein Z is selected from -O-. -S-, and -N(Rn)-; wherein R11is selected from hydrogen and C1-C4 alkyl; wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, and C1-C4 aminoalkyl; wherein Cy1is a structure represented by a formula selected from:R14a. N R1R R VR14eR14fwherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2; wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-membered aryl, and is substituted wi th 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, and C1-C4 aminoalkyl; and wherein R13is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, andAttorney Docket No. 38235.0016P1one 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.

[0489] 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.

[0490] In one aspect, disclosed are kits comprising compound selected from:Attorney Docket No. 38235.0016P1or 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.

[0491] In one apect, disclosed are kits comprising compound having a structure represented by a formula:R5Cwherein each of R2a, R2b, R2c, R2d, and R3is 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; wherein R4is selected from hydrogen and C1-C4 alkyl; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyd, 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 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.

[0492] In one aspect, disclosed are kits comprising a compound selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No.38235.0016P1or 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.

[0493] 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 yet a further aspect, the cancer is selected from renal cell cancer pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer. In a still further raspect, renal cell cancer is clear cell renal cell cancer.

[0494] In a further aspect, the cancer is associated with cells that express a mutant pVHL. In yet a further aspect, the mutant pVHL is a genetic mutation. In yet a further aspect, the mutant pVHL is a somatic mutation. In an even further aspect, the mutant pVHL contains a mutation at an amino acid residue at a position selected from 111, 89, 80, 162, 151, 86, 78, 115, 88, 65, 117, 109, 110, 158, 155, 166, 184, 153, and 163. In a still further aspect.Attorney Docket No. 38235.0016P1the mutant pVHL contains a mutation at an amino acid residue at a position selected from 86, 78, 65, and 153. In yet a further aspect, the mutant pVHL contains a mutation selected from P86S, L89H, and S65W.

[0495] 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.

[0496] 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.

[0497] 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.

[0498] 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.

[0499] 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.

[0500] In a further aspect, the mTor inhibitor agent is selected from everolimus, sirolimus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0501] In a further aspect, the DNA damage-inducing agent is selected from doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothecin, methotrexate, carboplatin, oxaliplatin, or ionizing radiation.

[0502] 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.

[0503] 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.Attorney Docket No.38235.0016P1

[0504] 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.

[0505] 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.

[0506] 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

[0507] 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.

[0508] 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. CHEMICAL EXPERIMENTALAttorney Docket No. 38235.0016P1a. COMPOUND STORAGE AND STOCK PREPARATION

[0509] Compounds purchased from Enamine arrived as dried powders / oils in amber vials. The initial 18 CP series compounds were dissolved in DMSO to a final concentration of 40 mM and several initial 40 pL aliquots were prepared in small amber vials. Aliquots (along with remaining volume in original vials) were frozen at -20 °C. Prior to initial screening experiment using STD-NMR, aliquots of each compound were pooled into a pre- weighed vial and lyophilized overnight to dryness. Compounds were subsequently re-dissolved in DMSO-d6 to a final concentration of 160 mM (CPI, CP3, CP4, CP9. CP 10, CPU. CP 12, CP14, CP17, CP18), 80 mM (CP2, CP5), or 40 mM (CP6, CP7, CP8, CP13, CP15) depending on solubility and frozen at -20 °C. The compound designated CP16 was not included in the initial screen.

[0510] Subsequent batches of CP4 were later delivered from Enamine and diluted to 80 mM in DMSO-d6. 10 pL aliquots were prepared in amber 1.5 mL microcentrifuge tubes and frozen at -80 °C.

[0511] Compounds synthesized in-house (including CP4.29, CP4.35, CP4.36, CP4.40, CP4.41, CP4.42, CP4.43, CP4.44, CP4.45, and CP4.46) were dissolved into DMSO-d6 at a concentration of 160 mM and aliquoted. A single aliquot of each compound was further diluted to 40 mM, aliquoted, and frozen at -20 °C in anticipation of cellular testing. Remaining aliquots of the 160 mM stocks were frozen at -80 °C.

[0512] Additional analogs of CP4.29, termed CP4.1-CP4.34, were delivered from Enamine as either dry powders or oils in amber vials. The compounds designated CP4.33 and CP4.34 were not included in experimental characterization. Compounds were dissolved to a final concentration of either 80 mM or 160 mM in DMSO-d6 (depending on solubility) and frozen at -20 °C.

[0513] Additional batches of CP4.29 used for experiments other than the initial screen were purchased directly from Enamine (catalog number Z5717230270), dissolved to 160 mM in DMSO-d6, and frozen at -80 °C. The equivalence of our synthesized CP4.29 and the batches purchased from Enamine was confirmed by comparing each purchased batch to our reference 'H and13C NMR spectra (FIG. 2A and FIG. 2B).

[0514] Synthesized derivatives of CP4.29 were dissolved in DMSO-d6 to a final concentration of 40 mM and aliquoted into 1.5 mL microcentrifuge tubes. Two aliquots of each compound were frozen at -20 °C for immediate use in cellular testing. Additional compound was frozen at -80 °C for long term storage.Attorney Docket No. 38235.0016P1

[0515] Sitagliptin phosphate was purchased as a powder and stored at -20 °C. 8 mg of sitagliptin phosphate was dissolved in DMSO-d6 to a final concentration of 49.6 mM and aliquoted as 15 pL aliquots in 1.5 mL amber microcentrifuge tubes and frozen at -80 °C. VH298 was purchased from Sigma Aldrich (catalog number SML1896-5MG) and dissolved to 40 mM in DMSO-d6. Aliquots of 15 pL were prepared in amber 1.5 mL microcentrifuge tubes and frozen at -80 °C.b. METHODS FOR CHEMICAL SYNTHESISi. SYNTHESIS ...

Claims

Attorney Docket No. 38235.0016P1CLAIMSWhat is claimed is:

1. A compound having a structure represented by a formula:wherein n is selected from 0 and 1;wherein R1is selected from hydrogen and C1-C4 alkyl;wherein each of R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6his independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=;wherein each occurrence of R10, when present, 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-C4Attorney Docket No. 38235.0016P1haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and Cy3;wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Z is selected from -O-, -S-, and -N(Rn)-;wherein R11is selected from hydrogen and C1-C4 alkyl;wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Cy1is a structure represented by a formula selected from:wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2;wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7- membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6- 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 cyanoalky l. C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4Attorney Docket No. 38235.0016P1aminoalkyl; andwherein R13is selected from hydrogen and C1-C4 alkyl;wherein each of R14a, R14b, R14c, R14d, R14e. R14f, R14gand R1411is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalky 1, C1-C4 alkoxy, Cl- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino,provided that when n is 0 and Cy1is:then Ar1is not indole or benzofuran,provided that when n is 0, Cy1is:and Ar1is:then each of Q1, Q2, Q2, Q4, Q5, Q6, and Q7is -C(R10)=,provided that when n is 1 and Cy1is:then R1is a C1-C4 alkyl,provided that the compound is not:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein n is 0.

3. The compound of claim 1 or claim 2, wherein each of R6a, R6b, R6c, R6d, R6e, R6f, R6g. and R6his hydrogen.

4. The compound of any one of claims 1 to 3, wherein Ar1is a structure represented by a formula selected from:

5. The compound of any one of claims 1 to 3, wherein Ar1is a structure represented by a formula:

6. The compound of claim 5, wherein Ar1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1R107. The compound of claim 6, wherein each occurrence of R10is independently selected from hydrogen, halogen, C1-C4 alkyd, C1-C4 alkoxy, and Cy3.

8. The compound of any one of claims 1 to 3, wherein Ar1is a structure represented by a formula:

9. The compound of claim 8, wherein Ar1is a structure represented by a formula:

10. The compound of claim 9, wherein each occurrence of R10is independently selected from hydrogen, halogen, and C1-C4 alkyl.

11. The compound of claim 9, wherein Ar1is a structure represented by a formula:

12. The compound of claim 8, wherein Ar1is a structure represented by a formula selected from:Attorney Docket No.38235.0016P113. The compound of claim 12, wherein each occurrence of R10is independently selected from hydrogen, halogen, and C1-C4 alkyl.

14. The compound of any one of claims 1 to 3, wherein Ar1is a structure represented by a formula:

15. The compound of claim 14, wherein Ar1is a structure represented by a formula:R1016. The compound of claim 14, wherein Ar1is a structure represented by a formula:

17. The compound of any one of claims 1 to 3, wherein Ar1is a structure represented by a formula:

18. The compound of any one of claims 1 to 17, wherein Cy1is a structure represented by a formula:Attorney Docket No. 38235.0016P119. The compound of claim 18, wherein Cy1is a structure represented by a formula selected from:

20. The compound of any one of claims 1 to 17. wherein Cy1is a structure represented by a formula:

21. The compound of claim 20, wherein Cy1is a structure represented by a formula:N~22. The compound of any one of claims 1 to 17, wherein Cy1is a structure represented by a formula:

23. The compound of claim 22, wherein Cy1is a structure represented by a formula:Attorney Docket No.38235.0016P124. The compound of claim 1, wherein the compound has a structure represented by a formula:Oor a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.Attorney Docket No.38235.0016P128. The compound of claim 1, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, wherein the compound has a structure represented by a formula:Oor a pharmaceutically acceptable salt thereof.Attorney Docket No.38235.0016P132. The compound of claim 1, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.Attorney Docket No. 38235.0016P134. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. A method of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

36. A method of restoring pVHL activity' in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

37. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

38. A method of treating von Hippel-Lindau disease (VHLD) in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

39. A method of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

40. A kit comprising the compound of any one of claims 1 to 33 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.

41. A compound selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.Attorney Docket No. 38235.0016P142. A pharmaceutical composition comprising an effective amount of the compound of claim 41 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

43. A method of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a cell, the method comprising contacting the cell with an effective amount of the compound of claim 41 or a pharmaceutically acceptable salt thereof.

44. A method of restoring pVHL activity in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 41 or a pharmaceutically acceptable salt thereof.

45. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 41 or a pharmaceutically acceptable salt thereof.

46. A method of treating von Hippel-Lindau disease (VHLD) in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 41 or a pharmaceutically acceptable salt thereof.

47. A method of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of the compound of claim 41 or a pharmaceutically acceptable salt thereof.

48. A kit comprising the compound of claim 41 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.

49. A pharmaceutical composition comprising an effective amount of a compound having a structure represented by a formula:Attorney Docket No. 38235.0016P1wherein n is selected from 0 and 1;wherein R1is selected from hydrogen and C1-C4 alkyl;wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q2, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=. provided that no more than three of Q1, Q2, Q2, Q4, Q5, Q6, and Q7are simultaneously -N=;wherein each occurrence of R10, when present, is 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, and Cy3;wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4Attorney Docket No.38235.0016P1aminoalkyl;wherein Z is selected from -O-, -S-, and -N(Rn)-;wherein R11is selected from hydrogen and C1-C4 alkyl;wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, Cl- C4 cyanoalkyl. C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2;wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7- membered heterocycloalkyl, a 5- to 6-membered heteroaryl. and a 6- 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, and C1-C4 aminoalkyl; andwherein R13is selected from hydrogen and C1-C4 alkyl,or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

50. The pharmaceutical composition of claim 49, wherein the compound is selected from:Attorney Docket No. 38235.0016P1Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.

51. The pharmaceutical composition of claim 49, wherein the compound is:or a pharmaceutically acceptable salt thereof.

52. The pharmaceutical composition of claim 49, wherein the compound is selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

53. A method of restoring activity of von Hippel Lindau tumor suppressor protein (pVHL) in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:wherein n is selected from 0 and 1;Attorney Docket No.38235.0016P1wherein R1is selected from hydrogen and C1-C4 alkyl;wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q2, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1. Q2, Q2, Q4, Q5, Q6, and Q7are simultaneously -N=;wherein each occurrence of R10, when present, is 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, and Cy3;wherein each occurrence of Cy3is independently selected from a 3- to 7- membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6- membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl;wherein Z is selected from -O-, -S-, and -N(Rn)-;wherein R11is selected from hydrogen and C1-C4 alkyl;wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, Cl-Attorney Docket No.38235.0016P1C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Cy1is a structure represented by a formula selected from:wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2;wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7- membered heterocy cloalkyl, a 5- to 6-membered heteroar l. and a 6- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -Nth, -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; andwherein R13is selected from hydrogen and C1-C4 alkyl,or a pharmaceutically acceptable salt thereof.

54. The method of claim 53, wherein the cell is a cancer cell.

55. The method of claim 53 or claim 54. wherein the cell is present in a tissue sample.

56. The method of claim 55, wherein the tissue sample is a malignant tissue sample.

57. The method of any one of claims 53 to 56. wherein the cell is human.

58. The method of any one of claims 53 to 57, wherein the cell has been isolated from a human prior to the contacting step.

59. The method of any one of claims 53 to 56, wherein contacting is via administration to a subject.Attorney Docket No. 38235.0016P160. The method of claim 59, wherein the subject has been diagnosed with a need for restoration of pVHL activity prior to the administering step.

61. The method of claim 59, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

62. A method of restoring pVHL activity 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 n is selected from 0 and 1;wherein R1is selected from hydrogen and C1-C4 alkyl;wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=;wherein each occurrence of R10, when present, is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyd, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl,Attorney Docket No. 38235.0016P1and Cy3;wherein each occurrence of Cy3is independently selected from a 3- to 7- membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6- membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl;wherein Z is selected from -O-, -S-, and -N(Rn)-;wherein R11is selected from hydrogen and C1-C4 alkyl;wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Cy1is a structure represented by a formula selected from:wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2;wherein Cy2is selected from a 3- to 7-membered cycloalkyd, a 3- to 7- membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6- 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 cyanoalkyd, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andAttorney Docket No. 38235.0016P1wherein R13is selected from hydrogen and C1-C4 alkyl,or a pharmaceutically acceptable salt thereof.

63. The method of claim 62, wherein the subject is a mammal.

64. The method of claim 62, wherein the subject is a human.

65. The method of any one of claims 62 to 64. wherein the subject has been diagnosed with a need for restoration of pVHL activity prior to the administering step.

66. The method of any one of claims 62 to 64, wherein the subject has been diagnosed with a need for treatment of a disorder related to loss of pVHL activity prior to the administering step.

67. The method of claim 66, wherein the disorder is cancer.

68. The method of claim 67. wherein the cancer is clear cell renal cell carcinoma (ccRCC).

69. 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 n is selected from 0 and 1;wherein R1is selected from hydrogen and C1-C4 alkyl;wherein Ar1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=;wherein each occurrence of R10, when present, is selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, 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, and Cy3;wherein each occurrence of Cy3is independently selected from a 3- to 7- membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6- membered heteroaryl, and a 6-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, and C1-C4 aminoalkyl:wherein Z is selected from -O-, -S-, and -N(Rn)-;wherein R11is selected from hydrogen and C1-C4 alkyl;wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Cy1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2;wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7- membered heterocycloalkyd, a 5- to 6-membered heteroaryl, and a 6- 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 cyanoalky l. C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R13is selected from hydrogen and C1-C4 alkyl,or a pharmaceutically acceptable salt thereof.

70. The method of claim 69, wherein the effective amount is a therapeutically effective amount.

71. The method of claim 69, wherein the effective amount is a prophylactically effective amount.

72. The method of any one of claims 69 to 71, wherein the subject is a mammal.

73. The method of claim 72, wherein the mammal is a human.

74. The method of any one of claims 69 to 73, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

75. The method of any one of claims 69 to 74, wherein the subject has been diagnosed with von Hippel-Lindau disease (VHLD) prior to the administering step.

76. The method of any one of claims 69 to 75, further comprising the step of identifying a subject in need of treatment of cancer.Attorney Docket No. 38235.0016P177. The method of any one of claims 69 to 76, wherein the cancer is a primary or secondary tumor.

78. The method of claim 77, wherein the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.

79. The method of any one of claims 69 to 76, 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, nonsmall cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).

80. The method of any one of claims 69 to 76, wherein the cancer is renal cell carcinoma.

81. The method of any one of claims 69 to 76, wherein the cancer is associated with loss of pVHL activity.

82. The method of any one of claims 69 to 76. wherein the cancer is associated with cells that express a mutant pVHL.

83. The method of claim 82, wherein the mutant pVHL is a genetic mutation.

84. The method of claim 82, wherein the mutant pVHL is a somatic mutation.

85. The method of claim 82, wherein the mutant pVHL contains a mutation at an amino acid residue at a position selected from 111, 89, 80, 162, 151. 86, 78, 115, 88, 65, 117, 109, 110, 158. 155, 166, 184. 153, and 163.

86. The method of claim 82, wherein the mutant pVHL contains a mutation at an amino acid residue at a position selected from 86, 78, 65, and 153.

87. The method of claim 82, wherein the mutant pVHL contains a mutation selected from P86S, L89H, and S65W.Attorney Docket No. 38235.0016P188. The method of any one of claims 69 to 77, wherein administering is oral or parental administration.

89. The method of claim 88, wherein the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

90. The method of any one of claims 69 to 89, further comprising administering a therapeutically effective amount of an anti-cancer agent or radiotherapy to the subject.

91. The method of claim 90, wherein the anti-cancer agent or radiotherapy is administered prior to administration of the compound.

92. The method of claim 90, wherein the anti-cancer agent or radiotherapy is administered subsequent to administration of the compound.

93. A method of treating von Hippel-Lindau disease (VHLD) 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 n is selected from 0 and 1;wherein R1is selected from hydrogen and C1-C4 alkyl;wherein Ar1is a structure represented by a formula selected from:Attorney Docket No. 38235.0016P1wherein each of Q1, Q2, Q2, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=. provided that no more than three of Q1, Q2, Q2, Q4, Q5, Q6, and Q7are simultaneously -N=;wherein each occurrence of R10, when present, is 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, and Cy3;wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaiy 1, and a 6-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, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Z is selected from -O-, -S-, and -N(Rn)-;wherein R11is selected from hydrogen and C1-C4 alky 1;wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, Cl- C4 cyanoalkyl. C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Cy1is a structure represented by a formula selected from:and wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2;Attorney Docket No.38235.0016P1wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7- membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6- 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 haloalky 1, C1-C4 cyanoalkyd, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R13is selected from hydrogen and C1-C4 alkyl,or a pharmaceutically acceptable salt thereof.

94. The method of claim 93, wherein the effective amount is a therapeutically effective amount.

95. The method of claim 93, wherein the effective amount is a prophylactically effective amount.

96. The method of any one of claims 93 to 95, wherein the subject is a mammal.

97. The method of claim 96, wherein the mammal is a human.

98. The method of any one of claims 93 to 97, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

99. The method of any one of claims 93 to 98. wherein the cancer is renal cell carcinoma.

100. The method of any one of claims 93 to 99, wherein the subject has not been diagnosed with a need for treatment of cancer prior to the administering step.

101. The method of any one of claims 93 to 100, wherein the subject has been diagnosed with VHLD prior to the administering step.

102. The method of one of claims 93 to 101, further comprising the step of identifying a subject in need of treatment of VHLD.

103. The method of one of claims 93 to 102, wherein VHLD is associated with loss of pVHL activity.Attorney Docket No. 38235.0016P1104. The method of one of claims 93 to 103, wherein the VHLD is associated with cells that express a mutant pVHL.

105. The method of claim 104, wherein the mutant pVHL contains a mutation selected from P86S, L89H, and S65W.

106. The method of one of claims 93 to 105, wherein administering is oral or parental administration.

107. The method of claim 106, wherein the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

108. A method of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein n is selected from 0 and 1;wherein R1is selected from hydrogen and C1-C4 alkyl;wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q3, Q4, Q5, Q6, and Q7is independently selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q3, Q4, Q5, Q6, and Q7are simultaneously -N=;Attorney Docket No. 38235.0016P1wherein each occurrence of R10, when present, is 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, and Cy3;wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Z is selected from -O-, -S-, and -N(Rn)-;wherein R11is selected from hydrogen and C1-C4 alkyl;wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, Cl- C4 cyanoalkyl. C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Cy1is a structure represented by a formula selected from:R14b R NVR' z^R1R12^R146wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2;wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7- membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6- membered aryl, and is substituted with 0, 1, 2, or 3 groups independentlyAttorney Docket No.38235.0016P1selected 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, and C1-C4 aminoalkyl; andwherein R13is selected from hydrogen and C1-C4 alkyl,or a pharmaceutically acceptable salt thereof.

109. A kit comprising compound having a structure represented by a formula:wherein n is selected from 0 and 1;wherein R1is selected from hydrogen and C1-C4 alkyl;wherein Ar1is a structure represented by a formula selected from:wherein each of Q1, Q2, Q2, Q4, Q5, Q6, and Q7is independently7selected from -C(R10)= and -N=, provided that no more than three of Q1, Q2, Q2, Q4, Q5, Q6, and Q7are simultaneously -N=;wherein each occurrence of R10, when present, is 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,Attorney Docket No. 38235.0016P1and Cy3;wherein each occurrence of Cy3is independently selected from a 3- to 7-membered cycloalkyl, a 3- to 7-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6-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, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Z is selected from -O-, -S-, and -N(Rn)-;wherein R11is selected from hydrogen and C1-C4 alkyl;wherein Ar2is selected from a 6-membered aryl and a 5- to 10-membered heteroaryl, 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, Cl- C4 cyanoalky 1, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein Cy1is a structure represented by a formula selected from:wherein R12is selected from hydrogen, C1-C4 alkyl, and Cy2;wherein Cy2is selected from a 3- to 7-membered cycloalkyl, a 3- to 7- membered heterocycloalkyl, a 5- to 6-membered heteroaryl, and a 6- membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cy anoalkyd, C1-C4 hydroxyalky l, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andAttorney Docket No. 38235.0016P1wherein R13is selected from hydrogen and C1-C4 alkyl,or a pharmaceutically acceptable salt thereof, and one or more selected from:(d) an anti-cancer agent;(e) instructions for administering the compound in connection with treating cancer; and(f) instructions for treating cancer.

110. The kit of claim 109, 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.

111. The kit of claim 110, 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.

112. The kit of claim 110, 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.

113. The kit of claim 110. wherein 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.

114. The kit of claim 110, 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.

115. The kit of claim 110, wherein the mTor inhibitor agent is selected from everolimus, sirolimus, and temsirolimus, or a pharmaceutically acceptable salt thereof.Attorney Docket No.38235.0016P1116. The kit of claim 110, wherein the DNA damage-inducing agent is selected from doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothecin, methotrexate, carboplatin, oxaliplatin, or ionizing radiation.

117. The kit of any one of claims 109 to 116, wherein the compound and the anti-cancer agent are co-packaged.

118. The kit of any one of claims 109 to 116, wherein the compound and the anti-cancer agent are co-formulated.

119. A compound selected from:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

120. A pharmaceutical composition comprising an effective amount of the compound of claim 119, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

121. A method of restoring activity of pVHL in a cell, the method comprising contacting the cell with an effective amount of the compound of claim 119, or a pharmaceutically acceptable salt thereof.

122. A method of restoring activity of pVHL in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 119, or a pharmaceutically acceptable salt thereof.

123. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 119, or a pharmaceutically acceptable salt thereof.

124. A kit comprising the compound of claim 119, 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.

125. A pharmaceutical composition comprising an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

126. A method of restoring activity of pVHL in a cell, the method comprising contacting the cell with an effective amount of a compound selected from:or a pharmaceutically acceptable salt thereof.Attorney Docket No. 38235.0016P1127. A method of restoring pVHL activity 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.

128. 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:Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

129. A method of treating VHLD 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.

130. A method of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No.38235.0016P1or a pharmaceutically acceptable salt thereof.

131. A kit comprising compound selected from:Attorney Docket No.38235.0016P1Bror 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.

132. A pharmaceutical composition comprising an effective amount of a compound having a structure represented by a formula:R5Cwherein each of R2a, R2b, R2c, R2d, and R3is 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, (C 1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein R4is selected from hydrogen and C1-C4 alkyl; andwherein each of R5a, R5b, and R5cis 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.Attorney Docket No. 38235.0016P1133. The pharmaceutical composition of claim 132, wherein each of R2a. R2b, R2c, and R2dis independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy.

134. The pharmaceutical composition of claim 132 or claim 133, wherein R3is selected from hydrogen, halogen, and C1-C4 alkyl.

135. The pharmaceutical composition of any one of claims 134, wherein R4is C1-C4 alkyl.

136. The pharmaceutical composition of any one of claims 134, wherein R4is methyl.

137. The pharmaceutical composition of any one of claims 136, wherein each of R5a, R5b, and R5Cis independently selected from hydrogen, halogen, and C1-C4 alkyl.

138. The pharmaceutical composition of claim 132, wherein R5ais halogen.

139. The pharmaceutical composition of claim 132, wherein R5ais -F.

140. The pharmaceutical composition of claim 132, wherein R5bis C1-C4 alkyl.

141. The pharmaceutical composition of claim 132, wherein R5bis ethyl.

142. The pharmaceutical composition of claim 132, wherein R5cis hydrogen.

143. The pharmaceutical composition of claim 132, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

144. The pharmaceutical composition of claim 143, wherein each of R2a. R2b, R2c, and R2dis independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy.

145. The pharmaceutical composition of claim 132, wherein the compound is selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

146. The pharmaceutical composition of claim 132, wherein the compound is:or a pharmaceutically acceptable salt thereof.

147. A method of restoring activity of pVHL in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:wherein each of R2a, R2b. R2c, R2d, and R3is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyd, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein R4is selected from hydrogen and C1-C4 alkyl; andwherein each of R5a, R5b. and R5° 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 C 1 -C4 aminoalky 1,Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

148. A method of restoring pVHL activity 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:R5Cwherein each of R2a, R2b, R2c, R2d, and R3is 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, (C 1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein R4is selected from hydrogen and C1-C4 alkyl; andwherein each of R5a, R5b, and R5cis 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.

149. 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 each of R2a, R2b, R2c, R2d, and R3is independently selected from hydrogen,Attorney Docket No. 38235.0016P1halogen, -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;wherein R4is selected from hydrogen and C1-C4 alkyl; andwherein each of R5a, R5b, and R5cis 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.

150. A method of treating VHLD 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:R5Cwherein each of R2a, R2b, R2c, R2d, and R3is 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;wherein R4is selected from hydrogen and C1-C4 alkyl; andwherein each of R5a, R5b, and R5cis 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 C 1 -C4 aminoalkyl,or a pharmaceutically acceptable salt thereof.Attorney Docket No. 38235.0016P1151. A method of treating cancer in a subj ect having VHLD, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein each of R2a, R2b, R2c, R2d, and R3is 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;wherein R4is selected from hydrogen and C1-C4 alkyl; andwherein each of R5a, R5b. and R5cis 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 C 1 -C4 aminoalkyl,or a pharmaceutically acceptable salt thereof.

152. A kit comprising compound having a structure represented by a formula:wherein each of R2a, R2b, R2c, R2d, and R3is 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, (C 1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;Attorney Docket No. 38235.0016P1wherein R4is selected from hydrogen and C1-C4 alkyl; andwherein each of R5a, R5b, and R5cis 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 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.

153. 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:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

154. A method of treating von Hippel-Lindau disease (VHLD) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

155. A method of treating cancer in a subject having VHLD, the method comprising administering to the subject an effective amount of a compound selected from:Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or a pharmaceutically acceptable salt thereof.

156. A kit comprising a compound selected from.Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1Attorney Docket No. 38235.0016P1or 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.

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